Midazolam Exacerbates Morphine Tolerance and Morphine-induced Hyperactive Behaviors in Young Rats with Burn Injury

PubMed Central

Song, Li; Wang, Shuxing; Zuo, Yunxia; Chen, Lucy; Martyn, Jeevendra A.; Mao, Jianren

2014-01-01

Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether 1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and 2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3 to 4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10 mg/kg, subcutaneous, s.c.), followed 30 min later by either saline or midazolam (2 mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10 mg/kg, s.c.), midazolam (2 mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor 10 nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism. PMID:24713351

[Use of midazolam in hospitalized patients: analysis of medical practice].

PubMed

Giroud, Mathilde; Sellier, Elodie; Laval, Guillemette

2013-09-01

To evaluate the prevalence and the characteristics of use of midazolam among hospitalized patients and to analyze physicians' representation of this medicine. We conducted a retrospective study between 1st May and 22nd May 2011 in Grenoble University Hospital in France. All patients receiving midazolam during the study period were included, excepted if the prescription was performed in intensive care units, operating rooms or in pediatric units. Physicians from the different units were asked about the characteristics of patients receiving midazolam and about their practice concerning the use of midazolam. Forty-four patients were included, 82 % of whom having a cancer. The prevalence of prescription of midazolam was 3.3 % (44/1,323), 2.8 % (37/1,323) for anxiety relieving and 0.8 % (11/1,323) for sedation. The main refractory symptoms that justified the prescription were dyspnea (36.4 %), confusion (29.5 %), pain (27.3 %) and psychological suffering (27.3 %). Twenty-eight physicians were asked about their practice. The main representations of midazolam were the stop of active treatment (46.5 %) and premature cause of death (46.5 %). Practice of sedation is under-estimated by physicians as they have difficulties to differentiate anxiety relieving and sedation and they have difficulties to initiate a sedation. A guideline to help physicians using midazolam could improve practice.

The lack of bicuculline and picrotoxin influence on midazolam depressant action on brain oxygen consumption.

PubMed

Obradović, Dragan I; Savić, Miroslav M; Obradović, Miljana M; Ugresić, Nenad D; Bokonjić, Dubravko R

2006-04-24

In the previous study of the rat frontal cortex slices oxygen consumption (QO2), polarographically determined using the biological oxygen monitor, a moderate respiratory depressant action of midazolam ex vivo (1.0 mg/kg) has been observed. Antagonist of the benzodiazepine binding site, flumazenil, blocked the effect of the agonist. However, midazolam-gamma-aminobutyric acid (GABA) interactions pointed to the possibility that a part of midazolam action is independent of the classical GABA potentiation. To test this presumption, GABAA receptor antagonists bicuculline and picrotoxin were administered. Both blockers antagonized the QO2 reducing effect of the combination of per se effective doses of midazolam (1.0 mg/kg) and GABA (5 x 10(-4) mol/l), as well as of GABA (5 x 10(-4) mol/l) itself. However, neither effects of midazolam (1.0 mg/kg) on its own, nor those of midazolam in presence of the physiological, per se ineffective, concentration of GABA (10(-6) mol/l), were susceptible to antagonism. These results show that ex vivo influence of midazolam on cerebral metabolic activity should be partly ascribed to some of its cellular mechanisms probably associated to the GABA modulation, but distinct from the standard GABA-potentiating effects of benzodiazepines.

Two Oral Midazolam Preparations in Pediatric Dental Patients: A Prospective Randomised Clinical Trial

PubMed Central

Kamranzadeh, Shaqayegh; Kousha, Maryam; Shaeghi, Shahnaz; AbdollahGorgi, Fatemeh

2015-01-01

Pharmacological sedation is an alternative behavior management strategy in pediatric dentistry. The aim of this study was to compare the behavioral and physiologic effects of “commercially midazolam syrup” versus “orally administered IV midazolam dosage form (extemporaneous midazolam (EF))” in uncooperative pediatric dental patients. Eighty-eight children between 4 to 7 years of age received 0.2–0.5 mg/kg midazolam in this parallel trial. Physiologic parameters were recorded at baseline and every 15 minutes. Behavior assessment was conducted objectively by Houpt scale throughout the sedation and North Carolina at baseline and during injection and cavity preparation. No significant difference in behavior was noted by Houpt or North Carolina scale. Acceptable behavior (excellent, very good, and good) was observed in 90.9% of syrup and 79.5% of EF subjects, respectively. Physiological parameters remained in normal range without significant difference between groups and no adverse effect was observed. It is concluded that EF midazolam preparation can be used as an acceptable alternative to midazolam syrup. PMID:26120325

Chronic alcohol abuse and the acute sedative and neurophysiologic effects of midazolam.

PubMed

Bauer, L O; Gross, J B; Meyer, R E; Greenblatt, D J

1997-10-01

The aim of the present investigation was to examine benzodiazepine sensitivity in abstinent alcoholics. For this purpose, two escalating doses of the benzodiazepine midazolam were i.v. administered to nine alcohol-dependent patients after 2-3 weeks of abstinence and 12 healthy, non-alcoholic volunteers. A variety of dependent measures were examined, including the power spectrum of the resting electroencephalogram (EEG) and evoked EEG responses, saccadic eye movements, self-reported sedation, and vigilance task performance. Analyses revealed a significant association between plasma midazolam levels and changes in EEG beta power, pattern shift visual evoked potential amplitude, heart rate, and saccade amplitude and velocity. The patient and control groups differed significantly in the onset latencies of their saccadic eye movements, and marginally in EEG beta power, both before and after midazolam. However, no differences were detected between the groups in the dose of midazolam required to produce sedation or in midazolam's neurophysiological effects.

Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study.

PubMed

Isbister, Geoffrey K; Calver, Leonie A; Page, Colin B; Stokes, Barrie; Bryant, Jenni L; Downes, Michael A

2010-10-01

We determine whether droperidol, midazolam, or the combination is more effective for intramuscular sedation in violent and acute behavioral disturbance in the emergency department (ED). We conducted a blinded randomized controlled trial of intramuscular sedation for violent and acute behavioral disturbance, comparing droperidol (10 mg), midazolam (10 mg), and droperidol (5 mg)/midazolam (5 mg). Inclusion criteria were patients requiring physical restraint and parenteral sedation. The primary outcome was the duration of the violent and acute behavioral disturbance, defined as the time security staff were required. Secondary outcomes included time until additional sedation was administered, staff and patient injuries, further episodes of violent and acute behavioral disturbance, and drug-related adverse effects. From 223 ED patients with violent and acute behavioral disturbance, 91 patients were included; 33 received droperidol, 29 received midazolam, and 29 received the combination. There was no difference in the median duration of the violent and acute behavioral disturbance: 20 minutes (interquartile range [IQR] 11 to 37 min) for droperidol, 24 minutes (IQR 13 to 35 minutes) for midazolam, and 25 minutes (IQR 15 to 38 minutes) for the combination. Additional sedation was required in 11 (33%; 95% confidence interval [CI] 19% to 52%) droperidol patients, 18 (62%; 95% CI 42% to 79%) midazolam patients, and 12 (41%; 95% CI 24% to 61%) in the combination group. The hazard ratio for additional sedation in the midazolam versus droperidol group was 2.31 (95% credible interval 1.01 to 4.71); for the combination versus droperidol, 1.18 (95% credible interval 0.46 to 2.50). Patient and staff injuries and number of further episodes of violent and acute behavioral disturbance did not differ between groups. There were two adverse effects for droperidol (6%; 95% CI 1% to 22%), 8 for midazolam (28%; 95% CI 13% to 47%), and 2 for the combination (7%; 95% CI 1% to 24%). An abnormal QT occurred in 2 of 31 (6%; 95% CI 1% to 23%) droperidol patients, which was not different from the other groups. Intramuscular droperidol and midazolam resulted in a similar duration of violent and acute behavioral disturbance, but more additional sedation was required with midazolam. Midazolam caused more adverse effects because of oversedation, and there was no evidence of QT prolongation associated with droperidol compared with midazolam. Copyright © 2010 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

Speed of recovery and side-effect profile of sevoflurane sedation compared with midazolam.

PubMed

Ibrahim, A E; Ghoneim, M M; Kharasch, E D; Epstein, R H; Groudine, S B; Ebert, T J; Binstock, W B; Philip, B K

2001-01-01

Sedation for surgical procedures performed with regional or local anesthesia has usually been achieved with intravenous medications, whereas the use of volatile anesthetics has been limited. The use of sevoflurane for sedation has been suggested because of its characteristics of nonpungency, rapid induction, and quick elimination. The purpose of this investigation was to assess the quality, recovery, and side effects of sevoflurane sedation compared with midazolam. One hundred seventy-three patients undergoing surgery with local or regional anesthesia were enrolled in a multicenter, open-label, randomized investigation comparing sedation with sevoflurane versus midazolam. Sedation level was titrated to an Observer's Assessment of Alertness--Sedation score of 3 (responds slowly to voice). Recovery was assessed objectively by Observer's Assessment of Alertness--Sedation, Digit Symbol Substitution Test (DSST), and memory scores, and subjectively by visual analog scales. Significantly more patients in the sevoflurane group had to be converted to general anesthesia because of excessive movement (18 sevoflurane and 2 midazolam; P = 0.043). Of remaining patients, 141 were assessable for efficacy and recovery data (93 sevoflurane and 48 midazolam). Sevoflurane and midazolam produced dose-related sedation. Sevoflurane patients had higher DSST and memory scores during recovery. Seventy-six percent (sevoflurane) compared with 35% (midazolam) returned to baseline DSST at 30 min postoperatively (P < 0.05). More frequent excitement-disinhibition was observed with sevoflurane (15 [16%] vs. midazolam; P = 0.008). Sevoflurane for sedation produces faster recovery of cognitive function as measured by DSST and memory scores compared with midazolam. However, sevoflurane for sedation is complicated by a high incidence of intraoperative excitement.

Intranasal sedatives in pediatric dentistry

PubMed Central

AlSarheed, Maha A.

2016-01-01

Objectives: To identify the intranasal (IN) sedatives used to achieve conscious sedation during dental procedures amongst children. Methods: A literature review was conducted by identifying relevant studies through searches on Medline. Search included IN of midazolam, ketamine, sufentanil, dexmedetomidine, clonidine, haloperidol and loranzepam. Studies included were conducted amongst individuals below 18 years, published in English, and were not restricted by year. Exclusion criteria were articles that did not focus on pediatric dentistry. Results: Twenty studies were included. The most commonly used sedatives were midazolam, followed by ketamine and sufentanil. Onset of action for IN midazolam was 5-15 minutes (min), however, IN ketamine was faster (mean 5.74 min), while both IN sufentanil (mean 20 min) and IN dexmedetomidine (mean 25 min) were slow in comparison. Midazolam was effective for modifying behavior in mild to moderately anxious children, however, for more invasive or prolonged procedures, stronger sedatives, such as IN ketamine, IN sufentanil were recommended. In addition, ketamine fared better in overall success rate (89%) when compared with IN midazolam (69%). Intranasal dexmedetomidine was only used as pre-medication amongst children. While its’ onset of action is longer when compared with IN midazolam, it produced deeper sedation at the time of separation from the parent and at the time of anesthesia induction. Conclusion: Intranasal midazolam, ketamine and sufentanil are effective and safe for conscious sedation, while intranasal midazolam, dexmedetomidine and sufentanil have proven to be effective premedications. PMID:27570849

Intranasal sedatives in pediatric dentistry.

PubMed

AlSarheed, Maha A

2016-09-01

To identify the intranasal (IN) sedatives used to achieve conscious sedation during dental procedures amongst children. A literature review was conducted by identifying relevant studies through searches on Medline. Search included IN of midazolam, ketamine, sufentanil, dexmedetomidine, clonidine, haloperidol, and loranzepam. Studies included were conducted amongst individuals below 18 years, published in English, and were not restricted by year. Exclusion criteria were articles that did not focus on pediatric dentistry.  Twenty studies were included. The most commonly used sedatives were midazolam, followed by ketamine and sufentanil. Onset of action for IN midazolam was 5-15 minutes (min), however, IN ketamine was faster (mean 5.74 min), while both IN sufentanil (mean 20 min) and IN dexmedetomidine (mean 25 min) were slow in comparison. Midazolam was effective for modifying behavior in mild to moderately anxious children, however, for more invasive or prolonged procedures, stronger sedatives, such as IN ketamine, IN sufentanil were recommended. In addition, ketamine fared better in overall success rate (89%) when compared with IN midazolam (69%). Intranasal dexmedetomidine was only used as pre-medication amongst children. While its' onset of action is longer when compared with IN midazolam, it produced deeper sedation at the time of separation from the parent and at the time of anesthesia induction. Intranasal midazolam, ketamine, and sufentanil are effective and safe for conscious sedation, while intranasal midazolam, dexmedetomidine, and sufentanil have proven to be effective premedications.

Intrathecal Midazolam as an Adjuvant in Pregnancy-Induced Hypertensive Patients Undergoing an Elective Caesarean Section: A Clinical Comparative Study

PubMed Central

Dodawad, Ravichandra; G. B., Sumalatha; Pandarpurkar, Sandeep; Jajee, Parashuram

2016-01-01

Background A pain-free postoperative period is essential following a caesarean section so new mothers may care for and bond with their neonates. Intrathecal adjuvants are often administered during this procedure to provide significant analgesia, but they may also have bothersome side effects. Intrathecal midazolam produces effective postoperative analgesia with no significant side effects. Objectives This prospective, randomized, double-blind study was designed to compare the analgesic efficacy and safety of intrathecal midazolam vs. plain bupivacaine as an adjunct to bupivacaine in pregnancy-induced hypertension patients scheduled for elective caesarean section. Methods Sixty patients diagnosed with pregnancy-induced hypertension on regular treatment who were scheduled for a caesarean section were randomly allocated into two groups: a control group (Group BC, n = 30) and a midazolam group (Group BM, n = 30). Both groups received 10 mg (2 mL) of 0.5% hyperbaric bupivacaine. Group BC received 0.4 mL of distilled water, while group BM received 0.4 mL (2 mg) of midazolam intrathecally. The duration of postoperative analgesia, analgesic requirements during the first 24 hours after surgery, onset times and durations of sensory and motor blocks, incidence of hypotension, vasopressor requirements, and side effects were recorded. Results Postoperative analgesia was significantly longer in the midazolam group compared to the control group (201.5 minutes vs. 357.6 minutes). The mean onset times of the sensory and motor blocks were significantly faster (P < 0.01) in the midazolam group compared to the control group. The mean times to attain the maximum sensory level and motor blocks were also significantly faster in the midazolam group compared to the control group (P < 0.05). The incidence of hypotension was 6.6% in the midazolam group and 36.6% in the control group, which was highly significant. In addition, the number of patients with side effects was significantly lower in the midazolam group compared to the control group. Conclusions Intrathecal midazolam 2 mg provides significantly longer and effective postoperative analgesia with no side effects. PMID:27847698

The Pharmacokinetics of the CYP3A Substrate Midazolam After Steady-state Dosing of Delafloxacin.

PubMed

Paulson, Susan K; Wood-Horrall, Rebecca N; Hoover, Randall; Quintas, Megan; Lawrence, Laura E; Cammarata, Sue K

2017-06-01

Delafloxacin is a novel anionic fluoroquinolone in Phase III development for the treatment of serious skin infections. The objective of this study was to evaluate the effects of delafloxacin on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A substrate. CYP3A activity using midazolam as a probe was assessed before and after multiple doses of delafloxacin to reach steady state. In this nonrandomized, open-label, single-sequence, Phase I study, 22 healthy male and female subjects were administered a single 5-mg oral dose of midazolam on days 1 and 8, with oral delafloxacin 450 mg every 12 hours administered from days 3 to 8. Full pharmacokinetic profiles were obtained on days 1 and 8 (midazolam and 1-hydroxymidazolam) and days 3 and 7 (delafloxacin). The geometric mean ratios (90% CIs) for AUC 0-∞ and C max of midazolam coadministered with delafloxacin versus midazolam alone were 89.4 (83.2-96.0) and 93.6 (83.7-104.6). Similarly, the geometric ratio for the AUC 0-∞ of 1-hydroxymidazolam, the primary metabolite of midazolam, was 105.7 (97.7-114.3); the ratio of C max was not equivalent at 116.1 (101.7-132.4), which was outside the CI of 80% to 125%. Multiple doses of oral delafloxacin for 6 days were generally well tolerated. Steady-state dosing of delafloxacin produced no significant changes in midazolam pharmacokinetics, except for a small but not clinically relevant change in the C max of 1-hydroxymidazolam. ClinicalTrials.gov identifier: NCT02505997. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

[Towards a better use of midazolam in end of life: A survey in a department of medical oncology].

PubMed

Beneton, Aurélie; Vallard, Alexis; Brosse, Christelle; Poenou, Géraldine; Pacaut, Cécile; Magné, Nicolas; Morisson, Stéphanie

2017-11-01

At the end of life of cancer patients, sedation is sometimes needed, in order to palliate unbearable symptoms that other treatments fail to relieve. Midazolam is currently recommended for sedation and its prescription is guided by national guidelines. The aim of the present study was to evaluate the practices of midazolam prescription in a department of medical oncology and to compare the results with French national recommendations in order to improve the midazolam use in case of sedation. We conducted a retrospective survey studying midazolam prescriptions in patients who died between 2014 and 2015 in the medical oncology department. Compliance rates with recommendations were reviewed. A total of 99 medical files were analyzed. Fifty-three patients received midazolam: 64.4% for refractory symptoms, 22% for anxiolyse, 10.2% for acute respiratory distress syndrome. When reported, the titration indications and modalities systematically conformed to guidelines. In case of sedation for refractory symptoms, adherence to guidelines was 76% regarding the family information, 63% regarding the patient information, 61% regarding the collegial nature of the initiation decision, 34% regarding the titration achievement and 5% regarding the pluridisciplinary nature of the initiation decision. Although limited justifications in midazolam prescriptions could have resulted in an overestimate of sedation and in an underestimate of titrations, current guideline are not enough applied in routine, especially regarding the necessity of a pluridisciplinary decision-making. A list of requirements before midazolam initiation is suggested, to increase the adherence to guidelines. Our results highlight the necessity of a better midazolam use in life-end sedations. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Nutritional Status Differentially Alters Cytochrome P450 3A4 (CYP3A4) and Uridine 5'-Diphospho-Glucuronosyltransferase (UGT) Mediated Drug Metabolism: Effect of Short-Term Fasting and High Fat Diet on Midazolam Metabolism.

PubMed

Lammers, Laureen A; Achterbergh, Roos; Romijn, Johannes A; Mathôt, Ron A A

2018-06-06

Previous studies have shown that nutritional status can alter drug metabolism which may result in treatment failure or untoward side effects. This study assesses the effect of two nutritional conditions, short-term fasting, and a short-term high fat diet (HFD) on cytochrome P450 3A4 (CYP3A4) and uridine 5'-diphospho-glucuronosyltransferase (UGT) mediated drug metabolism by studying the pharmacokinetics of midazolam and its main metabolites. In a randomized-controlled cross-over trial, nine healthy subjects received a single intravenous administration of 0.015 mg/kg midazolam after: (1) an overnight fast (control); (2) 36 h of fasting; and (3) an overnight fast after 3 days of a HFD consisting of 500 ml of cream supplemented to their regular diet. Pharmacokinetic parameters were analyzed simultaneously using non-linear mixed-effects modeling. Short-term fasting increased CYP3A4-mediated midazolam clearance by 12% (p < 0.01) and decreased UGT-mediated metabolism apparent 1-OH-midazolam clearance by 13% (p < 0.01) by decreasing the ratio of clearance and the fraction metabolite formed (ΔCL 1-OH-MDZ /f 1-OH-MDZ ). Furthermore, short-term fasting decreased apparent clearance of 1-OH-midazolam-O-glucuronide (CL 1-OH-MDZ-glucuronide /(f 1-OH-MDZ-glucuronide  × f 1-OH-MDZ )) by 20% (p < 0.01). The HFD did not affect systemic clearance of midazolam or metabolites. Short-term fasting differentially alters midazolam metabolism by increasing CYP3A4-mediated metabolism but by decreasing UGT-mediated metabolism. In contrast, a short-term HFD did not affect systemic clearance of midazolam.

Electroencephalographic response following midazolam-induced general anesthesia: relationship to plasma and effect-site midazolam concentrations.

PubMed

Miyake, Wakako; Oda, Yutaka; Ikeda, Yuko; Hagihira, Satoshi; Iwaki, Hiroyoshi; Asada, Akira

2010-06-01

To examine the relationships between effect-site concentrations and electroencephalographic parameters after the induction of general anesthesia with midazolam. Twenty-four patients with American Society of Anesthesiologists status I or II were randomly allocated to receive either an intravenous (i.v.) bolus of midazolam 0.2 mg kg(-1) (small-dose group, n = 12) or 0.3 mg kg(-1) (large-dose group, n = 12) for induction of general anesthesia in a double-blind experimental design. The bispectral index (BIS), 95% spectral edge frequency (SEF95), spectral power density, and plasma concentrations of midazolam were measured for 60 min following the induction of general anesthesia. Plasma and simulated effect-site concentrations of midazolam were significantly higher in the large-dose group than in the small-dose group (P = 0.005 and <0.001, respectively). There was a correlation between the relative beta ratio and BIS (r (2) = 0.30, P < 0.001; n = 168); however, effect-site concentrations of midazolam showed no association with BIS, relative beta ratio, or SEF95 (r (2) = 0.07, 0.11 and 0.01, respectively; n = 168). The electroencephalographic spectral power density in the beta-band (>/=13 and <30 Hz) was significantly increased after induction and was significantly larger in the large-dose group than in the small-dose group (P = 0.009). Following the induction of general anesthesia with i.v. midazolam 0.2 or 0.3 mg kg(-1), the BIS was positively correlated with the relative beta ratio. Despite a rapid decrease in the plasma and effect-site concentrations of midazolam, the average BIS remained >60 for 60 min after induction, reflecting an increased power of the electroencephalographic high-frequency band.

Midazolam or diazepam administration during electroencephalography helps to diagnose subacute sclerosing panencephalitis (SSPE).

PubMed

Yilmaz, Kutluhan; Sahin, Derya Aydin

2010-08-01

Although diagnostic contribution of intravenous diazepam administration during electroencephalography (EEG) recording in subacute sclerosing panencephalitis has been known, no another drug with less potential side effects has been studied in this procedure. In this study, diazepam is compared with midazolam in 25 subacute sclerosing panencephalitis-diagnosed children and 10 children with subacute sclerosing panencephalitis-suggesting symptoms, normal EEG findings and no certain diagnosis. Neither midazolam nor diazepam affected typical periodic slow-wave complexes. However, in the patients with atypical EEG abnormalities, midazolam, like diazepam, attenuated sharp or sharp-and-slow waves, and therefore made the identification of periodic slow-wave paroxysms easier. In the patients with normal EEGs, both midazolam and diazepam revealed typical periodic complexes on EEG recording in the same 3 patients. Cerebrospinal fluid examination verified the diagnosis of subacute sclerosing panencephalitis. The findings suggest that midazolam or diazepam administration increases the contribution of EEG recording in atypical cases with subacute sclerosing panencephalitis.

Administration order of midazolam/fentanyl for moderate dental sedation.

PubMed

Lobb, Douglas; Clarke, Alix; Lai, Hollis

2018-02-01

The purpose of this study is to investigate the effects of administration order when a sedative drug (midazolam) and an opioid analgesic drug (fentanyl) is applied for moderate intravenous (IV) sedation in dentistry. A retrospective chart review was conducted in one dental clinic during its transition from a midazolam-first to a fentanyl-first protocol for dental procedures requiring moderate IV sedation. Physiological parameters, drug administration times, patient recovery times, drug dosages, and patient recall and satisfaction were investigated for differences. A total of 76 charts (40 midazolam-first and 36 fentanyl-first administrations), were used in the analysis. Administering midazolam first resulted in an average 4.38 min (52%) decrease in administration times (P < 0.001), and a decrease in procedural recollection immediately following the procedure (P = 0.03), and 24 to 48 hours later (P = 0.009). Administering fentanyl first required an average of 2.43 mg (29%) less midazolam (P < 0.001). No significant differences were found for change in vital signs, minimum oxygen saturation levels, recovery times, and patient satisfaction (P > 0.05). Oxygen saturation levels did not drop below 90% for either group; however, 5 cases in the fentanyl-first group fell to between 90% and 92%, compared with 0 cases in the midazolam-first group. The administration order of fentanyl and midazolam may have different effects on patients and the sedation procedure. Findings from this study should be used to facilitate discussion among dental practitioners and to guide additional research investigating this topic.

The Anxiolytic Effect of Midazolam in Third Molar Extraction: A Systematic Review

PubMed Central

Chen, Qi; Wang, Lufei; Ge, Lina; Gao, Yuan; Wang, Hang

2015-01-01

Purpose To assess the efficacy of midazolam for anxiety control in third molar extraction surgery. Methods Electronic retrievals were conducted in Medline (via PubMed, 1950-2013.12), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3), Embase (via OVID 1974-2013.12), and the System for Information on Grey Literature in Europe (SIGLE). The bibliographies of relevant clinical trials were also checked. Randomized controlled trials satisfying the inclusion criteria were evaluated, with data extraction done independently by two well-trained investigators. Disagreements were resolved by discussion or by consultation with a third member of the review team. Results Ten studies were included, but meta-analysis could not be conducted because of the significant differences among articles. All but one article demonstrated that midazolam could relieve anxiety. One article demonstrated that propofol offered superior anxiolysis, with more rapid recovery than with midazolam. Compared with lorazepam and diazepam, midazolam did not distinctly dominate in its sedative effect, but was safer. Two articles used midazolam in multidrug intravenous sedation and proved it to be more effective than midazolam alone. Conclusion It was found, by comparison and analysis, that midazolam might be effective for use for anxiety control during third molar extraction and can be safely administered by a dedicated staff member. It can also be used with other drugs to obtain better sedative effects, but the patient’s respiratory function must be monitored closely, because multidrug sedation is also more risky. PMID:25849859

The anxiolytic effect of midazolam in third molar extraction: a systematic review.

PubMed

Chen, Qi; Wang, Lufei; Ge, Lina; Gao, Yuan; Wang, Hang

2015-01-01

To assess the efficacy of midazolam for anxiety control in third molar extraction surgery. Electronic retrievals were conducted in Medline (via PubMed, 1950-2013.12), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3), Embase (via OVID 1974-2013.12), and the System for Information on Grey Literature in Europe (SIGLE). The bibliographies of relevant clinical trials were also checked. Randomized controlled trials satisfying the inclusion criteria were evaluated, with data extraction done independently by two well-trained investigators. Disagreements were resolved by discussion or by consultation with a third member of the review team. Ten studies were included, but meta-analysis could not be conducted because of the significant differences among articles. All but one article demonstrated that midazolam could relieve anxiety. One article demonstrated that propofol offered superior anxiolysis, with more rapid recovery than with midazolam. Compared with lorazepam and diazepam, midazolam did not distinctly dominate in its sedative effect, but was safer. Two articles used midazolam in multidrug intravenous sedation and proved it to be more effective than midazolam alone. It was found, by comparison and analysis, that midazolam might be effective for use for anxiety control during third molar extraction and can be safely administered by a dedicated staff member. It can also be used with other drugs to obtain better sedative effects, but the patient's respiratory function must be monitored closely, because multidrug sedation is also more risky.

Role of neurosteroids in the anticonvulsant activity of midazolam.

PubMed

Dhir, Ashish; Rogawski, Michael A

2012-04-01

Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA(A) receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA(A) receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the i.v. pentylenetetrazol (PTZ) threshold test. Midazolam (500-5000 µg·kg(-1) , i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5α-reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11β-hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 µg·kg(-1) ) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO. Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines, even those that only weakly interact with TSPO. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Role of neurosteroids in the anticonvulsant activity of midazolam

PubMed Central

Dhir, Ashish; Rogawski, Michael A

2012-01-01

BACKGROUND AND PURPOSE Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABAA receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABAA receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action. EXPERIMENTAL APPROACH Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the i.v. pentylenetetrazol (PTZ) threshold test. KEY RESULTS Midazolam (500–5000 µg·kg−1, i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5α-reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11β-hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 µg·kg−1) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO. CONCLUSION AND IMPLICATIONS Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines, even those that only weakly interact with TSPO. PMID:22014182

Effects of propofol, midazolam and thiopental sodium on outcome and amino acids accumulation in focal cerebral ischemia-reperfusion in rats.

PubMed

Chen, Lianhua; Gong, Qinyan; Xiao, Changsi

2003-02-01

To investigate the effects of propofol, midazolam and thiopental sodium on outcomes and amino acid accumulation in focal cerebral ischemia-reperfusion in rats. Male Sprague Dawley (SD) rats were scheduled to undergo 3-hour middle cerebral artery occlusion by intraluminal suture and 24-hour reperfusion. Neurologic outcomes were scored on a 0-5 grading scale. Infarct volume was shown with triphenyltetrazolium chloride staining and measured by an image analysis system. Concentrations of various amino acids (aspartate, glutamate, glycine, taurine, and gama-aminobutyric acid) were measured after 3 hours of reperfusion using high performance liquid chromatography. Propofol, midazolam and thiopental sodium were given intraperitoneally at the beginning of reperfusion. Both propofol and midazolam attenuated neurological deficits and reduced infarct and edema volumes. Propofol showed better neurological protection than midazolam while thiopental sodium did not exhibit any protective effect. Both propofol and midazolam decreased excitatory amino acids accumulation, while propofol increased gama-aminobutyric acid accumulation in ischemic areas in reperfusion. Propofol and midazolam, but not thiopental sodium, may provide protective effects against reperfusion induced injury in rats subjected to focal cerebral ischemia. This neurological protection may be due to the acceleration of excitatory amino acids elimination in reperfusion.

Pharmacology of midazolam.

PubMed

Pieri, L; Schaffner, R; Scherschlicht, R; Polc, P; Sepinwall, J; Davidson, A; Möhler, H; Cumin, R; Da Prada, M; Burkard, W P; Keller, H H; Müller, R K; Gerold, M; Pieri, M; Cook, L; Haefely, W

1981-01-01

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

Prophylactic antiemetic effects of Midazolam, Ondansetron, and their combination after middle ear surgery.

PubMed

Honarmand, Azim; Safavi, Mohammadreza; Chegeni, Mansoureh; Hirmanpour, Anahita; Nazem, Masoud; Sarizdi, Seyyad Hamid

2016-01-01

The purpose of the present study was to evaluate the efficacy of midazolam-ondansetron combination in prevention of postoperative nausea and vomiting (PONV) after middle ear surgery and its comparison with using midazolam or ondansetron alone. One hundred and forty patients were enrolled in four groups to receive midazolam 0.75 mg/kg in group M, ondansetron 4 mg in group O, midazolam 0.75 mg/kg and ondansetron 4 mg in group MO, and saline 0.90% in group S intravenously just before anesthesia. Assessment of nausea, vomiting, rescue antiemetic, and side effects of study drugs such as headache and dizziness was carried out postoperatively for 24 h. The incidence of PONV was significantly smaller in group MO than group M and group O, while there was no significant difference between group M and group O during the first 24 h postoperatively. Requirement to the additional antiemetic was significantly more in group S (71.4%) compared to other groups, while in group MO (11.4%) was lower than group M (31.4%) and group O (34.3%). Our study showed that prophylactic administration of midazolam 0.75 mg/kg combined with ondansetron 4 mg was more effective than using midazolam or ondansetron alone in prevention of PONV after middle ear surgery.

Prophylactic antiemetic effects of Midazolam, Ondansetron, and their combination after middle ear surgery

PubMed Central

Honarmand, Azim; Safavi, Mohammadreza; Chegeni, Mansoureh; Hirmanpour, Anahita; Nazem, Masoud; Sarizdi, Seyyad Hamid

2016-01-01

Objective: The purpose of the present study was to evaluate the efficacy of midazolam-ondansetron combination in prevention of postoperative nausea and vomiting (PONV) after middle ear surgery and its comparison with using midazolam or ondansetron alone. Methods: One hundred and forty patients were enrolled in four groups to receive midazolam 0.75 mg/kg in group M, ondansetron 4 mg in group O, midazolam 0.75 mg/kg and ondansetron 4 mg in group MO, and saline 0.90% in group S intravenously just before anesthesia. Assessment of nausea, vomiting, rescue antiemetic, and side effects of study drugs such as headache and dizziness was carried out postoperatively for 24 h. Findings: The incidence of PONV was significantly smaller in group MO than group M and group O, while there was no significant difference between group M and group O during the first 24 h postoperatively. Requirement to the additional antiemetic was significantly more in group S (71.4%) compared to other groups, while in group MO (11.4%) was lower than group M (31.4%) and group O (34.3%). Conclusion: Our study showed that prophylactic administration of midazolam 0.75 mg/kg combined with ondansetron 4 mg was more effective than using midazolam or ondansetron alone in prevention of PONV after middle ear surgery. PMID:26985431

Evident cognitive impairments in seemingly recovered patients after midazolam-based light sedation during diagnostic endoscopy.

PubMed

Hsu, Yen-Hsuan; Lin, Feng-Sheng; Yang, Chi-Cheng; Lin, Chih-Peng; Hua, Mau-Sun; Sun, Wei-Zen

2015-06-01

Midazolam is a widely used sedative agent during colonoscopy, with cognitive toxicity. However, the potential cognitive hazard of midazolam-based light sedation has not been sufficiently examined. We aimed to examine the cognitive safety and vulnerability profile under midazolam light sedation, with a particular focus on individual variations. We conducted a prospective case-controlled study in an academic hospital. In total, 30 patients undergoing sedative colonoscopy as part of a health check-up were recruited. Neuropsychological testing on the full cognitive spectrum was evaluated at 15 minutes and 120 minutes after low-dose midazolam administration. The modified reliable change index (RCI) was used for intrapersonal comparisons and controlling for practice effects. Midazolam affected psychomotor speed (48%), memory (40%), learning (32%), working memory (17%), and sustained attention (11%), while sparing orientation and the fluency aspect of executive function at the acute stage. Residual memory (10%) and learning (10%) impairments at 2 hours after administration were evidenced in some patients. The three object recall and digit symbol coding tests can serve as useful screening tools. Midazolam-based light sedation induced selective cognitive impairments and prolonged cognitive impairments occurred in patients with advanced age. A longer observation time and further screening were recommended for patients due to their at risk state. Copyright © 2013. Published by Elsevier B.V.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilat, E.; Kadar, T.; Levy, A.

Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 {+-} 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsantmore » effect (53 {+-} 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.« less

Randomized, controlled, cross-over clinical trial comparing intravenous midazolam sedation with nitrous oxide sedation in children undergoing dental extractions.

PubMed

Wilson, K E; Girdler, N M; Welbury, R R

2003-12-01

The use of benzodiazepines for paediatric dental sedation has received limited attention with regard to research into clinical effectiveness. A study was therefore designed to investigate the use of midazolam, for i.v. sedation in paediatric dental patients. The aim of the study was to assess the effectiveness of i.v. midazolam in a randomized, controlled, cross-over trial. Children aged 12-16 yr (ASA I and II), requiring two appointments for equivalent but contralateral dental extractions for orthodontic purposes, were recruited. Conscious sedation with either i.v. midazolam titrated at 0.5 mg x min(-1), to a maximum of 5 mg, or nitrous oxide/oxygen titrated to 30%/70% inhalation sedation was used at the first visit, the alternative being used at the second visit. Vital signs including blood pressure, arterial oxygen saturation and ventilatory frequency, as well as sedation levels and behavioural scores, were recorded every 2 min. Forty patients, mean age 13.2 yr (range 12-16 yr), participated in the trial. A mean dose of midazolam 2.8 mg was administered in the test group. The median time to the maximum level of sedation was 8 min for midazolam compared with 6 min for nitrous oxide (P<0.001). Vital signs for both treatments were comparable and within acceptable clinical limits and communication with the patient was maintained at all times. The median (range) lowest arterial oxygen saturation level recorded for midazolam was 97 (91-99)% compared with 97 (92-100)% for nitrous oxide. The mean (range) recovery time for midazolam was 51.6 (39-65) min and 23.3 (20-34) min for nitrous oxide (P<0.0001). Fifty-one per cent said they preferred i.v. midazolam, 38% preferred nitrous oxide, and 11% had no preference. I.V. midazolam sedation (0.5 mg x min(-1) to a maximum of 5 mg) appears to be as effective as nitrous oxide sedation in 12-16-yr-old healthy paediatric dental patients.

Midazolam fails to prevent neurological damage in children with convulsive refractory febrile status epilepticus.

PubMed

Nagase, Hiroaki; Nishiyama, Masahiro; Nakagawa, Taku; Fujita, Kyoko; Saji, Yohsuke; Maruyama, Azusa

2014-07-01

We conducted a retrospective study to compare the outcome of intravenous midazolam infusion without electroencephalography or targeted temperature management and barbiturate coma therapy with electroencephalography and targeted temperature management for treating convulsive refractory febrile status epilepticus. Of 49 consecutive convulsive refractory febrile status epilepticus patients admitted to the pediatric intensive care unit of our hospital, 29 were excluded because they received other treatments or because of various underlying illnesses. Thus, eight patients were treated with midazolam and 10 with barbiturate coma therapy using thiamylal. Midazolam-treated patients were intubated only when necessary, whereas barbiturate coma therapy patients were routinely intubated. Continuous electroencephalography monitoring was utilized only for the barbiturate coma group. The titration goal for anesthesia was clinical termination of status epilepticus in the midazolam group and suppression or burst-suppression patterns on electroencephalography in the barbiturate coma group. Normothermia was maintained using blankets and neuromuscular blockade in the barbiturate coma group and using antipyretics in the midazolam group. Prognoses were measured at 1 month after onset; children were classified into poor and good outcome groups. Good outcome was achieved in all the barbiturate coma group patients and 50% of the midazolam group patients (P = 0.02, Fisher's exact test). Although the sample size was small and our study could not determine which protocol element is essential for the neurological outcome, the findings suggest that clinical seizure control using midazolam without continuous electroencephalography monitoring or targeted temperature management is insufficient in preventing neurological damage in children with convulsive refractory febrile status epilepticus. Copyright © 2014 Elsevier Inc. All rights reserved.

Perioperative effects of oral midazolam premedication in children undergoing skin laser treatment. A double-blinded randomized placebo-controlled trial.

PubMed

Shoroghi, Mehrdad; Arbabi, Shahriyar; Farahbakhsh, Farshid; Sheikhvatan, Mehrdad; Abbasi, Ali

2011-08-01

To investigate and compare the efficacy of oral midazolam with two different dosages in orange juice on perioperative hemodynamics and behavioral changes in children who underwent skin laser treatment in an academic educational Hospital. Ninety children, candidates for skin laser treatment were randomly assigned to 1 of 3 groups of 30 each: the placebo group received 0.1 ml/kg orange flavored juice, group 2 and 3 receiving 0.5 and 1 mg/kg of injectable midazolam mixed with an equal volume of orange juice, respectively. The main outcome measures included the mask acceptance, patients' behavioral scales and postoperative events. There were no significant differences in heart rate, respiratory rate, and systolic blood pressure among the three groups. However, arterial oxygen saturation was significantly reduced in those given 1 mg.kg(-1) midazolam. The median scores of anxiety, separation from parent, preparing an intravenous line, acceptance of the oxygen mask, good sedation, crying reduction and consciousness level were better in midazolam group. Postoperative agitation and re-crying were also more frequent in placebo receivers. Those given 1 mg.kg(-1) midazolam were significantly more optimal for sedation, crying, consciousness, preparing an intravenous line, and postoperative re-crying compared with 0.5 mg.kg(-1) midazolam receivers. As a preanaesthetic medication, the 1 mg.kg(-1) dose of orally given midazolam especially in a volume of orange juice and can optimize the children's behavior during skin laser treatment with no serious adverse effects, enhancing their parents' satisfactions about the sedative protocol.

Dreaming in sedation during spinal anesthesia: a comparison of propofol and midazolam infusion.

PubMed

Kim, Duk-Kyung; Joo, Young; Sung, Tae-Yun; Kim, Sung-Yun; Shin, Hwa-Yong

2011-05-01

Although sedation is often performed during spinal anesthesia, the details of intraoperative dreaming have not been reported. We designed this prospective study to compare 2 different IV sedation protocols (propofol and midazolam infusion) with respect to dreaming during sedation. Two hundred twenty adult patients were randomly assigned to 2 groups and received IV infusion of propofol or midazolam for deep sedation during spinal anesthesia. Patients were interviewed on emergence and 30 minutes later to determine the incidence, content, and nature of their dreams. Postoperatively, patient satisfaction with the sedation was also evaluated. Two hundred fifteen patients (108 and 107 in the propofol and midazolam groups, respectively) were included in the final analysis. The proportion of dreamers was 39.8% (43/108) in the propofol group and 12.1% (13/107) in the midazolam group (odds ratio=4.78; 95% confidence interval: 2.38 to 9.60). Dreams of the patients receiving propofol were more memorable and visually vivid than were those of the patients receiving midazolam infusion. The majority of dreams (36 of 56 dreamers, 64.3%) were simple, pleasant ruminations about everyday life. A similarly high level of satisfaction with the sedation was observed in both groups. In cases of spinal anesthesia with deep sedation, dreaming was almost 5 times more common in patients receiving propofol infusion than in those receiving midazolam, although this did not influence satisfaction with the sedation. Thus, one does not need to consider intraoperative dreaming when choosing propofol or midazolam as a sedative drug in patients undergoing spinal anesthesia. © 2011 International Anesthesia Research Society

Administration of midazolam in infancy does not affect learning and memory of adult mice.

PubMed

Xu, Hua; Liu, Zhi-Qiang; Liu, Yi; Zhang, Wei-Shi; Xu, Bo; Xiong, Yuan-Chang; Deng, Xiao-Ming

2009-12-01

1. Midazolam is a common fast-acting GABA(A) receptor agonist. Recent data suggest that exposure to midazolam in early life may cause long-term effects on brain function through stable epigenetic reprogramming. The aim of the present study was to determine whether the administration of midazolam to infant mice would affect their learning and memory in adulthood. 2. An open-field test was conducted before and then 3, 24, 48 and 72 h after administration of midazolam (50 mg/kg, i.p.) to infant mice. Saline control mice received an equal volume of saline i.p. 3 h before the open-field test. Total movements, total movement time, total movement distance and velocity were analysed. Novel object recognition (NOR), Morris water-maze and passive avoidance tests were performed when the treated mice grew to adulthood (105 days of age). 3. The results of open-field test showed that midazolam significantly reduced locomotor activity (total movements, total movement time, total movement distance and velocity) in infant mice 3 and 24 h after drug administration and that these effects had disappeared by 72 h after drug administration. The results of the water-maze, NOR and passive avoidance tests in adulthood (at 105 days of age) indicated that administration of midazolam in infancy had no long-term effects on the learning and memory behaviours of adult mice compared with the saline control. 4. Acute midazolam administration to infant mice affected spontaneous locomotor activity for approximately 2 days, but did not seem to have any significant impact on cognitive functioning that lasted into adulthood.

Administration order of midazolam/fentanyl for moderate dental sedation

PubMed Central

2018-01-01

Background The purpose of this study is to investigate the effects of administration order when a sedative drug (midazolam) and an opioid analgesic drug (fentanyl) is applied for moderate intravenous (IV) sedation in dentistry. Methods A retrospective chart review was conducted in one dental clinic during its transition from a midazolam-first to a fentanyl-first protocol for dental procedures requiring moderate IV sedation. Physiological parameters, drug administration times, patient recovery times, drug dosages, and patient recall and satisfaction were investigated for differences. Results A total of 76 charts (40 midazolam-first and 36 fentanyl-first administrations), were used in the analysis. Administering midazolam first resulted in an average 4.38 min (52%) decrease in administration times (P < 0.001), and a decrease in procedural recollection immediately following the procedure (P = 0.03), and 24 to 48 hours later (P = 0.009). Administering fentanyl first required an average of 2.43 mg (29%) less midazolam (P < 0.001). No significant differences were found for change in vital signs, minimum oxygen saturation levels, recovery times, and patient satisfaction (P > 0.05). Oxygen saturation levels did not drop below 90% for either group; however, 5 cases in the fentanyl-first group fell to between 90% and 92%, compared with 0 cases in the midazolam-first group. Conclusions The administration order of fentanyl and midazolam may have different effects on patients and the sedation procedure. Findings from this study should be used to facilitate discussion among dental practitioners and to guide additional research investigating this topic. PMID:29556559

Episodic Representations Support Early Semantic Learning: Evidence from Midazolam Induced Amnesia

ERIC Educational Resources Information Center

Merritt, Paul; Hirshman, Elliot; Zamani, Shane; Hsu, John; Berrigan, Michael

2006-01-01

Current controversy exists regarding the role of episodic representations in the formation of long-term semantic memories. Using the drug "midazolam" to induce temporary amnesia we tested participants' memories for newly learned facts in a semantic cue condition or an episodic and semantic cue condition. Following midazolam administration, memory…

COMPARISON OF INTRAMUSCULAR FENTANYL-MIDAZOLAM, FENTANYL-MIDAZOLAM-KETAMINE, AND KETAMINE-MEDETOMIDINE FOR IMMOBILIZATION OF JAPANESE MACAQUES ( MACACA FUSCATA).

PubMed

Ølberg, Rolf-Arne; Sinclair, Melissa; Barker, Ian K; Crawshaw, Graham

2018-03-01

The combination of fentanyl and midazolam is commonly used as a sedative in humans. The objective of this study was to evaluate the sedative properties and physiological effects of fentanyl-midazolam and fentanyl-midazolam-ketamine compared with medetomidine-ketamine given intramuscularly in Japanese macaques ( Macaca fuscata). In a randomized crossover design, eight Japanese macaques were hand-injected with either 30 μg/kg fentanyl + 0.3 mg/kg midazolam (FM), 15 μg/kg fentanyl + 0.3 mg/kg midazolam + 5.0 mg/kg ketamine (FMK), or 0.05 mg/kg medetomidine + 5.0 mg/kg ketamine (MedK). Heart rate; indirect systolic, mean, and diastolic arterial pressure; respiratory rate; blood gas concentrations; rectal temperature; and duration of immobilization were recorded. Mixed linear models were used to evaluate the effects of drug treatment on all continuous variables, with a significance level of P < 0.05. Only three of seven animals receiving FM were successfully immobilized. All eight animals in both the FMK and MedK treatment groups had a rapid, smooth induction and were successfully immobilized. Both FMK and MedK treatments resulted in significant hypoxia and the animals required supplemental oxygen via face mask. The mean duration of FMK immobilization was 42 ± 10 min, significantly shorter than the 65 ± 14 min for the animals receiving MedK. Immobilization with MedK resulted in significantly lower heart rates, and significantly higher arterial pressure compared with FMK. Hypoventilation was significantly more pronounced in FMK-treated animals compared with MedK treatments. Immobilization with FMK resulted in a gradual, slow recovery whereas MedK-treated animals woke up more rapidly. Fentanyl-midazolam alone is not a useful sedative in Japanese macaques. A combination of fentanyl and midazolam with ketamine can be used as an alternative to medetomidine-ketamine in this species.

Unpredictable drug reaction in a child with Cornelia de Lange syndrome.

PubMed

Stevic, Marija; Milojevic, Irina; Bokun, Zlatko; Simic, Dusica

2015-02-01

Preoperative use of midazolam sedation is mandatory during induction of anesthesia in noncooperative and hyperactive children to prevent possible obstacles. Unusual drug reactions rarely occur in patients undergoing anesthesia or in intensive care unit. This report describes an unpredictable drug reaction after a routine midazolam premedication in a patient with no history of allergy. There has been no literature data yet to show that midazolam can provoke respiratory problems in patients with Cornelia de Lange Syndrome. In our opinion midazolam should be avoided in patients with Cornelia de Lange Syndrome, which we enforced after first unpredictable reaction.

Development and validation of a sensitive assay for analysis of midazolam, free and conjugated 1-hydroxymidazolam and 4-hydroxymidazolam in pediatric plasma: Application to Pediatric Pharmacokinetic Study.

PubMed

Moorthy, Ganesh S; Jogiraju, Harini; Vedar, Christina; Zuppa, Athena F

2017-11-01

Pharmacokinetic, pharmacodynamic and pharmacogenomic studies of midazolam are currently being performed in critically ill children to find suitable dose regimens. Sensitive assays using small volumes of plasma are necessary to determine the concentrations of midazolam and its respective metabolites in pediatric studies. Midazolam is metabolized to hydroxylated midazolam isomers, which are present as free as well as the corresponding glucuronide conjugates. A high-performance liquid chromatographic method with tandem mass spectrometry has been developed and validated for the quantification of midazolam, and free and total 1-hydroxymidazolam and 4-hydroxymidazolam metabolites in small volumes of plasma. Cleanup consisted of 96-well μ-elution solid phase extraction (SPE). The analytes were separated by gradient elution using a C 18 analytical column with a total run time of 5min. Multiple reaction monitoring was employed using precursor to product ion transitions of m/z 326.2→291.3 for midazolam, m/z 342.1→203.0 for 1-hydroxymidazolam, m/z 342.1→325.1 for 4-hydroxymidazolam and m/z 330.2→295.3 for 2 H 4 -midazolam (internal standard). Since authentic hydroxymidazolamglucuronide standards are not available, samples were hydrolyzed with β-glucuronidase under optimized conditions. Assay conditions were modified and optimized to provide appropriate recovery and stability because 4-hydroxymidazolam was very acid sensitive. Standard curves were linear from 0.5 to 1000ng/mL for all three analytes. Intra- and inter day accuracy and precision for quality control samples (2, 20, 200 and 800ng/mL) were within 85-115% and 15% (coefficient of variation), respectively. Stability in plasma and extracts were sufficient under assay conditions. Plasma samples were processed and analyzed for midazolam, and free 1-hydroxymidazolam and 4-hydroxymidazolam metabolites. Plasma samples that were hydrolyzed with β-glucuronidase were processed and analyzed for midazolam, and total 1-hydroxymidazolam and 4-hydroxymidazolam metabolites under the same assay conditions. The difference in concentration between the total and free hydroxymidazolam metabolites provided an estimate of conjugated hydroxymidazolam metabolites. The combination of 96-well μ-elution SPE and LC-MS/MS allows reliable quantification of midazolam and its metabolites in small volumes of plasma for pediatric patients. This assay is currently being successfully utilized for analysis of samples from ongoing clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.

Sedative effects of midazolam and xylazine with or without ketamine and detomidine alone following intranasal administration in Ring-necked Parakeets.

PubMed

Vesal, Nasser; Eskandari, Mohammad H

2006-02-01

To evaluate the effects of intranasal administration of midazolam and xylazine (with or without ketamine) and detomidine and their specific antagonists in parakeets. Prospective study. 17 healthy adult Ring-necked Parakeets (Psittacula krameri) of both sexes (mean weight, 128.83+/-10.46 g [0.28+/-0.02 lb]). The dose of each drug or ketamine-drug combination administered intranasally that resulted in adequate sedation (ie, unrestrained dorsal recumbency maintained for >or=5 minutes) was determined; the onset of action, duration of dorsal recumbency, and duration of sedation associated with these treatments were evaluated. The efficacy of the reversal agents flumazenil, yohimbine, and atipamezole was also evaluated. In parakeets, intranasal administration of midazolam (7.3 mg/kg [3.32 mg/lb]) or detomidine (12 mg/kg [5.45 mg/lb]) caused adequate sedation within 2.7 and 3.5 minutes, respectively. Combinations of midazolam (3.65 mg/kg [1.66 mg/lb]) and xylazine (10 mg/kg [4.55 mg/lb]) with ketamine (40 to 50 mg/kg [18.2 to 22.7 mg/lb]) also achieved adequate sedation. Compared with detomidine, duration of dorsal recumbency was significantly longer with midazolam. Intranasal administration of flumazenil (0.13 mg/kg [0.06 mg/lb]) significantly decreased midazolam-associated recumbency time. Compared with the xylazineketamine combination, duration of dorsal recumbency was longer after midazolam-ketamine administration. Intranasal administration of flumazenil, yohimbine, or atipamezole significantly decreased the duration of sedation induced by midazolam, xylazine, or detomidine, respectively. Intranasal administration of sedative drugs appears to be an acceptable method of drug delivery in Ring-necked Parakeets. Reversal agents are also effective when administered via this route.

An Evaluation of Oral Midazolam for Anxiety and Pain in First-Trimester Surgical Abortion: A Randomized Controlled Trial.

PubMed

Bayer, Lisa L; Edelman, Alison B; Fu, Rongwei; Lambert, William E; Nichols, Mark D; Bednarek, Paula H; Miller, Kelsey; Jensen, Jeffrey T

2015-07-01

To estimate the effect of oral midazolam on patient pain and anxiety perception during first-trimester surgical abortion. Between May and December 2013, we conducted a randomized, double-blind, placebo-controlled trial. Patients between 6 0/7 and 10 6/7 weeks of gestation received 10 mg oral midazolam or placebo 30-60 minutes before surgical abortion. All patients received ibuprofen and a paracervical block. We powered the study (power=80%; significance level=.025) to detect a 15-mm difference in our two a priori primary outcomes of pain and anxiety with uterine aspiration on a 100-mm visual analog scale. Secondary outcomes were pain and anxiety at additional time points, memory, satisfaction, side effects, and adverse events. Demographics were similar between groups (placebo=62, midazolam=62). Compared with those randomized to placebo, patients who received midazolam had significantly less anxiety preoperatively (room entry: 51.4 mm compared with 34.5 mm, P<.001; positioning: 56.6 mm compared with 45.4 mm, P=.02). There was no difference in pain (P=.28) or anxiety (P=.14) during uterine aspiration or at other procedural time points. A significantly greater number of patients in the midazolam group reported partial amnesia (31/61 compared with 16/61, P=.005) and dizziness (30/61 compared with 18/61, P=.03). Controlling for baseline differences, patients who received midazolam reported more postoperative sleepiness (P<.001) and less postoperative nausea (P=.004). There was no difference in overall satisfaction (P=.88). Although oral midazolam reduces preprocedural anxiety, it does not reduce pain or anxiety with uterine aspiration during first-trimester surgical abortions. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01830881. I.

Continued midazolam versus diphenhydramine in difficult-to-sedate patients: a randomized double-blind trial.

PubMed

Sachar, Hamita; Pichetshote, Nipaporn; Nandigam, Kavitha; Vaidya, Keta; Laine, Loren

2018-05-01

Current guidelines recommend diphenhydramine in patients undergoing endoscopy who are not adequately sedated with a benzodiazepine and opioid combination. Because this practice has not been adequately assessed, we performed a randomized, double-blind trial comparing diphenhydramine with continued midazolam in such patients. Patients undergoing elective colonoscopy with moderate sedation were eligible. Sedation was measured with the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score with adequate sedation defined as 3 on a 0- to 5-point scale. Patients not adequately sedated with midazolam 5 mg and fentanyl 100 μg were randomly assigned to diphenhydramine 25 mg versus continued midazolam 1.5 mg. Adequacy of sedation was assessed 3 minutes after each study medication dose. If MOAA/S was 4 to 5, study medication was repeated, to a maximum of 3 doses. The primary endpoint was adequate sedation. The planned enrollment of 200 patients (100 in each study group) was attained. Adequate sedation was achieved less often with diphenhydramine than midazolam (27% vs 65%, difference = -38%; 95% CI, -50% to -24%; P < .0001). After study medications were completed, more patients required additional medication for sedation or analgesia with diphenhydramine versus midazolam (84% vs 68%, P = .008), whereas the time to discharge from the recovery unit was similar (134 vs 129 minutes). Treatment effect was consistent across subgroups including age ≤55, substance abuse, benzodiazepine use, opioid use, and psychiatric medication use. Endoscopists performing moderate sedation should continue midazolam rather than switching to diphenhydramine in patients who do not achieve adequate sedation with usual doses of midazolam and an opioid. (Clinical trial registration number: NCT01769586.). Published by Elsevier Inc.

Systemic or Intra-Amygdala Injection of a Benzodiazepine (Midazolam) Impairs Extinction but Spares Re-Extinction of Conditioned Fear Responses

ERIC Educational Resources Information Center

Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

2009-01-01

Rats were subjected to one or two cycles of fear conditioning and extinction, injected with a benzodiazepine, midazolam, before the first or second extinction, and tested for long-term inhibition of fear responses (freezing). In Experiment 1, inhibition of context-conditioned fear was spared when midazolam was injected before the second…

The Effect of Oral Midazolam and Chloral Hydrate Before Echocardiography in Pediatric Patients: A Randomized Double-Blind Clinical Trial.

PubMed

Salehi, Forod; Riasi, Hamid Reza; Ebrahimzadeh, Ali; Askari Janatabadi, Sima

2017-01-01

This study aimed to compare the effects of oral midazolam and chloral hydrate in pre-echocardiography sedation of children. In this double-blind clinical trial, 68 children were randomly assigned to midazolam (0.2 mg/kg) or chloral hydrate (50 mg/kg). The intensity, duration, and onset of the drugs' effects were assessed. Data were analyzed using the χ 2 and Mann-Whitney tests ( P ≤ .05). The average onset and duration of sedation in the children assigned to midazolam was shorter than in those assigned chloral hydrate (6.35 ± 3.65 and 19.14 ± 5.86 minutes, P = .0001, and 27.64 ± 8.34 and 48.97 ± 14.81 minutes, P = .0001). Gastrointestinal side effects were more frequent in the chloral hydrate group (23.5% against 0%, P = .003). According to the results of the present study, chloral hydrate and midazolam can be appropriate choices for pre-echocardiography sedation of patients without cardiovascular risk factors. Considering the similar effectiveness, more rapid onset, and shorter duration of sedation, besides less side effects in the midazolam group, researchers recommend the routine use of this drug.

Comparison of biochemical stress indicators in juvenile captive estuarine crocodiles (Crocodylus porosus) following physical restraint or chemical restraint by midazolam injection.

PubMed

Olsson, Annabelle; Phalen, David

2013-07-01

Using a prospective, randomized study design we demonstrate that midazolam sedation minimizes acidosis compared with physical restraint in captive juvenile estuarine crocodiles during handling or noninvasive procedures at preferred body temperature. A dose of midazolam (5.0 mg/kg) was administered intramuscularly into the forelimb of 20 male estuarine crocodiles weighing 2-3.5 kg. Their heart and respiratory rate and degree of sedation were monitored until recovery and then daily for 7 subsequent days. Blood samples were taken at 30, 60, 90, 180, and 360 min. We recorded lactate, partial pressure of carbon dioxide (CO2), hematocrit, glucose, and blood pH. A second group (1.9-2.6 kg) was physically restrained for 5 min and the same parameters recorded. Physically restrained animals demonstrated elevated heart rate, respiratory rate, glucose, lactate, and anion gap compared with the midazolam-treated group. Physically restrained animals had lower pH, bicarbonate, and partial pressure of CO2 compared with the midazolam-treated group. Behavior in the physically restrained group in the days following the study was disrupted, with reluctance to feed and bask, compared with midazolam-treated animals whose behavior was normal. We conclude that midazolam administered in the forelimb of captive estuarine crocodiles of 2-3.5 kg provides predictable onset and duration of sedation enabling physical examination, sample collection, and translocation of the animals with minimal disturbance to lactate, pH, and CO2. Behavior following recovery appears normal.

Spinal anaesthesia with midazolam in the rat.

PubMed

Bahar, M; Cohen, M L; Grinshpon, Y; Chanimov, M

1997-02-01

This study examined in an animal model whether intrathecal midazolam, alone or with fentanyl, can achieve anaesthesia sufficient for laparotomy, comparable to lidocaine. Effects on consciousness and whether anaesthesia was segmental were also examined. The haemodynamic and respiratory changes were compared with those of intrathecal lidocaine or intrathecal fentanyl alone. Sixty Wistar strain rats, with nylon catheters chronically implanted in the lumbar subarachnoid theca, were divided into six groups. Group 1 (n = 12) received 75 microL intrathecal lidocaine 2%. Group 2 (n = 12) received 75 microL intrathecal midazolam 0.1%, Group 3 (n = 12) received intrathecal 37.5 microL midazolam 0.1%, plus 37.5 microL fentanyl 0.005%. Group 4 (n = 12) received intrathecal 50 microL fentanyl 0.005%. Group 5 (n = 6) received 75 microL midazolam 0.1% iv. Group 6 (n = 6) received halothane 0.6% in oxygen by inhalation. Both groups that received intrathecal midazolam, alone or combined with fentanyl, developed effective segmental sensory and motor blockade of the hind limbs and abdominal wall, sufficient for a pain-free laparotomy procedure. Neither of these groups, unlike the group that received intrathecal lidocaine, developed a reduction in blood pressure or change in heart rate at the time of maximal sensory or motor blockade, nor were there changes in the arterial blood gases or respiratory rate. Midazolam, when injected intrathecally, produces reversible, segmental, spinally mediated antinociception, sufficient to provide balanced anaesthesia for abdominal surgery.

A Systematic Review of the Use of Buccal Midazolam in the Emergency Treatment of Prolonged Seizures in Adults with Learning Disabilities

ERIC Educational Resources Information Center

Marshall, Thomas

2007-01-01

Background: Buccal midazolam is widely used in children for the emergency treatment of epilepsy, and these children are graduating into adult learning disability services. Aims: The aim of this paper was to appraise the evidence for buccal midazolam as a treatment for prolonged seizures in adults with learning disabilities. Method: A literature…

A randomized, double-blind pilot study of dexmedetomidine versus midazolam for intensive care unit sedation: patient recall of their experiences and short-term psychological outcomes.

PubMed

MacLaren, Robert; Preslaski, Candice R; Mueller, Scott W; Kiser, Tyree H; Fish, Douglas N; Lavelle, James C; Malkoski, Stephen P

2015-03-01

Sedation with dexmedetomidine may facilitate ventilator liberation and limit the occurrence of delirium. No trial has assessed patient recall or the development of psychological outcomes after dexmedetomidine sedation. This pilot study evaluated whether transitioning benzodiazepine sedation to dexmedetomidine alters patient recall and the incidence of anxiety, depression, or acute stress disorder (ASD). This investigation was a randomized, double-blind, single-center study. Existing continuous benzodiazepine sedation was converted to dexmedetomidine or midazolam when patients qualified for daily awakenings. Sedation was titrated to achieve Riker sedation agitation scores of 3 to 4. The intensive care unit (ICU) Stressful Experiences Questionnaire, hospital anxiety and depression scale, and the impact of event scale-revised were administered before hospital discharge to assess recall, anxiety, depression, and manifestations of ASD. A total of 11 patients received dexmedetomidine, and 12 patients received midazolam. Median dosing was 0.61 µg/kg/h for 3.5 days for dexmedetomidine and 3.7 mg/h for 3 days for midazolam. Attainment of goal sedation and analgesia was similar; however, more dexmedetomidine patients experienced agitation and pain. The median duration of mechanical ventilation from study drug initiation to extubation was 3.4 days in dexmedetomidine patients and 2.9 days in midazolam patients. Dexmedetomidine patients remembered 18.5 experiences compared with 8.5 in midazolam patients (P = .015). Rates of anxiety and depression were similar. In all, 5 (62.5%) dexmedetomidine patients and 1 (12.5%) midazolam patient manifested ASD (P = .063), and 1 dexmedetomidine patient and 5 midazolam patients developed new-onset delirium (P = .07). Hypotension occurred in 10 (90.9%) dexmedotomidine patients and 6 (50%) midazolam patients (P = .069). Transitioning benzodiazepine sedation to dexmedetomidine when patients qualify for daily awakenings may reduce the development of delirium and facilitate remembrance of ICU experiences but may lead to manifestations of ASD. Monitoring hypotension is required for both the sedatives. Additional comparative studies focusing on the long-term impact of ICU recall and psychological outcomes are needed. © The Author(s) 2013.

Intravenous sufentanil-midazolam versus sevoflurane anaesthesia in medetomidine pre-medicated Himalayan rabbits undergoing ovariohysterectomy.

PubMed

Hedenqvist, Patricia; Jensen-Waern, Marianne; Fahlman, Åsa; Hagman, Ragnvi; Edner, Anna

2015-07-01

To compare physiological effects of sufentanil-midazolam with sevoflurane for surgical anaesthesia in medetomidine premedicated rabbits. Prospective, randomized controlled experimental study. Eighteen female Himalayan rabbits, weight 2.1 ± 0.1 kg. Premedication with 0.1 mg kg(-1) medetomidine and 5 mg kg(-1) carprofen subcutaneously, was followed by intravenous anaesthetic induction with sufentanil (2.3 μg mL(-1)) and midazolam (0.45 mg mL(-1)). After endotracheal intubation, anaesthesia was maintained with sufentanil-midazolam (n = 9) or sevoflurane (n = 9). Ovariohysterectomy was performed. Intermittent positive pressure ventilation was performed as required. Physiological variables were studied perioperatively. Group means of physiologic data were generated for different anaesthetic periods. Data were compared for changes from sedation, and between groups by anova. Post-operatively, 0.05 mg kg(-1) buprenorphine was administered once and 5 mg kg(-1) carprofen once daily for 2-3 days. Rabbits were examined and weighed daily until one week after surgery. Smooth induction of anaesthesia was achieved within 5 minutes. Sufentanil and midazolam doses were 0.5 μg kg(-1) and 0.1 mg kg(-1), during induction and 3.9 μg kg(-1) hour(-1) and 0.8 mg kg(-1) hour(-1) during surgery, respectively. End-tidal sevoflurane concentration was 2.1% during surgery. Assisted ventilation was required in nine rabbits receiving sufentanil-midazolam and four receiving sevoflurane. There were no differences between groups in physiologic data other than arterial carbon dioxide. In rabbits receiving sevoflurane, mean arterial pressure decreased pre-surgical intervention, heart rate increased 25% during and after surgery and body weight decreased 4% post-operatively. Post-operative problems sometimes resulted from catheterization of the ear artery. Sevoflurane and sufentanil-midazolam provided surgical anaesthesia of similar quality. Arterial blood pressure was sustained during sufentanil-midazolam anaesthesia and rabbits receiving sevoflurane lost body weight following ovariohysterectomy. Mechanical ventilation was required with both anaesthetic regimens. Anaesthesia with sufentanil-midazolam in medetomidine premedicated healthy rabbits is useful in the clinical and the research setting, as an alternative to sevoflurane. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Comparison of the Effect of Thiopental Sodium with Midazolam-ketamine on Post-tonsillectomy Agitation in Children.

PubMed

Toliyat, Maryam; Zangoee, Maliheh; Ahrari, Shahnaz; Zangoee, Reza

2015-10-01

The aim of this study was to determine the effect of thiopental sodium with that of midazolam-ketamine on relieving agitation after tonsillectomy in children. In a clinical trial, 50 children aged 5-10 years, candidates for tonsillectomy, were randomly divided into two 25-member groups. In the first group, thiopental sodium 5mg/kg/IV, and in the second group combination of midazolam 0.01 mg/kg/IV and ketamine 1 mg/kg/IV were used to induce anesthesia. The level of sedation was assessed after surgery with the Ramsay scale. There were no significant differences between the two groups in terms of heart rate, arterial oxygen pressure (PO2), and duration of anesthesia. The Ramsay sedation score was significantly higher in the thiopental sodium group than in the midazolam-ketamine group (P=0.01). Thiopental sodium can be more effective than the combination of midazolam-ketamine for controlling agitation after tonsillectomy in children.

[Evaluation of N2O inhalation and oral midazolam conscious sedation in pediatric dentistry of children with intellectual disability].

PubMed

Tian, Xiao-hua; Yang, Yan-zhong; Li, Xiao-feng

2015-06-01

To evaluate the effect of N2O inhalation and oral midazolam sedation on uncooperative patients with intellectual disability in pediatric dentistry. N2O inhalation (35%-50%) and oral midazolam conscious sedation (dosages range: 0.50-0.75 mg/kg) were applied to 67 uncooperative pediatric patients with intellectual disability in outpatient department. The patients were divided into 2 groups: group A (N2O inhalation conscious sedation) and group B(oral midazolam conscious sedation).Treatment results and safety were statistically analyzed by Chi-square test with SPSSl3.0 software package. The mean success rate was 70%. The success rate in group B (75%) was higher than group A (67%). The overall incidence of adverse reactions was 13%(9/67). The adverse reaction rate in group B (25%) was significantly higher than group A (5%, P<0.05). N2O inhalation and oral midazolam conscious sedation are effective and safe in pediatric dental uncooperative patients with intellectual disability.

[Midazolam sedation in the general dental practice].

PubMed

Bertens, J; Abraham-Inpijn, L; Meuwissen, P J

1994-03-01

The general dental practitioner is occasionally confronted with patients who, on the basis of psychological--and often somatic--criteria, are difficult to treat. Medicinal sedation in combination with anxiety reduction may be deemed appropriate for such patients. In the Netherlands inhalation sedation by means of a combination of oxygen and nitrous oxide is generally used. The limitations and disadvantages of this method have directed attention towards sedation by means of midazolam, a quick-acting benzodiazepine. In view of the complications which may accompany the administration of midazolam, the general practitioner working alone or in a group practice is advised against using midazolam sedation. Such use should be reserved for a dentist working in a hospital setting, who is able to consult with a physician regarding the advisability of administering midazolam. Even then, the safety of the patient requires that the practitioners have a proper insight into the physical state of the patient, work according to a protocol and in accordance with clearly defined responsibilities, and provide adequate accommodation during and after treatment.

Oral Midazolam Sedation For Uncooperative Children In Outpatient Paedodontics: Time For Reappraisal.

PubMed

Kapur, Aditi; Jain, Kajal; Goyal, A; Mahoney, Greg

2016-01-01

Sedation is frequently desired to facilitate dental procedures in uncooperative paediatric patients. Oromucosal Midazolam sedation is a popular choice among paediatric dentists world wide due to its many advantages such as ease of administration, good efficacy, presence of reversal agents and a wide margin of safety. On the other hand, many investigators have reported that midazolam sedation may not be successful for carrying out all types of dental procedures. This may be attributed to diverse nature of various treatment plans coupled with the extent of behavioural changes in the child and operator's experience. Due to the heterogeneity involved in treatment of paediatric dental procedures, the specific indications for oral midazolam use that ensure its success rate, probably need to be defined. This may enable the clinicians to have a convenient and quicker option for managing the cases rather than facing sedation failure or at times, ending up giving general anaesthetics. This article therefore brings forth the possible causes of midazolam sedation failure and proposes a 'case selection criterion'.

Episodic representations support early semantic learning: evidence from midazolam induced amnesia.

PubMed

Merritt, Paul; Hirshman, Elliot; Zamani, Shane; Hsu, John; Berrigan, Michael

2006-07-01

Current controversy exists regarding the role of episodic representations in the formation of long-term semantic memories. Using the drug midazolam to induce temporary amnesia we tested participants' memories for newly learned facts in a semantic cue condition or an episodic and semantic cue condition. Following midazolam administration, memory performance was superior in the episodic and semantic condition, suggesting early semantic learning is supported by episodic representations.

Subcutaneous Midazolam with and without Ketamine for Sedation In Children Undergoing Dental Treatment: A Pilot Study.

PubMed

Flores-Castillo, D; Martínez-Rider, R; Ruiz-Rodríguez, S; Garrocho-Rangel, A; Lara-Guevara, J; Pozos-Guillén, A

2015-01-01

The objective of this study was to evaluate the efficacy of subcutaneous (SC) sedation using midazolam with and without ketamine in non-cooperative pediatric patients undergoing dental treatment. A prospective, randomized, controlled, double-blind, crossover pilot clinical trial was carried out in 13 children, aged between 17-46 months, ASA l, Frankl 1. Two sedation schemes were administered SC: Midazolam alone (M), and a combination of Midazolam-Ketamine (MK). Both regimens were administered to the same patient in two consecutive treatment sessions, in accordance with a random assignment. Overall behavior, movement, and crying were assessed according to the modified Houpt scale. Heart rate, blood pressure, blood oxygen saturation, and possible side effects were also monitored. The percentage of non-crying children was always higher in the treatment with MK compared with the treatment with M, but without a significant statistical difference. Regarding variable body movement, the percentage of children without movement was higher in the MK group, although only up to minute 10; no significant differences were found at 20, 30, and 40 minutes, and from minute 40, body movement was lower in the M group. Midazolam alone and the midazolam-ketamine combination administered subcutaneously resulted in a safe and efficient pharmacological method for providing moderate sedation to non-cooperative pediatric patients undergoing dental treatment.

The use of temazepam elixir in surgical dental sedation: a comparison with intravenous midazolam.

PubMed

Skelly, A M; Girdler, N M; File, S E

1992-02-22

Out-patients attending for removal of at least one lower third molar were randomly allocated to treatment with temazepam elixir (n = 7) or intravenous midazolam (n = 8), as well as local analgesia. Patients were tested prior to drug administration and at the end of surgery. Both drugs increased heart rate and midazolam also decreased diastolic blood pressure. The two drugs caused significant, equal increases in ratings of sedation, but the reduction of anxiety was significant only for midazolam. There was significant amnesia for material presented after drug administration, as well as for dental events and this was significantly greater for midazolam. The effects of these drugs in dental patients were compared with those in normal volunteers treated in an identical manner, but without oral surgery. The drugs had similar significant cardiovascular and amnesic effects in the volunteers and the same effects on mood ratings, even though volunteers and patients differed in their pretreatment levels of anxiety and discontent. The dentist's ratings of the sedation and operating conditions were excellent in both cases. Thus temazepam elixir provided a useful sedative for oral surgery, avoiding the complications of intravenous administration. However, for equivalent levels of sedation, midazolam had greater anxiolytic and amnesic effects than temazepam.

Amnesia for electric dental pulp stimulation and picture recall test under different levels of propofol or midazolam sedation.

PubMed

Matsuki, Y; Ichinohe, T; Kaneko, Y

2007-01-01

To compare the amnesic effect of propofol and midazolam to electric dental pulp stimulation (invasive) and picture recall test (non-invasive) at two sedation levels with the aid of bispectral index (BIS) monitoring. The subjects were 10 male volunteers (24-34 years) classified as ASA physical status I. Propofol was administered to achieve a sedation score of three with a target-controlled infusion technique; it was then regulated to give a sedation score of two (P group). Midazolam was administered by a titration dosage to achieve a sedation score of three (M group). It then gradually decreased to give a sedation score of two. The BIS score, sedation score, plasma/serum concentration of propofol and midazolam, blood pressure, pulse rate, respiratory rate, end-tidal CO(2) tension and arterial oxygen saturation were observed at each sedation level in both groups. Amnesic effects were evaluated using a picture recall test and electric dental pulp stimulation. No difference was observed in the amnesic effect evaluated by picture recall test at the two sedation levels. Likewise, there was no difference at a sedation score of three when the amnesic effect was evaluated by electric dental pulp stimulation. In contrast, a significant difference was observed at a sedation score of two; midazolam produced amnesia in more subjects than did propofol. Propofol and midazolam did not show any significant difference in amnesic effects to non-invasive stimuli. For invasive stimuli, midazolam showed a stronger amnesic effect at the moderate sedation level, but not at the deeper sedation level.

A randomized clinical trial of intrathecal magnesium sulfate versus midazolam with epidural administration of 0.75% ropivacaine for patients with preeclampsia scheduled for elective cesarean section.

PubMed

Paleti, Sophia; Prasad, P Krishna; Lakshmi, B Sowbhagya

2018-01-01

Magnesium sulfate and midazolam have been used as adjuvants to local anesthetics via intrathecal and epidural routes to augment the quality of block and prolong postoperative analgesia. This study compares addition of intrathecal magnesium sulfate versus intrathecal midazolam to epidurally administered isobaric ropivacaine as a part of combined spinal epidural technique in pre-eclamptic parturients undergoing elective cesarean section. After institutional ethics committee approval and written informed consent, 50 pre-eclamptic parturients were randomly allocated to one of the two groups of 25 each to either receive intrathecal magnesium sulfate (50 mg) or intrathecal midazolam (1 mg) in combination with epidural ropivacaine (0.75%; 14-16 ml). The onset and duration of sensory and motor blockade, duration of postoperative analgesia, postoperative visual analogue scores for pain, and perioperative side effects were noted. Data were analyzed statistically using Graphpad.com software. Onset times to sensory and motor blockade were faster in midazolam than in magnesium group ( P < 0.01). Duration of sensory and motor blockade, and time to first request of analgesia were significantly longer in the magnesium group compared to the midazolam group ( P < 0.01). The fetal outcomes according to APGAR scores were comparable in both the groups, the median APGAR score at 1 minute was 8 and at 5 minutes was 10 in both the groups. Intrathecal magnesium with epidural ropivacaine significantly prolonged postoperative analgesia compared to intrathecal midazolam without any complications. Perioperative hemodynamics were comparable in both groups.

Postmortem determination of the biological distribution of sufentanil and midazolam after an acute intoxication.

PubMed

Ferslew, K E; Hagardorn, A N; McCormick, W F

1989-01-01

A case is presented of a death caused by self-injection of sufentanil and midazolam. Biological fluids and tissues were analyzed for midazolam by high performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS) and for sufentanil by GC/MS. Midazolam was extracted from basified fluids or tissues homogenated with n-butyl chloride and analyzed by HPLC by using a phosphate buffer: acetonitrile (60:40) mobile phase on a mu-Bondapak C18 column at 240 nm. Sufentanil was extracted from basified fluids and tissue homogenates with hexane:ethanol (19:1). GC/MS methodology for both compounds consisted of chromatographic separation on a 15-m by 0.25-mm inside diameter (ID) DB-5 (1.0-micron-thick film) bonded phase fused silica capillary column with helium carrier (29 cm/s) splitless injection at 260 degrees C; column 200 degrees C (0.8 min) 10 degrees C/min to 270 degrees C; and electron ionization and multiple ion detection for midazolam (m/z 310), methaqualone (IS, m/z 235), sufentanil (m/z 289), and fentanyl (IS, m/z 245). Sufentanil concentrations were: blood 1.1 ng/mL, urine 1.3 ng/mL, vitreous humor 1.2 ng/mL, liver 1.75 ng/g, and kidney 5.5 ng/g. Midazolam concentrations were: blood 50 ng/mL, urine 300 ng/mL, liver 930 ng/g, and kidney 290 ng/g. Cause of death was attributed to an acute sufentanil/midazolam intoxication and manner of death a suicide.

Sedation during mechanical ventilation: a trial of benzodiazepine and opiate in combination.

PubMed

Richman, Paul S; Baram, Daniel; Varela, Marie; Glass, Peter S

2006-05-01

To compare the efficacy of continuous intravenous sedation with midazolam alone vs. midazolam plus fentanyl ("co-sedation") during mechanical ventilation. A randomized, prospective, controlled trial. A ten-bed medical intensive care unit at a university hospital. Thirty patients with respiratory failure who were expected to require >48 hrs of mechanical ventilation and who were receiving a sedative regimen that did not include opiate pain control. An intravenous infusion of either midazolam alone or co-sedation was administered by a nurse-implemented protocol to achieve a target Ramsay Sedation Score set by the patient's physician. Study duration was 3 days, with a brief daily "wake-up." We recorded the number of hours/day that patients were "off-target" with their Ramsay Sedation Scores, the number of dose titrations per day, the incidence of patient-ventilator asynchrony, and the time required to achieve adequate sedation as measures of sedative efficacy. We also recorded sedative cost in U.S. dollars and adverse events including hypotension, hypoventilation, ileus, and coma. Compared with the midazolam-only group, the co-sedation group had fewer hours per day with an "off-target" Ramsay Score (4.2 +/- 2.4 and 9.1 +/- 4.9, respectively, p < .002). Fewer episodes per day of patient-ventilator asynchrony were noted in the co-sedation group compared with midazolam-only (0.4 +/- 0.1 and 1.0 +/- 0.2, respectively, p < .05). Co-sedation also showed nonsignificant trends toward a shorter time to achieve sedation, a need for fewer dose titrations per day, and a lower total sedative drug cost. There was a trend toward more episodes of ileus with co-sedation compared with midazolam-only (2 vs. 0). In mechanically ventilated patients, co-sedation with midazolam and fentanyl by constant infusion provides more reliable sedation and is easier to titrate than midazolam alone, without significant difference in the rate of adverse events.

Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial.

PubMed

Yap, Celene Y L; Taylor, David McD; Knott, Jonathan C; Taylor, Simone E; Phillips, Georgina A; Karro, Jonathan; Chan, Esther W; Kong, David C M; Castle, David J

2017-07-01

To examine the efficacy and safety of (1) midazolam-droperidol versus droperidol and (2) midazolam-droperidol versus olanzapine for methamphetamine-related acute agitation. A multi-centre, randomized, double-blind, controlled, clinical trial was conducted in two Australian emergency departments, between October 2014 and September 2015. Three hundred and sixty-one patients, aged 18-65 years, requiring intravenous medication sedation for acute agitation, were enrolled into this study. We report the results of a subgroup of 92 methamphetamine-affected patients. Patients were assigned randomly to receive either an intravenous bolus of midazolam 5 mg-droperidol 5 mg combined, droperidol 10 mg or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg or olanzapine 5 mg, respectively. The primary outcome was the proportion of patients sedated adequately at 10 minutes. Odds ratios with 95% confidence intervals (ORs, 95% CI) were estimated. The baseline characteristics of patients in the three groups were similar. At 10 minutes, significantly more patients in the midazolam-droperidol group [29 of 34 (85.3%)] were sedated adequately compared with the droperidol group [14 of 30 (46.7%), OR = 6.63, 95% CI = 2.02-21.78] or with the olanzapine group [14 of 28 (50.0%), OR 5.80, 95% CI = 1.74-19.33]. The number of patients who experienced an adverse event (AE) in the midazolam-droperidol, droperidol and olanzapine groups was seven of 34, two of 30 and six of 28, respectively. The most common AE was oxygen desaturation. A midazolam-droperidol combination appears to provide more rapid sedation of patients with methamphetamine-related acute agitation than droperidol or olanzapine alone. © 2017 Society for the Study of Addiction.

Effect of drinks that are added as flavoring in oral midazolam premedication on sedation success.

PubMed

Isik, Berrin; Baygin, Ozgül; Bodur, Haluk

2008-06-01

Midazolam is one of the most frequently used agents for sedation in pediatric dentistry. The injectable form of midazolam can also be given orally. However, its bad taste has negative effects on ingestion of the drug. In this study, we aimed to evaluate the effect of drinks which were added to mask the bitter taste of midazolam for drug acceptance and sedation. In the laboratory; the pH values of 2.5 ml midazolam (15 mg x 3 ml(-1)) and the mixtures of Pepsi Cola, 10% sodium citrate, fresh pomegranate juice, and fresh grapefruit juice in equal volumes were measured. Seventy-five patients between 2 and 8 years of age who were assessed to have anxiety with the Frankl Behavior Scale and whose dental treatment was planned under sedation were randomly divided into five groups. Pepsi Cola (Group I), 10% sodium citrate (Group II), pomegranate juice (Group III), and grapefruit juice (Group IV) which were added to 0.75 mg x kg(-1) midazolam in equal volumes, and (Group V) 0.75 mg x kg(-1) midazolam given orally to children. The drug compliance of children was evaluated. After 15 min, 4-5 l x min(-1) of N(2)O : O(2) (40 : 60) inhalation was started via a nasal hood. During the procedure, heart rate, and SpO2 were monitored with pulse oximetry and sedation levels with the Ramsay Sedation Scale (RSS). Anesthetist, dentist, and parental satisfaction levels were recorded. The groups had similar demographics, drug ingestion was better in Groups I and II, but the mean RSS was the highest in Group II (P < 0.05). As well as making drug ingestion much simpler, the addition of sodium citrate to the midazolam administered orally to the children increased the effectiveness of sedation.

Refractory Status Epilepticus in Children: intention-to-treat with continuous infusions of midazolam and pentobarbital

PubMed Central

Tasker, Robert C; Goodkin, Howard P; Fernández, Iván Sánchez; Chapman, Kevin E; Abend, Nicholas S; Arya, Ravindra; Brenton, James N; Carpenter, Jessica L; Gaillard, William D; Glauser, Tracy A; Goldstein, Joshua; Helseth, Ashley R; Jackson, Michele C; Kapur, Kush; Mikati, Mohamad A; Peariso, Katrina; Wainwright, Mark S; Wilfong, Angus A; Williams, Korwyn; Loddenkemper, Tobias

2016-01-01

Objective To describe pediatric patients with convulsive refractory status epilepticus (RSE) in whom there is intention-to-use an intravenous anesthetic for seizure control. Design Two-year prospective observational study evaluating patients (age range one month to 21 years) with RSE not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent. Setting Nine pediatric hospitals in the United States. Patients In a cohort of 111 patients with RSE (median age 3.7 years, 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment. Main Results The median (interquartile range, IQR) intensive care unit length-of-stay was 10 (3–20) days. Up to four ‘cycles’ of serial anesthetic therapy were used and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9–34) hours for the first cycle, and longer when a second cycle was required (30 [4,−120] hours, p=0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam non-responders, transition to a second agent occurred after a median of one day. Most patients (94%) experienced seizure termination with these two therapies. Conclusions Midazolam and pentobarbital remains the mainstay of continuous infusion therapy for RSE in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study. PMID:27500721

Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital.

PubMed

Tasker, Robert C; Goodkin, Howard P; Sánchez Fernández, Iván; Chapman, Kevin E; Abend, Nicholas S; Arya, Ravindra; Brenton, James N; Carpenter, Jessica L; Gaillard, William D; Glauser, Tracy A; Goldstein, Joshua; Helseth, Ashley R; Jackson, Michele C; Kapur, Kush; Mikati, Mohamad A; Peariso, Katrina; Wainwright, Mark S; Wilfong, Angus A; Williams, Korwyn; Loddenkemper, Tobias

2016-10-01

To describe pediatric patients with convulsive refractory status epilepticus in whom there is intention to use an IV anesthetic for seizure control. Two-year prospective observational study evaluating patients (age range, 1 mo to 21 yr) with refractory status epilepticus not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent. Nine pediatric hospitals in the United States. In a cohort of 111 patients with refractory status epilepticus (median age, 3.7 yr; 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment. The median (interquartile range) ICU length of stay was 10 (3-20) days. Up to four "cycles" of serial anesthetic therapy were used, and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9-34) hours for the first cycle and longer when a second cycle was required (30 [4-120] hr; p = 0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam nonresponders, transition to a second agent occurred after a median of 1 day. Most patients (94%) experienced seizure termination with these two therapies. Midazolam and pentobarbital remain the mainstay of continuous infusion therapy for refractory status epilepticus in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study.

The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease.

PubMed

Tawfic, Qutaiba A; Faris, Ali S; Kausalya, Rajini

2014-02-01

Acute pain is one of the main causes of hospital admission in sickle cell disease, with variable intensity and unpredictable onset and duration. We studied the role of a low-dose intravenous (IV) ketamine-midazolam combination in the management of severe painful sickle cell crisis. A retrospective analysis was performed with data from nine adult patients who were admitted to the intensive care unit with severe painful sickle cell crises not responding to high doses of IV morphine and other adjuvant analgesics. A ketamine-midazolam regimen was added to the ongoing opioids as an initial bolus of ketamine 0.25mg/kg, followed by infusion of 0.2-0.25mg/kg/h. A midazolam bolus of 1mg followed by infusion of 0.5-1mg/h was added to reduce ketamine emergence reactions. Reduction in morphine daily requirements and improvement in pain scores were the determinants of ketamine-midazolam effect. The t-tests were used for statistical analysis. Nine patients were assessed, with mean age of 27±11 years. Morphine requirement was significantly lower after adding the IV ketamine-midazolam regimen. The mean±SD IV morphine requirement (milligram/day) in the pre-ketamine day (D0) was 145.6±16.5, and it was 112±12.2 on Day 1 (D1) of ketamine treatment (P=0.007). The Numeric Rating Scale scores on D0 ranged from eight to ten (mean 9.1), but improved to range from five to seven (mean 5.7) on D1. There was a significant improvement in pain scores after adding ketamine-midazolam regimen (P=0.01). Low-dose ketamine-midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis. Further controlled studies are required to prove this effect. Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Comparison of the Intramuscular, Intranasal or Sublingual Routes of Midazolam Administration for the Control of Soman-Induced Seizures

DTIC Science & Technology

2008-01-01

23, 2008) Abstract: This study evaluated the anticonvulsant effectiveness of midazolam to stop seizures elicited by the nerve agent soman when...seizure activity that was detected in the electroencephalographic record. When given immediately after seizure onset, the anticonvulsant ED 50 of...that time. At the 40-min. treatment delay, the anticonvulsant ED 50 s of intramuscular or intranasal midazolam did not differ and both were

The effects of intrathecal midazolam on sympathetic nervous system reflexes in man--a pilot study.

PubMed Central

Goodchild, C S; Noble, J

1987-01-01

Nine patients were given intrathecal injections of midazolam (dose 0.3-2 mg dissolved in 3 ml 5% dextrose). No changes in motor power or general sensation were produced. Resting heart rate and blood pressure were unchanged and normal valsalva manoeuvres were elicited 30 min post-injection. Cardiovascular responses were provoked at a light plane of anaesthesia by intubation of the trachea and manipulation of peritoneum and bowel but not by surgical incision of the skin. Intrathecal administration of midazolam relieved post-operative pain of somatic origin but not of visceral origin. It is concluded that intrathecal midazolam in the dosage used interrupts somatic nociceptive afferent pathways but not abdominal visceral nociceptive afferent pathways. PMID:3567043

Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A.

PubMed

Kinirons, M T; O'Shea, D; Kim, R B; Groopman, J D; Thummel, K E; Wood, A J; Wilkinson, G R

1999-09-01

Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability, and an in vivo probe to measure such differences would serve several purposes. The erythromycin breath test (ERBT) is an established approach that has proven useful in this regard, but it has several limitations. More recently, the hydroxylation of midazolam has been suggested as an alternative in vivo probe approach, because it is possible to estimate CYP3A activity in the intestinal epithelium as well as in the liver. The purpose of this study was to investigate the relationship, if any, between the ERBT and midazolam's CYP3A-mediated metabolism. Twenty healthy, medication-free young (24 to 46 years) European Americans (10 women) each received on separate days, in random order, either 3 microCi [14C-N-methyl]-erythromycin intravenously, 1 mg midazolam intravenously, or 2 mg midazolam orally. An ERBT value was determined 60 minutes after administration, and clearances were estimated after midazolam administration. In addition, an endogenous 0- to 4-hour urinary 6beta-hydroxycortisol/cortisol ratio was measured. All three measured drug trait values varied approximately threefold to fivefold, whereas the endogenous phenotype measure exhibited far greater variability (>100-fold). No statistically significant (P < .05) correlations existed between any of the trait values, including the ERBT value, obtained after intravenous administration of the radiolabeled probe and the systemic clearance of midazolam, expressed in terms of either total or unbound drug, or on an absolute or a body weight-corrected basis (r = 0.03 to r = 0.24; P = .08 to P = .90). Substratification according to sex generally did not improve such relationships. Although both erythromycin N-demethylation and the metabolism of midazolam by hydroxylation are mediated by CYP3A, the phenotypic trait measures associated with these two in vivo probe drugs do not provide the same information about the catalytic activity of the enzyme. An indirect measure such as the ERBT may reflect CYP3A activity and be useful for some purposes, but the estimation of the oral and intravenous clearance of midazolam has additional advantages, and they may be more applicable and have broader usefulness as quantitative estimates of CYP3A activity.

Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

PubMed

van Gerven, J M; Roncari, G; Schoemaker, R C; Massarella, J; Keesmaat, P; Kooyman, H; Heizmann, P; Zell, M; Cohen, A F; Dingemanse, J

1997-11-01

This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. The study was double-blind and five-way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg in the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as mg min(-1)) among doses. Midazolam was infused at 0.1 mg(-1) kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/-121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48-8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48-8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4-fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The influence of this metabolite during prolonged administration should be further investigated. These results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48-8684 with repeated administration of rising doses due to as yet undetermined factors.

Investigation of the in vivo activity of CYP3A in Brazilian volunteers: comparison of midazolam and omeprazole as drug markers.

PubMed

Rocha, Adriana; Coelho, Eduardo B; Moussa, Soraia A P; Lanchote, Vera L

2008-09-01

This study compares midazolam with omeprazole as marker drugs for the evaluation of CYP3A activity in nine healthy self-reported white Brazilian volunteers. Omeprazole was also used to evaluate the CYP2C19 phenotype. The volunteers received p.o. 20 mg omeprazole, and blood samples were collected 3.5 h after drug administration. After a washout period of 10 days, the volunteers received p.o. 15 mg midazolam maleate, and serial blood samples were collected up to 6 h after administration of the drug. CYP2C19 was genotyped for the allelic variants CYP2C19*1, CYP2C19*2, CYP2C19*3, and CYP2C19*17. Analysis of omeprazole, hydroxyomeprazole, omeprazole sulfone, and midazolam in plasma was carried out by LC-MS/MS. The volunteers genotyped as CYP2C19*1*17, CYP2C19*17*17, CYP2C19*1*1 (n = 8), or CYP2C19*17*2 (n = 1) presented a median hydroxylation index (omeprazole/hydroxyomeprazole) of 1.35, indicating that all of them were extensive metabolizers of CYP2C19. The volunteers (n = 9) presented a 0.12 log of the omeprazole/sulfone ratio and a median oral clearance of midazolam of 17.89 ml min(-1) kg(-1), suggesting normal CYP3A activity. Orthogonal regression analysis between midazolam clearance and log of the plasma concentrations of the omeprazole/omeprazole sulfone ratio (R = -0.7544, P < 0.05) suggests that both midazolam and omeprazole can be used as markers of CYP3A activity in the population investigated.

Ketamine versus midazolam in bipolar depression with suicidal thoughts: A pilot midazolam-controlled randomized clinical trial.

PubMed

Grunebaum, Michael F; Ellis, Steven P; Keilp, John G; Moitra, Vivek K; Cooper, Thomas B; Marver, Julia E; Burke, Ainsley K; Milak, Matthew S; Sublette, M Elizabeth; Oquendo, Maria A; Mann, J John

2017-05-01

To evaluate feasibility and effects of a sub-anesthetic infusion dose of ketamine versus midazolam on suicidal ideation in bipolar depression. Neurocognitive, blood and saliva biomarkers were explored. Sixteen participants with bipolar depression and a Scale for Suicidal Ideation (SSI) score of ≥4 were randomized to ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg). Current pharmacotherapy was maintained excluding benzodiazepines within 24 hours. The primary clinical outcome was SSI score on day 1 post-infusion. Results supported feasibility. Mean reduction of SSI after ketamine infusion was almost 6 points greater than after midazolam, although this was not statistically significant (estimate=5.84, SE=3.01, t=1.94, P=.074, 95% confidence interval ([CI)]=-0.65 to 12.31). The number needed to treat for response (SSI <4 and at least 50% below baseline) was 2.2, and for remission (SSI=0) was 3.2. The strongest neurocognitive correlation was between memory improvement on the Selective Reminding Test (SRT) and reduction in SSI score on day 1 after ketamine (ρ=-.89, P=.007). Pre- to post-infusion decrease in serum brain derived neurotrophic factor (BDNF) correlated with reduction in SSI from baseline to day 1 after ketamine (n=5, ρ=0.90, P=.037) but not midazolam (P=.087). The study demonstrated feasibility. Suicidal thoughts were lower after ketamine than after midazolam at a trend level of significance, likely due to the small pilot sample. Memory improvement and BDNF are promising biomarkers. Replication is needed in an adequately powered full-scale trial. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment.

PubMed

Shrot, Shai; Ramaty, Erez; Biala, Yoav; Bar-Klein, Guy; Daninos, Moshe; Kamintsky, Lyn; Makarovsky, Igor; Statlender, Liran; Rosman, Yossi; Krivoy, Amir; Lavon, Ophir; Kassirer, Michael; Friedman, Alon; Yaari, Yoel

2014-09-02

Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Risk factors for apnea in pediatric patients transported by paramedics for out-of-hospital seizure.

PubMed

Bosson, Nichole; Santillanes, Genevieve; Kaji, Amy H; Fang, Andrea; Fernando, Tasha; Huang, Margaret; Lee, Jumie; Gausche-Hill, Marianne

2014-03-01

Apnea is a known complication of pediatric seizures, but patient factors that predispose children are unclear. We seek to quantify the risk of apnea attributable to midazolam and identify additional risk factors for apnea in children transported by paramedics for out-of-hospital seizure. This is a 2-year retrospective study of pediatric patients transported by paramedics to 2 tertiary care centers. Patients were younger than 15 years and transported by paramedics to the pediatric emergency department (ED) for seizure. Patients with trauma and those with another pediatric ED diagnosis were excluded. Investigators abstracted charts for patient characteristics and predefined risk factors: developmental delay, treatment with antiepileptic medications, and seizure on pediatric ED arrival. Primary outcome was apnea defined as bag-mask ventilation or intubation for apnea by paramedics or by pediatric ED staff within 30 minutes of arrival. There were 1,584 patients who met inclusion criteria, with a median age of 2.3 years (Interquartile range 1.4 to 5.2 years). Paramedics treated 214 patients (13%) with midazolam. Seventy-one patients had apnea (4.5%): 44 patients were treated with midazolam and 27 patients were not treated with midazolam. After simultaneous evaluation of midazolam administration, age, fever, developmental delay, antiepileptic medication use, and seizure on pediatric ED arrival, 2 independent risk factors for apnea were identified: persistent seizure on arrival (odds ratio [OR]=15; 95% confidence interval [CI] 8 to 27) and administration of field midazolam (OR=4; 95% CI 2 to 7). We identified 2 risk factors for apnea in children transported for seizure: seizure on arrival to the pediatric ED and out-of-hospital administration of midazolam. Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

Can intravenous conscious sedation with midazolam be effective at facilitating surgical dentistry in adolescent orthodontic patients? - A service evaluation

PubMed Central

Stamp, A.J.; Dorman, M.L.; Vernazza, C.R.; Deeming, G.; Reid, C.; Wilson, K.E.; Girdler, N.M.

2017-01-01

Background Surgical dentistry during orthodontic care often occurs in adolescence and may involve surgical removal or exposure of teeth. The invasive nature of treatment, combined with dental anxiety, means care is often provided under GA. Best-practice guidelines however endorse conscious sedation as an alternative, where appropriate. Although a limited number of studies have shown safe and effective use of intravenous conscious sedation (IVCS) with midazolam in this cohort, robust evidence to support routine its use is lacking. Aim To assess whether IVCS with midazolam can effectively facilitate surgical dentistry in adolescent orthodontic patients in primary care. Method A retrospective service evaluation was undertaken reviewing clinical records of adolescents (aged 12-15 years) undergoing surgical exposure and/or surgical removal of teeth under IVCS midazolam. Results A total of 174 adolescents (mean age 14.2 years) attended for treatment between 2009 and 2015. Of these adolescent, 98.9% (n=172) allowed cannulation with all surgical dentistry completed during a single visit. Midazolam dose ranged from 2-7mg with 79.1% patients having good or excellent co-operation and three minor adverse events occurring. Conclusion This service evaluation shows IVCS midazolam can effectively facilitate surgical orthodontics in carefully selected adolescents. There is however a distinct need to further explore potential for this technique to provide a viable alternative to GA. PMID:28127013

Evaluation of plasma levels of melatonin after midazolam or sodium thiopental anesthesia in children.

PubMed

Muñoz-Hoyos, Antonio; Heredia, Francisco; Moreno, Francisco; García, Joaquín José; Molina-Carballo, Antonio; Escames, Germaine; Acuña-Castroviejo, Darío

2002-05-01

Midazolam and sodium thiopental are two commonly used drugs in anesthesia for minor surgical procedures in children. A relationship exists between benzodiazepines (BNZ), barbiturates and melatonin. Whereas these drugs increase pineal melatonin production, the indoleamine amplifies the effects of both BNZ and barbiturates on the central nervous system (CNS). Our purpose was thus to analyze the plasma levels of melatonin before and during midazolam or sodium thiopental anesthesia in children subjected to ambulatory surgical procedures. Midazolam (0.4 mg/kg) or sodium thiopental (5 mg/kg) were administered i.v. to 33 and 32 children (aged between 2 and 14 yr), respectively, and blood samples were taken before and 5, 10 and 20 min after the drugs were administered. Melatonin was measured in plasma by a commercial radioimmunoassay kit previously standardized in our laboratory. The results showed that neither midazolam nor sodium thiopental anesthesia significantly affected the levels of melatonin studied at anytime. Significant correlations were found comparing the levels of melatonin between the different times studied. These results suggest that midazolam or sodium thiopental did not affect melatonin production by the pineal gland, thus avoiding a possible potentiating effect of the indoleamine on the central effects of these drugs during anesthesia. However, the possibility that changes in melatonin had been masked by the antioxidant role of the neurohormone are discussed.

Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers.

PubMed

Skerjanec, Andrej; Wang, Jixian; Maren, Kelly; Rojkjaer, Lisa

2010-02-01

Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single-dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated-dose administration of deferasirox. After rifampin, a significant reduction (44%) in plasma exposure (AUC) to deferasirox was observed. Upon coadministration of midazolam, there was a modest reduction of up to 22% in midazolam exposure (AUC, C(max)), suggesting a modest induction of CYP3A4/5 by deferasirox. Def erasirox caused increases in repaglinide plasma C(max) and AUC of 1.5-fold to over 2-fold, respectively, with little change in blood glucose measures. Specific patient prescribing recommendations were established when coadministering deferasirox with midazolam, repaglinide, and rifampin. These recommendations may also apply to other substrates of CYP3A4/5 and CYP2C8 or potent inducers of glucuronidation.

Effects of preanesthetic administration of midazolam, clonidine, or dexmedetomidine on postoperative pain and anxiety in children.

PubMed

Schmidt, André P; Valinetti, Emilia A; Bandeira, Denise; Bertacchi, Maria F; Simões, Cláudia M; Auler, José Otávio C

2007-07-01

A growing interest in the possible influences of pre- and postoperative anxiety and pain scores as outcomes of surgical treatment and benefits of anxiety or pain-reducing interventions has emerged. The aim of this study was to evaluate the influence of three different premedication regimens on postoperative pain and anxiety in children. A prospective, randomized, open-label clinical trial enrolled 60 schoolchildren. They were randomized for premedication with oral midazolam 0.5 mgxkg(-1), oral clonidine 4 microgxkg(-1), or transmucosal dexmedetomidine (DEX) 1 mug.kg(-1), submitted to a pre- and postoperative evaluation of anxiety with the State-Trait Anxiety Inventory for Children and asked to report any pain in verbal and visual analog scales. We also evaluated secondary outcomes such as parents' anxiety, sedation, separation from parents, adverse effects and hemodynamic status. Dexmedetomidine and clonidine were related to lower scores of pain than midazolam. alpha(2)-agonists produced lower scores of peroperative mean arterial pressure and heart rate than midazolam. Both groups had similar levels of postoperative state-anxiety in children. There was no difference in preanesthesia levels of sedation and response to separation from parents between groups. These findings indicate that children receiving clonidine or DEX preoperatively have similar levels of anxiety and sedation postoperatively as those receiving midazolam. However, children given alpha(2)-agonists had less perioperative sympathetic stimulation and less postoperative pain than those given midazolam.

Can intravenous conscious sedation with midazolam be effective at facilitating surgical dentistry in adolescent orthodontic patients? A service evaluation.

PubMed

Stamp, A J; Dorman, M L; Vernazza, C R; Deeming, G; Reid, C; Wilson, K E; Girdler, N M

2017-01-27

Background Surgical dentistry during orthodontic care often occurs in adolescence and may involve surgical removal or exposure of teeth. The invasive nature of treatment, combined with dental anxiety, means care can often be provided under general anaesthesia (GA). Best-practice guidelines however endorse conscious sedation as an alternative, where appropriate. Although a limited number of studies have shown safe and effective use of intravenous conscious sedation (IVCS) with midazolam in this cohort, robust evidence to support routine use is lacking. Aim To assess whether IVCS with midazolam can effectively facilitate surgical dentistry in adolescent orthodontic patients in primary care.Method A retrospective service evaluation was undertaken reviewing clinical records of adolescents (aged 12-15 years) undergoing surgical exposure and/or surgical removal of teeth under IVCS with midazolam.Results A total of 174 adolescents (mean age 14.2 years) attended for treatment between 2009 and 2015. Of these adolescents, 98.9% (N = 172) allowed cannulation, with all surgical dentistry completed during a single visit. Midazolam dose ranged from 2-7 mg with 79.1% of patients having good or excellent cooperation and three minor adverse events occurring.Conclusion This service evaluation shows IVCS with midazolam can effectively facilitate surgical orthodontics in carefully selected adolescents. There is however a distinct need to further explore potential for this technique to provide a viable alternative to GA.

[Assessment of the efficacy and tolerance of a benzodiazepine antagonist (Ro 15-1788)].

PubMed

Rouiller, M; Forster, A; Gemperle, M

1987-01-01

The aim of this study was to evaluate the efficacy and the tolerance of Ro 15-1788, a specific benzodiazepine antagonist, in reversing the effects of midazolam. Six healthy male volunteers (mean age 32 +/- 3 years; mean weight 75.5 +/- 5 kg) took part in this study. Two of the three following drugs: midazolam (0.15 mg X kg-1), Ro 15-1788 (0.1 mg X kg-1) or placebo, diluted in 10 ml isotonic saline, were injected intravenously in 15 s at 5 min intervals in a double-blind manner in each subject during six randomized sessions: midazolam-placebo; Ro-placebo; placebo-midazolam; placebo-Ro; midazolam-Ro; Ro-midazolam. At least four days were allowed between each session for each subject. The evaluation of the effects on the central nervous system was as follows. At the time of injection of the first drug and, if possible, at the time of injection of the second drug, the subject was asked to count aloud to 150. The following variables were timed: start of dysarthria, cessation of counting, abolition and duration of absence of the ciliary reflex and duration of induced sleep. Retrograde and anterograde amnesia were evaluated by the recall of a playing card and a number. Haemodynamic effects (variations of systolic and diastolic pressures and pulses rate) as well as respiratory ones (apnoea) were also studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Midazolam

MedlinePlus

... to cause drowsiness, relieve anxiety, and prevent any memory of the event. Midazolam is in a class ... if your child is taking certain medications for human immunodeficiency virus (HIV) including amprenavir (Agenerase), atazanavir (Reyataz), ...

Effects of acepromazine or methadone on midazolam-induced behavioral reactions in dogs

PubMed Central

Simon, Bradley T.; Scallan, Elizabeth M.; Siracusa, Carlo; Henderson, Amy; Sleeper, Meg M.; Larenza Menzies, M. Paula

2014-01-01

This study evaluated whether acepromazine or methadone reduced behavioral parameters, overall excitement, and activity associated with midazolam administration to healthy dogs. Dogs received midazolam (M) alone [M: 0.25 mg/kg body weight (BW)] or with methadone (MM) (MM: 0.75 mg/kg BW) or acepromazine (MA) (MA: 0.03 mg/kg BW) or saline (S) solution alone, all intramuscularly. Two blinded observers evaluated behavioral parameters using video recordings 30 min before and after injection of drugs. Accelerometery was used to evaluate “total activity counts” (TAC) at baseline and post-treatment. Post-treatment excitement scores were significantly higher in M and MA compared to baseline, M and MM compared to S, and M compared to MA. Behavioral parameters showed significantly higher proportions of “pacing” post-treatment in all groups receiving midazolam, and “restlessness,” “chewing/licking,” and “sniffing” in M. No significant differences were found for TAC at baseline and post-treatment. Midazolam-induced paradoxical behavioral changes (excitation, panting, pacing, restlessness, licking/chewing, and vocalization) were not prevented by acepromazine or methadone in healthy dogs. PMID:25183896

Assessment of GABA(A)benzodiazepine receptor (GBzR) sensitivity in patients on benzodiazepines.

PubMed

Potokar, J; Coupland, N; Wilson, S; Rich, A; Nutt, D

1999-09-01

To measure GABA(A) benzodiazepine receptor sensitivity in patients taking benzodiazepines and compare with matched controls. Seven patients who were on prescribed benzodiazepines for an anxiety disorder or insomnia were recruited from general practice and an adult mental health service outpatient clinic. They were matched with seven volunteers. All subjects received an intravenous injection of midazolam 50 microgram/kg in 10 ml normal saline over 10 min. Objective responses to midazolam were assessed using saccadic eye movement velocity slowing and subjective assessments using visual analogue scales. Measurements were recorded for 120 min and plasma midazolam concentrations obtained at 15-min intervals post-infusion to 120 min. Ratios of pharmacodynamic/pharmacokinetic effects were obtained for each individual to estimate GABA(A) benzodiazepine receptor sensitivity. Patients had an attenuated response to midazolam on both subjective and objective measures. GABA(A) benzodiazepine receptor sensitivity was significantly reduced in the patient group. Chronic treatment with benzodiazepines was associated with reduced effects of midazolam. Saccadic eye movement velocity was especially sensitive as a measure of attenuated response.

Pharmacology of saccadic eye movements in man. 1. Effects of the benzodiazepine receptor ligands midazolam and flumazenil.

PubMed

Ball, D M; Glue, P; Wilson, S; Nutt, D J

1991-01-01

A paradigm for assessing benzodiazepine receptor sensitivity was developed using intravenous midazolam in normal volunteers. After administration of incremental doses of midazolam, alterations in saccadic eye movement parameters and psychological self ratings were assessed. Significant changes included dose-dependent slowing of peak velocity, peak acceleration, peak deceleration, reduced saccade acceleration/deceleration ratio and saccade accuracy, and increased sedation self-ratings. Changes in saccade variables and sedation ratings were significantly correlated, and also correlated with plasma midazolam concentrations. No significant changes were seen in saccade latency or anxiety self-ratings. Pharmacological specificity of these changes was demonstrated by their reversal with the benzodiazepine antagonist flumazenil. This challenge paradigm appears to be a sensitive means of assessing benzodiazepine receptor function in man.

The effect of nasal midazolam premedication on parents-child separation and recovery time in dental procedures under general anaesthesia.

PubMed

Eskandarian, T; Arabzade Moghadam, S; Reza Ghaemi, S; Bayani, M

2015-06-01

For many children medical and dental procedures, unfamiliar dental staff and treatment places are disturbing and stressful. Stress in children often makes them uncooperative. General anaesthesia is indicated for anxious uncooperative children or those who are disabled, immature or too young to undergo dental treatment by other means. Moreover parents' separation while entering the operative room is a traumatic experience for children. Thus premedication such as midazolam is recommended to decrease child's stress. In these situations the increased recovery time was considered as one of the midazolam side effects. There is no study that evaluated the effect of midazolam both in parents-child separation and recovery time in long dental procedure. The purpose of this study was to evaluate the effect of nasal midazolam premedication with placebo on parents-child separation and recovery times in uncooperative paediatric patients undergoing long-lasting general anaesthesia for dental procedures. This randomised, double-blind study was done on 60 uncooperative patients (ASA physical status I or II) aged 2-4 years who were scheduled for general anaesthesia for dental treatment. Group A received 0.2 mg/kg intranasal midazolam as premedication, and group B received the same volume of intranasal placebo 20 minutes before entering the operating room for general anaesthesia. General anaesthesia was done with the same method for all patients, then parent-child separation and recovery times were compared between the two groups. Statical significance was set at P≤0.05. Statically analysis was performed using SPSS version17.Chi-squared and student t-tests were applied to analyse the data. We found significant differences in parents- child separation assessment between two groups. Nasal midazolam premedication had a positive effect on parents-child separation; but there was no significant difference between the two groups in terms of recovery time. Premedication of nasal midazolam before induction of general anaesthesia did not prolong recovery time but made the separation of children from their parents easier by showing a better behaviour.

Evaluation of limited sampling models for prediction of oral midazolam AUC for CYP3A phenotyping and drug interaction studies.

PubMed

Mueller, Silke C; Drewelow, Bernd

2013-05-01

The area under the concentration-time curve (AUC) after oral midazolam administration is commonly used for cytochrome P450 (CYP) 3A phenotyping studies. The aim of this investigation was to evaluate a limited sampling strategy for the prediction of AUC with oral midazolam. A total of 288 concentration-time profiles from 123 healthy volunteers who participated in four previously performed drug interaction studies with intense sampling after a single oral dose of 7.5 mg midazolam were available for evaluation. Of these, 45 profiles served for model building, which was performed by stepwise multiple linear regression, and the remaining 243 datasets served for validation. Mean prediction error (MPE), mean absolute error (MAE) and root mean squared error (RMSE) were calculated to determine bias and precision The one- to four-sampling point models with the best coefficient of correlation were the one-sampling point model (8 h; r (2) = 0.84), the two-sampling point model (0.5 and 8 h; r (2) = 0.93), the three-sampling point model (0.5, 2, and 8 h; r (2) = 0.96), and the four-sampling point model (0.5,1, 2, and 8 h; r (2) = 0.97). However, the one- and two-sampling point models were unable to predict the midazolam AUC due to unacceptable bias and precision. Only the four-sampling point model predicted the very low and very high midazolam AUC of the validation dataset with acceptable precision and bias. The four-sampling point model was also able to predict the geometric mean ratio of the treatment phase over the baseline (with 90 % confidence interval) results of three drug interaction studies in the categories of strong, moderate, and mild induction, as well as no interaction. A four-sampling point limited sampling strategy to predict the oral midazolam AUC for CYP3A phenotyping is proposed. The one-, two- and three-sampling point models were not able to predict midazolam AUC accurately.

Plasma concentrations of midazolam during continuous subcutaneous administration in palliative care.

PubMed

Bleasel, M D; Peterson, G M; Dunne, P F

1994-01-01

We have investigated the steady-state plasma concentrations of midazolam during continuous subcutaneous administration in palliative care. Using a sensitive gas chromatography with electron capture detector assay, plasma concentrations of midazolam were measured in 11 patients (median age 68 years; range 47-82 years; six females) receiving the drug by continuous subcutaneous infusion (median rate 20 mg/day; range 10-60 mg/day). While not significant, the infusion rate tended to decrease with increasing age of the patient (Spearman's p = -0.51; p = 0.11). The steady-state plasma concentration range was 10-147 ng/ml, with a median of 30 ng/ml. Infusion rates and plasma concentrations of midazolam were correlated (Spearman's p = 0.71; p < 0.05). No other significant relationships were found between plasma concentrations and the variables of age, sex and liver function.

Comparison of Oral and Buccal Midazolam for Pediatric Dental Sedation: A Randomized, Cross-Over, Clinical Trial for Efficacy, Acceptance and Safety

PubMed Central

Tavassoli-Hojjati, Sara; Mehran, Majid; Haghgoo, Roza; Tohid-Rahbari, Monireh; Ahmadi, Rahil

2014-01-01

Abstract Objective Providing a safe and efficient dental treatment for a young patient is a challenge for the dentist and the child. The purpose of this study was to investigate the effectiveness, safety and acceptability of buccal midazolam in dental pediatric patients and to compare it with oral Midazolam. Methods Eighteen uncooperative healthy children aged 2.5-6 years were randomized to each of buccal midazolam (0.3mg/kg) or oral midazolam (0.5mg/kg) at the first visit, the alternative has been used at the second visit in a cross-over manner. The study took place at pediatric dentistry clinic of Shahed University, Tehran, from November 2011 to June 2012. The patients‘ vital signs and behavioral scores were recorded. The patient, the operator and the observer were blinded to the applied medication. Post operatively, patients‘ and parents‘ satisfaction were assessed by Visual Analogue Score and a questionnaire respectively. The P-value was set at 0.05 for significance level. Findings There were no significant differences in physiologic factors in the medication groups at time 0, 10, 20, 30 minutes and discharge. There was also no significant difference between the two groups in behavioral parameters. The majority of parents rated both sedative agents as “effective” or “very effective” and their children mostly were without anxiety or with minor anxiety. Conclusion Buccal midazolam may be safely and efficiently used in sedation of pediatric dental patients. PMID:25535540

Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis.

PubMed

Tokuda, Kazuhiro; O'Dell, Kazuko A; Izumi, Yukitoshi; Zorumski, Charles F

2010-12-15

Benzodiazepines (BDZs) enhance GABA(A) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors [translocator protein (18 kDa) (TSPO)] and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ, with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectively. Midazolam, but not clonazepam, increased neurosteroid levels in CA1 pyramidal neurons without changing TSPO immunostaining. Midazolam, but not clonazepam, also augmented a form of spike inhibition after stimulation adjacent to the pyramidal cell layer and inhibited induction of long-term potentiation. These effects were prevented by finasteride, an inhibitor of neurosteroid synthesis, or 17PA [17-phenyl-(3α,5α)-androst-16-en-3-ol], a blocker of neurosteroid effects on GABA(A) receptors. Moreover, the synaptic effects were mimicked by a combination of clonazepam with FGIN (2-[2-(4-fluorophenyl)-1H-indol-3-yl]-N,N-dihexylacetamide), a selective TSPO agonist, or a combination of clonazepam with exogenous allopregnanolone. Consistent with these in vitro results, finasteride abolished the effects of midazolam on contextual fear learning when administrated 1 d before midazolam injection. Thus, dual activation of CBRs and TSPO appears to result in unique actions of clinically important BDZs. Furthermore, endogenous neurosteroids are shown to be important regulators of pyramidal neuron function and synaptic plasticity.

Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis

PubMed Central

Tokuda, Kazuhiro; O’Dell, Kazuko A.; Izumi, Yukitoshi; Zorumski, Charles F.

2010-01-01

Benzodiazepines (BDZs) enhance γ-aminobutyric acid-A (GABAA) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors (translocator protein 18kDa, TSPO) and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectively. Midazolam, but not clonazepam, increased neurosteroid levels in CA1 pyramidal neurons without changing TSPO immunostaining. Midazolam, but not clonazepam, also augmented a form of spike inhibition following stimulation adjacent to the pyramidal cell layer and inhibited induction of long-term potentiation. These effects were prevented by finasteride, an inhibitor of neurosteroid synthesis, or 17PA (17-phenyl-(3α, 5α)-androst-16-en-3-ol), a blocker of neurosteroid effects on GABAA receptors. Moreover, the synaptic effects were mimicked by a combination of clonazepam with FGIN, a selective TSPO agonist, or a combination of clonazepam with exogenous allopregnanolone. Consistent with these in vitro results, finasteride abolished the effects of midazolam on contextual fear learning when administrated one day prior to midazolam injection. Thus, dual activation of CBRs and TSPO appears to result in unique actions of clinically-important BDZs. Furthermore, endogenous neurosteroids are shown to be important regulators of pyramidal neuron function and synaptic plasticity. PMID:21159950

GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study.

PubMed

Lingford-Hughes, A R; Wilson, S J; Cunningham, V J; Feeney, A; Stevenson, B; Brooks, D J; Nutt, D J

2005-08-01

Gamma-aminobutyric acid (GABA)-benzodiazepine receptor function is hypothesised to be reduced in alcohol dependence. We used positron emission tomography (PET) with [11C]flumazenil, a non-selective tracer for brain GABA-benzodiazepine (GABA-BDZ) receptor binding, to determine in vivo the relationship between BDZ receptor occupancy by an agonist, midazolam, and its functional effects. Abstinent male alcohol dependent subjects underwent [11C]flumazenil PET to measure occupancy of BDZ receptors by midazolam whilst recording its pharmacodynamic effects on behavioural and physiological measures. Rate constants describing the exchange of [11C]flumazenil between the plasma and brain compartments were derived from time activity curves. A 50% reduction in electroencephalography (EEG)-measured sleep time was seen in the alcohol dependent group despite the same degree of occupancy by midazolam as seen in the control group. The effects of midazolam on other measures of benzodiazepine receptor function, increasing EEG beta1 power and slowing of saccadic eye movements, were similar in the two groups. No differences in midazolam or flumazenil metabolism were found between the groups. In summary, our study suggests that alcohol dependence in man is associated with a reduced EEG sleep response to the benzodiazepine agonist, midazolam, which is not explained by reduced BDZ receptor occupancy, and is consistent with reduced sensitivity in this measure of GABA-BDZ receptor function in alcohol dependence. The lack of change in other functional measures may reflect a differential involvement of particular subtypes of the GABA-BDZ receptor.

Inhibitory effect of midazolam on MMP-9, MMP-1 and MMP-13 expression in PMA-stimulated human chondrocytes via recovery of NF-κB signaling.

PubMed

Wang, Jen-Jui; Huan, Steven Kuan-Hua; Hsieh, Kuo-Hsien; Chou, Hsiu-Chu; Hsiao, George; Jayakumar, Thanasekaran; Sheu, Joen-Rong

2013-04-20

Midazolam, a benzodiazepine, has a hypnotic effect and is widely used as an intravenous sedative. Past studies have clearly established that midazolam has beneficial effects in attenuating ischemia-reperfusion injury more than other currently used sedative drugs. However, the role of midazolam on chondroprotection via inhibition of matrix metalloproteinases (MMPs) is warrant investigation. The aim of this study was to examine the mechanisms of action of midazolam on MMP expression via nuclear factor κB (NF-κB) signaling in activated chondrosarcoma cells maintained in vitro. Chondrocytes, SW1353 cells, were stimulated with phorbol 12-myristate 13-acetate (PMA) in the absence or presence of various concentrations of midazolam (5-20 µM). Release of MMP-9 into the culture media was determined by gelatin zymography. The expressions of MMP-1, MMP-9 and MMP-13, phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinases and degradation of IκB-α were determined by western blotting assay. Midazolam significantly down-regulated PMA-induced MMP-9 protein expression at concentrations of 5, 10 and 20 µM, the values were 1.95 ±0.09 (p < 0.01), 1.71 ±0.12 (p < 0.01) and 1.35 ±0.20 (p < 0.001), respectively. At concentrations of 5, 10 and 20 µM, it was significantly inhibited the PMA-induced expressions of MMP-1 (2.27 ±0.10, 1.98 ±0.11 and 1.56 ±0.15; p < 0.001) and MMP-13 (0.89 ±0.04, 0.81 ±0.07, and 0.74 ±0.09; p < 0.001), respectively. Midazolam at concentrations of 10 and 20 µM for 15 min significantly reversed the rate of degradation (0.895 ±0.051; p < 0.05 and 0.926 ±0.060; p < 0.01, respectively) of IκB-α in PMA-chondrocyte cells. In addition, this sedative drug inhibited PMA-induced levels of phos-ERK (1.243 ±0.12, 1.108 ±0.16 and 0.903 ±0.19, respectively) and phos-p38 (1.146 ±0.10, 1.063 ±0.13 and 0.946 ±0.18, at concentrations of (5, 10 and 20 µM), respectively. These results are important for understanding the mechanism of midazolam in inhibiting PMA-induced MMP expression through the signaling pathways of either NF-κB or ERK/p38 MAPKs down-regulation.

Evaluation of the anxiolytic properties of myristicin, a component of nutmeg, in the male Sprague-Dawley rat.

PubMed

Leiter, Emily; Hitchcock, Gavin; Godwin, Stuart; Johnson, Michelle; Sedgwick, William; Jones, Wendy; McCall, Suzanne; Ceremuga, Thomas E

2011-04-01

The purpose of this study was to investigate the anxiolytic effects of myristicin, a major compound found in nutmeg, and its potential interaction with the gamma-aminobutyric acid (GABA(A)) receptor in male Sprague-Dawley rats. Nutmeg has traditionally been used as a spice in food preparation and as an herbal remedy in the treatment of many medical conditions, including anxiety. Fifty-five rats were divided equally into 5 groups: control (vehicle); myristicin; midazolam (positive control); flumazenil and myristicin; and midazolam and myristicin. The behavioral component of anxiety was examined by using the elevated plus-maze (open-arm and closed-arm times) along with analysis of gross and fine motor movements. Data analysis was performed using a 2-tailed multivariate analysis of variance (MANOVA) and least significant difference post-hoc test. Our data suggest that myristicin does not decrease anxiety by modulation of the GABA(A) receptor but may promote anxiogenesis. When myristicin was combined with midazolam, an antagonist-like effect similar to the flumazenil and myristicin combination was exhibited by a decrease in anxiolysis compared with the midazolam-only group. Myristicin may antagonize the anxiolytic effects of midazolam, increase anxiety, and affect motor movements.

Comparison of the changes in blood glucose level during sedation with midazolam and propofol in implant surgery: a prospective randomized clinical trial.

PubMed

Kaviani, Nasser; Koosha, Farzad; Shahtusi, Mina

2014-09-01

Reducing the patients' stress can prevent, or at least, limit the increase in blood glucose level. The study compares the effect of propofol and midazolam on blood glucose level in the patients undergoing dental implant surgery. The effect of pre-operational stress on blood glucose level during the surgery is also evaluated. This prospective randomized clinical trial recruited 33 patients undergoing dental implant surgery and divided into two groups. Conscious sedation was performed by midazolam in one group and with propofol in another group. The pre-operational stress was scored and the blood glucose level was measured in 4 different stages; before the operation, two minutes after the local anesthetic injection; thirty minutes after the onset of operation and at the end of the operation. The results were analyzed by employing ANOVA and Pearson test. The p Value was adopted 0.05 and the confidence coefficient was assumed 95%. The average levels of the blood glucose in midazolam and propofol group were 93.82 mg/dl and 94 mg/dl before the operation which displayed a meaningful increase of blood glucose level in both groups as the operation went on. The values were 103.76 mg/dl for midazolam and 108.56 mg/dl for the propofol group (p< 0.05) at the end of the operation. No statistically significant difference was found in the average blood glucose level between two groups in the different stages of the operation (p= 0.466). The Pearson correlation coefficient test revealed a higher increase in the blood glucose level in the patients with a higher pre-operational stress score (r= 0.756, p< 0.001). Based on the results yielded by this study, patients who receive venous sedation, either by midazolam or propofol, experience increase in the blood glucose level while undergoing an operation. No statistically significant difference was detected between midazolam and propofol.

A Comparison of Fospropofol to Midazolam for Moderate Sedation During Outpatient Dental Procedures

PubMed Central

Yen, Philip; Prior, Simon; Riley, Cara; Johnston, William; Smiley, Megann; Thikkurissy, Sarat

2013-01-01

Moderate intravenous (IV) sedation combined with local anesthesia is common for outpatient oral surgery procedures. An ideal sedative agent must be safe and well tolerated by patients and practitioners. This study evaluated fospropofol, a relatively new sedative/hypnotic, in comparison to midazolam, a commonly used benzodiazepine, for IV moderate sedation during oral and maxillofacial surgery. Sixty patients were randomly assigned to either the fospropofol or the midazolam group. Each participant received 1 μg/kg of fentanyl prior to administration of the selected sedative. Those in the fospropofol group received an initial dose of 6.5 mg/kg, with 1.6 mg/kg supplemental doses as needed. Those in the midazolam group received initial doses of 0.05 mg/kg, followed by 0.02 mg/kg supplemental doses. The quality of sedation in each patient was evaluated with regard to (a) onset of sedation, maintenance, and recovery profile; (b) patient and surgeon satisfaction; and (c) hemodynamic stability and adverse effects. The fospropofol group demonstrated shorter physical recovery times than midazolam patients, taking a mean of 11.6 minutes versus 18.4 minutes for physical recovery (P = .007). Cognitive recovery comparison did not find any difference with a mean of 7.5 minutes versus 8.8 minutes between the 2 drug groups (P = .123). The fospropofol group had a higher rate of local anesthetic injection recall (90.5 vs 44.4%, P = .004). Other parameters of recall were comparable. Two adverse effects demonstrated significance, with more patients in the midazolam group experiencing tachycardia (48.2 vs 9.4%, P = .001), and more patients in the fospropofol group experiencing perineal discomfort (40.6 vs 0, P < .001). No significant difference was found in any other measures of sedation safety, maintenance, or satisfaction. Fospropofol, when administered intravenously by a dentist anesthesiologist at the indicated dose in this study, appears to be a safe, well-tolerated alternative to midazolam for intravenous moderate sedation during minor oral surgery procedures. PMID:24423419

Conscious Sedation Procedures Using Intravenous Midazolam for Dental Care in Patients with Different Cognitive Profiles: A Prospective Study of Effectiveness and Safety

PubMed Central

Collado, Valérie; Faulks, Denise; Nicolas, Emmanuel; Hennequin, Martine

2013-01-01

The use of midazolam for dental care in patients with intellectual disability is poorly documented. This study aimed to evaluate the effectiveness and safety of conscious sedation procedures using intravenous midazolam in adults and children with intellectual disability (ID) compared to dentally anxious patients (DA). Ninety-eight patients with ID and 44 patients with DA programmed for intravenous midazolam participated in the study over 187 and 133 sessions, respectively. Evaluation criteria were success of dental treatment, cooperation level (modified Venham scale), and occurrence of adverse effects. The mean intravenous dose administered was 8.8±4.9 mg and 9.8±4.1 mg in ID and DA sessions respectively (t-test, NS). 50% N2O/O2 was administered during cannulation in 51% of ID sessions and 61% of DA sessions (NS, Fisher exact test). Oral or rectal midazolam premedication was administered for cannulation in 31% of ID sessions and 3% of DA sessions (p<0,001, Fisher exact test). Dental treatment was successful in 9 out of 10 sessions for both groups. Minor adverse effects occurred in 16.6% and 6.8% of ID and DA sessions respectively (p = 0.01, Fisher exact test). Patients with ID were more often very disturbed during cannulation (25.4% ID vs. 3.9% DA sessions) and were less often relaxed after induction (58.9% ID vs. 90.3% DA) and during dental treatment (39.5% ID vs. 59.7% DA) (p<0.001, Fisher exact test) than patients with DA. When midazolam sedation was repeated, cooperation improved for both groups. Conscious sedation procedures using intravenous midazolam, with or without premedication and/or inhalation sedation (50% N2O/O2), were shown to be safe and effective in patients with intellectual disability when administered by dentists. PMID:23940729

Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil.

PubMed

Bourgoin, Aurélie; Albanèse, Jacques; Wereszczynski, Nicolas; Charbit, Martine; Vialet, Renaud; Martin, Claude

2003-03-01

The aim of the study was to compare the safety concerning cerebral hemodynamics of ketamine and sufentanil used for sedation of severe head injury patients, both drugs being used in combination with midazolam. Prospective, randomized, double-blind study. Intensive care unit in a trauma center. Twenty-five patients with severe head injury. Twelve patients received sedation with a continuous infusion of ketamine-midazolam and 13 with a continuous infusion of sufentanil-midazolam. All patients were mechanically ventilated with moderate hyperventilation. Prognostic indicators (age, Glasgow Coma Scale scores, computed tomography diagnosis, and Injury Severity Scale score) were similar in the two groups at study entry. Measurements were carried out during the first 4 days of sedation. The average infusion rates during this time were 82 +/- 25 micro x kg x min ketamine and 1.64 +/- 0.5 microg x kg x min midazolam in the ketamine group and 0.008 +/- 0.002 microg x kg x min sufentanil and 1.63 +/- 0.37 microg x kg x min midazolam in the sufentanil group. No significant differences were observed between the two groups in the mean daily values of intracranial pressure and cerebral perfusion pressure. The numbers of intracranial pressure elevations were similar in both groups. The requirements of neuromuscular blocking agents, propofol, and thiopental were similar. Heart rate values were significantly higher in the ketamine group on therapy days 3 and 4 ( <.05). With regard to arterial pressure control, more fluids were given on the first therapy day and there was a trend toward greater use of vasopressors in the sufentanil group. Sedative costs were similar in the two groups. The results of this study suggest that ketamine in combination with midazolam is comparable with a combination of midazolam-sufentanil in maintaining intracranial pressure and cerebral perfusion pressure of severe head injury patients placed under controlled mechanical ventilation.

Impact of organic solvents on cytochrome P450 probe reactions: filling the gap with (S)-Warfarin and midazolam hydroxylation.

PubMed

González-Pérez, Vanessa; Connolly, Elizabeth A; Bridges, Arlene S; Wienkers, Larry C; Paine, Mary F

2012-11-01

(S)-Warfarin 7-hydroxylation and midazolam 1'-hydroxylation are among the preferred probe substrate reactions for CYP2C9 and CYP3A4/5, respectively. The impact of solvents on enzyme activity, kinetic parameters, and predicted in vivo hepatic clearance (Cl(H)) associated with each reaction has not been evaluated. The effects of increasing concentrations [0.1-2% (v/v)] of six organic solvents (acetonitrile, methanol, ethanol, dimethyl sulfoxide, acetone, isopropanol) were first tested on each reaction using human liver microsomes (HLMs), human intestinal microsomes (midazolam 1'-hydroxylation only), and recombinant enzymes. Across enzyme sources, relative to water, acetonitrile and methanol had the least inhibitory effect on (S)-warfarin 7-hydroxylation (0-58 and 9-96%, respectively); acetonitrile, methanol, and ethanol had the least inhibitory effect on midazolam 1'-hydroxylation (0-29, 0-22, and 0-20%, respectively). Using HLMs, both acetonitrile and methanol (0.1-2%) decreased the V(max) (32-60 and 24-65%, respectively) whereas methanol (2%) increased the K(m) (100%) of (S)-warfarin-hydroxylation. (S)-Warfarin Cl(H) was underpredicted by 21-65% (acetonitrile) and 13-84% (methanol). Acetonitrile, methanol, and ethanol had minimal to modest impact on both the kinetics of midazolam 1'-hydroxylation (10-24%) and predicted midazolam Cl(H) (2-20%). In conclusion, either acetonitrile or methanol at ≤0.1% is recommended as the primary organic solvent for the (S)-warfarin 7-hydroxylation reaction; acetonitrile is preferred if higher solvent concentrations are required. Acetonitrile, methanol, and ethanol at ≤2% are recommended as primary organic solvents for the midazolam 1'-hydroxylation reaction. This information should facilitate optimization of experimental conditions and improve the interpretation and accuracy of in vitro-in vivo predictions involving these two preferred cytochrome P450 probe substrate reactions.

The compatibility and stability of midazolam and dexamethasone in infusion solutions.

PubMed

Good, Phillip D; Schneider, Jennifer J; Ravenscroft, Peter J

2004-05-01

The delivery of subcutaneous medication by continuous infusion is common in palliative medicine. Many centers combine multiple medications, but the analytical confirmation of the compatibility and stability of these combinations has rarely been performed. This study examined the compatibility and stability of midazolam and dexamethasone using high performance liquid chromatography. Nine different solutions were prepared in polypropylene syringes by combining these two drugs with 0.9% sodium chloride. When these two drugs were combined in a syringe, there was significant loss of midazolam over 48 hours, with only 60-80% of the initial concentration remaining in syringes stored at 35-39 degrees C. This study demonstrates that cloudiness of a solution is not the only predictor of drug loss and that drug loss may occur even in solutions that remain clear at time of preparation. The clinical implications of these results are that dexamethasone and midazolam should not be combined in syringe driver solutions.

A comparison of midazolam with remifentanil for the prevention of myoclonic movements following etomidate injection.

PubMed

Hwang, J-Y; Kim, J-H; Oh, A-Y; Do, S-H; Jeon, Y-T; Han, S-H

2008-01-01

Etomidate is a popular anaesthetic induction agent, but it frequently causes myoclonic movements. Although both benzodiazepines and opioids reduce myoclonus, there has been no comparative study between these agents. Thus, we conducted a prospective, randomized study to compare midazolam and remifentanil as pre-treatment agents for reducing etomidate-induced myoclonus in 90 adults undergoing surgery. Patients were pre-treated before the etomidate injection, either with saline (Group C), midazolam 0.5 mg/kg (Group M) or remifentanil 1 microg/kg (Group R). Both Groups M and R showed a significantly lower incidence of myoclonus compared with Group C (17%, 17% and 77%, respectively). The incidence of myoclonus was not significantly different between Groups M and R, but 10% (n = 10) of the patients in Group R experienced remifentanil-related side-effects. We conclude that midazolam is probably a better choice than remifentanil for reducing etomidate-induced myoclonus during anaesthesia induction.

Complete recovery from intractable complex regional pain syndrome, CRPS-type I, following anesthetic ketamine and midazolam.

PubMed

Kiefer, Ralph-Thomas; Rohr, Peter; Ploppa, Annette; Altemeyer, Karl-Heinz; Schwartzman, Robert Jay

2007-06-01

To describe the treatment of an intractable complex regional pain syndrome I (CRPS-I) patient with anesthetic doses of ketamine supplemented with midazolam. A patient presented with a rapidly progressing contiguous spread of CRPS from a severe ligamentous wrist injury. Standard pharmacological and interventional therapy successively failed to halt the spread of CRPS from the wrist to the entire right arm. Her pain was unmanageable with all standard therapy. As a last treatment option, the patient was transferred to the intensive care unit and treated on a compassionate care basis with anesthetic doses of ketamine in gradually increasing (3-5 mg/kg/h) doses in conjunction with midazolam over a period of 5 days. On the second day of the ketamine and midazolam infusion, edema, and discoloration began to resolve and increased spontaneous movement was noted. On day 6, symptoms completely resolved and infusions were tapered. The patient emerged from anesthesia completely free of pain and associated CRPS signs and symptoms. The patient has maintained this complete remission from CRPS for 8 years now. In a patient with severe spreading and refractory CRPS, a complete and long-term remission from CRPS has been obtained utilizing ketamine and midazolam in anesthetic doses. This intensive care procedure has very serious risks but no severe complications occurred. The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within 1 month of treatment. This case report illustrates the effectiveness and safety of high-dose ketamine in a patient with generalized, refractory CRPS.

Prehospital Agitation and Sedation Trial (PhAST): A Randomized Control Trial of Intramuscular Haloperidol versus Intramuscular Midazolam for the Sedation of the Agitated or Violent Patient in the Prehospital Environment.

PubMed

Isenberg, Derek L; Jacobs, Dorian

2015-10-01

Violent patients in the prehospital environment pose a threat to health care workers tasked with managing their medical conditions. While research has focused on methods to control the agitated patient in the emergency department (ED), there is a paucity of data looking at the optimal approach to subdue these patients safely in the prehospital setting. Hypothesis This study evaluated the efficacy of two different intramuscular medications, midazolam and haloperidol, to determine their efficacy in sedating agitated patients in the prehospital setting. This was a prospective, randomized, observational trial wherein agitated patients were administered intramuscular haloperidol or intramuscular midazolam to control agitation. Agitation was quantified by the Richmond Agitation and Sedation Scale (RASS). Paramedics recorded the RASS and vital signs every five minutes during transport and again upon arrival to the ED. The primary outcome was mean time to achieve a RASS less than +1. Secondary outcomes included mean time for patients to return to baseline mental status and adverse events. Five patients were enrolled in each study group. In the haloperidol group, the mean time to achieve a RASS score of less than +1 was 24.8 minutes (95% CI, 8-49 minutes), and the mean time for the return of a normal mental status was 84 minutes (95% CI, 0-202 minutes). Two patients required additional prehospital doses for adequate sedation. There were no adverse events recorded in the patients administered haloperidol. In the midazolam group, the mean time to achieve a RASS score of less than +1 was 13.5 minutes (95% CI, 8-19 minutes) and the mean time for the return of normal mental status was 105 minutes (95% CI, 0-178 minutes). One patient required additional sedation in the ED. There were no adverse events recorded among the patients administered midazolam. Midazolam and haloperidol administered intramuscularly appear equally effective for sedating an agitated patient in the prehospital setting. Midazolam appears to have a faster onset of action, as evidenced by the shorter time required to achieve a RASS score of less than +1 in the patients who received midazolam. Haloperidol offers an alternative option for the sedation of an agitated patient. Further studies should focus on continued investigation into appropriate sedation of agitated patients in the prehospital setting.

Factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors.

PubMed

Skrobik, Yoanna; Leger, Caroline; Cossette, Mariève; Michaud, Veronique; Turgeon, Jacques

2013-04-01

Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier. To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU. In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1β, and monocyte chemotactic protein-1. Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05). Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.

Use of fentanyl and midazolam in mechanically ventilated children--Does the method of infusion matter?

PubMed

da Silva, Paulo Sérgio Lucas; Reis, Maria Eunice; de Aguiar, Vânia Euzébio; Fonseca, Marcelo Cunio Machado

2016-04-01

Benzodiazepines and opioids are commonly used in pediatric intensive care unit. However, there is no previous study assessing the use of administering these drugs combined (single solution) or separately. We sought to evaluate the impact of these 2 different methods of providing sedation/analgesia in pediatric intensive care unit. One hundred twelve patients mechanically ventilated for more than 48 hours were randomized to receive a protocolized sedation regime comprising midazolam and fentanyl either separately (group 1, 57 patients) or combined as a single solution (group 2, 55 patients). Primary end point variable was the cumulated dose of midazolam and fentanyl. The median cumulated doses of both fentanyl (0.19 vs 0.37 mg/kg, P < .05) and midazolam (28.8 vs 45.6 mg/kg, P < .05) required in group 2 were higher when compared with those of group 1. Moreover, group 2 patients had a significantly longer time of vasopressor drugs requirement and a higher number of patients developing tolerance. Patients who received a single solution of midazolam and fentanyl had a higher cumulated dose of compared with those patients who did not. The potential risk for long-term neurologic effects on developing brains associated with this finding should be considered. Copyright © 2015 Elsevier Inc. All rights reserved.

Propofol-alfentanyl versus midazolam-alfentanyl in inducing procedural amnesia of upper gastrointestinal endoscopy in children--blind randomised trial.

PubMed

Sienkiewicz, Edyta; Albrecht, Piotr; Ziółkowski, Janusz; Dziechciarz, Piotr

2015-11-01

In paediatric patients, esophagogastroduodenoscopy (EGD) is commonly performed with the use of sedation. The aim of the study was to compare the effectiveness of propofol and midazolam in providing procedural amnesia and controlling behaviour in children undergoing diagnostic EGD. Children (9-16 years), classified to the first or second class of the American Society of Anaesthesiologists' physical status classification referred for EGD, were randomly assigned to receive propofol with alfentanyl or midazolam with alfentanyl for sedation during the procedure. Within 120 min after the procedure, patients were repeatedly investigated for memory of the procedure and for memory of pain intensity during EGD with the use of the visual analogue scale. Activity and cooperation of the patient during the procedure was assessed with the relative adequacy scale. Of the 51 children, 48 completed the study. Propofol was significantly better than midazolam in inducing amnesia of procedural pain (mean difference 11.53 mm; 95 % confidence interval [CI] 0.96 to 22.10), loss of memory of the procedure (relative risk 0.4; 95 % CI 0.21 to 0.59) and controlling behaviour (relative risk 2.12; 95 % CI 1.33 to 3.36). In children sedated for EGD, propofol is significantly better than midazolam at providing procedural amnesia and controlling behaviour during the procedure.

Simultaneous pharmacokinetics evaluation of human cytochrome P450 probes, caffeine, warfarin, omeprazole, metoprolol and midazolam, in common marmosets (Callithrix jacchus).

PubMed

Uehara, Shotaro; Inoue, Takashi; Utoh, Masahiro; Toda, Akiko; Shimizu, Makiko; Uno, Yasuhiro; Sasaki, Erika; Yamazaki, Hiroshi

2016-01-01

1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) composite, after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg(-1), respectively, to four male common marmosets were investigated. 2. The plasma concentrations of caffeine and warfarin decreased slowly in a monophasic manner but those of omeprazole, metoprolol and midazolam decreased extensively after intravenous and oral administrations, in a manner that approximated those as reported for pharmacokinetics in humans. 3. Bioavailabilities were ∼100% for caffeine and warfarin, but <25% for omeprazole and metoprolol. Bioavailability of midazolam was 4% in marmosets, presumably because of contribution of marmoset P450 3A4 expressed in small intestine and liver, with a high catalytic efficiency for midazolam 1'-hydroxylation as evident in the recombinant system. 4. These results suggest that common marmosets, despite their rapid clearance of some human P450 probe substrates, could be an experimental model for humans and that marmoset P450s have functional characteristics that differ from those of human and/or cynomolgus monkey P450s in some aspects, indicating their importance in modeling in P450-dependent drug metabolism studies in marmosets and of further studies.

[Functional state of serotoninergic system on a background of different pharmacokinetic of Midazolam].

PubMed

Kapanadze, L R; Zurabashvili, Z A; Arveladze, M N

2007-01-01

A comprehensive investigation of the high-performance liquid chromatographic separation of Midazolam and his ozidized metabolits, their bases and other low-molecular-weight UV-absorbing compounds that might be found in serum is reported. The drug was administrated (2,0mg/kg) to 40 white mouses and the blood samples were collecetd for further analysis followind 30, 60, 90, 120 and 180 min. after the injection. The serotoninergic systems has been analyzed. Quantitative data were calculated by inner standart method. Oxidazed forms of Midazolam were qualitatively and quantitatively identified. Our data proved the ability of Midazolam to adsorb on the albumin and globulin fraction of plasma. Metabolism of serotonin and triptopchan is closely dependent on the concentration of psychotropic drug. Concentration of aminoacids (triptophan, tirosyn) in the blood is synshronized with the course of pharmacokinetic of the psychotropic preparation and functional state of serotoninergic system. Alterations may be due, on the one hand, to exhaustion of the stores, and on the other hand, to deterioration of the monoamines' synthesis process. The investigation of pharmacokinetics of invariable form of Midazolam and its oxidized metabolits is very important for practical medicine. Effective action of pshychotropic drugs is impossible without extensive knowlege of their phramacokinetics and pharmacodynamics. They are concerned with the need to dermine concentration in body fluids.

Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers.

PubMed

Hostler, David; Zhou, Jiangquan; Tortorici, Michael A; Bies, Robert R; Rittenberger, Jon C; Empey, Philip E; Kochanek, Patrick M; Callaway, Clifton W; Poloyac, Samuel M

2010-05-01

The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4 degrees C saline infusions and 4 degrees C saline + magnesium) and two normothermia groups (37 degrees C saline infusions and 37 degrees C saline + magnesium). The lowest temperatures achieved in the 4 degrees C saline + magnesium and 4 degrees C saline infusions were 35.4 +/- 0.4 and 35.8 +/- 0.3 degrees C, respectively. A significant decrease in the formation clearance of the major metabolite 1'-hydroxymidazolam was observed during the 4 degrees C saline + magnesium compared with that in the 37 degrees C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5 degrees C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted.

Midazolam versus diazepam for combined esophogastroduodenoscopy and colonoscopy.

PubMed

Brouillette, D E; Leventhal, R; Kumar, S; Berman, D; Kajani, M; Yoo, Y K; Carra, J; Tarter, R; Van Thiel, D H

1989-08-01

This study compares the effects of two different benzodiazepines used for conscious sedation during combined upper gastrointestinal endoscopy (EGD) and colonoscopy. Subjects were assessed for their degree of analgesia and amnesia for the procedure, prior experience with endoscopy, and willingness to undergo another similar procedure should such be necessary. The patients were randomized single blind to receive either midazolam or diazepam for their preprocedure sedation. The amount of preprocedure sedation utilized was determined by titration of the dose to achieve slurring of speech. Prior to receiving either agent, the subjects were shown a standard card containing pictures of 10 common objects, were asked to name and remember them, and were told they would be "quizzed" (at 30 min and 24 hr) after being sedated for their recollection as to the objects pictured on the card. Each subject filled out a questionnaire addressing their perceived discomfort during the endoscopic procedure and their memory of the procedure 24 hr after the procedure. Sixty-three percent of the midazolam-sedated subjects reported total amnesia for their colonoscopy vs 20% of diazepam-sedated patients (P less than 0.001). Fifty-three percent of midazolam-sedated patients reported total amnesia of their upper gastrointestinal endoscopy vs only 23% of diazepam-sedated subjects (P less than 0.05). The midazolam-sedated subjects reported experiencing less pain with both upper gastrointestinal endoscopy (P less than 0.05) and colonoscopy (P less than 0.001) than did the diazepam-sedated group. Most importantly, the midazolam group was more willing to undergo another similar endoscopic procedure should they be asked to do so by their physician (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients

PubMed Central

de Winter, Brenda C. M.; Masman, Anniek D.; van Dijk, Monique; Baar, Frans P. M.; Tibboel, Dick; Koch, Birgit C. P.; van Gelder, Teun; Mathot, Ron A. A.

2017-01-01

Aims Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response. Method A population PD analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check. Results The effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and interindividual variability on the overall effect. The EC50 value was 68.7 μg l–1 for a Ramsay score of 3–5 and 117.1 μg l–1 for a Ramsay score of 6. Comedication with haloperidol was the only significant covariate. The visual predictive check of the final model showed good model predictability. Conclusion We were able to describe the clinical response to midazolam accurately. As expected, there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication, as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure. PMID:28960387

Oral ketamine/midazolam is superior to intramuscular meperidine, promethazine, and chlorpromazine for pediatric cardiac catheterization.

PubMed

Auden, S M; Sobczyk, W L; Solinger, R E; Goldsmith, L J

2000-02-01

An IM combination of meperidine, promethazine, and chlorpromazine (DPT) has been given as sedation for pediatric procedures for more than 40 years. We compared this IM combination to oral (PO) ketamine/midazolam in children having cardiac catheterization. A total of 51 children, ages 9 mo to 10 yr, were enrolled and randomized in this double-blinded study. All children received an IM injection at time zero and PO fluid 15 minutes later. We observed acceptance of medication, onset of sedation and sleep, and sedative efficacy. The cardiorespiratory changes were evaluated. Sedation was supplemented with IV propofol as required. Recovery time, parental satisfaction, and patient amnesia were assessed. Ketamine/midazolam given PO was better tolerated (P < 0.0005), had more rapid onset (P < 0.001), and provided superior sedation (P < 0.005). Respiratory rate decreased after IM DPT only. Heart rate and shortening fraction were stable. Oxygen saturation and mean blood pressure decreased minimally in both groups. Supplemental propofol was more frequently required (P < or = 0.02) and in larger doses (P < 0.05) after IM DPT. Parental satisfaction ratings were higher (P < 0.005) and amnesia was more reliably obtained (P = 0.007) with PO ketamine/midazolam. Two patients needed airway support after the PO medication, as did two other patients when PO ketamine/midazolam was supplemented with IV propofol. Although PO ketamine/midazolam provided superior sedation and amnesia compared to IM DPT, this regimen may require the supervision of an anesthesiologist for safe use. Oral medication can be superior to IM injections for sedating children with congenital heart disease; however, the safety of all medications remains an issue.

Stability of midazolam hydrochloride injection 1-mg/mL solutions in polyvinyl chloride and polyolefin bags.

PubMed

Karlage, Kelly; Earhart, Zachary; Green-Boesen, Kelly; Myrdal, Paul B

2011-08-15

The stability of midazolam hydrochloride injection 1-mg/mL solutions in polyvinyl chloride (PVC) and polyolefin bags under varying conditions was evaluated. Triplicate solutions of midazolam hydrochloride 1-mg/mL were prepared in polyolefin and PVC i.v. bags by diluting midazolam hydrochloride injection 5 mg/mL with 5% dextrose injection. Bags were then stored under refrigeration (3-4 °C), exposed to light at room temperature (20-25 °C), or protected from light in amber bags at room temperature. Samples were taken immediately after preparation (day 0) and on days 1, 2, 3, 6, 13, 20, and 27 for analysis with a stability-indicating high-performance liquid chromatography assay in order to determine solution concentration. Stability was defined as retention of at least 90% of the initial drug concentration. The pH of each solution was also measured weekly. Sterility of the i.v. bags was determined at the end of the study by microbiological testing with culture in growth media. Differences in concentrations under the various storage conditions and bags used were analyzed using analysis of variance. All solutions retained over 98% of the initial midazolam hydrochloride concentration, with no statistically significant (p ≥ 0.05) change in concentration over the four-week period. Stability was not affected by temperature, exposure to light, or bag type. The pH of all solutions remained between 3.2 and 3.4 throughout the study. Sterility after 28 days was retained. Midazolam hydrochloride 1-mg/mL solutions diluted in 5% dextrose injection remained stable over 27 days in both polyolefin and PVC i.v. bags, regardless of storage condition.

Cerebral vasomotor responsiveness to carbon dioxide is preserved during propofol and midazolam anesthesia in humans.

PubMed

Strebel, S; Kaufmann, M; Guardiola, P M; Schaefer, H G

1994-05-01

Carbon dioxide reactivity, as measured by transcranial Doppler ultrasonography, was determined during total intravenous anesthesia with propofol or midazolam in comparison with an awake control group. Thirty ASA physical status I neurosurgical patients undergoing lumbar laminectomy participated in the study. In randomized order they were subjected to a CO2 reactivity challenge, either under an intravenous anesthesia technique or in the awake state. CO2 reactivity was calculated in each study group as a relative change in middle cerebral artery (MCA) flow velocity per mm Hg change in end-tidal CO2 (PETCO2) (%/mm Hg). The cerebrovascular response to changes in CO2 was preserved during intravenous anesthesia. There was a significant difference (P < 0.05) in the reactivity slopes between the awake and the anesthetized patients with a small but not significant difference between the propofol and the midazolam group. We conclude that hypocarbia is effective in reducing cerebral blood flow velocity (CBFV) during intravenous anesthesia, either with propofol or midazolam.

Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells

PubMed Central

2011-01-01

Background Peripheral-type benzodiazepine receptor (PBR) expression levels are low in normal human brain, but their levels increase in inflammation, brain injury, neurodegenerative states and gliomas. It has been reported that PBR functions as an immunomodulator. The mechanisms of action of midazolam, a benzodiazepine, in the immune system in the CNS remain to be fully elucidated. We previously reported that interleukin (IL)-1β stimulates IL-6 synthesis from rat C6 glioma cells and that IL-1β induces phosphorylation of inhibitory kappa B (IκB), p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription (STAT)3. It has been shown that p38 MAP kinase is involved in IL-1β-induced IL-6 release from these cells. In the present study, we investigated the effect of midazolam on IL-1β-induced IL-6 release from C6 cells, and the mechanisms of this effect. Methods Cultured C6 cells were stimulated by IL-1β. IL-6 release from C6 cells was measured using an enzyme-linked immunosorbent assay, and phosphorylation of IκB, the MAP kinase superfamily, and STAT3 was analyzed by Western blotting. Results Midazolam, but not propofol, inhibited IL-1β-stimulated IL-6 release from C6 cells. The IL-1β-stimulated levels of IL-6 were suppressed by wedelolactone (an inhibitor of IκB kinase), SP600125 (an inhibitor of SAPK/JNK), and JAK inhibitor I (an inhibitor of JAK 1, 2 and 3). However, IL-6 levels were not affected by PD98059 (an inhibitor of MEK1/2). Midazolam markedly suppressed IL-1β-stimulated STAT3 phosphorylation without affecting the phosphorylation of p38 MAP kinase, SAPK/JNK or IκB. Conclusion These results strongly suggest that midazolam inhibits IL-1β-induced IL-6 release in rat C6 glioma cells via suppression of STAT3 activation. Midazolam may affect immune system function in the CNS. PMID:21682888

Intranasal sedation using ketamine and midazolam for pediatric dental treatment (NASO): study protocol for a randomized controlled trial.

PubMed

Gomes, Heloisa Sousa; Miranda, Analya Rodrigues; Viana, Karolline Alves; Batista, Aline Carvalho; Costa, Paulo Sucasas; Daher, Anelise; Machado, Geovanna de Castro Morais; Sado-Filho, Joji; Vieira, Liliani Aires Candido; Corrêa-Faria, Patrícia; Hosey, Marie Therese; Costa, Luciane Rezende

2017-04-11

Uncooperative children may need to receive dental treatment under sedation, which is indicated when nonpharmacological behavior guidance is unsuccessful. There are randomized controlled trials (RCTs) comparing different sedative protocols for dental procedures; however, the evidence for superiority of one form over another is weak. The primary aim of this study is to investigate the efficacy of intranasally administered ketamine plus midazolam for the dental treatment of children. We have designed a three-armed, parallel RCT to assess intranasal sedation using ketamine/midazolam in terms of the following measures: efficacy, safety, and cost-effectiveness. Two- to 6-year-old healthy children, referred for dental treatment in a dental sedation center in Brazil due to uncooperative behavior and requiring restorative dental procedures, will be recruited. Each child will be randomly assigned to one of the three groups: A - Intranasal administration of ketamine (4.0 mg/kg, maximum 100 mg) and midazolam (0.2 mg/kg, maximum 5.0 mg); B - Oral administration of ketamine (4.0 mg/kg, maximum 100 mg) and midazolam (0.5 mg/kg, maximum 20 mg); and C - Oral administration of midazolam (1.0 mg/kg, maximum 20 mg). The primary outcome is the child's behavior assessed through an observational scale using digital videos of the restorative dental treatment under sedation. The secondary outcomes are as follows: acceptance of sedative administration; memory of intraoperative events; the child's stress; adverse events; the child's pain during the procedure; the parent's, dentists', and child's perceptions of sedation; and economic analysis. Measures will be taken at baseline and drug administration and during and after the dental procedure. The necessary sample size was estimated to be 84 children after a blinded interim analysis of the first 30 cases. This study will provide data that can substantially add to science and pediatric dentistry as it examines the effect of sedative regimes from different perspectives (outcomes). ClinicalTrials.gov, identifier: NCT02447289 . Registered on 11 May 2015, named "Midazolam and Ketamine Effect Administered Through the Nose for Sedation of Children for Dental Treatment (NASO)."

Effectiveness and acceptability of intravenous sedation in child and adolescent dental patients: report of a case series at King's College Hospital, London.

PubMed

Lourenço-Matharu, L; Roberts, G J

2011-06-24

Conscious sedation for young patients continues to be challenging. Few studies have shown positive results using intravenous midazolam when sedating young patients. This case series reports an investigation of conscious sedation using intravenous midazolam for young patients receiving dental treatment. To determine acceptance, safety and efficacy of intravenous midazolam for conscious sedation in children and adolescent patients undergoing dental treatment.Patients and methods Patients from seven to 16 years of age, ASA I, II and III, opted to have extractions, minor oral surgery and/or conservative treatment with IV midazolam and local anaesthesia. A pulse oximeter was used to monitor vital signs and the Houpt scale to assess overall behaviour. A total of 552 patients, 234 boys and 318 girls with mean ages of 13.3 years and 13.5 years respectively, were included. Three hundred and sixty-five patients (66%) claimed to be anxious or very anxious before treatment. The average dose given was 5.7 mg and dosage ranged from 2 to 10 mg. Four hundred and fifty-seven patients (83%) scored 'very good' and 'excellent' for overall behaviour. Side-effects included crying, drowsiness and amnesia. Intravenous midazolam is accepted by patients and is a safe and effective method of sedation for use in children and adolescents, producing some level of tearfulness.

The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs.

PubMed

KuKanich, B; Hubin, M

2010-02-01

Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 microg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 microg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

Sedation with intranasal midazolam of Angolan children undergoing invasive procedures.

PubMed

Kawanda, Lumana; Capobianco, Ivan; Starc, Meta; Felipe, Daniel; Zanon, Davide; Barbi, Egidio; Munkela, Nadine; Rodrigues, Verónica; Malundo, Lúis; Not, Tarcisio

2012-07-01

Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient's pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures. Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay's reactivity score, we gave a score to four different types of children's behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty). Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001). These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon's job easier. © 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.

Intravenous Dexmedetomidine Provides Superior Patient Comfort and Tolerance Compared to Intravenous Midazolam in Patients Undergoing Flexible Bronchoscopy

PubMed Central

Goneppanavar, Umesh; Periyadka Janardhana, Bhavya; Krishna Achar, Shreepathi

2015-01-01

Dexmedetomidine, an α 2 agonist, has demonstrated its effectiveness as a sedative during awake intubation, but its utility in fiberoptic bronchoscopy (FOB) is not clear. We evaluated the effects of midazolam and dexmedetomidine on patient's response to FOB. The patients received either midazolam, 0.02 mg/kg (group M, n = 27), or dexmedetomidine, 1 µg/kg (group D, n = 27). A composite score of five different parameters and a numerical rating scale (NRS) for pain intensity and distress were used to assess patient response during FOB. Patients rated the quality of sedation and level of discomfort 24 h after the procedure. Ease of bronchoscopy, rescue medication requirement, and haemodynamic variables were noted. Ideal or acceptable composite score was observed in 15 and 26 patients, respectively, in group M (14.48 ± 3.65) and group D (9.41 ± 3.13), p < 0.001. NRS showed that 11 patients in group M had severe pain and discomfort as compared to one patient with severe pain and two with severe discomfort in group D during the procedure, p < 0.001. Rescue midazolam requirement was significantly higher in group M (p = 0.023). We conclude that during FOB, under topical airway anaesthesia, IV dexmedetomidine (1 µg/kg) provides superior patient comfort and tolerance as compared to IV midazolam (0.02 mg/kg). PMID:26543645

Effect of peripheral benzodiazepine receptor ligands on lipopolysaccharide-induced tumor necrosis factor activity in thioglycolate-treated mice.

PubMed Central

Matsumoto, T; Ogata, M; Koga, K; Shigematsu, A

1994-01-01

To investigate the effect of peripheral and central benzodiazepine receptor ligands on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) activity in mouse macrophages, three types of ligands, 4'-chlorodiazepam (pure peripheral), midazolam (mixed), and clonazepam (pure central), were compared. Midazolam and 4'-chlorodiazepam significantly suppressed LPS (1-microgram/ml)-induced TNF activity in thioglycolate-elicited mouse macrophages. In every concentration examined (0.001 to 100 microM), 4'-chlorodiazepam was the most effective agent, clonazepam was the least effective agent, and midazolam had an effect intermediate between those of the other two ligands. The peripheral benzodiazepine receptor ligands had a dose-dependent suppressive effect, and the 50% inhibitory concentrations were 0.01 microM for 4'-chlorodiazepam and 5 microM for midazolam. Concomitant use of PK 11195 (10 microM), an antagonist of the peripheral benzodiazepine receptor, reversed this suppressive effect with 4'-chlorodiazepam (10 microM) or midazolam (10 microM). PK 11195 showed this antagonistic effect in a dose-dependent manner. Intravenous 4'-chlorodiazepam (5 mg/kg of body weight) significantly suppressed LPS (100-micrograms)-induced TNF activity of sera (2 h postchallenge with LPS) from thioglycolate-treated mice. The present findings suggest that the peripheral benzodiazepine receptor plays an important role in modulating LPS-induced TNF activity in mouse macrophages. PMID:8031051

Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: the SLEEPS (Safety profiLe, Efficacy and Equivalence in Paediatric intensive care Sedation) study.

PubMed Central

Wolf, Andrew; McKay, Andrew; Spowart, Catherine; Granville, Heather; Boland, Angela; Petrou, Stavros; Sutherland, Adam; Gamble, Carrol

2014-01-01

BACKGROUND Children in paediatric intensive care units (PICUs) require analgesia and sedation but both undersedation and oversedation can be harmful. OBJECTIVE Evaluation of intravenous (i.v.) clonidine as an alternative to i.v. midazolam. DESIGN Multicentre, double-blind, randomised equivalence trial. SETTING Ten UK PICUs. PARTICIPANTS Children (30 days to 15 years inclusive) weighing ≤ 50 kg, expected to require ventilation on PICU for > 12 hours. INTERVENTIONS Clonidine (3 µg/kg loading then 0-3 µg/kg/hour) versus midazolam (200 µg/kg loading then 0-200 µg/kg/hour). Maintenance infusion rates adjusted according to behavioural assessment (COMFORT score). Both groups also received morphine. MAIN OUTCOME MEASURES Primary end point Adequate sedation defined by COMFORT score of 17-26 for ≥ 80% of the time with a ± 0.15 margin of equivalence. Secondary end points Percentage of time spent adequately sedated, increase in sedation/analgesia, recovery after sedation, side effects and safety data. RESULTS The study planned to recruit 1000 children. In total, 129 children were randomised, of whom 120 (93%) contributed data for the primary outcome. The proportion of children who were adequately sedated for ≥ 80% of the time was 21 of 61 (34.4%) - clonidine, and 18 of 59 (30.5%) - midazolam. The difference in proportions for clonidine-midazolam was 0.04 [95% confidence interval (CI) -0.13 to 0.21], and, with the 95% CI including values outside the range of equivalence (-0.15 to 0.15), equivalence was not demonstrated; however, the study was underpowered. Non-inferiority of clonidine to midazolam was established, with the only values outside the equivalence range favouring clonidine. Times to reach maximum sedation and analgesia were comparable hazard ratios: 0.99 (95% CI 0.53 to 1.82) and 1.18 (95% CI 0.49 to 2.86), respectively. Percentage time spent adequately sedated was similar [medians clonidine 73.8% vs. midazolam 72.8%: difference in medians 0.66 (95% CI -5.25 to 7.24)]. Treatment failure was 12 of 64 (18.8%) on clonidine and 7 of 61 (11.5%) on midazolam [risk ratio (RR) 1.63, 95% CI 0.69 to 3.88]. Proportions with withdrawal symptoms [28/60 (46.7%) vs. 30/58 (52.6%)] were similar (RR 0.89, 95% CI 0.62 to 1.28), but a greater proportion required clinical intervention in those receiving midazolam [11/60 (18.3%) vs. 16/58 (27.6%) (RR 0.66, 95% CI 0.34 to 1.31)]. Post treatment, one child on clonidine experienced mild rebound hypertension, not requiring intervention. A higher incidence of inotropic support during the first 12 hours was required for those on clonidine [clonidine 5/45 (11.1%) vs. midazolam 3/52 (5.8%)] (RR 1.93 95% CI 0.49 to 7.61). CONCLUSIONS Clonidine is an alternative to midazolam. Our trial-based economic evaluation suggests that clonidine is likely to be a cost-effective sedative agent in the PICU in comparison with midazolam (probability of cost-effectiveness exceeds 50%). Rebound hypertension did not appear to be a significant problem with clonidine but, owing to its effects on heart rate, specific cardiovascular attention needs to be taken during the loading and early infusion phase. Neither drug in combination with morphine provided ideal sedation, suggesting that in unparalysed patients a third background agent is necessary. The disappointing recruitment rates reflect a reluctance of parents to provide consent when established on a sedation regimen, and reluctance of clinicians to allow sedation to be studied in unstable critically ill children. Future studies will require less exacting protocols allowing enhanced recruitment. TRIAL REGISTRATION Current Controlled Trials ISRCTN02639863. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 71. See the NIHR Journals Library website for further project information. PMID:26099138

[Midazolam as a premedication for gastroscopy].

PubMed

Eisner, M

1984-04-01

Midazolam (Ro 21-3981; Dormicum ) is a new water-soluble benzodiazepine. Compared with diazepam and flunitrazepam, it has the advantage of a short half-life and good tolerability after intravenous administration. It induces light sleep 1/2 to 2 min after injection, and anterograde amnesia. It has minimal hemodynamic and respiratory effects. We administered midazolam by intravenous injection in a dose of 3-7 mg to 100 patients about to undergo esophago-, gastro-, or duodenoscopy. The patient became quiet and relaxed, falling into a light sleep but remaining capable of following simple instructions. After completion of the endoscopy, the patients were half awake, and listened attentively to the report. They subsequently usually slept for 1-2 h, afterwards remembering nothing of the procedure. Two (at most, 3) hours after injection, the patients were again completely awake and able to go home or back to work. In some cases, concentration was slightly impaired for the rest of the day. Compared with other premedications , midazolam is better suited for use in endoscopy, owing to its rapid onset and short duration of action.

Propofol dose and incidence of dreaming during sedation.

PubMed

Eer, Audrey Singyi; Padmanabhan, Usha; Leslie, Kate

2009-10-01

Dreaming is commonly reported after propofol-based sedation. We measured the incidence of dreaming and bispectral index (BIS) values in colonoscopy patients sedated with combinations of propofol, midazolam and fentanyl. Two hundred patients presenting for elective outpatient colonoscopy were sedated with combinations of propofol, midazolam and fentanyl. BIS was monitored throughout the procedure. Patients were interviewed immediately after they emerged from sedation. The primary end point was a report of dreaming during sedation. Ninety-seven patients were administered propofol alone, 44 were administered propofol and fentanyl, 16 were administered propofol and midazolam and 43 were administered propofol, midazolam and fentanyl. Dreaming was reported by 19% of patients. Dreamers received higher doses of propofol and had lower BIS values during sedation. Age of 50 years or less, preoperative quality of recovery score of less than 14, higher home dream recall, propofol dose of more than 300 mg and time to Observers' Assessment of Alertness/Sedation score equalling 5 of 8 min or less were independent predictors of dreaming. Dreaming during sedation is associated with higher propofol dose and lower BIS values.

Effect of preoperative oral midazolam sedation on separation anxiety and emergence delirium among children undergoing dental treatment under general anesthesia.

PubMed

El Batawi, Hisham Yehia

2015-01-01

To investigate the possible effects of preoperative oral Midazolam on parental separation anxiety, emergence delirium, and post-anesthesia care unit time on children undergoing dental rehabilitation under general anesthesia. Randomized, prospective, double-blind study. Seventy-eight American Society of Anesthesiology (ASA) I children were divided into two groups of 39 each. Children of the first group were premedicated with oral Midazolam 0.5 mg/kg, while children of the control group were premedicated with a placebo. Scores for parental separation, mask acceptance, postoperative emergence delirium, and time spent in the post-anesthesia care unit were compared statistically. The test group showed significantly lower parental separation scores and high acceptance rate for anesthetic mask. There was no significant difference between the two groups regarding emergence delirium and time spent in post-anesthesia care unit. Preoperative oral Midazolam could be a useful adjunct in anxiety management for children suffering dental anxiety. The drug may not reduce the incidence of postoperative emergence delirium. The suggested dose does not seem to affect the post-anesthesia care unit time.

Oral midazolam reduces cortisol levels during local anaesthesia in children: a randomised controlled trial.

PubMed

Gomes, Heloisa Sousa; Corrêa-Faria, Patrícia; Silva, Tarcília Aparecida; Paiva, Saul Martins; Costa, Paulo Sérgio Sucasas; Batista, Aline Carvalho; Costa, Luciane Rezende

2015-01-01

Little is known about whether midazolam sedation can reduce salivary cortisol levels and consequently influence children's behaviour during dental treatment. The aim of this study was to evaluate the effect of midazolam sedation on salivary cortisol and its correlation with children's behaviour during restorative dental treatment. Eighteen healthy children, aged two to five years, were randomly assigned to two dental treatment appointments, both with physical restraint: oral midazolam 1 mg/kg (MS) and placebo (PS). An observer assessed the children's behaviour (videos) using the Ohio State University Behavioral Rating Scale (OSUBRS). The children's saliva was collected just after waking up, on arrival at the dental school, 25 minutes after local anaesthesia, and 25 minutes after the end of the procedure. Salivary cortisol levels were determined using the enzyme-linked immunoabsorbent assay. The data were analysed by bivariate tests and multivariate analysis of variance (5% level). Salivary cortisol levels were lower in the MS group than in the PS group at the time of anaesthesia (p = 0.004), but did not vary during the appointment within sedation (p = 0.319) or placebo (p = 0.080) groups. Children's behaviour was negative most of the time and did not differ between MS and PS; however, the behaviour (OSUBRS) did not correlate with salivary cortisol levels. Oral midazolam is able to control salivary cortisol levels during dental treatment of pre-schoolers, which might not lead to better clinical behaviour.

Sedation and Analgesia Using Medications Delivered via the Extravascular Route in Children Undergoing Laceration Repair

PubMed Central

Capino, Amanda C.; Thomas, Amber; Couloures, Kevin; Johnson, Peter N.

2018-01-01

OBJECTIVES To describe the method of delivery, dosage regimens, and outcomes of sedatives and analgesics administered via the extravascular route for laceration repair in children METHODS Medline, Embase, and International Pharmaceutical Abstracts were searched using the keywords “child,” “midazolam,” “ketamine,” dexmedetomidine,” “fentanyl,” “nitrous oxide” (N2O), and “laceration repair.” Articles evaluating the use of extravascular sedation in children for laceration repair published in the English language between 1946 and June 2017 were included. Two authors independently screened each article for inclusion. Reports were excluded if they did not contain sufficient details on dosage regimen and outcomes. RESULTS A total of 16 reports representing 953 children receiving sedatives and analgesics via the extravascular route were included for analyses. A statistical analysis was not performed because of heterogeneity in dosing and types of analyses conducted. Midazolam and N2O were the most common agents, with oral (PO) midazolam being the most common agent. Other agents that have supporting data were intranasal (IN) dexmedetomidine, IN ketamine, IN midazolam, PO diazepam, PO ketamine, transmucosal (TM) midazolam, and TM fentanyl. CONCLUSIONS Most of the agents administered through the extravascular route were efficacious. Selection of the agents should be based on perceived need for analgesia versus sedation, patient accessibility, and adverse drug events. Future research is needed to determine the optimal agent and route for laceration repair. PMID:29720907

Reduced incidence of laryngospasm with remifentanil-midazolam anaesthesia compared to halothane-fentanyl.

PubMed

Ali, Shahriari

2008-03-01

To compare the incidence of laryngospasm by using halothane-fentanyl anaesthesia and midazolam-remifentanil anaesthesia in paediatric patients undergoing eye surgery. We enrolled 120 ASA physical status I children aged 7-12 years scheduled for eye surgery from March 2004 to February 2006 in this prospective clinical trial study. Children suffering from any medical condition that could affect airway reflexes such as active upper respiratory infection, symptomatic asthma, obesity, patients with predicted difficulty in tracheal intubation were not included in the study. Patients with prolonged or difficult intubation or those who received another drug before extubation were excluded from the study. Using a random numbers table, participants were allocated to two equal groups. After induction of anaesthesia, in one group Halothane 1% was administered for the maintenance of anaesthesia in addition with intravenous fentanyl 1.5 microg kg(-1), and for the patients of the other group midazolam with a dose of 0.1 mg kg(-1) and remifentanil infusion by a dose of 0.1 microg kg(-1) min(-1) was administered. The patients were extubated in a unique plan of anaesthesia, using the sign of swallowing as a clinical indicator for extubation of patients. The incidence of laryngospasm was lower in midazolam-remifentanil group (0%) in comparison with halothane-fentanyl group (6.6%). The results of our study suggest that remifentanil combined with midazolam in children undergoing eye surgery provided a better condition for extubation of the patients.

Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats.

PubMed

Dostalek, M; Hadasova, E; Hanesova, M; Pistovcakova, J; Sulcova, A; Jurica, J; Tomandl, J; Linhart, I

2005-01-01

Methamphetamine is the fourth most frequently reported compound associated with drug abuse on admission of patients to treatment centres after cocaine, heroin and marijuana. It is metabolized in the organism with a reaction that is catalyzed by cytochrome P450, mainly by the CYP2D and CYP3A subfamily, 4-hydroxyamphetamine and amphetamine being dominant metabolites. The present pharmacokinetic study was undertaken to investigate the possible influence of methamphetamine (10 mg/kg, i.p., once daily for six days) on the pharmacokinetics of dextromethorphane as a model substrate for rat cytochrome P-4502D2 and midazolam as a model substrate for CYP3A1/2. Animals received a single injection of dextromethorphane (10 mg/kg) or midazolam (5 mg/kg) in the tail vein 24 h after the last dose of methamphetamine or administration of placebo. The results of pharmacokinetic analysis showed a significantly increased rate of dextrorphane and 3-hydroxymorphinan formation, and a marked stimulatory effect of methamphetamine on CYP2D2 metabolic activity. Similarly, the kinetics of midazolam's metabolic conversion to hydroxy derivates of midazolam indicated a significant increase in CYP3A1/2 activity. The results showed that the administration of methamphetamine significantly stimulated the metabolic activity of CYP2D2 as well as that of CYP3A1/2. With regard to the high level of homology between human and rat CYP isoforms studied, the results may have a clinical impact on future pharmacotherapy for methamphetamine abuse.

Effects of aging and rifampicin pretreatment on the pharmacokinetics of human cytochrome P450 probes caffeine, warfarin, omeprazole, metoprolol and midazolam in common marmosets genotyped for cytochrome P450 2C19.

PubMed

Toda, Akiko; Uehara, Shotaro; Inoue, Takashi; Utoh, Masahiro; Kusama, Takashi; Shimizu, Makiko; Uno, Yasuhiro; Mogi, Masayuki; Sasaki, Erika; Yamazaki, Hiroshi

2018-07-01

1. The pharmacokinetics were investigated for human cytochrome P450 probes after single intravenous and oral administrations of 0.20 and 1.0 mg/kg, respectively, of caffeine, warfarin, omeprazole, metoprolol and midazolam to aged (10-14 years old, n = 4) or rifampicin-treated/young (3 years old, n = 3) male common marmosets all genotyped as heterozygous for a cytochrome P450 2C19 variant. 2. Slopes of the plasma concentration-time curves after intravenous administration of warfarin and midazolam were slightly, but significantly (two-way analysis of variance), decreased in aged marmosets compared with young marmosets. The mean hepatic clearances determined by in silico fitting for individual pharmacokinetic models of warfarin and midazolam in the aged group were, respectively, 23% and 56% smaller than those for the young group. 3. Significantly enhanced plasma clearances of caffeine, warfarin, omeprazole and midazolam were evident in young marmosets pretreated with rifampicin (25 mg/kg daily for 4 days). Two- to three-fold increases in hepatic intrinsic clearance values were observed in the individual pharmacokinetic models. 4. The in vivo dispositions of multiple simultaneously administered drugs in old, young and P450-enzyme-induced marmosets were elucidated. The results suggest that common marmosets could be experimental models for aged, induced or polymorphic P450 enzymes in P450-dependent drug metabolism studies.

Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data

PubMed Central

Gupta, Pankaj; Alvey, Christine; Wang, Rong; Dowty, Martin E; Fahmi, Odette A; Walsky, Robert L; Riese, Richard J; Krishnaswami, Sriram

2012-01-01

AIMS To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies. METHODS In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration–time profile, from time 0 to infinity (AUC(0,∞)). RESULTS In vitro studies demonstrated low potential for CYP inhibition (IC50 estimates tofacitinib >30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (Cmax) (95.98, 108.87) was also wholly within this acceptance region. CONCLUSIONS These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole. PMID:22233204

Clinical comparative study on Nitrous Oxide inhalation versus intravenous propofol and Midazolam sedation in Transnasal Gastroscopy.

PubMed

Xiaoqian, Zhou; Tao, Zhang; Bingsong, Luo; Jing, Li; Yu, Deng; Weilan, Zhong

2017-01-01

To investigate the Clinical practice value of nitrous oxide inhalation and intravenous propofol and midazolam sedation in transnasal gastroscopy. From December 2012 to April 2014, two hundred patients receiving painless transnasal gastroscopy on a voluntary basis were selected in Endoscopy center, The First People's Hospital of GuiYang. Patients were divided into two groups: Group-1 consisted of one hundred patients sedated by nitrous oxide inhalation and Group-2 consisted of one hundred patients sedated by intravenous propofol and midazolam. Patients were then examined by transnasal gastroscopy. Patient blood pressure, heart rate, pulse rate and oxygen saturation before, during and after gastroscopy were recorded for both groups. The duration of the gastroscopy and the time of awakening were also recorded. After examination, the patients were asked to assess the level of discomfort experiences during the gastroscopy procedure. All patients successfully underwent the transnasal gastroscopy. There were 57 males and 43 females in the nitrous oxide inhalation group with an average age of 43.11±8.27 years. The average duration of examination and time of awaking in the nitrous oxide inhalation group was of 152.7±9.80 secs and 50±7.89 secs respectively. For the intravenous propofol and midazolam sedation group, there were 53 males and 47 females with an average age of 41.26±7.98 years. The average duration of examination and time of awaking in the intravenous propofol and midazolam sedation group was of 149.07±10.25 seconds and 390±20.89 # seconds respectively. The two groups showed no significant difference in the duration of examination. There was no difference in the age or sex. The former had a less significant impact on heart rate, oxygen saturation and blood pressure, while the intravenous propofol and midazolam sedation decreased blood pressure dramatically and this effect persisted after examination. Nitrous oxide inhalation has higher safety and tolerance with a brighter application prospect for transnasal gastroscopy.

Sedation improves early outcome in severely septic Sprague Dawley rats

PubMed Central

2009-01-01

Introduction Sepsis, a systemic inflammatory response to infective etiologies, has a high mortality rate that is linked both to excess cytokine activity and apoptosis of critical immune cells. Dexmedetomidine has recently been shown to improve outcome in a septic cohort of patients when compared to patients randomized to a benzodiazepine-based sedative regimen. We sought to compare the effects of dexmedetomidine and midazolam, at equi-sedative doses, on inflammation and apoptosis in an animal model of severe sepsis. Methods After central venous access, Sprague Dawley rats underwent cecal ligation and intestinal puncture (CLIP) with an 18 G needle without antibiotic cover and received either saline, or an infusion of comparable volume of saline containing midazolam (0.6 mg.kg-1.h-1) or dexmedetomidine (5 ug.kg-1.h-1) for 8 hours. Following baseline measurements and CLIP, blood was sampled for cytokine measurement (tumour necrosis factor (TNF)-alpha and interleukin (IL)-6; n = 4-6 per group) at 2, 4 and 5 hours, and animal mortality rate (MR) was monitored (n = 10 per group) every 2 hours until 2 hours had elapsed. In addition, spleens were harvested and apoptosis was assessed by immunoblotting (n = 4 per group). Results The 24 hour MR in CLIP animals (90%) was significantly reduced by sedative doses of either dexmedetomidine (MR = 20%) or midazolam (MR = 30%). While both sedatives reduced systemic levels of the inflammatory cytokine TNF-alpha (P < 0.05); only dexmedetomidine reduced the IL-6 response to CLIP, though this narrowly missed achieving significance (P = 0.05). Dexmedetomidine reduced splenic caspase-3 expression (P < 0.05), a marker of apoptosis, when compared to either midazolam or saline. Conclusions Sedation with midazolam and dexmedetomidine both improve outcome in polymicrobial severely septic rats. Possible benefits conveyed by one sedative regimen over another may become evident over a more prolonged time-course as both IL-6 and apoptosis were reduced by dexmedetomidine but not midazolam. Further studies are required to evaluate this hypothesis. PMID:19691839

CYP3A5 Contributes significantly to CYP3A-mediated drug oxidations in liver microsomes from Japanese subjects.

PubMed

Yamaori, Satoshi; Yamazaki, Hiroshi; Iwano, Shunsuke; Kiyotani, Kazuma; Matsumura, Keiko; Honda, Goro; Nakagawa, Kazuko; Ishizaki, Takashi; Kamataki, Tetsuya

2004-04-01

The purpose of this study was to evaluate a contribution of polymorphic cytochrome P450 (CYP) 3A5 to the oxidation of diltiazem, midazolam and testosterone by liver microsomes from Japanese subjects. Twenty-seven liver samples were classified into three groups according to the CYP3A5 genotypes; CYP3A5(*)1/(*)1 (n=3), (*)1/(*)3 (n=12) and (*)3/(*)3 (n=12). The results of genotyping and immunochemical quantitation of CYP3A5 protein showed a good accordance between the CYP3A5 genotype and CYP3A5 content but not CYP3A4 content in liver microsomes. The expression levels of hepatic CYP3A5 protein ranged from 20 to 60% of the sum of CYP3A4 and CYP3A5 contents in subjects with at least one wild type allele ((*)1). The CYP3A5 contents correlated well with liver microsomal activities of diltiazem N-demethylation, midazolam 1'- and 4-hydroxylations and testosterone 6beta-hydroxylation among subjects carrying at least one (*)1 allele. In addition, the correlation coefficients of CYP3A5 contents with the rates of diltiazem N-demethylation, midazolam 1'-hydroxylation and testosterone 6beta- hydroxylation were higher than those of CYP3A4, although the value of CYP3A5 with the midazolam 4-hydroxylation rate was similar to that of CYP3A4. Kinetic analyses revealed a biphasic diltiazem N-demethylation in liver microsomes from subjects carrying the (*)1 allele. The apparent V(max)/K(m) values for recombinant CYP3A5 indicated the greater contributions to diltiazem N-demethylation and midazolam 1'-hydroxylation as compared with CYP3A4. These results suggest that polymorphic CYP3A5 contributes markedly to the drug oxidations, particularly diltiazem N-demethylation, midazolam 1'- hydroxylation and testosterone 6beta-hydroxylation by liver microsomes from Japanese subjects.

Addition of low-dose ketamine to midazolam and low-dose bupivacaine improves hemodynamics and postoperative analgesia during spinal anesthesia for cesarean section

PubMed Central

Basuni, Ahmed Sobhy

2016-01-01

Background and Aims: Spinal anesthesia for cesarean section (CS) is associated with an incidence of hypotension of 60-94%. This study hypothesizes that intrathecal combination of low-dose ketamine, midazolam, and low-dose bupivacaine improves hemodynamics and postoperative analgesia compared with fentanyl and low-dose bupivacaine during CS. Material and Methods: Fifty parturients undergoing elective CS were randomized equally to receive ketamine (10 mg), midazolam (2 mg) and 0.5% hyperbaric bupivacaine (8 mg) in group ketamine-midazolam-bupivacaine (KMB) or fentanyl (25 μg) and 0.5% hyperbaric bupivacaine (8 mg) in group fentanyl-bupivacaine (FB). Heart rate (HR), mean arterial blood pressure (MAP), oxygen saturation, sensorimotor block characteristics, pain-free period, side-effects including: hypotension, bradycardia, nausea, vomiting, sedation, pruritus, respiratory depression and dissociative manifestations, Apgar score at 1 and 5 min, and patients' satisfaction visual analog scores (VAS) were recorded. Patients in group KMB were followed for 6 months in order to assess any neurological disorder. Results: Group KMB showed higher sensory level (P = 0.006), rapid sensory (P = 0.001) and motor (P = 0.005) onsets, prolonged sensory (P = 0.008) and motor (P = 0.002) blocks, and prolonged pain free period (P = 0.002). Ketamine-midazolam stabilized HR and MAP, and significantly reduced incidence of hypotension (P = 0.002), bradycardia (P = 0.013) and vomiting (P = 0.019). Apgar scores at 1 and 5 min were comparable in both groups (P = 0.699 and 0.646 respectively). Patients' satisfaction VAS scores were significantly higher in group KMB (P = 0.001). No patients in KMB group showed dissociative or neurotoxic manifestations. Conclusion: Intrathecal low-dose ketamine combined with midazolam and low-dose bupivacaine stabilizes hemodynamics and prolongs postoperative analgesia without significant side-effects in parturients undergoing CS. PMID:27006540

A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail.

PubMed

Morcos, Peter N; Chang, Linda; Kulkarni, Rohit; Giraudon, Mylene; Shulman, Nancy; Brennan, Barbara J; Smith, Patrick F; Tran, Jonathan Q

2013-11-01

The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C. A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated. Danoprevir/r and placebo/r significantly increased midazolam area under the time-concentration curve (AUC0-∞) and reduced the midazolam metabolic ratio while S-warfarin AUC0-∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC0-∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC0-∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar. Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.

Physiologically based pharmacokinetic model of mechanism-based inhibition of CYP3A by clarithromycin.

PubMed

Quinney, Sara K; Zhang, Xin; Lucksiri, Aroonrut; Gorski, J Christopher; Li, Lang; Hall, Stephen D

2010-02-01

The prediction of clinical drug-drug interactions (DDIs) due to mechanism-based inhibitors of CYP3A is complicated when the inhibitor itself is metabolized by CYP3Aas in the case of clarithromycin. Previous attempts to predict the effects of clarithromycin on CYP3A substrates, e.g., midazolam, failed to account for nonlinear metabolism of clarithromycin. A semiphysiologically based pharmacokinetic model was developed for clarithromycin and midazolam metabolism, incorporating hepatic and intestinal metabolism by CYP3A and non-CYP3A mechanisms. CYP3A inactivation by clarithromycin occurred at both sites. K(I) and k(inact) values for clarithromycin obtained from in vitro sources were unable to accurately predict the clinical effect of clarithromycin on CYP3A activity. An iterative approach determined the optimum values to predict in vivo effects of clarithromycin on midazolam to be 5.3 microM for K(i) and 0.4 and 4 h(-1) for k(inact) in the liver and intestines, respectively. The incorporation of CYP3A-dependent metabolism of clarithromycin enabled prediction of its nonlinear pharmacokinetics. The predicted 2.6-fold change in intravenous midazolam area under the plasma concentration-time curve (AUC) after 500 mg of clarithromycin orally twice daily was consistent with clinical observations. Although the mean predicted 5.3-fold change in the AUC of oral midazolam was lower than mean observed values, it was within the range of observations. Intestinal CYP3A activity was less sensitive to changes in K(I), k(inact), and CYP3A half-life than hepatic CYP3A. This semiphysiologically based pharmacokinetic model incorporating CYP3A inactivation in the intestine and liver accurately predicts the nonlinear pharmacokinetics of clarithromycin and the DDI observed between clarithromycin and midazolam. Furthermore, this model framework can be applied to other mechanism-based inhibitors.

Aerosolized intranasal midazolam for safe and effective sedation for quality computed tomography imaging in infants and children.

PubMed

Mekitarian Filho, Eduardo; de Carvalho, Werther Brunow; Gilio, Alfredo Elias; Robinson, Fay; Mason, Keira P

2013-10-01

This pilot study introduces the aerosolized route for midazolam as an option for infant and pediatric sedation for computed tomography imaging. This technique produced predictable and effective sedation for quality computed tomography imaging studies with minimal artifact and no significant adverse events. Copyright © 2013 Mosby, Inc. All rights reserved.

Supra-recommendation Treatment of Super-refractory Status Epilepticus.

PubMed

Vyas, Devashish Dhiren; Dash, Gopal Krishna

2016-06-01

A 28-year old female was admitted with recurrent seizures following 2 days of febrile illness, after which she developed status epilepticus. Midazolam and later thiopentone infusions were started after failure of regular intravenous antiepileptics. Burst suppression was achieved at doses of 3 mg/kg/hr for midazolam and 6 mg/kg/hr of thiopentone. Adjunctive medications included methylprednisolone, intravenous immunoglobulin and acyclovir. Imaging and biochemical parameters were normal. She required 3 cycles of midazolam and 2 cycles of thiopentone for complete cessation of seizures. She recovered with mild attentional and recent memory deficits on follow up. Treatment of super-refractory status epilepticus requires individualized regimens and may need doses beyond conventional limits. To the best of our knowledge, there is no such reported case from India.

[Analgesia and sedation in neonatal-pediatric intensive care].

PubMed

Schlünder, C; Houben, F; Hartwig, S; Theisohn, M; Roth, B

1991-01-01

In pediatric intensive care, analgesia and sedation has become increasingly important for newborns as well as prematures in recent years. However, its importance is frequently not well recognized and sedation is confounded with analgesia. In our intensive-care unit (ICU), fentanyl and midazolam have proved to be useful. In newborn and premature infants, fentanyl alone has been sufficient because of its analgesic and sedative action. In a study on 20 newborns and prematures suffering from severe respiratory problems as compared with a historical group that did not receive fentanyl, we could show that in subjects receiving fentanyl, considerably less treatment with sedatives and other analgesics was necessary. Cardiopulmonary tolerance was satisfactory. The highest bilirubin values were reached about 1 day earlier and were slightly higher than those measured in the control group, but oral nutrition could be initiated sooner. In small infants, additional midazolam was given after cardiac surgery. During the first 72 h, we found a correlation between serum levels of midazolam and the depth of sedation; however, after 72 h of medication, the dose had to be raised because of an increase in metabolic clearance. During the concomitant administration of midazolam and fentanyl, significantly less midazolam was needed to achieve appropriate analog-sedation. Prior to the administration of analgesics and sedatives, care should be taken to ensure that circulatory conditions are stable and that there is no hypovolemia, and the drugs must be given slowly during several minutes. Especially in a pediatric ICU, light and noise should be diminished and contact between the parents and the child should be encouraged, even when the child is undergoing mechanical ventilation.

Effect of preoperative oral midazolam sedation on separation anxiety and emergence delirium among children undergoing dental treatment under general anesthesia

PubMed Central

El Batawi, Hisham Yehia

2015-01-01

Aim: To investigate the possible effects of preoperative oral Midazolam on parental separation anxiety, emergence delirium, and post-anesthesia care unit time on children undergoing dental rehabilitation under general anesthesia. Methods: Randomized, prospective, double-blind study. Seventy-eight American Society of Anesthesiology (ASA) I children were divided into two groups of 39 each. Children of the first group were premedicated with oral Midazolam 0.5 mg/kg, while children of the control group were premedicated with a placebo. Scores for parental separation, mask acceptance, postoperative emergence delirium, and time spent in the post-anesthesia care unit were compared statistically. Results: The test group showed significantly lower parental separation scores and high acceptance rate for anesthetic mask. There was no significant difference between the two groups regarding emergence delirium and time spent in post-anesthesia care unit. Conclusions: Preoperative oral Midazolam could be a useful adjunct in anxiety management for children suffering dental anxiety. The drug may not reduce the incidence of postoperative emergence delirium. The suggested dose does not seem to affect the post-anesthesia care unit time. PMID:25992332

The effect of auricular acupuncture on pain during colonoscopy with midazolam and pethidine

NASA Astrophysics Data System (ADS)

Kusumastuti, R.; Srilestari, A.; Abdurrohim, K.; Abdullah, M.

2017-08-01

Colonoscopy is the standard procedure for colorectal cancer screening. One of its common complications is abdominal pain. Analgesia has not provided favorable outcomes so various complementary practices have been developed, including auricular acupuncture. In this study, a randomized controlled trial of 56 patients who underwent colonoscopy was conducted to determine the effect of acupuncture on the pain experienced during colonoscopy. Subjects were divided into two groups: The first received acupuncture combined with midazolam and pethidine, while the second were administered placebo puncture in addition to midazolam and pethidine. The median Critical Care Pain Observation Tool (CPOT) score was lower in the auricular acupuncture group than in the placebo puncture group(0.7 [0-4.83] vs. 1.9 [0-6.20] p = 0.010), while there were no significant differences to median Visual Analog Scale (VAS) scores (29 [0-100] vs. 44.5 [0-100] p = 0.147), heart rate changes (-2.58 [14.31] vs.-2.43 [12.28]; p = 0.970), or the mean time to the cecum (16 [8-51] vs. 22 [5-63] p = 0.206). Auricular acupuncture combined with midazolam and pethidine was found to be effective at reducing pain during colonoscopy.

Pharmacokinetic Evaluation of the Interactions of Amenamevir (ASP2151) with Ketoconazole, Rifampicin, Midazolam, and Warfarin in Healthy Adults.

PubMed

Kusawake, Tomohiro; den Adel, Martin; Groenendaal-van de Meent, Dorien; Garcia-Hernandez, Alberto; Takada, Akitsugu; Kato, Kota; Ohtsu, Yoshiaki; Katashima, Masataka

2017-11-01

Amenamevir is a nonnucleoside antiherpes virus compound available for treating herpes zoster infections. Four studies aimed to determine any potential interactions between amenamevir and ketoconazole, rifampicin, midazolam, or warfarin in healthy male participants. Two studies were open-label studies that evaluated the effects of multiple doses of ketoconazole (400 mg) and rifampicin (600 mg) on the pharmacokinetics of a single oral dose of amenamevir. The other two studies were randomized, double-blind, parallel-group studies that evaluated the effects of multiple doses of amenamevir on the pharmacokinetics of a single dose of midazolam (7.5 mg) and warfarin (25 mg). A drug interaction was considered to occur if the 90% confidence interval (CI) of the least squares geometric mean ratio (GMR) of amenamevir to the comparator was outside the prespecified interval of 0.80-1.25. Interactions were observed between amenamevir and ketoconazole, rifampicin, and midazolam, but not between amenamevir and warfarin. After a single 400-mg dose of amenamevir, the GMRs of amenamevir plus ketoconazole or rifampicin versus amenamevir alone for C max and the area under the plasma concentration-time curve from time zero to infinity (AUC inf ) were 1.30 (90% CI 1.17-1.45) and 2.58 (90% CI 2.32-2.87), respectively, for ketoconazole and 0.42 (90% CI 0.37-0.49) and 0.17 (90% CI 0.15-0.19), respectively, for rifampicin. Following multiple doses of amenamevir (400 mg), the GMRs of midazolam plus amenamevir versus midazolam alone for AUC inf and C max were 0.53 (90% CI 0.47-0.61) and 0.63 (90% CI 0.50-0.80), respectively. After a single dose of warfarin, the (S)-warfarin and (R)-warfarin mean C max increased and mean AUC inf decreased in the presence of amenamevir; however, the 90% CIs of the GMRs for these parameters remained within the predefined limits. These findings confirm that amenamevir (as a cytochrome P450 3A4 substrate) can interact with ketoconazole or rifampicin, and (as a cytochrome P450 3A4 inducer) can interact with midazolam; however, no interaction between amenamevir and (S)-warfarin was observed, indicating that amenamevir is not an inducer of cytochrome P450 2C9. Astellas Pharma. EudraCT2007-002227-33 (study 15L-CL-008), EudraCT2007-002228-14 (study 15L-CL-009), EudraCT2007-002761-13 (study 15L-CL-010), and EudraCT2007-002779-14 (study 15L-CL-018).

Systemic or Intra-Amygdala Infusion of the Benzodiazepine, Midazolam, Impairs Learning, but Facilitates Re-Learning to Inhibit Fear Responses in Extinction

ERIC Educational Resources Information Center

Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

2010-01-01

A series of experiments used rats to study the effect of a systemic or intra-amygdala infusion of the benzodiazepine, midazolam, on learning and re-learning to inhibit context conditioned fear (freezing) responses. Rats were subjected to two context-conditioning episodes followed by extinction under drug or vehicle, or to two cycles of context…

The Influence of Verapamil and Nicardipine on the Rate of Metabolism of Midazolam

DTIC Science & Technology

2000-10-01

premedicant and for induction and maintenance of anesthesia . Midazolam produces anxiolysis, amnesia, hypnosis , skeletal muscle relaxation, and anticonvulsant...Dean CIRRICULUM VITAE Name: Gregg Steven Lowe Major, United States Air Force, Nurse Corps Graduate Student - Nurse Anesthesia Program Uniformed Services...Nurse University of the Anesthesia Health Sciences Bethesda, Maryland 1993-1995 Midwestern State BSN May 1995 Nursing University Wichita Falls, Texas

Does Intravenous Midazolam Dose Influence the Duration of Recovery Room Stay Following Outpatient Third Molar Surgery?

PubMed

Ettinger, Kyle S; Jacob, Adam K; Viozzi, Christopher F; Van Ess, James M; Fillmore, W Jonathan; Arce, Kevin

2015-12-01

To evaluate the impact of intravenous midazolam dose on the duration of recovery room stay for patients undergoing outpatient third molar surgery. Using a retrospective cohort study design, a sample of patients undergoing outpatient third molar surgery under intravenous sedation at Mayo Clinic from 2010 to 2014 was identified. All patients underwent extraction of all 4 third molars during a single operative procedure and the age range was limited to 14 to 29 years. The primary predictor variable was the total dose of intravenous midazolam administered during sedation. The primary outcome variable was recovery room length of stay (LOS) after completion of surgery. Multiple covariates also abstracted included patient age, gender, American Society of Anesthesiologists (ASA) score, duration of surgical procedure, complexity of surgical procedure, types and dosages of all intravenous medications administered during sedation, and volume of crystalloid fluid administered perioperatively. Univariable and multivariable models were developed to evaluate associations between the primary predictor variable and covariates relative to the primary outcome variable. The study sample was composed of 2,610 patients. Mean age was 18.3 years (SD, 3.0 yr; range, 14 to 29 yr) and gender distribution was 52% female. Mean dosage of midazolam administered was 4.1 mg (SD, 1.1 mg; range, 0.5 to 10.0 mg). Variables predicting shorter LOS at multivariable analysis included older age (P < .001), male gender (P = .004), and administration of larger crystalloid fluid volumes (P < .001). Variables predicting longer LOS included higher ASA score (P < .001), administration of ketamine (P < .001), and administration of ketorolac (P < .001). The dose of midazolam administered during sedation was not found to be significantly associated with prolonged recovery room LOS in univariable or multivariable settings. Dosage of intravenous midazolam does not appear to significantly impact the duration of recovery room stay in the prototypical patients undergoing sedation for outpatient third molar surgery. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Optimal and safe standard doses of midazolam and propofol to achieve patient and doctor satisfaction with dental treatment: A prospective cohort study

PubMed Central

Nonaka, Mutsumi; Nishimura, Akiko; Gotoh, Kinuko; Oka, Shuichirou; Iijima, Takehiko

2017-01-01

Background The incidences of morbidity and mortality caused by pharmacosedation for dental treatment have not yet reached zero. Adverse events are related to inappropriate respiratory management, mostly originating from an overdose of sedatives. Since sedation is utilized for the satisfaction of both the dentist and the patient, the optimal dose should be minimized to prevent adverse events. We attempted to define the optimal doses of midazolam and propofol required to achieve high levels of patient and dentist satisfaction. Methods One thousand dental patients, including those undergoing third molar extractions, were enrolled in this study. A dose of 1 mg of midazolam was administered at 1-minute intervals until adequate sedation was achieved. Propofol was then infused continuously to maintain the sedation level. Both the patients and the dentists were subsequently interviewed and asked to complete a questionnaire. A multivariate logistic regression analysis was used to examine the factors that contributed to patient and dentist satisfaction. Results The peak midazolam dose resulting in the highest percentage of patient satisfaction was 3 mg. Both a lower dose and a higher dose reduced patient satisfaction. Patient satisfaction increased with an increasing dosage of propofol up until 4 mg/kg/hr, reaching a peak of 78.6%. The peak midazolam dose resulting in the highest percentage of dentist satisfaction (78.8%) was 2 mg. Incremental propofol doses reduced dentist satisfaction, in contrast to their effect on patient satisfaction. The strongest independent predictors of patient satisfaction and dentist satisfaction were no intraoperative memory (OR, 5.073; 95% CI, 3.532–7.287; P<0.001) and unintentional movements by the patient (OR, 0.035; 95% CI, 0.012–0.104; P<0.001), respectively. No serious adverse events were reported. Conclusion We found that 3 mg of midazolam and 3 mg/kg/hr of propofol may be the optimal doses for maximizing both patient and dentist satisfaction. Although this level of sedation is relatively light, memory loss and an absence of unintentional patient movements can be expected without adverse events. PMID:28182732

Propofol and midazolam inhibit conscious memory processes very soon after encoding: an event-related potential study of familiarity and recollection in volunteers.

PubMed

Veselis, Robert A; Pryor, Kane O; Reinsel, Ruth A; Li, Yuelin; Mehta, Meghana; Johnson, Ray

2009-02-01

Intravenous drugs active via gamma-aminobutyric acid receptors to produce memory impairment during conscious sedation. Memory function was assessed using event-related potentials (ERPs) while drug was present. The continuous recognition task measured recognition of photographs from working (6 s) and long-term (27 s) memory while ERPs were recorded from Cz (familiarity recognition) and Pz electrodes (recollection recognition). Volunteer participants received sequential doses of one of placebo (n = 11), 0.45 and 0.9 microg/ml propofol (n = 10), 20 and 40 ng/ml midazolam (n = 12), 1.5 and 3 microg/ml thiopental (n = 11), or 0.25 and 0.4 ng/ml dexmedetomidine (n = 11). End-of-day yes/no recognition 225 min after the end of drug infusion tested memory retention of pictures encoded on the continuous recognition tasks. Active drugs increased reaction times and impaired memory on the continuous recognition task equally, except for a greater effect of midazolam (P < 0.04). Forgetting from continuous recognition tasks to end of day was similar for all drugs (P = 0.40), greater than placebo (P < 0.001). Propofol and midazolam decreased the area between first presentation (new) and recognized (old, 27 s later) ERP waveforms from long-term memory for familiarity (P = 0.03) and possibly for recollection processes (P = 0.12). Propofol shifted ERP amplitudes to smaller voltages (P < 0.002). Dexmedetomidine may have impaired familiarity more than recollection processes (P = 0.10). Thiopental had no effect on ERPs. Propofol and midazolam impaired recognition ERPs from long-term memory but not working memory. ERP measures of memory revealed different pathways to end-of-day memory loss as early as 27 s after encoding.

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers

PubMed Central

Volak, Laurie P; Hanley, Michael J; Masse, Gina; Hazarika, Suwagmani; Harmatz, Jerold S; Badmaev, Vladimir; Majeed, Muhammed; Greenblatt, David J; Court, Michael H

2013-01-01

Aims Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. Methods A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Results Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05–0.08 μm and 0.6 μm, respectively). Conclusion The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. PMID:22725836

Evaluation of the use of midazolam as a co-induction agent with ketamine for anaesthesia in sedated ponies undergoing field castration.

PubMed

Allison, A; Robinson, R; Jolliffe, C; Taylor, P M

2018-05-01

There are limited investigations comparing ketamine to a ketamine-midazolam co-induction. To compare quality and safety of general anaesthesia induced using ketamine alone with anaesthesia co-induced using ketamine and midazolam. Randomised, double blinded, placebo controlled trial. After i.v. detomidine (20 μg/kg) thirty-eight ponies undergoing field castration received either 0.06 mg/kg (0.6 mL/50 kg) midazolam (group M) or 0.6 mL/50 kg placebo (group P) with 2.2 mg/kg ketamine i.v. for anaesthetic induction. Quality of anaesthetic induction, endotracheal intubation, surgical relaxation and recovery were scored using combinations of simple descriptive and visual analogue scales. Time of sedation, induction, start of endotracheal intubation, first movement, sternal recumbency and standing were recorded, as were time, number and total quantity of additional i.v. detomidine and ketamine injections. Cardiorespiratory variables were assessed every 5 min. Adverse effects were documented. Data were tested for normality and analysed with a mixed model ANOVA, Fisher's exact test, unpaired Students' t test and Wilcoxon Rank-sum as appropriate; P<0.05 was considered significant. Group M had better scores for induction (P = 0.005), intubation (P<0.001) and surgical relaxation (P<0.001) and required fewer additional injections of detomidine and ketamine (P = 0.04). Time (minutes) from induction to first movement (P<0.001), sternal recumbency (P =< 0.001) and standing was longer (P = 0.05) in group M. Recoveries were uneventful with no difference in quality between groups (P = 0.78). Clinical study with noninvasive monitoring undertaken in field conditions. Ketamine-midazolam co-induction compared to ketamine alone improved quality of induction, ease of intubation and muscle relaxation without impacting recovery quality. © 2017 EVJ Ltd.

[Premedication in fiber optic bronchoscopy from the patient's and the physician's viewpoint--a randomized study for the comparison of midazolam and hydrocodone].

PubMed

Mendes de Leon, C; Bezel, R; Karrer, W; Brändli, O

1986-09-13

To evaluate side effects and patients' assessment of fiberoptic bronchoscopy under local anesthesia, 122 consecutive patients answered questions from an outside interviewer (an experienced psychiatrist) and not from the endoscopists themselves. The effect of premedication with midazolam (5 mg i.m.) and hydrocodonum (15 mg i.m.) was compared in a randomized study. In a multiple choice questionnaire 68% of all patients indicated considerable fear in the days before bronchoscopy. They were more afraid of the possible diagnosis of cancer (23%) than of dyspnea or asphyxiation (14%). Coughing is considered the worst side effect of bronchoscopy by 25% of patients (36% of the endoscopists) followed by dyspnea during insertion of the scope (21%) and discomfort during local anesthesia. Although the patients premedicated with midazolam are more sedated (p = 0.025 by physicians' assessment vs. p = 0.11 in patients' view), they cough more (p = 0.001 vs. p = 0.22) and usually tolerate the examination less well (p = 0.009 vs. p = 0.08) than patients premedicated with hydrocodonum. 42% of patients premedicated with midazolam had anterograde amnesia. Although they did not remember all the unpleasant side effects, only 77% said they would repeat the procedure with the same premedication, compared with 90% of patients premedicated with hydrocodonum (p = 0.08). Before and two hours after premedication the reaction times had not changed (optical sign, Wiener reaction device) and were identical in the two patient groups. At that time 37% of the patients premedicated with midazolam and 27% of those premedicated with hydrocodonum were still sleepy and could not be regarded as fit for any form of travel.

The influence of midazolam on heart rate arises from cardiac autonomic tones alterations in Burmese pythons, Python molurus.

PubMed

Lopes, Ivã Guidini; Armelin, Vinicius Araújo; Braga, Victor Hugo da Silva; Florindo, Luiz Henrique

2017-12-01

The GABA A receptor agonist midazolam is a compound widely used as a tranquilizer and sedative in mammals and reptiles. It is already known that this benzodiazepine produces small to intermediate heart rate (HR) alterations in mammals, however, its influence on reptiles' HR remains unexplored. Thus, the present study sought to verify the effects of midazolam on HR and cardiac modulation in the snake Python molurus. To do so, the snakes' HR, cardiac autonomic tones, and HR variability were evaluated during four different experimental stages. The first stage consisted on the data acquisition of animals under untreated conditions, in which were then administered atropine (2.5mgkg -1 ; intraperitoneal), followed later by propranolol (3.5mgkg -1 ; intraperitoneal) (cardiac double autonomic blockade). The second stage focused on the data acquisition of animals under midazolam effect (1.0mgkg -1 ; intramuscular), which passed through the same autonomic blockade protocol of the first stage. The third and fourth stages consisted of the same protocol of stages one and two, respectively, with the exception that atropine and propranolol injections were reversed. By comparing the HR of animals that received midazolam (second and fourth stages) with those that did not (first and third stages), it could be observed that this benzodiazepine reduced the snakes' HR by ~60%. The calculated autonomic tones showed that such cardiac depression was elicited by an ~80% decrease in cardiac adrenergic tone and an ~620% increase in cardiac cholinergic tone - a finding that was further supported by the results of HR variability analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of the effects of intravenous premedication: Midazolam, Ketamine, and combination of both on reducing anxiety in pediatric patients before general anesthesia

PubMed Central

Sajedi, Parvin; Habibi, Bashir

2015-01-01

Objective: In some medical circumstances, pediatric patients may need premedication for transferring to the operating room. In these situations, using intravenous premedication is preferred. We assessed the efficacy and safety of intravenous midazolam, intravenous ketamine, and combination of both to reduce the anxiety and improve behavior in children undergoing general anesthesia. Methods: In a double-blind randomized clinical trial, 90 pediatric patients aged 6 months to 6 years with American Society of Anesthesiologist grade I or II were enrolled. Before anesthesia, children were randomly divided into three groups to receive intravenous midazolam 0.1 mg/kg, or intravenous ketamine 1 mg/kg, or combination of half doses of both. Behavior types and sedation scores were recorded before premedication, after premedication, before anesthesia, and after anesthesia in the postanesthesia care unit. Anesthesia time, recovery duration, blood pressure, and heart rate were also recorded. For comparing distribution of behavior types and sedation scores among three groups, we used Kruskal–Wallis test, and for comparing mean and standard deviation of blood pressure and heart rates, we used analysis of variance. Findings: After premedication, children's behavior was significantly better in the combination group (P < 0.001). After anesthesia, behavior type was same among three groups (P = 0.421). Sedation scores among three groups were also different after premedication and the combination group was significantly more sedated than the other two groups (P < 0.001). Conclusion: Combination of 0.05 mg/kg of intravenous midazolam and 0.5 mg/kg of intravenous ketamine as premedication produced more deep sedation and more desirable behavior in children compared with each midazolam 0.1 mg/kg or ketamine 1 mg/kg. PMID:26645024

A comparison of ketamine + midazolam to propofol for procedural sedation for lumbar puncture in pediatric oncology by nonanesthesiologists-a randomized comparative trial.

PubMed

Chayapathi, Varsha; Kalra, Manas; Bakshi, Anita S; Mahajan, Amita

2018-05-04

Both ketamine-midazolam and propofol are frequently used in pediatric oncology units for procedural sedation. However, there are no prospective, randomized comparative trials (RCT) comparing the two groups when the procedure is performed by nonanesthesiologists. To compare ketamine + midazolam (group A) and propofol (group B) as sedative agents for intrathecal chemotherapy with regard to efficacy, side effects, time to induction, time to recovery, and smoothness of recovery. A partially-blinded RCT was conducted between August 2015 and March 2017 after gaining institutional ethics committee approval. Children aged 1-12 years requiring intravenous sedation for intrathecal chemotherapy were included. Patients were allocated to two treatment arms using computer-generated randomization tables, after obtaining written consent. The initial doses used were: ketamine 2 mg/kg, midazolam 0.2 mg/kg, and propofol 2.5 mg/kg, as per standard recommendations. The patient, parents, and person analyzing the data were blinded. Time to sedation, dose required, depth of sedation, vital parameters, time and smoothness of recovery, and emergence phenomena were documented. We enrolled 152 patients (76 each in group A and B). Nine patients had a failure of sedation (all in group B). Mean time to sedation and recovery was shorter in group B (P < 0.001). Transient drop in saturation was more frequent in group B, without statistical significance (P = 0.174). Mean depth of sedation was greater in group A (P < 0.001). Emergence symptoms were more frequently experienced in group A (P < 0.001). Ketamine-midazolam combination is safer and more effective. Propofol is faster in onset and recovery, and has smoother emergence with poor efficacy at recommended initial doses. © 2018 Wiley Periodicals, Inc.

Intramuscular midazolam versus intravenous lorazepam for the prehospital treatment of status epilepticus in the pediatric population.

PubMed

Welch, Robert D; Nicholas, Katherine; Durkalski-Mauldin, Valerie L; Lowenstein, Daniel H; Conwit, Robin; Mahajan, Prashant V; Lewandowski, Christopher; Silbergleit, Robert

2015-02-01

To examine the effectiveness of intramuscular (IM) midazolam versus intravenous (IV) lorazepam for the treatment of pediatric patients with status epilepticus (SE) in the prehospital care setting. This multicenter clinical trial randomized patients diagnosed with SE to receive either IM midazolam or IV lorazepam administered by paramedics in the prehospital care setting. Included in this secondary analysis were only patients younger than 18 years of age. Evaluated were the associations of the treatment group (IM vs. IV) with the primary outcome, defined as seizure cessation prior to emergency department (ED) arrival, and with patient characteristics, time to important events, and adverse events. Descriptive statistics and 99% confidence intervals (CIs) were used for the analysis. Of 893 primary study subjects, 120 met criteria for this study (60 in each treatment group). There were no differences in important baseline characteristics or seizure etiologies between groups. The primary outcome was met in 41 (68.3%) and 43 (71.7%) of subjects in the IM and IV groups, respectively (risk difference [RD] -3.3%, 99% CI -24.9% to 18.2%). Similar results were noted for those younger than 11 years (RD -1.3%, 99% CI -25.7% to 23.1%). Time from initiating the treatment protocol was shorter for children who received IM midazolam, mainly due to the shorter time to administer the active treatment. Safety profiles were similar. IM midazolam can be rapidly administered and appears to be safe and effective for the management of children with SE treated in the prehospital setting. The results must be interpreted in the context of the secondary analysis design and sample size of the study. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Degradation of benzodiazepines after 120 days of EMS deployment.

PubMed

McMullan, Jason T; Jones, Elizabeth; Barnhart, Bruce; Denninghoff, Kurt; Spaite, Daniel; Zaleski, Erin; Silbergleit, Robert

2014-01-01

EMS treatment of status epilepticus improves outcomes, but the benzodiazepine best suited for EMS use is unclear, given potential high environmental temperature exposures. To describe the degradation of diazepam, lorazepam, and midazolam as a function of temperature exposure and time over 120 days of storage on active EMS units. Study boxes containing vials of diazepam, lorazepam, and midazolam were distributed to 4 active EMS units in each of 2 EMS systems in the southwestern United States during May-August 2011. The boxes logged temperature every minute and were stored in EMS units per local agency policy. Two vials of each drug were removed from each box at 30-day intervals and underwent high-performance liquid chromatography to determine drug concentration. Concentration was analyzed as mean (and 95%CI) percent of initial labeled concentration as a function of time and mean kinetic temperature (MKT). 192 samples were collected (2 samples of each drug from each of 4 units per city at 4 time-points). After 120 days, the mean relative concentration (95%CI) of diazepam was 97.0% (95.7-98.2%) and of midazolam was 99.0% (97.7-100.2%). Lorazepam experienced modest degradation by 60 days (95.6% [91.6-99.5%]) and substantial degradation at 90 days (90.3% [85.2-95.4%]) and 120 days (86.5% [80.7-92.3%]). Mean MKT was 31.6°C (95%CI 27.1-36.1). Increasing MKT was associated with greater degradation of lorazepam, but not midazolam or diazepam. Midazolam and diazepam experienced minimal degradation throughout 120 days of EMS deployment in high-heat environments. Lorazepam experienced significant degradation over 120 days and appeared especially sensitive to higher MKT exposure.

Cough suppression during flexible bronchoscopy using combined sedation with midazolam and hydrocodone: a randomised, double blind, placebo controlled trial

PubMed Central

Stolz, D; Chhajed, P; Leuppi, J; Brutsche, M; Pflimlin, E; Tamm, M

2004-01-01

Background: Current British Thoracic Society guidelines do not recommend routinely the combined use of a benzodiazepine and opiate during flexible bronchoscopy (FB). A randomised, placebo controlled, double blind study was undertaken to determine whether hydrocodone in combination with midazolan improves cough suppression during FB without increasing the risk of desaturation. Methods: 120 patients were randomised to receive midazolam and 5 mg IV hydrocodone or midazolam and placebo with topical anaesthesia. Pulse oximetry was recorded continuously during FB. Bronchoscopists and nurses charted their perception of cough and the patients rated their discomfort during the procedure on a 10 cm visual analogue scale (VAS). Results: There was no significant difference between the two groups with regard to the indication for FB, duration of procedure (21 (11) min v 22 (10) min, p = 0.570), doses of supplemental lignocaine (171 (60) mg v 173 (66) mg, p = 0.766) and midazolam (4.5 (2.3) mg v 4.9 (2.7) mg, p = 0.309), lowest oxygen saturation (94.8 (2.7) v 94.9 (2.7), p = 0.433), and desaturations ⩽90%. Perception of cough by both the bronchoscopist and the nurse was significantly lower in the hydrocodone group (3 (0–10) and 3 (0–10)) than in the placebo group (6 (0–10) and 6 (0–10)), respectively (p = 0.001). According to the VAS scale, patients' tolerance was also significantly better with hydrocodone than with placebo (2 (0–8) v 3 (0–9), p = 0.043). Conclusion: The combination of midazolam and hydrocodone markedly reduces cough during FB without causing significant desaturation, especially when invasive diagnostic procedures are performed. PMID:15333854

Midazolam as an active placebo in 3 fentanyl-validated nociceptive pain models.

PubMed

Prosenz, Julian; Gustorff, Burkhard

2017-07-01

The use of inactive placebos in early translational trials of potentially analgesic compounds is discouraged because of the side-effect profiles of centrally acting analgesics. Therefore, benzodiazepines are used, although their use has not been validated in this context. Whether benzodiazepines confound the results of acute pain tests is unknown. Midazolam (0.06 mg/kg) as an active placebo was investigated in 3 nociceptive models that included contact heat, electrical pain, and pressure pain thresholds in 24 healthy volunteers. Fentanyl (1 μg/kg) served as an internal validator in this randomized, placebo (saline) controlled, 3-way cross-over trial. The primary outcome parameter (contact heat pain) was analyzed using a one-way, repeated measures analysis of variance and Tukey's post test. Midazolam did not reduce pain ([numeric rating scale], 0-100) in a statistically significant manner compared with placebo for the contact heat (mean difference -1.7, 95% confidence interval -10.6 to 7.3; P = 0.89) or electrical pain (4.3, -5.1 to 13.7; P = 0.51) test, nor did it raise the pressure pain thresholds (-28 kPa, -122; 64 kPa, P = 0.73). The width of the confidence intervals suggested that there were no clinically meaningful analgesic effects compared with the placebo. In contrast, the analgesic efficacy of fentanyl was effectively demonstrated in all 3 models (P < 0.01 vs midazolam and placebo). The findings of this study show that midazolam can be used as an active placebo in analgesic drug trials. Furthermore, the proposed models were simple to implement and very effective in detecting analgesia. The test battery can be used in translational trials for new compounds and comes with an active placebo and an optional active comparator.

Exacerbation of benign familial neonatal epilepsy induced by massive doses of phenobarbital and midazolam.

PubMed

Maeda, Tomoki; Shimizu, Miki; Sekiguchi, Kazuhito; Ishii, Atsushi; Ihara, Yukiko; Hirose, Shinichi; Izumi, Tatsuro

2014-08-01

Barbiturates and benzodiazepines are the first-line anticonvulsants for neonatal seizures. However, in immature brains, those drugs may lead to paradoxical neuronal excitation. A patient with benign familial neonatal epilepsy developed epileptic encephalopathy after massive doses of phenobarbital that were followed by a continuous infusion of midazolam on postnatal day 3. Electroencephalography revealed rhythmic delta activity in clusters with migrating epileptic foci. After discontinuation of both drugs, the patient's consciousness promptly improved and her electroencephalography normalized on postnatal day 5. This baby developed persistent electroencephalographic seizures due to massive doses of phenobarbital and midazolam. Clinicians should be aware of this anticonvulsant-induced paradoxical neuronal excitation and the uncoupling phenomenon, especially in individuals with benign familial neonatal epilepsy, who have low seizure thresholds. Copyright © 2014 Elsevier Inc. All rights reserved.

Turning up the Noise or Turning Down the Volume? On the Nature of the Impairment of Episodic Recognition Memory by Midazolam

ERIC Educational Resources Information Center

Malmberg, Kenneth J.; Zeelenberg, Rene; Shiffrin, Richard M.

2004-01-01

E. Hirshman, J. Fisher, T. Henthom, J. Amdt, and A. Passanname (2002) found that Midazolam disrupts the mirror-patterned word-frequency effect for recognition memory by reversing the typical hit-rate advantage for low-frequency words. They noted that this result is consistent with dual-process accounts (e.g., R. C. Atkinson & J. F. Juola, 1974; G.…

The Effect of the Protease Inhibitor Ritonavir on the Rate of Metabolism of Midazolam

DTIC Science & Technology

2000-01-03

regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington... depression in the clinical setting. Key Words: midazolam protease inhibitor ritonavir HIV AIDS metabolism THE EFFECT OF THE PROTEASE INHIBITORS...system as a depressant and is prescribed for preoperative sedation and amnesia of preoperative events (Omoigui, 1995). It is also used for

Midazolam conscious sedation in a large Danish municipal dental service for children and adolescents.

PubMed

Uldum, Birgitte; Hallonsten, Anna-Lena; Poulsen, Sven

2008-07-01

The aim of this study was to describe the introduction and the first six years use of midazolam for conscious sedation in a municipal dental service in Denmark. In 1998, all dentists were introduced to midazolam conscious sedation. A sedation chart was filled in for each session, and parents' assessment was obtained. In 2004, all clinical materials were collected. Six hundred and eighty sessions were performed; 63.7% of the children were between 2 and 6 years of age; 88.5% belonged to American Society of Anesthesiologists grade 1; 74.8% of the sedations performed used the oral route of administration. Restorations were performed during 60.3% of the sessions, and extractions during 38.4%. Complications during the sessions were rare, the most frequent being double vision (6.1%), hiccups (2.7%), and paradoxical reaction (2.0%). Using Wilton's sedation scale, 42.9% were calm and 27.7% were agitated during treatment, whereas after treatment 61.7% were calm; 80.4% of the parents were very positive towards this sedation method. Sedation with midazolam for dental treatment of children with dental fear and anxiety is a feasible and an efficient method with a low rate of complications. It can probably reduce the need for dental treatment under general anaesthesia.

[Palliative sedation].

PubMed

Verhagen, E H; Hesselmann, G M; Besse, T C; de Graeff, A

2005-02-26

Palliative sedation is the intentional lowering of the level of consciousness ofa patient in the last phase of life by means of the administration of sedatives. The objective of palliative sedation is to relieve severe physical or psychological suffering that is otherwise untreatable. Sedation is used in 12% of all patients dying in the Netherlands. Refractory delirium, dyspnoea or pain are the most common indications. If deep palliative sedation is used, the estimated life expectancy should be a few days to at most one week. Midazolam is used most often for continuous sedation, usually by subcutaneous infusion; if the response is insufficient, a combination of midazolam with levomepromazine or phenobarbital or monotreatment with propofol may be used. If continuous infusion is not desired or feasible, intermittent administration of midazolam, diazepam, lorazepam or chlorpromazine may be considered. Provided that it is used under the right circumstances, palliative sedation does not shorten life.

Turning up the noise or turning down the volume? On the nature of the impairment of episodic recognition memory by midazolam.

PubMed

Malmberg, Kenneth J; Zeelenberg, Rene; Shiffrin, Richard M

2004-03-01

E. Hirshman, J. Fisher, T. Henthom, J. Amdt, and A. Passanname (2002) found that Midazolam disrupts the mirror-patterned word-frequency effect for recognition memory by reversing the typical hit-rate advantage for low-frequency words. They noted that this result is consistent with dual-process accounts (e.g., R. C. Atkinson & J. F. Juola, 1974; G. Mandler, 1980; A. P. Yonelinas, 1994) of the word frequency effect for recognition memory (S. Joordens & W. E. Hockley. 2000; L. M. Reder et al. 2000). The present authors show that this finding is also consistent with a variety of single-process, retrieving effectively- from-memory (REM) models (R. M. Shiffrin & M. Steyvers, 1997), the simplest of which assumes that Midazolam decreases the accuracy with which memory traces are stored. These findings therefore do not discriminate between single- and dual-process models of recognition memory.

Ketamine rapidly relieves acute suicidal ideation in cancer patients: a randomized controlled clinical trial.

PubMed

Fan, Wei; Yang, HaiKou; Sun, Yong; Zhang, Jun; Li, Guangming; Zheng, Ying; Liu, Yi

2017-01-10

This study was designed to examine the rapid antidepressant effects of single dose ketamine on suicidal ideation and overall depression level in patients with newly-diagnosed cancer. Forty-two patients were enrolled into the controlled trial and randomized into two groups: ketamine group and midazolam group. Patients from the two groups received a sub-anesthetic dose of racemic ketamine hydrochloride or midazolam. Suicidal ideation score, measured with the Beck Scale and suicidal part of the Montgomery-Asberg Depression Rating Scale, significantly decreased on day 1 and day 3 in ketamine-treated patients when compared to those treated with midazolam. Consistently, overall depression levels measured using the Montgomery-Asberg Depression Rating Scale indicated a significant relief of overall depression on day 1 in ketamine-treated patients. Collectively, this study provides novel information about the rapid antidepressant effect of ketamine on acute depression and suicidal ideation in newly-diagnosed cancer patients.

Effects of sevoflurane anaesthesia on recovery in children: a comparison with halothane.

PubMed

Lapin, S L; Auden, S M; Goldsmith, L J; Reynolds, A M

1999-01-01

We prospectively studied one hundred ASA physical status I-II children, ages six months to six years, undergoing myringotomy surgery. Children were randomly assigned to one of four anaesthetic groups receiving either halothane or sevoflurane for anaesthesia and oral midazolam premedication or no premedication. We found that children anaesthetized with sevoflurane had significantly faster recovery times and discharge home times than those who received halothane. Patients given oral midazolam premedication had significantly longer recovery times, but no delay in discharge home compared with those not premedicated. However, children anaesthetized with sevoflurane and no premedication had an unacceptably high incidence (67%) of postoperative agitation. The use of oral midazolam preoperatively did decrease the amount of postoperative agitation seen with sevoflurane. We conclude that although sevoflurane does shorten recovery times, the degree of associated postoperative agitation makes it unacceptable as a sole anaesthetic for myringotomy surgery.

The cost effectiveness of licensed oromucosal midazolam (Buccolam(®)) for the treatment of children experiencing acute epileptic seizures: an approach when trial evidence is limited.

PubMed

Lee, Dawn; Gladwell, Daniel; Batty, Anthony J; Brereton, Nic; Tate, Elaine

2013-04-01

In the UK, two treatment options are used for acute epileptic seizures in the community-rectal diazepam and unlicensed buccal midazolam. In practice, the former is rarely used, with unlicensed buccal midazolam being widely recommended and prescribed by physicians. In September 2011, Buccolam(®) (licensed midazolam oromucosal solution) became the first medicine to receive a Paediatric-Use Marketing Authorization (PUMA) and it is indicated for the treatment of prolonged, acute, convulsive seizures by caregivers in the community for children (aged 6 months to <18 years) diagnosed with epilepsy. The approval process for a PUMA product differs from other marketing authorization processes and may be based upon small population subsets and may not, in some cases, require new safety or efficacy data to be generated; a similar situation to that seen for orphan drugs. This can lead to challenges when conducting economic evaluations. The aim of this study was to assess the cost effectiveness of Buccolam(®) for children with a diagnosis of epilepsy suffering prolonged, acute, convulsive seizures occurring in the UK community setting. DESIGN AND PERSPECTIVE: A hybrid model was developed according to a UK payer perspective. The model included a time-to-event simulation for the frequency and location of occurrence of seizures, along with a decision-tree model that assessed the treatment pathway when a seizure occured. The model compared treatment with Buccolam(®) with standard care in the community (95 % unlicensed buccal midazolam and 5 % rectal diazepam) or either treatment alone. The model was informed by data from a variety of sources, including clinical effectiveness estimates, and costs based on published UK data, using 2012-13 prices, where possible. To determine current practice and real-world effectiveness, a Delphi panel and a survey of parents of children with epilepsy were conducted. Buccolam(®) showed a reduction in costs of £2,939 compared with standard care, £14,269 compared with rectal diazepam alone and £886 compared with unlicensed buccal midazolam alone. Increases of 0.025, 0.082 and 0.013 quality-adjusted life-years, respectively, were also seen. Buccolam(®) remained dominant across a range of scenario analyses. This model demonstrates the possibility of constructing a thorough economic case when trial or real-world data are not available. The results of the model show Buccolam(®) to be cost saving compared with rectal diazepam due to a reduction in the need for ambulance callouts and hospital stays, and compared with unlicensed buccal midazolam, through reduced drug costs and wastage.

Antagonism of the Ethanol-Like Discriminative Stimulus Effects of Ethanol, Pentobarbital, and Midazolam in Cynomolgus Monkeys Reveals Involvement of Specific GABAA Receptor SubtypesS⃞

PubMed Central

Rogers, Laura S. M.; Grant, Kathleen A.

2009-01-01

The γ-aminobutyric acid (GABA)A receptors mediating the discriminative stimulus effects of ethanol were studied by comparing the potency of ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazol(1,5-a)benzodiazepine-3-carboxylate (Ro15-4513) and ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol(1,5-a)-benzodiazepine-3-carboxylate (flumazenil, Ro15-1788) to antagonize ethanol, pentobarbital (PB), and midazolam substitution for ethanol. Ro15-4513 has high affinity for receptors containing α4/6 and α5 subunits and lower affinity for α1, α2, and α3 subunits. Flumazenil is nonselective for GABAA receptors containing α1, α2, α3, and α5 subunits and has low affinity for α4/6-containing receptors. Male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) were trained to discriminate ethanol (1.0 or 2.0 g/kg i.g., 30-min pretreatment) from water. Ethanol, PB, and midazolam dose-dependently substituted for ethanol (80% ethanol-appropriate responding). Ro15-4513 (0.003–0.56 mg/kg i.m., 5-min pretreatment) shifted the ethanol, PB, and midazolam dose-response functions rightward in a vast majority of monkeys tested (15/15, 16/17, and 11/12, respectively). In contrast, flumazenil (0.30–10.0 mg/kg i.m., 5-min pretreatment) shifted the ethanol, PB, and midazolam dose-response functions rightward in 9 of 16, 12 of 16, and 7 of 9 monkeys tested, respectively. In the monkeys showing antagonism with both Ro15-4513 and flumazenil, ethanol and PB substitution were antagonized more potently by Ro15-4513 than by flumazenil, whereas midazolam substitution was antagonized with similar potency. There were no sex or training dose differences, with the exception that flumazenil failed to antagonize ethanol substitution in males trained to discriminate 2.0 g/kg ethanol. GABAA receptors with high affinity for Ro15-4513 (i.e., containing α4/6 and α5 subunits) may be particularly important mediators of the multiple discriminative stimulus effects of ethanol through GABAA receptor systems. PMID:19641166

Pharmacokinetic evaluations of the co-administrations of vandetanib and metformin, digoxin, midazolam, omeprazole or ranitidine.

PubMed

Johansson, Susanne; Read, Jessica; Oliver, Stuart; Steinberg, Mark; Li, Yan; Lisbon, Eleanor; Mathews, David; Leese, Philip T; Martin, Paul

2014-09-01

Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655). Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1-4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. Vandetanib + metformin increased metformin area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0-last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug-drug interactions.

GABAA-benzodiazepine receptors in the dorsomedial (Dm) telencephalon modulate restraint-induced antinociception in the fish Leporinus macrocephalus.

PubMed

Wolkers, Carla Patricia Bejo; Barbosa Junior, Augusto; Menescal-de-Oliveira, Leda; Hoffmann, Anette

2015-08-01

The possibility that fish experience pain has been denied based on the absence of the neural substrates to support this "experience". In this context, the identification of brain regions involved in nociception modulation could provide important insights regarding the processing of nociceptive information in fish. Our study evaluated the participation of the GABAA-benzodiazepine receptor in the dorsomedial (Dm) telencephalon in restraint-induced antinociception in the fish Leporinus macrocephalus through the microinjection of the anxiolytic drug midazolam. The microinjection of midazolam in the Dm did not alter the nocifensive response; however, this drug did block the inhibition of the nocifensive response to formaldehyde promoted by restraint stress. The fish that received midazolam (40nmol) microinjection prior to restraint (3 or 5min), followed by subcutaneous injection with formaldehyde presented a higher distance traveled than the fish that received saline microinjection. This effect might reflect the specific action of midazolam on benzodiazepine receptors in the Dm telencephalon, as pre-treatment with flumazenil, a benzodiazepine receptor antagonist, inhibited the effects of this drug. In the present study, we present the first evidence demonstrating a role for the dorsomedial telencephalic region in the modulation of stress-induced antinociception in fish, revealing new perspectives in the understanding of nociceptive information processing in this group. Copyright © 2015 Elsevier Inc. All rights reserved.

No clinically relevant CYP3A induction after St. John's wort with low hyperforin content in healthy volunteers.

PubMed

Mueller, Silke C; Majcher-Peszynska, Jolanta; Mundkowski, Ralf G; Uehleke, Bernhard; Klammt, Sebastian; Sievers, Hartwig; Lehnfeld, Romanus; Frank, Bruno; Thurow, Kerstin; Kundt, Guenther; Drewelow, Bernd

2009-01-01

Induction of CYP3A by St. John's wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. Midazolam AUC(0-infinity) slightly decreased from 124.0 +/- 62.5 ng/ml.h at baseline to 105.6 +/- 53.2 ng/ml.h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: -22.8 to 0.21). No significant change in midazolam C(max), t(1/2) and t(max) was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70-1.43. Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant.

Analysis of Oxygen Saturations Recorded During Dental Intravenous Sedations: A Retrospective Quality Assurance of 3500 Cases

PubMed Central

Viljoen, Andre; Byth, Karen; Coombs, Malcolm; Mahoney, Greg; Stewart, Douglas

2011-01-01

The death of a patient under sedation in New South Wales, Australia, in 2002 has again raised the question of the safety of dental sedation. This study sought answers to 2 questions: Can safe oxygen saturation levels (≥94%) be consistently maintained by a single operator/sedationist? Does the additional use of propofol, in subanesthetic doses, increase the risk of exposure to hypoxemia? Three thousand five hundred cases generated between 1996 and 2006 were randomly examined and divided into 2 subcohorts: 1750 patients were sedated with midazolam and fentanyl, and 1750 patients received propofol, in subanesthetic increments, in addition to midazolam and fentanyl. Initial sedation was established using midazolam and fentanyl in both subcohorts. The second subcohort received propofol during times of noxious stimulation. Patient exposure to 2 or more oxygen desaturations below 94% was uncommon. The variables that were significantly associated with low saturations were age, gender, and weight. Neither the dose of midazolam nor the additional use of propofol was a significant risk factor. ASA classification (I or II) was not a determinant of risk. The data, within the limitations of the study, showed that a single operator/sedationist, supported by a well-trained team of nurses, can consistently maintain safe oxygen saturation levels. The additional use of propofol did not increase exposure to hypoxemia. PMID:21882986

Moderate sedation helps improve future behavior in pediatric dental patients - a prospective study.

PubMed

Antunes, Denise Espíndola; Viana, Karolline Alves; Costa, Paulo Sucasas; Costa, Luciane Rezende

2016-10-24

There is little evidence on the long-term effects of pharmacological management in children undergoing dental treatment. This study aimed to assess children's behavior in consecutive dental sessions following oral rehabilitation using different pharmacological regimens for behavioral control. Participants were preschoolers who were previously treated for caries under one of the following: no sedative, oral sedation with midazolam, oral sedation with midazolam/ketamine, or general anesthesia. The children's behavior in the follow-up sessions was assessed using the Ohio State University Behavioral Rating Scale (OSUBRS); higher scores represented less cooperative behavior (range 5-20). Follow-up assessments were conducted on 50 children under four years old for up to 29 months. Data were analyzed by the Friedman/Wilcoxon tests and Cox regression model. OSUBRS mean (standard deviation) scores for the whole sample decreased from 11.9 (5.4) before treatment to 6.8 (3.2) at the final recall session (p < 0.001). Moderate sedation with midazolam (OR 2.9, 95%CI 1.2-6.9) or midazolam/ketamine (OR 4.3, 95%CI 1.6-11.4) improved children's future behavior. The general anesthesia group (n = 4) had a small sample size and the results should be considered with caution. Although invasive dental treatment negatively affected the child's behavior in the dental chair, they became more cooperative over time. Moderately sedated children showed better prospective behavior than those in the non-sedation group.

Effect of Oral Midazolam Premedication on Children's Co-operation Before General Anesthesia in Pediatric Dentistry.

PubMed

Kaviani, Nasser; Shahtusi, Mina; Haj Norousali Tehrani, Maryam; Nazari, Sara

2014-09-01

Premedication is expedient in reducing the psychological trauma from recalling the unpleasant pre-anesthetic phases, hence, inducing a trouble-free anesthesia. This study aimed to determine the effectiveness of oral midazolam in co-operation of the subjects before general anesthesia and in recalling the pre-anesthetic phases, performed on children candidate for dental treatment under general anesthesia. In this prospective clinical trial study, 62 healthy non-cooperative children, candidate for dental treatment under general anesthesia, were randomly divided into study and control groups. The children received 20ml orange juice, 20 minutes before starting the anesthesia. The juice of the test group contained 0.5mg/kg of midazolam and that of the control group included no medication. The induction and the maintenance process of anesthesia were similar in both groups. The manner of subjects when separated from parents, their cooperation during intravenous catheterization, and recalling the pre-anesthetic events were recorded. Data were analyzed by adopting chi-square and Mann-Whitney tests. Most of the children in the test group had a comfortable separation from parents, restful IV catheterization and 90% of the subjects did not recall the pre-anesthetic events. Under the circumstances of this study, it could be concluded that 0.5mg/kg oral midazolam premedication is effective for comfortable separation of children from parents and restful IV catheterization and also forgetting the pre-anesthetic events.

Susceptibility-Weighted Phase Imaging and Oxygen Extraction Fraction Measurement during Sedation and Sedation Recovery using 7T MRI.

PubMed

Goodwin, Jonathan A; Kudo, Kohsuke; Shinohe, Yutaka; Higuchi, Satomi; Uwano, Ikuko; Yamashita, Fumio; Sasaki, Makoto

2015-01-01

In this work, we demonstrate oxygen extraction fraction (OEF) measurement using 7T MRI with susceptibility-weighted imaging (SWI), in sedated and nonsedated adults. Ten healthy subjects (30.3 ± 4.5 years, 9 men, 1 woman) formed control (n = 5) and sedation groups (n = 5). Midazolam and propofol injection was administered to the same sedation group subjects during 2 different scanning sessions. Two-dimensional SPGR imaging was performed before, during, and twice after (propofol, +10, +30 minutes; midazolam, +10, +40 minutes) conscious sedation. The equivalent procedure was performed with the control group without sedation. After SWI analysis, change in OEF between scans was quantified, and parcelated ΔOEF maps were generated with 77 gray matter (GM)-containing volumes-of-interest (VOIs). Significant decreases in OEF were shown in 14 GM VOIs during sedation relative to the control group, most notably during midazolam sedation (P < .05). In contrast, no significant decrease was observed after 10 minutes and in only 4 VOIs after 40 minutes recovery. Significant change in ΔOEF during conscious sedation using midazolam and propofol could be measured using SWI at 7T in vivo. This may be a potentially useful approach for the noninvasive assessment of OEF in the brain on a clinical basis. Copyright © 2014 by the American Society of Neuroimaging.

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers.

PubMed

Volak, Laurie P; Hanley, Michael J; Masse, Gina; Hazarika, Suwagmani; Harmatz, Jerold S; Badmaev, Vladimir; Majeed, Muhammed; Greenblatt, David J; Court, Michael H

2013-02-01

Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 μM and 0.6 μM, respectively). The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Hot and Cold Drugs: National Park Service Medication Stability at the Extremes of Temperature.

PubMed

Armenian, Patil; Campagne, Danielle; Stroh, Geoff; Ives Tallman, Crystal; Zeng, William Z D; Lin, Thomas; Gerona, Roy R

2017-01-01

National Park Service (NPS) Parkmedics provide medical care in austere environments. The objective of this study was to evaluate the stability of specific medications used by Parkmedics at extremes of temperatures likely to be faced in the field. This is a bench research study conducted in the laboratory setting over a 4-week period. Parenteral medications were separated into 4 temperature exposure groups: A) 45°C (hot); B) -20°C (cold); C) hot then cold temperatures alternating weekly; and D) cold then hot temperatures alternating weekly. At study start and the end of each week, three aliquots from each group were sampled to determine the remaining drug concentration through liquid chromatography-quadrupole time-of-flight mass spectrometry (Agilent LC 1260- QTOF/MS 6550). Quantitative analysis was done using Agilent MassHunter Quantitative Analysis software. The mean drug concentration from triplicate aliquots was expressed as percentage of its baseline concentration to monitor the drug's stability during storage. Eight medications were analyzed (atropine, diphenhydramine, fentanyl, hydromorphone, midazolam, morphine, naloxone, ondansetron). Hydromorphone, morphine, and ondansetron showed the greatest stability, at above 90% of original concentration in all study arms. Diphenhydramine, fentanyl and midazolam showed heat independent degradation, degrading the same way regardless of heat exposure. By the end of the study period, 51-56% midazolam remained in all groups. Atropine and naloxone showed heat dependent degradation, degrading more when exposed to heat. Atropine had the most degradation, being undetectable after 4 weeks of heat exposure. We recommend that EMS providers replace atropine, naloxone, diphenhydramine, fentanyl, and midazolam frequently if they are practicing in low call volume or high-temperature environments. Further studies will be needed to determine if re-dosing midazolam, naloxone, and atropine is the appropriate clinical strategy in this setting if adequate clinical effect is not reached with a single dose.

The efficacy of adding dexamethasone, midazolam, or epinephrine to 0.5% bupivacaine in supraclavicular brachial plexus block.

PubMed

El-Baradey, Ghada F; Elshmaa, Nagat S

2014-11-01

The aim was to assess the effectiveness of adding either dexamethasone or midazolam in comparison with epinephrine addition to 0.5% bupivacaine in supraclavicular brachial plexus block. This is a prospective randomized controlled observer-blinded study. This study was carried out in Tanta University Hospital on 60 patients of both sexes; American Society of Anesthesiologists physical Status I and II, age range from 18 to 45 years undergo elective surgery to upper limb. All patients were anesthetized with ultrasound guided supraclavicular brachial plexus block and randomly divided into three groups (each group 20 patients) Group E (epinephrine): 30 mL bupivacaine 0.5%with 1:200,000 epinephrine (5 μg/mL). Group D (dexamethasone): 30 mL bupivacaine 0.5% and dexamethasone 8 mg. Group M (midazolam): 30 ml bupivacaine 0.5% and midazolam 50 μg/kg. The primary outcome measures were onset and duration of sensory and motor block and time to first analgesic request. The windows version of SPSS 11.0.1 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Data were presented in form of mean ± standard deviation multiple analysis of variance (ANOVA) was used to compare the three groups and Scheffe test was used after ANOVA. Power of significance P < 0.05 was considered to be statistically significant. Onset of sensory and motor block was significantly rapid (P < 0.05) in Groups D and M in comparison with Group E. Time of administration of rescue analgesic, duration of sensory and motor block showed significant increase (P < 0.05) in Group D in comparison with Group M which showed significant increase (P < 0.05) in comparison with Group E. In comparison with epinephrine and midazolam addition of dexamethasone to bupivacaine had rapid onset of block and longer time to first analgesic request with fewer side-effects.

Adaptation of non-linear mixed amount with zero amount response surface model for analysis of concentration-dependent synergism and safety with midazolam, alfentanil, and propofol sedation.

PubMed

Liou, J-Y; Ting, C-K; Teng, W-N; Mandell, M S; Tsou, M-Y

2018-06-01

The non-linear mixed amount with zero amounts response surface model can be used to describe drug interactions and predict loss of response to noxious stimuli and respiratory depression. We aimed to determine whether this response surface model could be used to model sedation with the triple drug combination of midazolam, alfentanil and propofol. Sedation was monitored in 56 patients undergoing gastrointestinal endoscopy (modelling group) using modified alertness/sedation scores. A total of 227 combinations of effect-site concentrations were derived from pharmacokinetic models. Accuracy and the area under the receiver operating characteristic curve were calculated. Accuracy was defined as an absolute difference <0.5 between the binary patient responses and the predicted probability of loss of responsiveness. Validation was performed with a separate group (validation group) of 47 patients. Effect-site concentration ranged from 0 to 108 ng ml -1 for midazolam, 0-156 ng ml -1 for alfentanil, and 0-2.6 μg ml -1 for propofol in both groups. Synergy was strongest with midazolam and alfentanil (24.3% decrease in U 50 , concentration for half maximal drug effect). Adding propofol, a third drug, offered little additional synergy (25.8% decrease in U 50 ). Two patients (3%) experienced respiratory depression. Model accuracy was 83% and 76%, area under the curve was 0.87 and 0.80 for the modelling and validation group, respectively. The non-linear mixed amount with zero amounts triple interaction response surface model predicts patient sedation responses during endoscopy with combinations of midazolam, alfentanil, or propofol that fall within clinical use. Our model also suggests a safety margin of alfentanil fraction <0.12 that avoids respiratory depression after loss of responsiveness. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Acid-base status and cardiovascular function in mink (Mustela vison) anaesthetized with ketamine/midazolam.

PubMed

Wamberg, S; Svendsen, P; Johansen, B

1996-01-01

Heart rate, arterial blood pressure and blood acid-base status were determined in 18 adult female mink (mean (+/- SEM) body weight 1052 +/- 34 g) during long-term anaesthesia with either controlled ventilation (n=12) or spontaneous respiration (n=6). Surgical anaesthesia was induced by intramuscular injection of ketamine hydrochloride (Ketaminol Vet, 40.0 +/- 1.7 mg/kg) and midazolam hydrochloride (Dormicum 2.8 +/- 0.1 mg/kg) and maintained for at least 5 h by continuous intravenous infusion of this drug combination in 0.9% saline. For all animals, the mean rates of infusion of ketamine and midazolam were 48.4 +/- 1.6 and 1.61 +/- 0.12 mg/h, respectively. Following continuous infusion of the anaesthetics in isotonic saline, at a rate of 20 ml/h, a moderate 'dilution acidosis' developed, which could be corrected by replacement of part of the saline with sodium bicarbonate to a final concentration of approximately 25 mmol NaHCO3 per litre. However, when the animals were allowed to breathe spontaneously, an increase in heart rate and a combined respiratory and metabolic acidosis occurred, due to severe respiratory depression. Apart from these effects and a few cases of increased salivation, no adverse effects over time were observed on the arterial blood acid-base status and cardiovascular function of the animals during ketamine/midazolam anaesthesia. It is concluded that the procedure described for long-term anaesthesia in mink is convenient and safe for acute physiological experiments in this species, provided normal body temperature and pulmonary gas exchange is sufficiently maintained. Thus, the need for an adequately controlled artificial ventilation is strongly emphasized. Finally, a proposal for the composition of an intravenous solution, containing ketamine and midazolam hydrochloride, and sodium bicarbonate in saline, suitable for long-term anaesthesia in adult mink is presented.

Rifampin modulation of xeno- and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes.

PubMed

Gufford, Brandon T; Robarge, Jason D; Eadon, Michael T; Gao, Hongyu; Lin, Hai; Liu, Yunlong; Desta, Zeruesenay; Skaar, Todd C

2018-04-01

Rifampin is a pleiotropic inducer of multiple drug metabolizing enzymes and transporters. This work utilized a global approach to evaluate rifampin effects on conjugating enzyme gene expression with relevance to human xeno- and endo-biotic metabolism. Primary human hepatocytes from 7 subjects were treated with rifampin (10 μmol/L, 24 hours). Standard methods for RNA-seq library construction, EZBead preparation, and NextGen sequencing were used to measure UDP-glucuronosyl transferase UGT, sulfonyltransferase SULT, N acetyltransferase NAT, and glutathione-S-transferase GST mRNA expression compared to vehicle control (0.01% MeOH). Rifampin-induced (>1.25-fold) mRNA expression of 13 clinically important phase II drug metabolizing genes and repressed (>1.25-fold) the expression of 3 genes ( P  <   .05). Rifampin-induced miRNA expression changes correlated with mRNA changes and miRNAs were identified that may modulate conjugating enzyme expression. NAT2 gene expression was most strongly repressed (1.3-fold) by rifampin while UGT1A4 and UGT1A1 genes were most strongly induced (7.9- and 4.8-fold, respectively). Physiologically based pharmacokinetic modeling (PBPK) was used to simulate the clinical consequences of rifampin induction of CYP3A4- and UGT1A4-mediated midazolam metabolism. Simulations evaluating isolated UGT1A4 induction predicted increased midazolam N-glucuronide exposure (~4-fold) with minimal reductions in parent midazolam exposure (~10%). Simulations accounting for simultaneous induction of both CYP3A4 and UGT1A4 predicted a ~10-fold decrease in parent midazolam exposure with only a ~2-fold decrease in midazolam N-glucuronide metabolite exposure. These data reveal differential effects of rifampin on the human conjugating enzyme transcriptome and potential associations with miRNAs that form the basis for future mechanistic studies to elucidate the interplay of conjugating enzyme regulatory elements.

Allosteric activation of midazolam CYP3A5 hydroxylase activity by icotinib - Enhancement by ketoconazole.

PubMed

Zhuang, XiaoMei; Zhang, TianHong; Yue, SiJia; Wang, Juan; Luo, Huan; Zhang, YunXia; Li, Zheng; Che, JinJing; Yang, HaiYing; Li, Hua; Zhu, MingShe; Lu, Chuang

2016-12-01

Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4. When co-incubated with selective CYP3A4 inhibitor CYP3cide or monoclonal human CYP3A4 inhibitory antibody in HLM, the activation was extended to ∼60%, suggesting CYP3A5 might be the isozyme involved. Further, the relative activation was enhanced to ∼270% in rhCYP3A5 in the presence of ketoconazole. The activation was substrate and pathway dependent and observed only in the formation of 1'-OH-midazolam, and not 4-OH-midazolam, 6β-OH-testosterone, or oxidized nifedipine. The activation requires the presence of cytochrome b5 and it is only observed in the liver microsomes of dogs, monkeys, and humans, but not in rats and mice. Kinetic analyses of 1'-OH-midazolam formation showed that ICO increased the V max values in HLM and rhCYP3A5 with no significant changes in K m values. By adding CYP3cide with ICO to the incubation, the V max values increased 2-fold over the CYP3cide control. Addition of ketoconazole with ICO alone or ICO plus CYP3cide resulted in an increase in V max values and decrease in K m values compared to their controls. This phenomenon may be attributed to a new mechanism of CYP3A5 heterotropic activation, which warrants further investigation. Copyright © 2016 Elsevier Inc. All rights reserved.

[Analysis of palliative sedation in hospitalised elderly patients: Effectiveness of a protocol].

PubMed

Mateos-Nozal, Jesús; García-Cabrera, Lorena; Montero Errasquín, Beatriz; Cruz-Jentoft, Alfonso José; Rexach Cano, Lourdes

2016-01-01

To measure changes in the practice of palliative sedation during agony in hospitalised elderly patients before and after the implementation of a palliative sedation protocol. A retrospective before-after study was performed in hospitalised patients over 65 years old who received midazolam during hospital admission and died in the hospital in two 3-month periods, before and after the implementation of the protocol. Non-sedative uses of midazolam and patients in intensive care were excluded. Patient and admission characteristics, the consent process, withdrawal of life-sustaining treatments, and the sedation process (refractory symptom treated, drug doses, assessment and use of other drugs) were recorded. Association was analysed using the Chi(2) and Student t tests. A total of 143 patients were included, with no significant differences between groups in demographic characteristics or symptoms. Do not resuscitate (DNR) orders were recorded in approximately 70% of the subjects of each group, and informed consent for sedation was recorded in 91% before vs. 84% after the protocol. Induction and maintenance doses of midazolam followed protocol recommendations in 1.3% before vs 10.4% after the protocol was implemented (P=.02) and adequate rescue doses were used in 1.3% vs 11.9% respectively (P=.01). Midazolam doses were significantly lower (9.86mg vs 18.67mg, P<.001) when the protocol was used than when it was not used. Ramsay sedation score was used in 8% vs. 12% and the Palliative Care Team was involved in 35.5% and 16.4% of the cases (P=.008) before and after the protocol, respectively. Use of midazolam slightly improved after the implementation of a hospital protocol on palliative sedation. The percentage of adequate sedations and the general process of sedation were mostly unchanged by the protocol. More education and further assessment is needed to gauge the effect of these measures in the future. Copyright © 2015 SEGG. Published by Elsevier Espana. All rights reserved.

Predicting the Best Fit: A Comparison of Response Surface Models for Midazolam and Alfentanil Sedation in Procedures With Varying Stimulation.

PubMed

Liou, Jing-Yang; Ting, Chien-Kun; Mandell, M Susan; Chang, Kuang-Yi; Teng, Wei-Nung; Huang, Yu-Yin; Tsou, Mei-Yung

2016-08-01

Selecting an effective dose of sedative drugs in combined upper and lower gastrointestinal endoscopy is complicated by varying degrees of pain stimulation. We tested the ability of 5 response surface models to predict depth of sedation after administration of midazolam and alfentanil in this complex model. The procedure was divided into 3 phases: esophagogastroduodenoscopy (EGD), colonoscopy, and the time interval between the 2 (intersession). The depth of sedation in 33 adult patients was monitored by Observer Assessment of Alertness/Scores. A total of 218 combinations of midazolam and alfentanil effect-site concentrations derived from pharmacokinetic models were used to test 5 response surface models in each of the 3 phases of endoscopy. Model fit was evaluated with objective function value, corrected Akaike Information Criterion (AICc), and Spearman ranked correlation. A model was arbitrarily defined as accurate if the predicted probability is <0.5 from the observed response. The effect-site concentrations tested ranged from 1 to 76 ng/mL and from 5 to 80 ng/mL for midazolam and alfentanil, respectively. Midazolam and alfentanil had synergistic effects in colonoscopy and EGD, but additivity was observed in the intersession group. Adequate prediction rates were 84% to 85% in the intersession group, 84% to 88% during colonoscopy, and 82% to 87% during EGD. The reduced Greco and Fixed alfentanil concentration required for 50% of the patients to achieve targeted response Hierarchy models performed better with comparable predictive strength. The reduced Greco model had the lowest AICc with strong correlation in all 3 phases of endoscopy. Dynamic, rather than fixed, γ and γalf in the Hierarchy model improved model fit. The reduced Greco model had the lowest objective function value and AICc and thus the best fit. This model was reliable with acceptable predictive ability based on adequate clinical correlation. We suggest that this model has practical clinical value for patients undergoing procedures with varying degrees of stimulation.

Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans

PubMed Central

Hohmann, Nicolas; Kocheise, Franziska; Carls, Alexandra; Burhenne, Jürgen; Haefeli, Walter E; Mikus, Gerd

2015-01-01

Aim We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. Methods In an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics. Results Dose-normalized AUC and Cmax were 37.1 ng ml−1 h [95% CI 35.5, 40.6] and 39.1 ng ml−1 [95% CI 30.4, 50.2] for the microdose and 39.0 ng ml−1 h [95% CI 36.1, 42.1] and 37.1 ng ml−1 [95% CI 26.9, 51.3] for the milligram dose. CLmet was 253 ml min−1 [95% CI 201, 318] vs. 278 ml min−1 [95% CI 248, 311] for intravenous doses and 1880 ml min−1 [95% CI 1590, 2230] vs. 2050 ml min−1 [95% CI 1720, 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [95% CI 20.0, 27.3] vs. 20.9% [95% CI 17.1, 25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [95% CI 0.39, 0.49] and 0.53 [95% CI 0.45, 0.63] and compared well with those for milligram doses (0.43 [95% CI 0.37, 0.49] and 0.61 [95% CI 0.53, 0.70]). Conclusion The pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity. PMID:25588320

Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans.

PubMed

Hohmann, Nicolas; Kocheise, Franziska; Carls, Alexandra; Burhenne, Jürgen; Haefeli, Walter E; Mikus, Gerd

2015-02-01

We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. In an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics. Dose-normalized AUC and Cmax were 37.1 ng ml(-1 ) h [95% CI 35.5, 40.6] and 39.1 ng ml(-1) [95% CI 30.4, 50.2] for the microdose and 39.0 ng ml(-1 ) h [95% CI 36.1, 42.1] and 37.1 ng ml(-1) [95% CI 26.9, 51.3] for the milligram dose. CLmet was 253 ml min(-1) [95% CI 201, 318] vs. 278 ml min(-1) [95% CI 248, 311] for intravenous doses and 1880 ml min(-1) [95% CI 1590, 2230] vs. 2050 ml min(-1) [95% CI 1720, 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [95% CI 20.0, 27.3] vs. 20.9% [95% CI 17.1, 25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [95% CI 0.39, 0.49] and 0.53 [95% CI 0.45, 0.63] and compared well with those for milligram doses (0.43 [95% CI 0.37, 0.49] and 0.61 [95% CI 0.53, 0.70]). The pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity. © 2014 The British Pharmacological Society.

Evaluation of intestinal metabolism and absorption using the Ussing chamber system equipped with intestinal tissue from rats and dogs.

PubMed

Miyake, Masateru; Kondo, Satoshi; Koga, Toshihisa; Yoda, Noriaki; Nakazato, Satoru; Emoto, Chie; Mukai, Tadashi; Toguchi, Hajime

2018-01-01

The purpose of this study was to evaluate the intestinal metabolism and absorption in a mini-Ussing chamber equipped with animal intestinal tissues, based on the transport index (TI). TI value was defined as the sum of drug amounts transported to the basal-side component (X corr ) and drug amounts accumulated in the tissue (T corr ), which are normalized by AUC of a drug in the apical compartment, as an index for drug absorption. Midazolam was used as a test compound for the evaluation of intestinal metabolism and absorption. The metabolite formulation of midazolam was observed in both rats and dogs. Ketoconazole inhibited the intestinal metabolism of midazolam in rats and improved its intestinal absorption to a statistically significant extent. Therefore, the mini-Ussing chamber, equipped with animal intestinal tissues, showed potential to use the evaluation of the intestinal metabolism and absorption, including the assessment of species differences. Copyright © 2017. Published by Elsevier B.V.

The role of midazolam-induced sedation in bone marrow aspiration/trephine biopsies.

PubMed

Mainwaring, C J; Wong, C; Lush, R J; Smith, J G; Singer, C R

1996-12-01

This study was undertaken in 102 adult patients to evaluate the safety and efficacy of intravenous (i.v.) midazolam in the setting of bone marrow aspiration and trephine biopsy (BMAT). Combined local anaesthetic (LA) and sedation was used in 87% of patients and 13% received LA alone. Amnesia occurred in all sedated patients with only 9% experiencing a mild degree of post-procedure pain. This contrasted sharply with the non-sedated group, in whom 85% had intense pain during the biopsy followed by protracted local discomfort in approximately 54%. Drowsiness and some psychomotor impairment were the only notable sedation-related side-effects in approximately 20%. None required assisted ventilation. There was a resounding patient preference for BMAT with sedation. Considering the ease of use, safety and efficacy of i.v. midazolam, the availability of flumazenil as a reversal agent and the undoubted positive effects on quality of life, we would advocate using it in BMAT provided that there were no contraindications.

Spatial-temporal patterns of electrocorticographic spectral changes during midazolam sedation

PubMed Central

Nishida, Masaaki; Zestos, Maria M.; Asano, Eishi

2015-01-01

Objective To better understand ‘when’ and ‘where’ wideband electrophysiological signals are altered by sedation. Methods We generated animation movies showing electrocorticography (ECoG) amplitudes at eight spectral frequency bands across 1.0 to 116 Hz, every 0.1 second, on three-dimensional surface images of 10 children who underwent epilepsy surgery. We measured the onset, intensity, and variance of each band amplitude change at given nonepileptic regions separately from those at affected regions. We also determined the presence of differential ECoG changes depending on the brain anatomy. Results Within 20 seconds following injection of midazolam, beta (16–31.5 Hz) and sigma (12–15.5 Hz) activities began to be multifocally augmented with increased variance in amplitude at each site. Beta-sigma augmentation was most prominent within the association neocortex. Augmentation of low-delta activity (1.0–1.5 Hz) was relatively modest and confined to the somatosensory-motor region. Conversely, injection of midazolam induced attenuation of theta (4.0–7.5 Hz) and high-gamma (64–116 Hz) activities. Conclusions Our observations support the notion that augmentation beta-sigma and delta activities reflects cortical deactivation or inactivation, whereas theta and high-gamma activities contribute to maintenance of consciousness. The effects of midazolam on the dynamics of cortical oscillations differed across regions. Significance Sedation, at least partially, reflects a multi-local phenomenon at the cortical level rather than global brain alteration homogeneously driven by the common central control structure. PMID:26613652

A Survey of Hospice and Palliative Care Physicians Regarding Palliative Sedation Practices.

PubMed

Lux, Michael R; Protus, Bridget McCrate; Kimbrel, Jason; Grauer, Phyllis

2017-04-01

Patients nearing the end of life may experience symptoms that are refractory to standard therapeutic options. Physicians may consider palliative sedation to relieve intolerable suffering. There is limited clinical literature regarding preferred medications for palliative sedation. To determine the preferred medications physicians use when implementing palliative sedation. An Internet-based, cross-sectional survey of hospice and palliative care physicians in the United States. A link to the survey was e-mailed to 3130 physician members of the American Academy of Hospice and Palliative Medicine, of which 381 physicians completed the survey. Physicians were not required to answer all questions. Nearly all (n = 335, 99%) respondents indicated that palliative sedation may be used (acceptable by 73% [n = 248] for refractory symptoms and acceptable by 26% [n = 87] only for imminently dying patients). Seventy-nine percent (n = 252) believed that opioids should not be used to induce palliative sedation but should be continued to provide pain control. Midazolam was the most commonly selected first-line choice for palliative sedation (n = 155, 42%). The most commonly reported second-line agents for the induction of palliative sedation were lorazepam, midazolam (for those who did not select midazolam as first-line agent), and phenobarbital with a reported preference of 20% (n = 49), 19% (n = 46), and 17% (n = 40), respectively. Of the physicians surveyed, 99% (n = 335) felt that palliative sedation is a reasonable treatment modality. Midazolam was considered a drug of choice for inducing and maintaining sedation, and opioids were continued for pain control.

Complications associated with intravenous midazolam and fentanyl sedation in patients undergoing minor oral surgery

PubMed Central

2017-01-01

Background Anxiety control remains an important concern in dental practice. We evaluated the incidence, nature, and sequelae of complications during and after minor oral surgeries performed under intravenous midazolam and fentanyl sedation using the titration technique. Methods The medical records of patients who had undergone minor oral surgeries under moderate intravenous midazolam and fentanyl sedation at our institution between January 1, 2015 and December 31, 2015 were retrospectively evaluated. Age, sex, body mass index, medical history, American Society of Anesthesiologists (ASA) classification, indications for sedation, amount of sedative used, surgical duration, and recovery time were evaluated for all patients. Results In total, 107 patients aged 9–84 years were included. ASA class I and class II were observed for 56.1% and 43.9% patients, respectively. Complications associated with sedation occurred in 11 (10.2%) patients. There were no serious adverse events. Oxygen saturation reached 95% during the procedure in six patients; this was successfully managed by stimulating the patients to take a deep breath. Two patients exhibited deep sedation and one exhibited paradoxical excitement. After the procedure, one patient experienced nausea without vomiting and one exhibited a prolonged recovery time. The surgical procedures were completed in all patients. Obesity was found to be significantly associated with sedation-related complications. Conclusions Our results suggest that complications associated with intravenous midazolam and fentanyl sedation using the titration technique for minor oral surgeries are mostly minor and can be successfully managed with no prolonged sequelae. PMID:29090250

Efficacy of chloral hydrate-hydroxyzine and chloral hydrate-midazolam in pediatric magnetic resonance imaging sedation.

PubMed

Fallah, Razieh; Fadavi, Nafiseh; Behdad, Shekofah; Fallah Tafti, Mahmoud

2014-01-01

Magnetic resonance imaging (MRI) is a useful diagnostic tool for the evaluation of congenital or acquired brain lesions. But, in all of less than 8-year-old children, pharmacological agents and procedural sedation should be used to induce motionless conditions for imaging studies. The purpose of this study was to compare the efficacy and safety of combination of chloral hydrate-hydroxyzine (CH+H) and chloral hydrate-midazolam (CH+M) in pediatric MRI sedation. In a parallel single-blinded randomized clinical trial, sixty 1-7-year-old children who underwent brain MRI, were randomly assigned to receive chloral hydrate in a minimum dosage of 40 mg/kg in combination with either 2 mg/kg of hydroxyzine or 0.5 mg/kg of midazolam. The primary outcomes were efficacy of adequate sedation (Ramsay sedation score of five) and completion of MRI examination. The secondary outcome was clinical side-effects. Twenty-eight girls (46.7%) and 32 boys (53.3%) with the mean age of 2.72±1.58 years were studied. Adequate sedation and completion of MRI were achieved in 76.7% of CH+H group. Mild and transient clinical side-effects, such as vomiting of one child in each group and agitation in 2 (6.6 %) children of CH+M group, were also seen. The adverse events were more frequent in CH+M group. Combinations of chloral hydrate-hydroxyzine and chloral hydrate-midazolam were effective in pediatric MRI sedation; however, chloral hydrate-hydroxyzine was safer.

Physiological and biochemical variables in captive tigers (Panthera tigris) immobilised with dexmedetomidine and ketamine or dexmedetomidine, midazolam and ketamine.

PubMed

Clark-Price, S C; Lascola, K M; Schaeffer, D J

2015-12-05

Physiological and biochemical variables in captive tigers (Panthera tigris) immobilised with dexmedetomidine and ketamine or dexmedetomidine, midazolam and ketamine were evaluated. Thirty tigers received either dexmedetomidine (0.025 mg/kg) and ketamine (3 mg/kg) (group DK) or dexmedetomidine (0.0125 mg/kg), midazolam (0.1 mg/kg) and ketamine (3 mg/kg) (group DMK). Heart rate, SPO2 and blood pressure were measured at five-minute intervals. Arterial pH, PO2, PCO2, glucose, K+ and arterial and venous lactate were measured at 15 and 45 minutes after immobilisation. A generalised linear mixed model was used for statistical comparison. There was no difference within or between groups at any time point for any measured variable. Measured PO2 was 73.2±17.5 mm Hg and SPO2 was 88.9±10.8 per cent. Systolic, mean and diastolic blood pressures were 170.5±48.4, 138.9±41.8 and 121.8±37.2 mm Hg, respectively. Venous lactate was higher than arterial lactate within groups at each time point. Seizure-like behaviour was observed in 25 per cent of tigers in group DK but not in group DMK. The addition of midazolam into a protocol for immobilisation of tigers did not result in a difference in any of the measured variables but may have prevented the development of seizure-like behaviour. British Veterinary Association.

Influence of Panax ginseng on Cytochrome P450 (CYP)3A and P-glycoprotein (Pgp) Activity in Healthy Subjects

PubMed Central

Malati, Christine Y.; Robertson, Sarah M.; Hunt, Jennifer D.; Chairez, Cheryl; Alfaro, Raul M.; Kovacs, Joseph A.; Penzak, Scott R.

2012-01-01

A number of herbal preparations have been shown to interact with prescription medications secondary to modulation of cytochrome P450 (CYP) and/or P-glycoprotein (P-gp). The purpose of this study was to determine the influence of Panax ginseng on CYP3A and P-gp function using the probe substrates midazolam and fexofenadine, respectively. Twelve healthy subjects (8 males) completed this open label, single sequence pharmacokinetic study. Healthy volunteers received single oral doses of midazolam 8 mg and fexofenadine 120 mg, before and after 28 days of P. ginseng 500 mg twice daily. Midazolam and fexofenadine pharmacokinetic parameter values were calculated and compared pre-and post P. ginseng administration. Geometric mean ratios (post-ginseng/pre-ginseng) for midazolam area under the concentration vs. time curve from zero to infinity (AUC0-∞), half life (T1/2), and maximum concentration (Cmax) were significantly reduced at 0.66 (0.55 – 0.78), 0.71 (0.53 – 0.90), and 0.74 (0.56 – 0.93), respectively. Conversely, fexofenadine pharmacokinetics were unaltered by P. ginseng administration. Based on these results, Panax ginseng appeared to induce CYP3A activity in the liver and possibly the gastrointestinal tract. Patients taking Panax ginseng in combination with CYP3A substrates with narrow therapeutic ranges should be monitored closely for adequate therapeutic response to the substrate medication. PMID:21646440

[Effects of pretreatment of lipid, midazolam and propofol on ropivacaine-induced convulsion and LD50 in rats].

PubMed

Lü, Xiao-lan; Wan, Fu-hong; Zuo, Yun-xia

2012-09-04

To assess the effects of lipid on ropivacaine-induced convulsion and LD50 in rats and compare with those of the traditional anticonvulsants midazolam and propofol. Protocol 1: A total of 120 SD rats (60 males, 60 females), weighing 200-300 g, were randomly assigned into 4 groups with equal males and females: lipid (L), midazolam (M) and propofol (P) and control (C). Rats were pretreated with 10 ml/kg lipid intravenously in group L, saline and 0.23 mg/kg midazolam (10 ml/kg in volume) sequentially in group M, saline and 4 mg/kg propofol (10 ml/kg in volume) in group P and saline 10 ml/kg in group C. Then ropivacaine 44 mg/kg (0.75%) was injected intraperitoneally into each rat. The convulsion rate in each group and the time of convulsion after ropivacaine injection were observed. Meanwhile, the plasma concentration of ropivacaine at the time of convulsion was measured. Protocol 2: Additional 100 male SD rats were used for the measurements of ropivacaine LD50 with different pretreatments including lipid, midazolam, propofol and saline through the up-and-down method. Rats were randomly assigned into 4 groups similarly as protocol 1. The doses of ropivacaine in each group were determined according to our pilot study and 6 dosage levels with the same interval ratio 8.5 was applied in each group. The doses of these pretreatment drugs and administration methods were similarly as protocol 1. The convulsion rate after 44 mg/kg ropivacaine ip injection was 43.3% in group C, 0% in group M, 13.3% in group P and 70% in group L. Lipid increased the convulsion rate significantly. The plasma concentration of ropivacaine at the time of convulsion was 1.65 ± 0.30 µg/kg in group C, 1.73 ± 0.14 µg/kg in group P and 3.45 ± 0.26 µg/kg in group L. The LD50 of ropivacaine in group C was 64.39 mg/kg, 88.40 mg/kg in group M and 90.20 mg/kg in group P and 55.45 mg/kg in group L. Midazolam and propofol not only decrease the convulsion rate of ropivacaine, but also increase its LD50. Lipid not only increases the convulsion rate of ropivacaine, but also decreases its LD50. The application of lipid for the prevention of local anesthetic toxicity has potential risks.

Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol.

PubMed

Tuk, Bert; van Gool, Toon; Danhof, Meindert

2002-06-01

The pharmacokinetic and pharmacodynamic interactions of ethanol with the full benzodiazepine agonist midazolam, the partial agonist bretazenil and the benzodiazepine BZ1 receptor subtype selective agonist zolpidem have been determined in the rat in vivo, using an integrated pharmacokinetic-pharmacodynamic approach. Ethanol was administered as a constant rate infusion resulting in constant plasma concentrations of 0.5 g/l. The pharmacokinetics and pharmacodynamics of midazolam, bretazenil, and zolpidem were determined following an intravenous infusion of 5.0, 2.5, and 18 mg/kg respectively. The amplitude in the 11.5-30 Hz frequency band of the EEG was used as measure of the pharmacological effect. For each of the benzodiazepines the concentration-EEG effect relationship could be described by the sigmoid Emax pharmacodynamic model. Significant differences in both EC50 and Emax were observed. The values of the EC50 were 76 +/- 11, 12 +/- 3, and 512 +/- 116 ng/ml for midazolam, bretazenil, and zolpidem respectively. The values of the Emax were 113 +/- 9, 44 +/- 3, and 175 +/- 10 microV/s. In the presence of ethanol the values of the EC50 of midazolam and zolpidem were reduced to approximately 50% of the original value. The values for Emax and Hill-factor were unchanged Due to a large interindividual variability no significant change in EC50 was observed for bretazenil. Analysis of the data on basis of a mechanism-based model showed only a decrease in the apparent affinity constant KPD for all three drugs, indicating that changes in EC50 can be explained entirely by a change in the apparent affinity constant KPD without concomitant changes in the efficacy parameter ePD and the stimulus-effect relationship. The findings of this study show that the pharmacodynamic interactions with a low dose of ethanol in vivo are qualitatively and quantitatively similar for benzodiazepine receptor full agonists, partial agonists, and benzodiazepine BZ1 receptor subtype selective agonists. This interaction can be explained entirely by a change in the affinity of the biological system for each benzodiazepine.

Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women.

PubMed

Floyd, Michael D; Gervasini, Guillermo; Masica, Andrew L; Mayo, Gail; George, Alfred L; Bhat, Kolari; Kim, Richard B; Wilkinson, Grant R

2003-10-01

CYP3A activity in adults varies between individuals and it has been suggested that this has a genetic basis, possibly related to variant alleles in CYP3A4 and CYP3A5 genes. Accordingly, genotype-phenotype associations were investigated under constitutive and induced conditions. Midazolam's systemic and oral clearances, and the erythromycin breath test (ERBT) were determined in 57 healthy subjects: 23 (11 men, 12 women) European- and 34 (14 men, 20 women) African-Americans. Studies were undertaken in the basal state and after 14-15 days pretreatment with rifampin. DNA was characterized for the common polymorphisms CYP3A4*1B, CYP3A5*3, CYP3A5*6 and CYP3A5*7 by direct sequencing, and for exon 21 and exon 26 variants of MDR1 by allele-specific, real-time polymerase chain reaction. In 95% of subjects, the basal systemic clearance of midazolam was unimodally distributed and variability was less than four-fold whereas, in 98% of the study population, oral clearance varied five-fold. No population or sex-related differences were apparent. Similar findings were observed with the ERBT. Rifampin pretreatment markedly increased the systemic (two-fold) and oral clearance (16-fold) of midazolam, and the ERBT (two-fold) but the variabilities were unchanged. No associations were noted between these phenotypic measures and any of the studied genotypes, except for oral clearance and its fold-increase after rifampin. These were related to the presence of CYP3A4*1B and the inversely linked CYP3A5*3 polymorphism, with the extent of induction being approximately 50% greater in CYP3A5*3 homozygotes compared to wild-type subjects. In most healthy subjects, variability in intestinal and hepatic CYP3A activity, using midazolam as an in-vivo probe, is modest and common polymorphisms in CYP3A4 and CYP3A5 do not appear to have important functional significance.

Randomised clinical trial: a 'nudge' strategy to modify endoscopic sedation practice.

PubMed

Harewood, G C; Clancy, K; Engela, J; Abdulrahim, M; Lohan, K; O'Reilly, C

2011-07-01

In behavioural economics, a 'nudge' describes configuration of a choice to encourage a certain action without taking away freedom of choice. To determine the impact of a 'nudge' strategy - prefilling either 3mL or 5mL syringes with midazolam - on endoscopic sedation practice. Consecutive patients undergoing sedation for EGD or colonoscopy were enrolled. On alternate weeks, midazolam was prefilled in either 3mL or 5mL syringes. Preprocedure sedation was administered by the endoscopist to achieve moderate conscious sedation; dosages were at the discretion of the endoscopist. Meperidine was not prefilled. Overall, 120 patients received sedation for EGD [59 (5mL), 61 (3mL)] and 86 patients were sedated for colonoscopy [38 (5mL), 48 (3mL)]. For EGDs, average midazolam dose was significantly higher in the 5-mL group (5.2mg) vs. 3-mL group (3.3mg), (P<0.0001); for colonoscopies, average midazolam dose was also significantly higher in the 5-mL group (5.1mg) vs. 3-mL group (3.3mg), (P<0.0001). There was no significant difference in mean meperidine dose (42.1mg vs. 42.8mg, P=0.9) administered to both colonoscopy groups. No adverse sedation-related events occurred; no patient required reversal of sedation. These findings demonstrate that 'nudge' strategies may hold promise in modifying endoscopic sedation practice. Further research is required to explore the utility of 'nudges' in impacting other aspects of endoscopic practice. © 2011 Blackwell Publishing Ltd.

Challenges in the treatment of convulsive status epilepticus.

PubMed

Zaccara, Gaetano; Giannasi, Gianfranco; Oggioni, Roberto; Rosati, Eleonora; Tramacere, Luciana; Palumbo, Pasquale

2017-04-01

Convulsive status epilepticus (CSE) is a medical emergency associated with high mortality and morbidity. The most recent definition of CSE is a convulsive seizure lasting more than 5min or consecutive seizures without recovery of consciousness. In adults, for the treatment of the early stages of CSE, diazepam, lorazepam or midazolam are the most common treatments, although the choice of agent seems less important than rapid treatment. Midazolam, when administered intramuscularly (best evidence), buccally, or nasally, is effective and safe in the pre-hospital setting. The antiepileptic drugs, phenytoin, valproate, levetiracetam and, more recently lacosamide, are used in CSE that persists after first-line treatments (established CSE). Phenytoin is more difficult to administer and is less well tolerated. Evidence of the efficacy of lacosamide is scarce. Anaesthetics are the drugs of choice for the treatment of refractory CSE (not responding to second-line drugs). Midazolam seems to be the best tolerated and is the most often used drug, followed by propofol and thiopental (pentobarbital in the USA). A few studies indicate that ketamine is effective with the possible advantage that it can be co-administered with other anaesthetics, such as midazolam or propofol. CSE becomes super-refractory after more than 24h of appropriate treatments and may last weeks. Several anaesthetics have been proposed but evidence is scarce. Autoimmune refractory CSE has been recently identified, and early treatment with immuno-modulatory agents (corticosteroids and IV immunoglobulins and also second-line agents such as cyclophosphamide and rituximab followed by chronic immunosuppressive treatment) is now recommended by many experts. Copyright © 2017. Published by Elsevier Ltd.

A Retrospective Medical Records Review of Risk Factors for the Development of Respiratory Tract Secretions (Death Rattle) in the Dying Patient.

PubMed

Kolb, Hildegard; Snowden, Austyn; Stevens, Elaine; Atherton, Iain

2018-05-09

Identification of risk factors predicting the development of death rattle. Respiratory tract secretions, often called death rattle, are among the most common symptoms in dying patients around the world. It is unknown whether death rattle causes distress in patients, but it has been globally reported that distress levels can be high in family members. Although there is a poor evidence base, treatment with antimuscarinic medication is standard practice worldwide and prompt intervention is recognised as crucial for effectiveness. The identification of risk factors for the development of death rattle would allow for targeted interventions. A case ̶ control study was designed to retrospectively review two hundred consecutive medical records of mainly cancer patients who died in a hospice inpatient setting between 2009 - 2011. Fifteen potential risk factors including the original factors weight, smoking, final opioid dose and final Midazolam dose were investigated. Binary logistic regression to identify risk factors for death rattle development. Univariate analysis showed death rattle was significantly associated with final Midazolam doses and final opioid doses, length of dying phase and anticholinergic drug load in the pre-terminal phase. In the final logistic regression model only Midazolam was statistically significant and only at final doses of 20 mg/24hrs or over (OR 3.81 CI 1.41-10.34). Dying patients with a requirement for a high dose of Midazolam have an increased likelihood of developing death rattle. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Isolation and Identification of Intestinal CYP3A Inhibitors from Cranberry (Vaccinium macrocarpon) using Human Intestinal Microsomes

PubMed Central

Kim, Eunkyung; Sy-Cordero, Arlene; Graf, Tyler N.; Brantley, Scott J.; Paine, Mary F.; Oberlies, Nicholas H.

2010-01-01

Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, a cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC50) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and <10 μM, respectively, using HIM as the enzyme source and was 2.8, 4.3, and <10 μM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study. PMID:20717876

Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes.

PubMed

Kim, Eunkyung; Sy-Cordero, Arlene; Graf, Tyler N; Brantley, Scott J; Paine, Mary F; Oberlies, Nicholas H

2011-02-01

Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study. © Georg Thieme Verlag KG Stuttgart · New York.

Changes in blood glucose level during and after light sedations using propofol-fentanyl and midazolam-fentanyl in diabetic patients who underwent cataract surgery.

PubMed

Khalighinejad, Pooyan; Rahimi, Mojtaba; Naghibi, Khosro; Niknam, Negar

2015-01-01

Surgeries may trigger the stress response which leads to changes in blood glucose level, and studies suggest that different sedation and anesthesia methods have different effects on blood glucose level. The aim of this study was to investigate changes of blood glucose levels in diabetic patients and compare them in two sedation methods of propofol + fentanyl and midazolam + fentanyl. Totally, 80 diabetic candidates for cataract surgery who had all the inclusion criteria, underwent cataract surgery using two methods of propofol (1 mg/kg/h) + fentanyl (2 μg/kg) (Group P) and midazolam (0.03 mg/kg) + fentanyl (2 μg/kg) (Group M) for light sedation. In the end, 70 patients (Group P n = 35 and Group M n = 35) remained in the study. Patients' blood glucose levels, vital signs, and hemodynamic data were assessed 30 min prior to the surgery, each 15 min during surgery and at the end of surgery. Hemodynamic parameters did not have a statistically significant difference between the two groups mean blood glucose level in Group M was 149.15 mg/dl and in Group P was 149.2 mg/dl, and based on repeated measures analysis of variance test, significant differences were not observed between the two groups (P = 0.99). T-test showed no significant differences in the blood glucose level at any time of the study between the two groups. Light sedation methods of propofol + fentanyl and midazolam + fentanyl did not have any differences in alteration of blood glucose level.

Prophylactic use of intravenous ondansetron versus ketamine - midazolam combination for prevention of shivering during spinal anesthesia: A randomized double-blind placebo-controlled trial

PubMed Central

Safavi, Mohammadreza; Honarmand, Azim; Mohammadsadeqie, Sara

2015-01-01

Background: The aim of this study was to compare the efficacy intravenous (IV) ondansetron with ketamine plus midazolam for the prevention of shivering during spinal anesthesia (SA). Materials and Methods: Ninety patients, aged 18–65 years, undergoing lower extremity orthopedic surgery were included in the present study. SA was performed in all patients with hyperbaric bupivacaine 15 mg. The patients were randomly allocated to receive normal saline (Group C), ondansetron 8 mg IV (Group O) or ketamine 0.25 mg/kg IV plus midazolam 37.5 μg/kg IV (Group KM) immediately after SA. During surgery, shivering scores were recorded at 5 min intervals. The operating room temperature was maintained at 24°C. Results: The incidences of shivering were 18 (60%) in Group C, 6 (20%) in Group KM and 8 (26.6%) in Group O. The difference between Groups O and Group KM with Group C was statistically significant (P < 0.05). No significant difference was noted between Groups KM with Group O in this regard (P > 0.05). Peripheral and core temperature changes throughout surgery were not significantly different among three groups (P > 0.05). Incidence (%) of hallucination was not significantly different between the three groups (0, 3.3, 0 in Group O, Group KM, Group C respectively, P > 0.05). Conclusion: Prophylactic use of ondansetron 8 mg IV was comparable to ketamine 0.25 mg/kg IV plus midazolam 37.5 μg/kg IV in preventing shivering during SA. PMID:26605236

Dexmedetomidine versus midazolam as adjuvants to intrathecal bupivacaine: A clinical comparison.

PubMed

Shukla, Usha; Prabhakar, Tallamraju; Malhotra, Kiran; Srivastava, Dheeraj

2016-01-01

Trials are being carried out to identify an adjuvant to intrathecal bupivacaine that preferably potentiates postoperative analgesia. This prospective, randomized, double-blind study was aimed to compare the onset and duration of sensory and motor block, postoperative analgesia and adverse effects of dexmedetomidine or midazolam given with 0.5% hyperbaric bupivacaine for spinal anesthesia. A total of 80 patients, scheduled for vaginal hysterectomies, were randomly allocated to Group D (n = 40) to receive intrathecally 3.0 mL 0.5% hyperbaric bupivacaine +5 ug dexmedetomidine in 0.5 mL of normal saline; and Group M (n = 40) to receive 3 mL of 0.5% hyperbaric bupivacaine +2 mg midazolam in 0.4 mL (5 mg/mL) +0.1 mL normal saline. The onset, duration of sensory and motor block, time to first postoperative analgesia and side effects were noted. Power and Sample size (PS) version 3.0.0.34 was used for power and sample size calculation. Statistical analysis was performed using Microsoft (MS) Office Excel software with the Student's t-test and Chi-square test (level of significance P = 0.05). Duration of sensory, motor blockade and time to the first requirement of analgesia were significantly higher in Group D. Postoperative visual analog scale was significantly less in Group D than Group M. Both groups were similar with respect to sedation, hemodynamic variables and side-effects. Intrathecal dexmedetomidine was better adjuvant than midazolam as it produces significantly longer duration of sensory block, reduced doses of postoperative analgesic agents with comparable side-effects.

Analgesia after feline ovariohysterectomy under midazolam-medetomidine-ketamine anaesthesia with buprenorphine or butorphanol, and carprofen or meloxicam: a prospective, randomised clinical trial.

PubMed

Polson, Sally; Taylor, Polly M; Yates, David

2012-08-01

One hundred female cats undergoing routine ovariohysterectomy under midazolam-medetomidine-ketamine anaesthesia were included in a blinded, randomised, prospective clinical study to compare postoperative analgesia produced by four analgesic drug combinations given preoperatively (n = 25 per group). A secondary aim was to assess the effects in kittens and pregnant animals. Buprenorphine 180 µg/m(2) or butorphanol 6 mg/m(2) were given with either carprofen 4 mg/kg (groups BUPC and BUTC, respectively) or meloxicam 0.3 mg/kg (groups BUPM or BUTM, respectively). Medetomidine was not antagonised. A simple, descriptive scale (SDS; 0-4), a dynamic and interactive visual analogue scale (DIVAS; 0-100 mm) and mechanical nociceptive thresholds (MT; 2.5-mm diameter probe) were used to evaluate postoperative pain. All pain scores were low (DIVAS <10 mm, SDS <2 and MT >10 N) and there were no significant differences between the groups. It was concluded that all protocols provided adequate analgesia and when used with midazolam-medetomidine-ketamine are effective for routine feline ovariohysterectomy.

The effectiveness of flumazenil in reversing the sedation and amnesia produced by intravenous midazolam.

PubMed

Ochs, M W; Tucker, M R; Owsley, T G; Anderson, J A

1990-03-01

In this double-blind study 31 outpatients undergoing third molar extraction were randomly assigned to one of two groups. All patients were sedated with intravenous midazolam (IV) by titration method. The flumazenil group (n = 20) received an average of 0.8 +/- 0.17 mg of flumazenil IV. The placebo patients (n = 11) each received 10 mL of normal saline. By both observer and patient alertness ratings, patients receiving flumazenil appeared significantly more alert than placebo patients at 5, 15, 30, and 60 minutes following reversal. After reversal the flumazenil group had significantly higher scores than the placebo group at all intervals through 60 minutes. All the patients receiving flumazenil were able to walk without assistance at 5 minutes, compared with only one patient in the placebo group, and more patients in the flumazenil group recognized the picture card shown to them at 5, 15, 30, and 60 minutes postreversal. Flumazenil is effective in terminating the amnestic properties of midazolam, but this appears to occur to a lesser extent than the reversal of its sedative properties.

Evaluation of the anxiolytic and antidepressant effects of asiatic acid, a compound from Gotu kola or Centella asiatica, in the male Sprague Dawley rat.

PubMed

Ceremuga, Tomás Eduardo; Valdivieso, Debra; Kenner, Catherine; Lucia, Amy; Lathrop, Keith; Stailey, Owen; Bailey, Heather; Criss, Jonathan; Linton, Jessica; Fried, Jordan; Taylor, Andrew; Padron, Gina; Johnson, Arthur Don

2015-04-01

Herbal medication use continues to rise and interactions with existing medications propose risks and may have significant effects and consequences on the administration of anesthesia. The purpose of this study was to investigate the anxiolytic and antidepressant effects of asiatic acid and its potential modulation of the γ-aminobutyric acid (GABAA) receptor. Fifty-five male Sprague Dawley rats were divided into 5 groups: vehicle (DMSO), asiatic acid (AA), midazolam, or a combination of flumazenil + AA or midazolam + AA, and injected intraperitoneally 30 minutes prior to testing. The rats were tested on the Elevated Plus Maze (EPM) and the Forced Swim Test (FST). Data were analyzed using a two-tailed multivariate analysis of variance (MANOVA). Significance was found regarding the ratio of open arm time, maximum speed, and time spent mobile in the AA group and the midazolam + AA group (P < .05). Flumazenil decreased the anxiolytic effects, suggesting that AA modulates the benzodiazepine site on the GABAA receptor. Further studies are recommended to determine the efficacy of prolonged treatment for anxiety and depression.

Anaesthesia with medetomidine-ketamine-isoflurane with and without midazolam, in eight captive chimpanzees (Pan troglodytes) premedicated with oral zuclopenthixol.

PubMed

Adami, C; Wenker, C; Hoby, S; Morath, U; Bergadano, A

2013-08-01

In 8 captive adult chimpanzees of various ages premedicated with oral zuclopenthixol anaesthesia was induced intramuscularly with a combination of medetomidine and ketamine (40 or 50 µg/kg and 5 mg/kg, IM, respectively), with and without midazolam (0.05 mg/kg), and maintained with isoflurane in oxygen. At the end of the procedure, sedation was reversed with atipamezole (0.25 mg/kg, IM) and sarmazenil (0.005 mg/kg, IM) when midazolam had been administered. Oral zuclopenthixol resulted in tranquillization of the whole group and only one animal required a second dart injection to achieve adequately deep anaesthesia. Effective and reliable anaesthesia was achieved in all apes; the depth of hypnosis was stable and sudden arousal did not occur. Physiological parameters remained within normal ranges in the majority of the animals; however, manageable anaesthesia-related complications, namely apnoea after darting, hypotension, hypoventilation, hypoxemia and prolonged recovery, occurred in 6 out of 8 animals. The use of monitoring devices was essential to guarantee adequate management of these complications.

Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: Comparison of a milk thistle and black cohosh product to rifampin and clarithromycin

PubMed Central

Gurley, Bill; Hubbard, Martha A.; Williams, D. Keith; Thaden, John; Tong, Yudong; Gentry, W. Brooks; Breen, Philip; Carrier, Danielle J.; Cheboyina, Shreekar

2007-01-01

Phytochemical-mediated modulation of cytochrome P450 enzymes (CYPs) may underlie many herb-drug interactions. This study’s purpose was to assess the effects of milk thistle and black cohosh supplementation on CYP3A activity and compare them to a clinically recognized inducer, rifampin, and inhibitor, clarithromycin. Healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg) or black cohosh (80 mg) supplement for 14 days. Subjects also received rifampin (600 mg) and clarithromycin (1000 mg) for 7 days as positive controls for CYP3A induction and inhibition, respectively. Midazolam was administered orally before and after each supplementation and control period. The effects of milk thistle, black cohosh, rifampin, and clarithromycin on midazolam pharmacokinetics were determined using noncompartmental techniques. Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics were unaffected by milk thistle or black cohosh. Milk thistle and black cohosh appear to have no clinically relevant effect on CYP3A activity in vivo. PMID:16432272

The effects of central administration of physostigmine in two models of anxiety.

PubMed

Sienkiewicz-Jarosz, H; Maciejak, Piotr; Krzaścik, Paweł; Członkowska, Agnieszka I; Szyndler, Janusz; Bidziński, Andrzej; Kostowski, Wojciech; Płaźnik, Adam

2003-05-01

The effects of intracerebroventricular and intraseptal (the medial septum) administration of a prototypical acetylcholinesterase inhibitor (AChE-I), physostigmine, and a classic benzodiazepine midazolam on rat behavior in the open field test of neophobia and in the conditioned fear test (freezing reaction) were examined in rats. In the open field test of neophobia midazolam and physostigmine increased at a limited dose range, rat exploratory activity, after intracerebroventricular injection. Physostigmine produced in addition the hyperlocomotory effect. Following intraseptal injections, only physostigmine selectively prolonged the time spent by animals in the central sector of the open field. In the model of a conditioned fear, both midazolam and physostigmine inhibited rat freezing reaction to the aversively conditioned context after intracerebroventricular, but not after intraseptal, pretrial drug administration. The presented data support the notion about the selective anxiolytic-like effects of some AChE-Is. It appears, therefore, that the calming and sedative effects of AChE-Is observed in patients with Alzheimer's disease may be directly related to their anxiolytic action, independent of an improvement in cognitive functions, which in turn may decrease disorientation-induced distress and anxiety.

Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin.

PubMed

Gurley, Bill; Hubbard, Martha A; Williams, D Keith; Thaden, John; Tong, Yudong; Gentry, W Brooks; Breen, Philip; Carrier, Danielle J; Cheboyina, Shreekar

2006-02-01

Phytochemical-mediated modulation of cytochrome P450 enzymes (CYPs) may underlie many herb-drug interactions. This study's purpose was to assess the effects of milk thistle and black cohosh supplementation on CYP3A activity and compare them to a clinically recognized inducer, rifampin, and inhibitor, clarithromycin. Healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg) or black cohosh (80 mg) supplement for 14 days. Subjects also received rifampin (600 mg) and clarithromycin (1000 mg) for 7 days as positive controls for CYP3A induction and inhibition, respectively. Midazolam was administered orally before and after each supplementation and control period. The effects of milk thistle, black cohosh, rifampin, and clarithromycin on midazolam pharmacokinetics were determined using noncompartmental techniques. Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by milk thistle or black cohosh. Milk thistle and black cohosh appear to have no clinically relevant effect on CYP3A activity in vivo.

Dexmedetomidine: a review of its use for sedation in mechanically ventilated patients in an intensive care setting and for procedural sedation.

PubMed

Hoy, Sheridan M; Keating, Gillian M

2011-07-30

Dexmedetomidine (Precedex®), a pharmacologically active dextroisomer of medetomidine, is a selective α(2)-adrenergic receptor agonist. It is indicated in the US for the sedation of mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of dexmedetomidine in randomized, double-blind, placebo-controlled, multicentre studies in these indications. Post-surgical patients in an intensive care setting receiving dexmedetomidine required less rescue sedation with intravenous propofol or intravenous midazolam to achieve and/or maintain optimal sedation during the assisted ventilation period than placebo recipients, according to two randomized, double-blind, multinational studies. Moreover, significantly more dexmedetomidine than placebo recipients acquired and/or maintained optimal sedation without rescue sedation. Sedation with dexmedetomidine was also effective in terms of the total dose of morphine administered, with dexmedetomidine recipients requiring less morphine than placebo recipients; with regard to patient management, dexmedetomidine recipients were calmer and easier to arouse and manage than placebo recipients. Intravenous dexmedetomidine was effective as a primary sedative in two randomized, double-blind, placebo-controlled, multicentre studies in adult patients undergoing awake fibre-optic intubation or a variety of diagnostic or surgical procedures requiring monitored anaesthesia care. In one study, significantly fewer dexmedetomidine than placebo recipients required rescue sedation with intravenous midazolam to achieve and/or maintain optimal sedation; conversely, in another study, rescue sedation with intravenous midazolam was not required by significantly more dexmedetomidine than placebo recipients. Primary sedation with intravenous dexmedetomidine was also effective in terms of the secondary efficacy endpoints, including the mean total dose of midazolam and fentanyl administered and the percentage of patients requiring further sedation (in addition to dexmedetomidine or placebo and midazolam), with, for the most part, significant between-group differences observed in favour of dexmedetomidine over placebo. In general, no significant differences were observed between the dexmedetomidine and placebo treatment groups in the anaesthesiologists' assessment of ease of intubation, haemodynamic stability, patient cooperation and/or respiratory stability. Intravenous dexmedetomidine is generally well tolerated when utilized in mechanically ventilated patients in an intensive care setting and for procedural sedation in non-intubated patients. Dexmedetomidine is associated with a lower rate of postoperative delirium than midazolam or propofol; it is not associated with respiratory depression. While dexmedetomidine is associated with hypotension and bradycardia, both usually resolve without intervention. Thus, intravenous dexmedetomidine provides a further option as a short-term (<24 hours) primary sedative in mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures.

Sub-clinical hepatic encephalopathy in cirrhotic patients is not aggravated by sedation with propofol compared to midazolam: a randomized controlled study.

PubMed

Khamaysi, Iyad; William, Nseir; Olga, Alexandrov; Alex, Isakson; Vladimir, Mysh; Kamal, Dabbah; Nimer, Assy

2011-01-01

The risk of exacerbating sub-clinical hepatic encephalopathy (HE) by propofol has not been established. The aim of this study is to determine whether the use of propofol, for upper endoscopy in patients with cirrhosis, precipitates sub-clinical HE. Sixty-one patients with compensated HCV and HBV cirrhosis (CP score 5-6) were randomly selected and divided into two groups (intent-to-treat population) matched for age, gender, and BMI. The first group received a single propofol sedation (N = 31, age 57 ± 12, dose range 70-100 mg/procedure) and the second group (N = 30, age 56 ± 12, dose 3-6 mg/procedure) received a single midazolam sedation, all done by an anesthesiologist. All patients completed number connection test (NCT), cognitive function score, time to recovery, time to discharge sheets, and hemodynamic parameters before sedation, and at discharge from the endoscopy unit, 1h post-procedure. Thirty control subjects without cirrhosis were matched to the cirrhotic patients who received sedation with regard to age, gender, BMI, and education level. A total of 58/61 cirrhotic patients (95%) had sub-clinical encephalopathy before the endoscopy (mean NCT 84.7 ± 77 s, normal < 30 s). No patient developed overt HE after sedation. There were no differences between groups in the incidence of adverse effects, cognitive function, MELD score, CP score, oxygen saturation, or respiratory and heart rates before and after sedation. Propofol did not exacerbate minimal HE when compared to midazolam (NCT changed from 87.5 ± 62 s prior to sedation to 74.2 ± 58 s after sedation in the propofol group versus 72.8 ± 62 s before to 85.6 ± 72 s after sedation in the midazolam group; p < 0.01). Time to recovery (4.1 ± 1.9 min vs. 11.5 ± 5.0 min, p < 0.001), and time to discharge (38.0 ± 9 min vs. 110 ± 42 min, p < 0.001) were significantly shorter with propofol than midazolam. Pre- and post-procedure NCT (from 25 ± 20 s to 24 ± 20 s), cognitive function score (from 25 to 26), time to recovery (3.5 ± 1.0 min), and time to discharge (35 ± 10 min) did not change in the healthy controls. Sedation with propofol has a shorter time recovery and a shorter time to discharge than midazolam and does not exacerbate sub-clinical hepatic encephalopathy in patients with compensated liver cirrhosis. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Current cytochrome P450 phenotyping methods applied to metabolic drug-drug interaction prediction in dogs.

PubMed

Mills, Beth Miskimins; Zaya, Matthew J; Walters, Rodney R; Feenstra, Kenneth L; White, Julie A; Gagne, Jason; Locuson, Charles W

2010-03-01

Recombinant cytochrome P450 (P450) phenotyping, different approaches for estimating fraction metabolized (f(m)), and multiple measures of in vivo inhibitor exposure were tested for their ability to predict drug interaction magnitude in dogs. In previous reports, midazolam-ketoconazole interaction studies in dogs have been attributed to inhibition of CYP3A pathways. However, in vitro phenotyping studies demonstrated higher apparent intrinsic clearances (CL(int,app)) of midazolam with canine CYP2B11 and CYP2C21. Application of activity correction factors and isoform hepatic abundance to liver microsome CL(int,app) values further implicated CYP2B11 (f(m) >or= 0.89) as the dog enzyme responsible for midazolam- and temazepam-ketoconazole interactions in vivo. Mean area under the curve (AUC) in the presence of the inhibitor/AUC ratios from intravenous and oral midazolam interaction studies were predicted well with unbound K(i) and estimates of unbound hepatic inlet inhibitor concentrations and intestinal metabolism using the AUC-competitive inhibitor relationship. No interactions were observed in vivo with bufuralol, although significant interactions with bufuralol were predicted with fluoxetine via CYP2D and CYP2C pathways (>2.45-fold) but not with clomipramine (<2-fold). The minor caffeine-fluvoxamine interaction (1.78-fold) was slightly higher than predicted values based on determination of a moderate f(m) value for CYP1A1, although CYP1A2 may also be involved in caffeine metabolism. The findings suggest promise for in vitro approaches to drug interaction assessment in dogs, but they also highlight the need to identify improved substrate and inhibitor probes for canine P450s.

Effectiveness of flumazenil on return of cognitive functions after a general anesthetic.

PubMed

Pregler, J L; Mok, M S; Steen, S N

1994-09-01

Benzodiazepines used intra-operatively can occasionally cause prolonged sedation. Flumazenil (Romazicon) is an imidazobenzodiazepine that functions as a benzodiazepine receptor antagonist. This clinical investigation was designed to evaluate the efficacy and of intravenous flumazenil in reversing the central effects of midazolam after a general anesthetic using midazolam for maintenance. 30 ASA I-III inpatients entered and completed this study. All were interviewed preoperatively and baseline performance on a battery of psychomotor tests was obtained. Parameters measured included an assessment of sleep status, vital signs, responsiveness to verbal stimuli, quality of speech, facial expression, eye coordination, recognition of a picture card, finger-finger-to-nose (FFN) coordination and overall discharge readiness. General anesthesia was induced with midazolam. Midazolam and fentanyl were the primary maintenance agents combined with N2O and O2 (70:30) and a limited concentration of isoflurane. In the recovery room the test drug was administered in a double-blinded, randomized manner. 20 patients received flumazenil (F), the rest placebo (P). Testing was done at times 0, 5, 15, 30, 60, 120, and 180 min in the PACU. Memory testing consisted of recall of study pictures at 180 min and recognition on the first postoperative day. Demographic data were similar for both groups with the exception of age. The F group had a higher mean composite score (comprising responsiveness to verbal stimuli, speech, facial expression and eye coordination) and better FFN scores at 5, 15, and 30 min (p < 0.01). There were no significant differences between groups at other times. F patients identified pictures better at 5 and 15 min (p < 0.004 and 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Optimization of drug-drug interaction study design: comparison of minimal physiologically based pharmacokinetic models on prediction of CYP3A inhibition by ketoconazole.

PubMed

Han, Bing; Mao, Jialin; Chien, Jenny Y; Hall, Stephen D

2013-07-01

Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f(m)) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

Effect of ketamine pretreatment for anaesthesia in patients undergoing percutaneous transluminal balloon angioplasty with continuous remifentanil infusion

PubMed Central

Jun, Na Hyung; Shim, Jae Kwang; Choi, Yong Sun; An, Seung Ho

2011-01-01

Background An appropriate level of sedation and pharmacological assist are essential during percutaneous transluminal balloon angioplasty (PTA). Ketamine provides good analgesia while preserving airway patency, ventilation, and cardiovascular stability with an opioid sparing effect suggesting that it would be ideal in combination with remifentanil and midazolam in spontaneously breathing patients. We evaluated the effect of a small dose of ketamine added to midazolam and remifentanil on analgesia/sedation for PTA procedures. Methods Sixty-four patients receiving PTA were enrolled. The Control group received midazolam 1.0 mg i.v. and continuous infusion of remifentanil 0.05 µg/kg/min. The Ketamine group received, in addition, an intravenous bolus of 0.5 mg/kg ketamine. Patients' haemodynamic data were monitored before remifentanil infusion, 5 min after remifentanil infusion, at 1, 3, 5, 30 min after incision, and at admission to the recovery room. Verbal numerical rating scales (VNRS) and sedation [OAA/S (Observer's Assessment of Alertness/Sedation)] scores were also recorded. Results The VNRS values at 1, 3, and 5 min after incision and OAA/S scores at 5 min after remifentanil infusion, and 1, 3, and 5 min after incision were lower in the Ketamine group than in the Control group. In the Control group, the VNRS value at 1 min after incision significantly increased and OAA/S values at 3, 5, and 30 min after incision significantly decreased compared to baseline values, while there were no significant changes in the ketamine group. Conclusions A small dose of ketamine as an adjunct sedative to the combination of midazolam and remifentanil produced a better quality of sedation and analgesia than without ketamine and provided stable respiration without cardiopulmonary deterioration. PMID:22110884

Sedative Effects of Intranasal Midazolam Administration in Wild Caught Blue-fronted Amazon (Amazona aestiva) and Orange-winged Amazon (Amazona amazonica) Parrots.

PubMed

Schaffer, Débora P H; de Araújo, Nayone L L C; Raposo, Ana Cláudia S; Filho, Emanoel F Martins; Vieira, João Victor R; Oriá, Arianne P

2017-09-01

Safe and effective sedation protocols are important for chemical restraint of birds in clinical and diagnostic procedures, such as clinical evaluations, radiographic positioning, and blood collection. These protocols may reduce stress and ease the management of wild-caught birds, which are susceptible to injury or death when exposed to stressful situations. We compare the sedative effect of intranasal midazolam in wild-caught blue-fronted (Amazona aestiva) and orange-winged (Amazona amazonica) Amazon parrots. Ten adult parrots of each species (n = 20), of unknown sex, weighing 0.337 ± 0.04 (blue-fronted) and 0.390 ± 0.03 kg (orange-winged), kg were used. Midazolam (2 mg/kg) was administered intranasally and the total volume of the drug was divided equally between the 2 nostrils. Onset time and total sedation time were assessed. Satisfactory sedation for clinical evaluation was induced in all birds. Onset time and total sedation times were similar in both species: 5.36 ± 1.16 and 25.40 ± 5.72 minutes, respectively, for blue-fronted Amazons and 5.09 ± 0.89 and 27.10 ± 3.73 minutes, respectively, for orange-winged Amazons. A total of 15 animals showed absence of vocalization, with moderate muscle relaxation and wing movement upon handling, and 2 animals presented with lateral recumbence, with intense muscle relaxation and no wing movement, requiring no restraint. Three blue-fronted Amazons had no effective sedation. Intranasally administered midazolam at a dose of 2 mg/kg effectively promoted sedative effects with a short latency time and fast recovery in wild-caught parrots.

Premedication in children: hypnosis versus midazolam.

PubMed

Calipel, Séverine; Lucas-Polomeni, Marie-Madeleine; Wodey, Eric; Ecoffey, Claude

2005-04-01

The main objectives of premedication in children are to facilitate the separation from the parents, to reduce preoperative anxiety, to smooth the induction of anesthesia and to lower the risk of postoperative behavioral disorders. The most common technique is sedative premedication with midazolam. Hypnosis enables a state of relaxation to be achieved and has never been evaluated as a premedication technique. The aim of the present study was to evaluate the efficacy of hypnosis on anxiety and perioperative behavioral disorders versus midazolam. Fifty children from 2 to 11 years of age were randomized into two groups: group H received hypnosis as premedication; group M were given 0.5 mg x kg(-1) midazolam orally, 30 min before surgery. Preoperative anxiety was evaluated using the Modified Yale Preoperative Anxiety Scale (mYPAS) score when arriving in the department (T1), when entering the operating room (T2), and when fitting the facemask (T3). Postoperative behavioral disorders were evaluated using the Posthospitalization Behavioral Questionnaire (PHBQ) at days 1, 7 and 14. The two groups showed no significant difference preoperatively with the PHBQ: (M) 21 (17-25) vs (H) 20 (8-25) and mYPAS score: (M) 28 (23-75) vs (H) 23 (23-78). The number of anxious children was less during induction of anesthesia in the hypnosis group (T3: 39% vs 68%) (P < 0.05). Postoperatively, hypnosis reduced the frequency of behavior disorders approximately by half on day 1 (30% vs 62%) and day 7 (26% vs 59%). Hypnosis seems effective as premedication in children scheduled for surgery. It alleviates preoperative anxiety, especially during induction of anesthesia and reduces behavioral disorders during the first postoperative week.

Feasibility of a cardiologist-only approach to sedation for electrical cardioversion of atrial fibrillation: a randomized, open-blinded, prospective study.

PubMed

Guerra, Federico; Pavoni, Ilaria; Romandini, Andrea; Baldetti, Luca; Matassini, Maria Vittoria; Brambatti, Michela; Luzi, Mario; Pupita, Giuseppe; Capucci, Alessandro

2014-10-20

Sedation with propofol should be administered by personnel trained in advanced airway management. To overcome this limitation, the use of short acting benzodiazepines by cardiologists spread widely, causing concerns about the safety of this procedure in the absence of anesthesiology assistance. The aim of the study was to compare feasibility of a cardiologist-only approach with an anesthesiologist-assisted sedation protocol during elective direct-current cardioversion (DCC) of persistent atrial fibrillation (AF). This prospective, open-blinded, randomized study included 204 patients, which were admitted for scheduled cardioversion of persistent AF, and randomized in a 1:1 fashion to either propofol or midazolam treatment arm. Patients in the propofol group underwent DCC with anesthesiologist assistance, while patients in the midazolam group saw the cardiologist as the only responsible for both sedation and DCC. Twenty-three adverse events occurred: 13 in the propofol group and 10 in the midazolam group (p=NS). Most of them were related to bradyarrhythmias and respiratory depressions. There was no need of intubation or other advanced resuscitation techniques in any of these patients. No differences were found regarding procedure tolerability and safety endpoints between the two groups. DCC procedures with anesthesiology support were burdened by higher delay from scheduled time and higher costs. Sedation with midazolam administered by cardiologist-only appears to be as safe as sedation with propofol and anesthesiologist assistance. Adverse events were few in both groups and easily handled by the cardiologist alone. A cardiologist-only approach to sedation provides less procedural delay, thus being easier to schedule and correlated with fewer costs. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Midazolam Plus Haloperidol as Adjuvant Analgesics to Morphine in Opium Dependent Patients: A Randomized Clinical Trial.

PubMed

Afzalimoghaddam, Mohammad; Edalatifard, Maryam; Nejati, Amir; Momeni, Mehdi; Isavi, Nader; Karimialavijeh, Ehsan

2016-01-01

Tolerance to opioids among opium-dependent patients creates obstacles for proper pain management of these patients in the emergency department (ED). The aim of the present study was to investigate the efficacy of intramuscular (IM) haloperidol plus midazolam on morphine analgesia among opium-dependent patients. Opium-dependent adults who were admitted to the ED for new-onset severe pain in the limbs or abdomen (within 24 hours of admission and a pain score of over six, using a numerical rating scale [NRS]) were recruited. Participants were randomly assigned into two groups. Group A received morphine 0.05 mg/kg intravenously (IV) and a mixture of midazolam 2.5 mg and haloperidol 2.5 mg (diluted in 5 cc of distilled water, IM); group B received morphine 0.05 mg/kg IV and distilled water 5 cc, IM. Measured outcomes were related to: 1) pain intensity; 2) total doses of morphine; 3) changes in hemodynamic status and level of consciousness of patients. NRS scores (zero to 10) before and one, three and six hours following intervention, as well as total doses of morphine, were recorded. We recruited 68 males (78.16%) and 19 females (21.83%). The mean age was 38.28±6.59 years. The pain score in group A declined more rapidly over six hours than that in group B. Moreover, as compared to group B, the amount of morphine use decreased significantly in group A. Based on the present data, adding haloperidol plus midazolam to morphine for pain management improved pain scores and lowered morphine consumption among opium-dependent patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Sedoanalgesia With Midazolam and Fentanyl Citrate Controls Probe Pain During Prostate Biopsy by Transrectal Ultrasound

PubMed Central

Tsuji, Fábio Hissachi; Chambó, Renato Caretta; Agostinho, Aparecido Donizeti; Trindade Filho, José Carlos Souza

2014-01-01

Purpose To assess the pain intensity of patients administered midazolam and fentanyl citrate before undergoing transrectal ultrasound-guided prostate biopsy. Materials and Methods This was a study in patients with different indications for prostate biopsy in whom 5 mg of midazolam and 50 µg of fentanyl citrate was administered intravenously 3 minutes before the procedure. After biopsy, pain was assessed by use of a visual analogue scale (VAS) in three stages: VAS 1, during probe introduction; VAS 2, during needle penetration into prostate tissue; and VAS 3, in the weeks following the exam. Pain intensity at these different times was tested with stratification by age, race, education, prostate volume, rebiopsy, and anxiety before biopsy. Pain was ranked according to the following scores: 0 (no pain), 1-3 (mild pain), 4-7 (moderate pain), and 8-10 (severe pain). Statistical analysis was performed by using Kruskal-Wallis and Wilcoxon two-tailed tests with a significance of 5%. Results Pain intensity was not influenced by any risk factors. The mean VAS 1 score was 1.95±1.98, the mean VAS 2 score was 2.73±2.55, and the mean VAS 3 score was 0.3±0.9, showing greater pain at the time of needle penetration than in other situations (VAS 2>VAS 1>VAS 3, p=0.0013, p=0.0001, respectively). Seventy-five percent of patients reported a VAS pain scale of less than 3.1 or mild pain. Conclusions Intravenous sedation and analgesia with midazolam and fentanyl citrate is a good method for reducing pain caused by prostate biopsy, even during probe insertion. PMID:24578806

Effectiveness of Sedoanalgesia in Percutaneous Liver Biopsy Premedication

PubMed Central

Sezgin, Orhan; Ates, Fehmi; Altintas, Engin; Saritas, Bunyamin

2017-01-01

Aim: Percutaneous needle liver biopsy (PLB) is frequently associated with pain and anxiety. This may discourage the patients for biopsy, and rebiopsies, if needed. We planned a study to investigate the efficacy of additional analgesia or sedation for PLB. Materials and methods: The study has been designed as a single-center, prospective study. The PLB was planned for 18- to 65-year-old consecutive patients who were included in the study. The patients were divided into three premedication groups as control, Meperidine, and Midazolam. Hospital Anxiety and Depression Scale (HADS) was used to measure each subject’s anxiety level. Fifteen minutes before the biopsy, 1 mL 0.9% NaCl subcutaneously (sc), 1 mg/kg (max 100 mg) Meperidine sc, or 0.1 mg/kg (max 5 mg) Midazolam intravenously was administered to patients respectively. Then PLB was done with 16 G Menghini needle. The day after, the patients were asked about feelings regarding biopsy. Results: Groups were similar by gender and age. The HADS scores prior to PLB and on visual analog scale (VAS, 1-10 points) score during PLB were similar. In the three groups, 7, 12, and 7 patients, respectively, experienced no pain. Other patients explained pain as mild or moderate or severe. The number of patients who agreed for possible rebiopsy was higher in Meperidine and Midazolam groups than in the control group. Conclusion: Premedication with Meperidine or Midazolam in PLB would improve patients’ tolerance, comfort, and attitude against a possible repeat PLB. How to cite this article: Sezgin O, Yaras S, Ates F, Altintas E, Saritas B. Effectiveness of Sedoanalgesia in Percutaneous Liver Biopsy Premedication. Euroasian J Hepato-Gastroenterol 2017;7(2):146-149. PMID:29201797

Liquid chromatography-tandem mass spectrometry method for simultaneous quantification of bisoprolol, ramiprilat, propranolol and midazolam in rat dried blood spots.

PubMed

Cvan Trobec, Katja; Trontelj, Jurij; Springer, Jochen; Lainscak, Mitja; Kerec Kos, Mojca

2014-05-01

Dried blood spot (DBS) sampling represents a suitable method for pharmacokinetic studies in rats, particularly if serial sampling is needed. To study the pharmacokinetics of drugs in a rat heart failure (HF) model, we developed and validated a method for the simultaneous determination of bisoprolol, ramiprilat, propranolol and midazolam in DBS samples. Bisoprolol and ramipril are widely used in the treatment of HF, and midazolam and propranolol are markers of hepatic metabolism, which can be altered in HF. A 20μL sample of rat blood was pipetted onto Whatman 903 Protein Saver Card and allowed to dry. The whole spot was excised and 300μL of solvent (methanol with 10% ultrapure water and 0.1% formic acid) was added. After mixing and incubating the sample in an ultrasonic bath, a mixture of isotopically labeled internal standards was added. After centrifugation, the extracts were cleaned on an Ostro™ plate and analyzed using liquid chromatography-tandem mass spectroscopy. The method was successfully validated. No significant interference was observed in the retention times of analytes or internal standards. The intraday and interday accuracy and precision were within a ±15% interval. The method was linear in the range 5-250μg/L and the lower limit of quantification was 5μg/L for all four analytes. The absolute matrix effect ranged from 98.7% for midazolam to 121% for ramiprilat. The recovery was lowest for ramiprilat and highest for propranolol. Samples were stable at all tested temperatures. The method has been used successfully in a real-time pharmacokinetic study in rats. Copyright © 2014 Elsevier B.V. All rights reserved.

The effects of midazolam and D-cycloserine on the release of glutamate and GABA in the basolateral amygdala of low and high anxiety rats during extinction trial of a conditioned fear test.

PubMed

Lehner, Małgorzata; Wisłowska-Stanek, Aleksandra; Taracha, Ewa; Maciejak, Piotr; Szyndler, Janusz; Skórzewska, Anna; Turzyńska, Danuta; Sobolewska, Alicja; Hamed, Adam; Bidziński, Andrzej; Płaźnik, Adam

2010-11-01

In this study, we investigated how midazolam and d-cycloserine regulate the tonic activity and/or phasic reactivity of brain neurotransmitter systems to fear-evoking stimuli in rats with varying intensities of a fear response. We used a new animal model composed of high (HR) and low (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of a freezing response was used as a discriminating variable). In these rats, we examined the effects of both drugs on the release of glutamate and GABA in the basolateral amygdala (BLA) during the first extinction trial of a conditioned fear test. The results showed that administration of d-cycloserine (15 mg/kg, i.p.) significantly enhanced the inhibition of an aversive context-induced freezing response observed during the extinction session in HR and LR rats. In contrast, midazolam (0.75 mg/kg, i.p.) accelerated the attenuation of fear responses only in HR rats. The less anxious behaviour of LR animals given saline was accompanied by elevated basal levels of glutamate in the BLA, in comparison with HR rats, and a stronger elevation of GABA in response to contextual fear. In HR animals, the pretreatment of rats with d-cycloserine and midazolam significantly increased the local concentration of GABA and inhibited the expression of contextual fear. These findings suggest that animals more vulnerable to stress have innate deficits in brain systems that control the activity of the BLA mediating the central effect of stress. These results contribute to our understanding of observed individual differences in the effects of anxiolytic drugs among patients with anxiety disorders. Copyright © 2010. Published by Elsevier Inc.

Emergence delirium with transient associative agnosia and expressive aphasia reversed by flumazenil in a pediatric patient.

PubMed

Drobish, Julie K; Kelz, Max B; DiPuppo, Patricia M; Cook-Sather, Scott D

2015-06-01

Multiple factors may contribute to the development of emergence delirium in a child. We present the case of a healthy 12-year-old girl who received preoperative midazolam with the desired anxiolytic effect, underwent a brief general anesthetic, and then exhibited postoperative delirium, consisting of a transient associative agnosia and expressive aphasia. Administration of flumazenil led to immediate and lasting resolution of her symptoms. We hypothesize that γ-aminobutyric acid type A receptor-mediated effects, most likely related to an atypical offset of midazolam, are an important subset of emergence delirium that is amenable to pharmacologic therapy with flumazenil.

Emergence Delirium with Transient Associative Agnosia and Expressive Aphasia Reversed by Flumazenil in a Pediatric Patient

PubMed Central

Drobish, Julie K.; Kelz, Max B.; DiPuppo, Patricia M.; Cook-Sather, Scott D.

2014-01-01

Multiple factors may contribute to the development of emergence delirium in a child. We present the case of a healthy 12-year-old girl who received preoperative midazolam with the desired anxiolytic effect, underwent a brief general anesthetic, and then exhibited postoperative delirium, consisting of a transient associative agnosia and expressive aphasia. Administration of flumazenil led to immediate and lasting resolution of her symptoms. We hypothesize that γ-aminobutyric acid type A receptor-mediated effects, most likely related to an atypical offset of midazolam, are an important subset of emergence delirium that is amenable to pharmacologic therapy with flumazenil. PMID:26035220

Intentional intra-arterial injection of midazolam in a patient with status epilepticus in the Intensive Care Unit

PubMed Central

Ali, Muhammad Asghar; Yahya, Muhammad

2017-01-01

Fundamental medical care includes intravenous (IV) access which provides prompt resuscitation and reliable delivery of analgesics, antibiotics, and vasoactive medication. Difficult access populations, especially in critical area, continue to challenge providers to consider and utilize alternative means to provide IV access. Potential options under such circumstances include intramuscular, intraosseous, and intratracheal drug administration, but in extreme cases where no other options are available, intra-arterial route might be considered. We present a case where midazolam was intentionally injected intra-arterially to abort seizure activity in a patient with status epilepticus in the Intensive Care Unit. PMID:29033730

Comparison of Haloperidol Alone and in Combination with Midazolam for the Treatment of Acute Agitation in an Inpatient Palliative Care Service.

PubMed

Ferraz Gonçalves, José António; Almeida, Ana; Costa, Isabel; Silva, Paula; Carneiro, Rui

2016-12-01

Agitation is a very distressing problem that must be controlled as quickly as possible, but using a safe method. The authors conducted a comparison of two protocols: a combination of haloperidol and midazolam and haloperidol alone. The combination drug protocol controlled 101 out of 121 (84%) episodes of agitation with only the first dose, whereas the haloperidol alone protocol controlled 47 out of 74 (64%) episodes. This difference is statistically significant (P =.002), with a post hoc analyzed power of 0.88. The median time from the first dose to the control of agitation was 15 minutes (range: 5-210) with the combination and 60 minutes (range: 10-430) with the other protocol, P <.001. There were no complications other than some transient somnolence, mainly with the combination protocol. The authors conclude that the combination of haloperidol and midazolam is effective and safe for the control of agitation in palliative care and it is more effective than haloperidol alone. Therefore, the combination should be adopted as the preferred protocol. It would be helpful if the usefulness of this protocol is confirmed by others.

Could conscious sedation with midazolam for dental procedures be an alternative to general anesthesia?

PubMed

Silay, E; Candirli, C; Taskesen, F; Coskuner, I; Ceyhanli, K T; Yildiz, H

2013-01-01

The aim of our study was to evaluate the likelihood that conscious sedation (CS) with intravenous midazolam could become an alternative modality to general anesthesia (GA) for dental procedures. In our study, 58 and 47 American Society of Anesthesiologists (ASA)-1 pediatric patients, aged 2-12 (mean 6) years, underwent dental procedures and minor oral surgical procedures under GA and CS with intravenous midazolam, respectively. The two groups were evaluated in terms of vital signs, duration of the treatment procedure, patient behavior, and the treatment comfort experienced by the physicians. The oxygen saturation level was significantly lower (GA: 99.0 ± 0.30, CS: 98.4 ± 1.02; P < 0.001) and the duration of the treatment procedure was significantly shorter (P < 0.001) in the sedation group compared with the GA group. The physicians encountered various difficulties during implementation of the treatment strategy in cases where they used CS. Minor oral surgical procedures and tooth extraction processes requiring no saline irrigation, however, could be performed successfully under CS. In cases requiring multiple dental management issues, the sedation method was not found to be a useful alternative to GA.

Midazolam intravenous conscious sedation in oral surgery. A retrospective study of 372 cases.

PubMed

Runes, J; Ström, C

1996-01-01

In 1987 the Swedish Dental Act was amended to allow Swedish dentists who have undergone a specific accreditation course to administer intra-venous sedation. Midazolam is a benzodiazepin derivate with express sedative and hypnotic qualities, powerful amnesia, a short half-life time and few secondary effects. From 1989-1994 midazolam intravenous conscious sedation (ICS) was administered in 372 cases in the Department of Oral and Maxillofacial Surgery, County Hospital, Falun. This study presents data on the 298 patients. Although surgical removal of impacted wisdom teeth predominated, implant surgery, reduction of fractures and correction of anomalies were also carried out. Supplementary sedative premedication was rarely used. Most patients were treated under local anaesthesia. The mean dosage was 10.45 mg (range 1.25-40 mg). Mean dosage/kg was 0.15 mg (range 0.03-0.50 mg). The average duration of anaesthesia was 50 minutes. The average recovery time was 94 minutes. Three hundred and sixty-nine of 372 planned treatments were completed. No serious complications occurred. The patients were co-operative during surgery and were satisfied with the treatment. Compared with full anaesthesia this method required less resources and is a valuable complement in management of anxious patients undergoing oral surgery.

Effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin, tizanidine, and midazolam--probes of CYP2C9, CYP1A2, and CYP3A4.

PubMed

Lilja, J J; Backman, J T; Neuvonen, P J

2007-06-01

Case reports suggest that cranberry juice can increase the anticoagulant effect of warfarin. We investigated the effects of cranberry juice on R-S-warfarin, tizanidine, and midazolam; probes of CYP2C9, CYP1A2, and CYP3A4. Ten healthy volunteers took 200 ml cranberry juice or water t.i.d. for 10 days. On day 5, they ingested 10 mg racemic R-S-warfarin, 1 mg tizanidine, and 0.5 mg midazolam, with juice or water, followed by monitoring of drug concentrations and thromboplastin time. Cranberry juice did not increase the peak plasma concentration or area under concentration-time curve (AUC) of the probe drugs or their metabolites, but slightly decreased (7%; P=0.051) the AUC of S-warfarin. Cranberry juice did not change the anticoagulant effect of warfarin. Daily ingestion of cranberry juice does not inhibit the activities of CYP2C9, CYP1A2, or CYP3A4. A pharmacokinetic mechanism for the cranberry juice-warfarin interaction seems unlikely.

[No inhibition of intestinal motility following ketamine-midazolam anesthesia. A comparison of anesthesia with enflurane and fentanyl/midazolam].

PubMed

Freye, E; Knüfermann, V

1994-02-01

Postoperative intestinal atonia is a complication which is likely to occur in patients predisposed for constipation and in patients after intra-abdominal operations. The postoperative delay of bowel movement, however, is often also related to the type of anaesthesia being used. In order to evaluate the magnitude of an anaesthetic-induced postoperative delay of bowel movement, two types of intravenous-based anaesthesia using fentanyl/midazolam (1 mg/25 mg; dosage 0.1 ml/kg/h), and ketamine/midazolam (250 mg/25 mg; dosage 0.1 ml/kg/h) respectively were compared with a volatile anaesthetic technique (enflurane; mean concentration 1.5 vol%). METHODS. In three groups of patients (each n = 15) undergoing elective surgery of the lower extremities, induction of anaesthesia was accomplished with methohexital (1-1.5 mg/kg) to facilitate intubation. For the maintenance of muscle relaxation vecuronium bromide was used. All patients were given droperidol to prevent postoperative emesis, and they were artificially ventilated with N2O/O2 (60:40) to normal end-expiratory CO2 concentrations. No anticholinergic agents were used at the end of operation since they are known to interfere with bowel motility. In order to determine gastro-intestinal motility, the H2 exhalation test was used. For this purpose 40 g lactulose in 100 ml of water was given to all patients via a gastral tube shortly before extubation. Lactulose is broken down by bacteria once it enters the colon, and H2 is released, taken up by the vascular system and exhaled. Postoperatively, patients were asked to exhale into a 20-ml syringe every 10 min. The content was analysed for hydrogen (ppm), using an electrochemical sensor (GMI exhaled hydrogen monitor). From the time of lactulose instillation to a threefold increase in end-expiratory hydrogen concentration (compared to the preoperative value), gastro-coecal transit time was computed. RESULTS. All three groups of patients were comparable in age, height and body weight. Also, the duration of operation was comparable in all three groups. Mean gastro-coecal transit time was 204 (+/- 19.6, SD) min following enflurane, 302 (+/- 32.8 SD) min following fentanyl/-midazolam and 210 (+/- 28.8 SD) min following ketamine/midazolam anaesthesia. The gastro-intestinal inhibition after the opioid-based anaesthetic technique was significantly prolonged (p < 0.001, Kruskal-Wallis test). There was no significance between patients after ketamine-based anaesthesia and those who had the volatile anaesthetic. DISCUSSION AND CONCLUSION. When using intravenous anaesthesia with an opioid, gastro-intestinal inhibition, especially in patients prone to have constipation, is likely to develop postoperatively. In classical neuroleptanaesthesia and in analgosedation in the ICU, the simultaneous use of the butyrophenone droperidol seems to counteract the inhibition of opioid-related gastrointestinal motility. In cases of opioid-related gastrointestinal atonia a gastrokinetic compound may be necessary to overcome this effect on intestinal motility.

Feasibility of atmospheric pressure desorption/ionization on silicon mass spectrometry in analysis of drugs.

PubMed

Huikko, K; Ostman, P; Sauber, C; Mandel, F; Grigoras, K; Franssila, S; Kotiaho, T; Kostiainen, R

2003-01-01

The feasibility of atmospheric pressure desorption/ionization on silicon mass spectrometry (AP-DIOS-MS) for drug analysis was investigated. It was observed that only compounds with relative high proton affinity are efficiently ionized under AP-DIOS conditions. The limits of detection (LODs) achieved in MS mode with midazolam, propranolol, and angiotensin II were 80 fmol, 20 pmol, and 1 pmol, respectively. In MS/MS mode the LODs for midazolam and propranolol were 10 fmol and 5 pmol, respectively. The good linearity (r(2) > 0.991), linear dynamic range of 3 orders of magnitude, and reasonable repeatability showed that the method is suitable for quantitative analysis. Copyright 2003 John Wiley & Sons, Ltd.

CARDIORESPIRATORY EFFECTS OF DEXMEDETOMIDINE-BUTORPHANOL-MIDAZOLAM (DBM): A FULLY REVERSIBLE ANESTHETIC PROTOCOL IN CAPTIVE AND SEMI-FREE-RANGING CHEETAHS (ACINONYX JUBATUS).

PubMed

Woc Colburn, A Margarita; Murray, Suzan; Hayek, Lee-Ann C; Marker, Laurie; Sanchez, Carlos R

2017-03-01

Multiple anesthesia protocols have been used in the cheetah ( Acinonyx jubatus ). Twenty healthy, captive cheetahs were immobilized with dexmedetomidine (15.8 ± 1.9 μg/kg), butorphanol (0.22 ± 0.03 mg/kg), and midazolam (0.18 ± 0.03 mg/kg) by intramuscular injection. Induction, recumbency, and recovery times were recorded, and physiologic parameters were monitored. Anesthesia was antagonized with atipamezole (0.125 ± 0.02 mg/kg) and naltrexone (0.1 ± 0.014 mg/kg) intramuscularly. All cheetahs were safely anesthetized with this protocol. Cheetahs were laterally recumbent by 8 ± 3.5 min. Cardiorespiratory values were stable throughout the length of anesthesia. Moderate hypertension, with systolic blood pressure ranging from 178 ± 19.8 mm Hg, was initially observed but decreased over time. There was a statistical decreasing trend in temperature; SpO2; and systolic, mean, and diastolic blood pressure, but not in heart rate and end-tidal CO 2 . Recoveries were rapid, with cheetahs standing by 11.3 ± 5.7 min postreversal administration. This is the first report of a dexmedetomidine-butorphanol-midazolam anesthetic combination in cheetahs. Overall, this anesthetic protocol proved to be safe and effective.

Efficacy of the bone injection gun in the treatment of organophosphate poisoning.

PubMed

Eisenkraft, Arik; Gilat, Eran; Chapman, Shira; Baranes, Shlomo; Egoz, Inbal; Levy, Aharon

2007-04-01

Immediate administration of antidotal treatment is crucial in severe organophosphate (OP) poisoning and the use of an open intravenous (i.v.) line might also be required. The state of casualties might prevent getting access to their veins. The bone injection gun (BIG) was established as a simple method for introducing an intraosseous (i.o.) line and could be applied while wearing a protective suit. The present study followed the pharmacokinetics of the anticonvulsive drug midazolam after i.o. administration in pigs compared with i.v. and the common intramuscular (i.m.) administration. A new method for monitoring midazolam concentrations in plasma was developed. Plasma concentrations following both i.v. and i.o. administrations peaked at 2 min post injection and only at 10 min following the i.m. route. In an antidotal treatment study against paraoxone poisoning, the anticonvulsive effect of midazolam appeared immediately following i.o. administration, while it took 5-10 min to exhibit a similar effect following i.m. administration. This study indicates that the use of i.o. administration after OP poisoning might provide the necessary fast response for rapid termination of convulsions. The BIG might offer a convenient method for treating casualties in the chemical arena by teams wearing full protective gear. Copyright (c) 2007 John Wiley & Sons, Ltd.

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

PubMed

Franken, L G; de Winter, B C M; van Esch, H J; van Zuylen, L; Baar, F P M; Tibboel, D; Mathôt, R A A; van Gelder, T; Koch, B C P

2016-06-01

A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

Success of Dental Treatments under Behavior Management, Sedation and General Anesthesia.

PubMed

Blumer, Sigalit; Costa, Liora; Peretz, Benjamin

To present comparative study aims to assist the practitioner to choose between behavior modification (BM) techniques, pharmacologic sedation (N 2 O-O 2 alone or combined with midazolam 0.5 mg/ kg) or routine general anesthesia (GA) for the most successful approach in enabling pediatric dental care. Dental records of 56 children treated in a university dental clinic between 2006-2016 were reviewed, and data on age, gender, required treatment (amalgam restorations, composite restorations, pulpotomy, and stainless steel crowns [SSC]), treatment approaches and therapeutic success at final follow-up were retrieved. Treatment under GA had the best success rates compared to both BM and pharmacologic sedation. N 2 O-O 2 alone had a 6.1-fold greater risk of failure compared to N 2 O-O 2 +midazolam (p- <0.008). Amalgam restorations had a 2.61-fold greater risk of failure than SSC (p- <0.008). The GA mode yielded significantly greater success than the N 2 O-O 2 mode alone. There were no significant differences in success rates between GA and combined midazolam 0.5 mg/kg+N 2 O-O 2 . When choosing restoration material, it is important to remember the high success rate of SSC compared to amalgam restoration.

Effectiveness of Oral Ketamine, Midazolam, and Atropine Cocktail Versus Oral Diphenhydramine for Pediatric Sedation in the Emergency Department

PubMed Central

Soleimanpour, Hassan; Mahmoodpoor, Ata; Eftekhari Milani, Farid; Shahsavari Nia, Kavous; Mehdizadeh Esfanjani, Robab; Safari, Saeid

2014-01-01

Background: Sedation is a condition of reduced level of consciousness (LOC) for a patient that is created to decrease irritability, anxiety, and restlessness. Objectives: In this study, we compared the sedative effect of oral administration of ketamine, midazolam, and atropine cocktail with diphenhydramine in the referent children to the emergency department. Patients and Methods: Based on the double-blind randomized clinical trial in this investigation, 80 children, who needed to repair their wounds with suture were randomly divided into two groups: group 1 and group 2, who have received oral diphenhydramine and oral ketamine, midazolam, and atropine cocktail, respectively. Behavioral changes were collected and recorded before, during intervention and two weeks after intervention. Statistical data were analyzed by SPSS-16 software and chi-square and Mann-Whitney U tests were employed to study the relations among variables. P < 0.05 was considered statistically significant. Results: There was no significant difference between two groups in terms of drug acceptance and anxiety degree in children before intervention. Group 2 had achieved better and deeper sedation than group 1 during 45-minute post-medication (P < 0.05, P = 0.01). Regarding pediatric general behavior such as crying or interruptive moves, there was also a significant statistical difference between group 2 and group 1 (P = 0.009) based on Houpt Classification. The mean recovery times in groups 1 and 2 were 34.37 ± 14.23 min and 27.25 ± 5.14 min, respectively (P = 0.003). In terms of behavioral changes, the rate of cumulative frequency was computed for behavioral changes two weeks after the discharge from emergency department in which there were less behavioral changes in group 2 than in group 1 (P = 0.04). Conclusions: Oral administration of ketamine, midazolam, and atropine cocktail induces better sedation than diphenhydramine with respect to its limited mood changes in children, who need a medical procedure at emergency department. PMID:25593736

Midazolam treatment before re-exposure to contextual fear reduces freezing behavior and amygdala activity differentially in high- and low-anxiety rats.

PubMed

Skórzewska, Anna; Lehner, Małgorzata; Wisłowska-Stanek, Aleksandra; Turzyńska, Danuta; Sobolewska, Alicja; Krząścik, Paweł; Płaźnik, Adam

2015-02-01

The aim of this study was to examine the effects of benzodiazepine (midazolam) administration on rat conditioned fear responses and on local brain activity (c-Fos and CRF expressions) of low- (LR) and high- (HR)anxiety rats after the first and second contextual fear test sessions. The animals were divided into LR and HR groups based on the duration of their conditioned freezing response in the first contextual fear test. The fear-re-conditioned LR and HR animals (28 days later) had increased freezing durations compared with those durations during the first conditioned fear test. These behavioral effects were accompanied by increased c-Fos expression in the medial amygdala (MeA), the basolateral amygdala (BLA), and the paraventricular hypothalamic nuclei and elevated CRF expression in the MeA. All these behavioral and immunochemical effects of fear re-conditioning were stronger in the LR group compared with the effects in the HR group. Moreover, in the LR rats, the re-conditioning led to decreased CRF expression in the primary motor cortex (M1) and to increased CRF expression in the BLA. The pretreatment of rats with midazolam before the second exposure to the aversive context significantly attenuated the conditioned fear response, lowered the serum corticosterone concentration, decreased c-Fos and CRF expressions in the MeA and in the BLA, and increased CRF complex density in M1 area only in the LR group. These studies have demonstrated that LR rats are more sensitive to re-exposure to fear stimuli and that midazolam pretreatment was associated with modified brain activity in the amygdala and in the prefrontal cortex in this group of animals. The current data may facilitate a better understanding of the neurobiological mechanisms responsible for individual differences in the psychopathological processes accompanying some anxiety disorders characterized by stronger reactivity to re-exposure to stressful challenges, e.g., posttraumatic stress disorder. Copyright © 2013 Elsevier Inc. All rights reserved.

Sedation at Sea of Entangled North Atlantic Right Whales (Eubalaena glacialis) to Enhance Disentanglement

PubMed Central

Moore, Michael; Walsh, Michael; Bailey, James; Brunson, David; Gulland, Frances; Landry, Scott; Mattila, David; Mayo, Charles; Slay, Christopher; Smith, Jamison; Rowles, Teresa

2010-01-01

Background The objective of this study was to enhance removal of fishing gear from right whales (Eubalaena glacialis) at sea that evade disentanglement boat approaches. Titrated intra muscular injections to achieve sedation were undertaken on two free swimming right whales. Methodology/Principal Findings Following initial trials with beached whales, a sedation protocol was developed for right whales. Mass was estimated from sighting and necropsy data from comparable right whales. Midazolam (0.01 to 0.025 mg/kg) was first given alone or with meperidine (0.17 to 0.25 mg/kg) either once or four times over two hours to whale #1102 by cantilevered pole syringe. In the last attempt on whale #1102 there appeared to be a mild effect in 20–30 minutes, with duration of less than 2 hours that included exhalation before the blowhole fully cleared the water. Boat avoidance, used as a measure of sedation depth, was not reduced. A second severely entangled animal in 2009, whale #3311, received midazolam (0.03 mg/kg) followed by butorphanol (0.03 mg/kg) an hour later, delivered ballistically. Two months later it was then given midazolam (0.07 mg/kg) and butorphanol (0.07 mg/kg) simultaneously. The next day both drugs at 0.1 mg/kg were given as a mixture in two darts 10 minutes apart. The first attempt on whale #3311 showed increased swimming speed and boat avoidance was observed after a further 20 minutes. The second attempt on whale #3311 showed respiration increasing mildly in frequency and decreasing in strength. The third attempt on whale #3311 gave a statistically significant increase in respiratory frequency an hour after injection, with increased swimming speed and marked reduction of boat evasion that enabled decisive cuts to entangling gear. Conclusions/Significance We conclude that butorphanol and midazolam delivered ballistically in appropriate dosages and combinations may have merit in future refractory free swimming entangled right whale cases until other entanglement solutions are developed. PMID:20231895

Determination of optimum time for intravenous cannulation after induction with sevoflurane and nitrous oxide in children premedicated with midazolam.

PubMed

Kilicaslan, Alper; Gök, Funda; Erol, Atilla; Okesli, Selmin; Sarkilar, Gamze; Otelcioglu, Seref

2014-06-01

It has been shown that early placement of an intravenous line in children administered sevoflurane anesthesia increased the incidence of laryngospasm and movement. However, the optimal time for safe cannulation after the loss of the eyelash reflex during the administration of sevoflurane and nitrous oxide is not known. The aim of the study was to determine the optimum time for intravenous cannulation after the induction of anesthesia with sevoflurane and nitrous oxide in children premedicated with oral midazolam. We performed a prospective, observer-blinded, up-down sequential, allocation study, and children, aged 2-6 years, ASA physical status I, scheduled for an elective procedure undergoing inhalational induction were included in the study. Anesthesia was induced with sevoflurane and nitrous oxide after premedication with oral midazolam. For the first child, 4 min after the loss of the eyelash reflex, the intravenous cannulation was attempted by an experienced anesthesiologist. The time for intravenous cannulation was considered adequate if movement, coughing, or laryngospasm did not occur. The time for cannulation was increased by 15 s if the time was inadequate in the previous patient, and conversely, the time for cannulation was decreased by 15 s if the time was adequate in the previous patient. The probit test was used in the analysis of up-down sequences. A total of 32 children were enrolled sequentially during the study period. The adequate time for effective intravenous cannulation after induction with sevoflurane and nitrous oxide in 50% and 95% of patients were 1.29 min (95% confidence interval, 0.96-1.54 min) and 1.86 min (95% confidence interval 1.58-4.35 min), respectively. We recommend waiting 2 min for attempting intravenous placement following the loss of the eyelash reflex in children sedated with midazolam and receiving an inhalation induction with sevoflurane and nitrous oxide. © 2014 John Wiley & Sons Ltd.

Marmoset Cytochrome P450 3A4 Ortholog Expressed in Liver and Small-Intestine Tissues Efficiently Metabolizes Midazolam, Alprazolam, Nifedipine, and Testosterone.

PubMed

Uehara, Shotaro; Uno, Yasuhiro; Nakanishi, Kazuyuki; Ishii, Sakura; Inoue, Takashi; Sasaki, Erika; Yamazaki, Hiroshi

2017-05-01

Common marmosets ( Callithrix jacchus ), small New World primates, are increasingly attracting attention as potentially useful animal models for drug development. However, characterization of cytochrome P450 (P450) 3A enzymes involved in the metabolism of a wide variety of drugs has not investigated in marmosets. In this study, sequence homology, tissue distribution, and enzymatic properties of marmoset P450 3A4 ortholog, 3A5 ortholog, and 3A90 were investigated. Marmoset P450 3A forms exhibited high amino acid sequence identities (88-90%) to the human and cynomolgus monkey P450 3A orthologs and evolutionary closeness to human and cynomolgus monkey P450 3A orthologs compared with other P450 3A enzymes. Among the five marmoset tissues examined, P450 3A4 ortholog mRNA was abundant in livers and small intestines where P450 3A4 ortholog proteins were immunologically detected. Three marmoset P450 3A proteins heterologously expressed in Escherichia coli membranes catalyzed midazolam 1'- and 4-hydroxylation, alprazolam 4-hydroxylation, nifedipine oxidation, and testosterone 6 β -hydroxylation, similar to cynomolgus monkey and human P450 3A enzymes. Among the marmoset P450 3A enzymes, P450 3A4 ortholog effectively catalyzed midazolam 1'-hydroxylation, comparable to microsomes from marmoset livers and small intestines. Correlation analyses with 23 individual marmoset liver microsomes suggested contributions of P450 3A enzymes to 1'-hydroxylation of both midazolam (human P450 3A probe) and bufuralol (human P450 2D6 probe), similar to cynomolgus monkey P450 3A enzymes. These results indicated that marmoset P450 3A forms had functional characteristics roughly similar to cynomolgus monkeys and humans in terms of tissue expression patterns and catalytic activities, suggesting marmosets as suitable animal models for P450 3A-dependent drug metabolism. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Injection anaesthesia with fentanyl-midazolam-medetomidine in adult female mice: importance of antagonization and perioperative care.

PubMed

Fleischmann, Thea; Jirkof, Paulin; Henke, Julia; Arras, Margarete; Cesarovic, Nikola

2016-08-01

Injection anaesthesia is commonly used in laboratory mice; however, a disadvantage is that post-anaesthesia recovery phases are long. Here, we investigated the potential for shortening the recovery phase after injection anaesthesia with fentanyl-midazolam-medetomidine by antagonization with naloxone-flumazenil-atipamezole. In order to monitor side-effects, the depth of anaesthesia, heart rate (HR), core body temperature (BT) and concentration of blood gases, as well as reflex responses, were assessed during a 50 min anaesthesia. Mice were allowed to recover from the anaesthesia in their home cages either with or without antagonization, while HR, core BT and spontaneous home cage behaviours were recorded for 24 h. Mice lost righting reflex at 330 ± 47 s after intraperitoneal injection of fentanyl-midazolam-medetomidine. During anaesthesia, HR averaged 225 ± 23 beats/min, respiratory rate and core BT reached steady state at 131 ± 15 breaths/min and 34.3 ± 0.25℃, respectively. Positive pedal withdrawal reflex, movement triggered by tail pinch and by toe pinch, still occurred in 25%, 31.2% and 100% of animals, respectively. Arterial blood gas analysis revealed acidosis, hypoxia, hypercapnia and a marked increase in glucose concentration. After anaesthesia reversal by injection with naloxone-flumazenil-atipamezole, animals regained consciousness after 110 ± 18 s and swiftly returned to physiological baseline values, yet they displayed diminished levels of locomotion and disrupted circadian rhythm. Without antagonization, mice showed marked hypothermia (22 ± 1.9℃) and bradycardia (119 ± 69 beats/min) for several hours. Fentanyl-midazolam-medetomidine provided reliable anaesthesia in mice with reasonable intra-anaesthetic side-effects. Post-anaesthetic period and related adverse effects were both reduced substantially by antagonization with naloxone-flumazenil-atipamezole. © The Author(s) 2016.

Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non-small-Cell Lung Cancer Receiving Erlotinib Treatment.

PubMed

Parra-Guillen, Zinnia P; Berger, Peter B; Haschke, Manuel; Donzelli, Massimiliano; Winogradova, Daria; Pfister, Bogumila; Früh, Martin; Gillessen, Silke; Krähenbühl, Stephan; Kloft, Charlotte; Joerger, Markus

2017-10-01

Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD was initiated, and the two oral probe drugs midazolam (2 mg) and caffeine (100 mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R 2  = 0.960, p < 0.0001), OSI-420 (R 2  = 0.971, p < 0.0001), midazolam (R 2  = 0.995, p < 0.0001) and caffeine (R 2  = 0.968, p < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R 2  = 0.33, p = 0.048), while midazolam clearance was not (R 2  = -0.09, p = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, p = 0.086 for Student's t-test). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in patients with cancer. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Phenobarbital and midazolam increase neonatal seizure-associated neuronal injury.

PubMed

Torolira, Daniel; Suchomelova, Lucie; Wasterlain, Claude G; Niquet, Jerome

2017-07-01

Status epilepticus is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. γ-Aminobutyric acidergic (GABAergic) drugs, the standard treatment for neonatal seizures, can have excitatory effects in the neonatal brain, which may worsen the seizures and their effects. Using a recently developed model of status epilepticus in postnatal day 7 rat pups that results in widespread neuronal injury, we found that the GABA A agonists phenobarbital and midazolam significantly increased status epilepticus-associated neuronal injury in various brain regions. Our results suggest that more research is needed into the possible deleterious effects of GABAergic drugs on neonatal seizures and on excitotoxic neuronal injury in the immature brain. Ann Neurol 2017;82:115-120. © 2017 American Neurological Association.

Oral versus intravenous premedication for small bowel biopsy in children: effect on procedure and fluoroscopy times.

PubMed

Stenhammar, L; Wärngård, O; Lewander, P; Nordvall, M

1993-01-01

Oral alimemazine and cisapride, or diazepam and cisapride, or iv midazolam and metoclopramide were given as premedication for small bowel biopsy to three groups of children from a total population of 185 individuals. The biopsy procedures were performed under intermittent fluoroscopy and times for both were recorded. The median biopsy procedure time was significantly shorter in children given iv midazolam and metoclopramide (6 min) compared to those given oral premedication (10 min) (p < 0.001). The median fluoroscopy time was very short in all groups, ranging between 3 and 6 s. It is concluded that iv premedication is superior to oral premedication for small bowel biopsy in children because more effective sedation is obtained.

Intra- and inter-individual variation of BIS-index and Entropy during controlled sedation with midazolam/remifentanil and dexmedetomidine/remifentanil in healthy volunteers: an interventional study.

PubMed

Haenggi, Matthias; Ypparila-Wolters, Heidi; Hauser, Kathrin; Caviezel, Claudio; Takala, Jukka; Korhonen, Ilkka; Jakob, Stephan M

2009-01-01

We studied intra-individual and inter-individual variability of two online sedation monitors, BIS and Entropy, in volunteers under sedation. Ten healthy volunteers were sedated in a stepwise manner with doses of either midazolam and remifentanil or dexmedetomidine and remifentanil. One week later the procedure was repeated with the remaining drug combination. The doses were adjusted to achieve three different sedation levels (Ramsay Scores 2, 3 and 4) and controlled by a computer-driven drug-delivery system to maintain stable plasma concentrations of the drugs. At each level of sedation, BIS and Entropy (response entropy and state entropy) values were recorded for 20 minutes. Baseline recordings were obtained before the sedative medications were administered. Both inter-individual and intra-individual variability increased as the sedation level deepened. Entropy values showed greater variability than BIS(R) values, and the variability was greater during dexmedetomidine/remifentanil sedation than during midazolam/remifentanil sedation. The large intra-individual and inter-individual variability of BIS and Entropy values in sedated volunteers makes the determination of sedation levels by processed electroencephalogram (EEG) variables impossible. Reports in the literature which draw conclusions based on processed EEG variables obtained from sedated intensive care unit (ICU) patients may be inaccurate due to this variability. clinicaltrials.gov Nr. NCT00641563.

Total intravenous anaesthesia in a goat undergoing craniectomy.

PubMed

Vieitez, Verónica; Álvarez Gómez de Segura, Ignacio; López Rámis, Víctor; Santella, Massimo; Ezquerra, Luis Javier

2017-09-15

Cerebral coenurosis is a disease of the central nervous system in sheep and goats, and is usually fatal unless surgical relief is provided. Information regarding neuroanaesthesia in veterinary medicine in goats is scant. We describe anaesthetic management of an intact female goat (2 years; 16 kg) presented for craniectomy. The goat was sedated with xylazine (0.05 mg kg -1 , i.m.) and morphine (0.05 mg kg -1 , i.m.). General anaesthesia was induced 20 min later with propofol and maintained with a constant rate infusion of propofol (0.2 mg kg -1  min -1 ). A cuffed endotracheal tube was placed and connected to a rebreathing (circle) system and mechanical ventilation with 100% oxygen was initiated. A bolus of lidocaine (1 mg kg -1 ), midazolam (0.25 mg kg -1 ) and fentanyl 2.5 μg kg -1 was delivered via the intravenous route followed immediately by a constant rate infusion of lidocaine (50 μg kg -1  min -1 ), midazolam (0.15 mg kg -1  h -1 ) and fentanyl (6 μg kg -1  h -1 ) administered via the intravenous route throughout surgery. Craniectomy was undertaken and the goat recovered uneventfully. Total intravenous anaesthesia with propofol, lidocaine, fentanyl and midazolam could be an acceptable option for anaesthesia during intracranial surgery in goats.

Safe and efficacious use of procedural sedation and analgesia by nonanesthesiologists in a pediatric emergency department.

PubMed

Pitetti, Raymond D; Singh, Sonia; Pierce, Mary Clyde

2003-11-01

Children often require relief of pain and anxiety when undergoing diagnostic or therapeutic procedures in the emergency department (ED). Procedural sedation and analgesia (PSA) has become standard practice in the outpatient setting for such procedures. Few studies have looked at the overall success and incidence of complications of PSA as performed by nonanesthesiologists. To prospectively describe PSA as performed in a pediatric ED and to report the success of sedation and incidence of complications. Prospective descriptive study. Setting and Population Subjects aged 0 to 21 years presenting to the ED of an urban, tertiary care, children's hospital between May 1, 1997, and April 30, 1999, requiring PSA for a diagnostic or therapeutic procedure. A PSA form was designed and used by ED personnel to record pertinent clinical and demographic characteristics of patients, information related to the procedure, vital signs, and occurrence of complications. Success of sedation was defined a priori as successful completion of the procedure in a minimally responsive subject. Complications were defined as apnea, hypoxia (sustained pulse oximetry, <93%), seizure, arrhythmia, laryngospasm, stridor, hypotension, rash, vomiting, disinhibition, or aspiration. Follow-up telephone calls were made to families within 24 to 48 hours of discharge from the ED to document further complications. Rate of success of sedation and incidence of complications. Procedural sedation and analgesia was performed 1244 times in 1215 patients during the study. The median age of the patients was 5.9 years (mean age, 6.9 years; range, 2 months to 19.4 years). There were 791 boys (65.1%) and 424 girls (34.9%). A little more than half of the patients (643 or 52.9%) required PSA for fracture reduction and 396 (32.6%) for laceration repair. Intravenous (IV) fentanyl citrate and midazolam hydrochloride was provided in 734 sedation events (59.0%); IV ketamine hydrochloride, midazolam, and atropine sulfate in 293 (23.6%); and intramuscular ketamine, midazolam, and atropine in 82 (6.6%). Procedural sedation and analgesia was successfully provided in 1177 (98.6%) of 1194 sedation events. Complications occurred in 207 (17.8%) of 1161 events. The most common complication was hypoxia (79.1% of patients), followed by vomiting (6.2% of patients). No patient required intubation. One patient had an oral airway placed, 3 patients received flumazenil, 3 patients received naloxone hydrochloride, and 1 patient received naloxone and bag-valve-mask ventilation. Seventy (9.8%) of 717 patients, following discharge from the ED, reported minor complications related to PSA. The most common complication was vomiting (76.7% of patients), followed by persistent dizziness (6.8% of patients). Patients who received IV fentanyl and midazolam were significantly more likely to experience a complication during PSA (P<.001), while patients sedated using IV ketamine, midazolam, and atropine (P =.006) or IV midazolam alone (P =.005) were less likely. No difference in success of sedation or incidence of complications at follow-up was found between the types of PSA provided. Complications related to PSA occurred in 17.9% of patients, but most commonly consisted of hypoxia that was easily treated. Sedation was successful in 98.6% of patients. Procedural sedation and analgesia can be safely and effectively provided by nonanesthesiologists in a pediatric ED.

The safety and efficacy of using a concentrated intranasal midazolam formulation for paediatric dental sedation.

PubMed

Wood, Michael

2011-01-01

To add to the evidence base for safe and effective paediatric conscious sedation techniques in primary dental care. To consider the safety and effectiveness of an alternative sedation technique for facilitating dental treatment in anxious children, thereby avoiding dental general anaesthetic. Leagrave Dental Sedation Clinic. A primary care-based general and referral clinic for anxious patients, special care dentistry and oral surgery. This is a prospective service evaluation of 114 selected anxious children requiring invasive dental treatment. Each child was administered 0.25 mg/kg intranasal midazolam using a concentrated 40 mg/ml midazolam (INM) in 2% lignocaine solution. Successful completion of intended dental treatment with a child who is co-operative and who meets the UK accepted definition of conscious sedation. 57% of the children found the administration of the new formulation acceptable. Of the 114 patients who received INM, 104 completed the treatment (91%). The 10 children who could not complete the treatment with INM were converted to intravenous sedation and treatment was completed successfully at the same appointment. During treatment there was no desaturation and only one patient desaturated briefly in the recovery area. Parents rated the technique acceptable in 76% of cases and would have the procedure repeated in 83% of cases. Parents rated this technique as having 8.3 out of 10 with only 5 parents awarding a score of less than 7 out of 10. Side effects included blurred vision, sneezing, headaches, restlessness with one patient having post-operative nausea and vomiting. In selected cases intranasal sedation provides a safe and effective alternative for dental GA in short invasive procedures limited to one or two quadrants in children. Other techniques, e.g., oral and intravenous sedation, appear to have a much higher acceptability of administration. This technique may be useful if inhalation sedation, oral sedation or intravenous sedation is considered and the child is still unco-operative, either as a technique on its own or to facilitate cannulation for intravenous sedation. It is recommended that this technique should only be used by dentists skilled in intravenous paediatric sedation with midazolam with the appropriate staff training and equipment at their disposal.

The safety and efficacy of intranasal midazolam sedation combined with inhalation sedation with nitrous oxide and oxygen in paediatric dental patients as an alternative to general anaesthesia.

PubMed

Wood, Michael

2010-01-01

Conscious Decision' was published in 2000 by the Department of Health, effectively ending the provision of dental general anaesthesia (DGA) outside the hospital environment. Other aspects of dental anxiety and behavioural management and sedation techniques were encouraged before the decision to refer for a DGA was reached. Although some anxious children may be managed with relative analgesia (RA), some may require different sedation techniques for dentists to accomplish dental treatment. Little evidence has been published in the UK to support the use of alternative sedation techniques in children. This paper presents another option using an alternative conscious sedation technique. to determine whether a combination of intranasal midazolam (IN) and inhalation sedation with nitrous oxide and oxygen is a safe and practical alternative to DGA. A prospective clinical audit of 100 cases was carried out on children referred to a centre for DGA. 100 children between 3 and 13 years of age who were referred for DGA were treated using this technique. Sedation was performed by intranasal midazolam followed by titrating a mixture of nitrous oxide and oxygen. A range of dental procedures was carried out while the children were sedated. Parents were present during the dental treatment. Data related to the patient, dentistry and treatment as well as sedation variables were collected at the treatment visit and a telephonic post-operative assessment from the parents was completed a week later. It was found that 96% of the required dental treatment was completed successfully using this technique, with parents finding this technique acceptable in 93% of cases. 50% of children found the intranasal administration of the midazolam acceptable. There was no clinically relevant oxygen desaturation during the procedure. Patients were haemodynamically stable and verbal contact was maintained throughout the procedure. In selected cases this technique provides a safe and effective alternative to DGA and could reduce the number of patients referred to hospitals for DGA. It is recommended that this technique should only be used by dentists skilled in sedation with the appropriate staff and equipment at their disposal.

Anxiolytic Treatment Impairs Helping Behavior in Rats

PubMed Central

Ben-Ami Bartal, Inbal; Shan, Haozhe; Molasky, Nora M. R.; Murray, Teresa M.; Williams, Jasper Z.; Decety, Jean; Mason, Peggy

2016-01-01

Despite decades of research with humans, the biological mechanisms that motivate an individual to help others remain poorly understood. In order to investigate the roots of pro-sociality in mammals, we established the helping behavior test, a paradigm in which rats are faced with a conspecific trapped in a restrainer that can only be opened from the outside. Over the course of repeated test sessions, rats exposed to a trapped cagemate learn to open the door to the restrainer, thereby helping the trapped rat to escape (Ben-Ami Bartal et al., 2011). The discovery of this natural behavior provides a unique opportunity to probe the motivation of rodent helping behavior, leading to a deeper understanding of biological influences on human pro-sociality. To determine if an affective response motivates door-opening, rats receiving midazolam, a benzodiazepine anxiolytic, were tested in the helping behavior test. Midazolam-treated rats showed less helping behavior than saline-treated rats or rats receiving no injection. Yet, midazolam-treated rats opened a restrainer containing chocolate, highlighting the socially specific effects of the anxiolytic. To determine if midazolam interferes with helping through a sympatholytic effect, the peripherally restricted beta-adrenergic receptor antagonist nadolol was administered; nadolol did not interfere with helping. The corticosterone response of rats exposed to a trapped cagemate was measured and compared to the rats’ subsequent helping behavior. Rats with the greatest corticosterone responses showed the least helping behavior and those with the smallest responses showed the most consistent helping at the shortest latency. These results are discussed in terms of their implications for the interaction between stress and pro-social behavior. Finally, we observed that door-opening appeared to be reinforcing. A novel analytical tool was designed to interrogate the pattern of door-opening for signs that a rat’s behavior on one session influenced his behavior on the next session. Results suggest that helping a trapped rat has a greater motivational value than does chocolate. In sum, this series of experiments clearly demonstrates the fundamental role of affect in motivating pro-social behavior in rodents and the need for a helper to resonate with the affect of a victim. PMID:27375528

Development and validation of a method using supported liquid extraction for the simultaneous determination of midazolam and 1'-hydroxy-midazolam in human plasma by liquid chromatography with tandem mass spectrometry detection.

PubMed

Svanström, Camilla; Hansson, Gunnar P; Svensson, Leif D; Sennbro, Carl Johan

2012-01-25

The metabolic conversion of midazolam (MDZ) to its main metabolite 1'-hydroxy-midazolam (1-OH-MDZ) can be used as a probe drug for cytochrome P450 3A (CYP3A) activity. A sensitive method for the simultaneous determination of MDZ and its metabolite 1-OH-MDZ in human plasma using supported liquid extraction (SLE) in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection was developed and validated. Plasma samples (100 μL) were diluted with 0.5M NH(3) (aq) containing deuterated internal standards. The samples were extracted with ethyl acetate on a 96-well SLE-plate. Separation was performed on a Symmetry Shield RP18 column using an acidic gradient running from 2% to 95% methanol in 3 min. Detection was performed using a triple quadrupole mass spectrometer running in positive electrospray selected reaction monitoring (SRM) mode. The validated dynamic range was 0.2-100 nmol/L for both analytes. In the concentration range 0.6-75 nmol/L the extraction recoveries were in the ranges 91.2-98.6% and 94.5-98.3% for MDZ and 1-OH-MDZ, respectively. Matrix effects were more pronounced for MDZ than for 1-OH-MDZ but the response was still 75.4% or higher compared to a reference. The overall repeatability was within 2.2-7.6% for both analytes, the overall reproducibility was within 3.1-10.2% for both analytes and the overall accuracy bias was within -1.1 to 7.5% for both analytes. The method was successfully applied to determine the plasma concentrations of MDZ and 1-OH-MDZ in 14 healthy volunteers up to 24h after administration of a single oral dose of 2mg MDZ. The SLE technology was found to be convenient and suitable for sample preparation, and the developed method was found to be rapid, selective and reproducible for the simultaneous determination of MDZ and 1-OH-MDZ in human plasma. Copyright © 2011 Elsevier B.V. All rights reserved.

Spinal myoclonus following intrathecal administration of diatrizoate meglumine.

PubMed

Sam, M C; Gutmann, L

1996-10-01

Life-threatening myoclonus developed in a patient following inadvertent intrathecal usage of 60% diatrizoate meglumine. Rhabdomyolysis and myoglobinuria occurred. The patient was successfully treated with midazolam and vecuronium and complete recovery occurred.

Effects of morphine-alfaxalone-midazolam premedication, alfaxalone induction and sevoflurane maintenance on intraocular pressure and tear production in dogs.

PubMed

Mayordomo-Febrer, A; Rubio, M; Martínez-Gassent, M; López-Murcia, M M

2017-05-13

Intraocular pressure (IOP) and tear production are commonly affected by general anaesthesia. It is necessary to have a good control of both to guarantee successful ophthalmic surgery. The purpose of this research was to evaluate if the protocol based on the administration of morphine-alfaxalone-midazolam as premedication, alfaxalone as induction and sevoflurane as maintenance, can induce changes on IOP and Schirmer's tear test (STT-1) in healthy dogs. Twenty-two adult mixed-breed dogs scheduled for an ovariohysterectomy were enrolled for the study. IOP and STT-1 were registered at baseline (T 0 ), 5 minutes (T 1 ), 10 minutes (T 2 ) and 15 minutes (T 3 ) after premedication with a morphine-alfaxalone-midazolam combination; 5 minutes (T 4 ) after induction with alfaxalone and 15 minutes (T 5 ) and 25 minutes (T 6 ) after maintenance with sevoflurane. A one-way analysis of variance was performed to analyse the difference between IOP and STT-1 over time, respectively. The present study shows a slightly statistically significant increase in IOP (P<0.05) after premedication, induction and maintenance that can be associated with this anaesthetic protocol. STT-1 showed a statistically significant reduction during all the procedures (P<0.001). These results should be taken into consideration, especially in dogs with damaged corneas, in those predisposed to glaucoma and in those due to undergo intraocular surgery. Ocular lubrication is necessary if this protocol is used. British Veterinary Association.

The Efficacy of Two Intravenous Sedative Drugs in Management of Uncooperative Children for Dental Treatments

PubMed Central

Kaviani, Nasser; Ashrafi, Sanaz; Jabbarifar, Seyed Ebrahim; Ghaffari, Elham

2015-01-01

Statement of the Problem Some children do not show an appropriate cooperation with their dentist. A number of them cannot be managed by local anesthesia and the usual techniques used to control behaviors, so further steps are required to control their pain and anxiety. Pharmaceutical control is recommended through sedation or general anesthesia. Purpose This study was aimed to evaluate two groups of drugs in intravenous sedation method. Materials and Method In this clinical trial intervention study, patients were randomly divided into two groups of 18 and 20 and each group received either intravenous midazolam-ketamine or midazolam-fentanyl. During the procedure, 0.25mg midazolam was administered to both groups if needed. The scores of intraoperative sedation and operation conditions were evaluated and recorded by dental sedation teacher groups (DSTG) system in the 10th, 20th, 30th and 40th minutes of the operation. The results were analyzed by SPSS (version 16) using independent T-test, Wilcoxon, Mann-Whitney and Pearson Chi-Square tests as appropriated. Results There was no significant difference between the two groups in sedation period (p= 0.55), recovery time (p= 0.18), Frankl score (p= 0.83(, score of intraoperative sedation and operating conditions (p> 0.05), and sedation complications (p= 0.612). In addition, no complication occurred in recovery. Conclusion There was no significant difference between the two drug groups; both were appropriate in controlling children’s behavior. PMID:26106632

Balanced propofol sedation administered by nonanesthesiologists: The first Italian experience

PubMed Central

Repici, Alessandro; Pagano, Nico; Hassan, Cesare; Carlino, Alessandra; Rando, Giacomo; Strangio, Giuseppe; Romeo, Fabio; Zullo, Angelo; Ferrara, Elisa; Vitetta, Eva; Ferreira, Daniel de Paula Pessoa; Danese, Silvio; Arosio, Massimo; Malesci, Alberto

2011-01-01

AIM: To assess the efficacy and safety of a balanced approach using midazolam in combination with propofol, administered by non-anesthesiologists, in a large series of diagnostic colonoscopies. METHODS: Consecutive patients undergoing diagnostic colonoscopy were sedated with a single dose of midazolam (0.05 mg/kg) and low-dose propofol (starter bolus of 0.5 mg/kg and repeated boluses of 10 to 20 mg). Induction time and deepest level of sedation, adverse and serious adverse events, as well as recovery times, were prospectively assessed. Cecal intubation and adenoma detection rates were also collected. RESULTS: Overall, 1593 eligible patients were included. The median dose of propofol administered was 70 mg (range: 40-120 mg), and the median dose of midazolam was 2.3 mg (range: 2-4 mg). Median induction time of sedation was 3 min (range: 1-4 min), and median recovery time was 23 min (range: 10-40 min). A moderate level of sedation was achieved in 1561 (98%) patients, whilst a deep sedation occurred in 32 (2%) cases. Transient oxygen desaturation requiring further oxygen supplementation occurred in 8 (0.46%; 95% CI: 0.2%-0.8%) patients. No serious adverse event was observed. Cecal intubation and adenoma detection rates were 93.5% and 23.4% (27.8% for male and 18.5% for female, subjects), respectively. CONCLUSION: A balanced sedation protocol provided a minimalization of the dose of propofol needed to target a moderate sedation for colonoscopy, resulting in a high safety profile for non-anesthesiologist propofol sedation. PMID:21987624

Feasibility of sedation and analgesia interruption following cannulation in neonates on extracorporeal membrane oxygenation

PubMed Central

Wildschut, E. D.; Hanekamp, M. N.; Vet, N. J.; Houmes, R. J.; Ahsman, M. J.; Mathot, R. A. A.; de Wildt, S. N.

2010-01-01

Purpose In most extracorporeal membrane oxygenation (ECMO) centers patients are heavily sedated to prevent accidental decannulation and bleeding complications. In ventilated adults not on ECMO, daily sedation interruption protocols improve short- and long-term outcome. This study aims to evaluate safety and feasibility of sedation interruption following cannulation in neonates on ECMO. Methods Prospective observational study in 20 neonates (0.17–5.8 days of age) admitted for ECMO treatment. Midazolam (n = 20) and morphine (n = 18) infusions were discontinued within 30 min after cannulation. Pain and sedation were regularly assessed using COMFORT-B and visual analog scale (VAS) scores. Midazolam and/or morphine were restarted and titrated according to protocolized treatment algorithms. Results Median (interquartile range, IQR) time without any sedatives was 10.3 h (5.0–24.1 h). Median interruption duration for midazolam was 16.5 h (6.6–29.6 h), and for morphine was 11.2 h (6.7–39.4 h). During this period no accidental extubations, decannulations or bleeding complications occurred. Conclusions This is the first study to show that interruption of sedatives and analgesics following cannulation in neonates on ECMO is safe and feasible. Interruption times are 2–3 times longer than reported for adult ICU patients not on ECMO. Further trials are needed to substantiate these findings and evaluate short- and long-term outcomes. PMID:20508914

Drug incompatibilities in the adult intensive care unit of a university hospital

PubMed Central

Marsilio, Naiane Roveda; da Silva, Daiandy; Bueno, Denise

2016-01-01

Objectives This study sought to identify the physical and chemical incompatibilities among the drugs administered intravenously to patients admitted to an adult intensive care unit. We also aimed to establish pharmaceutical guidelines for administering incompatible drugs. Methods This cross-sectional, prospective, and quantitative study was conducted from July to September 2015. Drug incompatibilities were identified based on an analysis of the patient prescriptions available in the hospital online management system. A pharmaceutical intervention was performed using the guidelines on the preparation and administration of incompatible drugs. Adherence to those guidelines was subsequently assessed among the nursing staff. Results A total of 100 prescriptions were analyzed; 68 were incompatible with the intravenous drugs prescribed. A total of 271 drug incompatibilities were found, averaging 4.0 ± 3.3 incompatibilities per prescription. The most commonly found drug incompatibilities were between midazolam and hydrocortisone (8.9%), between cefepime and midazolam (5.2%), and between hydrocortisone and vancomycin (5.2%). The drugs most commonly involved in incompatibilities were midazolam, hydrocortisone, and vancomycin. The most common incompatibilities occurred when a drug was administered via continuous infusion and another was administered intermittently (50%). Of the 68 prescriptions that led to pharmaceutical guidelines, 45 (66.2%) were fully adhered to by the nursing staff. Conclusion Patients under intensive care were subjected to a high rate of incompatibilities. Drug incompatibilities can be identified and eliminated by the pharmacist on the multidisciplinary team, thereby reducing undesirable effects among patients. PMID:27410410

Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society

PubMed Central

Shinnar, Shlomo; Gloss, David; Alldredge, Brian; Arya, Ravindra; Bainbridge, Jacquelyn; Bare, Mary; Bleck, Thomas; Dodson, W. Edwin; Garrity, Lisa; Jagoda, Andy; Lowenstein, Daniel; Pellock, John; Riviello, James; Sloan, Edward; Treiman, David M.

2016-01-01

CONTEXT: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. OBJECTIVE: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. DATA SOURCES: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. STUDY SELECTION: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. DATA EXTRACTION: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. RESULTS: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. CONCLUSIONS: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline. PMID:26900382

[Effect of dexmedetomidine and midazolam on respiration and circulation functions in patients undergoing open heart surgery under acupuncture-assisted general anesthesia].

PubMed

Tang, Wei; Wang, Jian; Fu, Guo-Qiang; Yuan, Lan

2014-06-01

To evaluate the effect of Dexmedetomidine and Midazolam on respiratory and circulation in patients experiencing open heart surgery under acupuncture-assisted general anesthesia. Sixty patients undergoing open heart surgery (cardiac valve replacement surgery and aortic valve replacement surgery) were randomly and equally divided into Dexmedetomidine (D) and Midazolam (M) groups. Electroacupuncture (EA) was applied to bilateral Yunmen (LU 2), Zhongfu (LU1), Lieque (LU7) and Neiguan (PC6). For patients of group D, Dexmedetomidine (i.v., loading dose: 1 microg/kg, and succedent dose: 0.2-1 microg x kg(-1) x h(-1)) was given. For patients of group M, Midazolam (i.v., loading dose: 0.05 mg/kg, succedent dose: 0.01-0.03 mg x kg(-1) x h(-1)) was given. Arterial oxygen pressure (PaO2), arterial carbondioxide tension (PaCO2), O2 saturation (SPO2), mean arterial pressure (MAP), heart rate (HR), anesthetic effect, time of spontaneous breathing recovery, and time of resuscitation were recorded before operation (T0), immediately after skin incision (T1), immediately after sternotomy (T2), before suspension of cardiopulmonary bypass (CPB, T3), immediately after cardiac re-beating (T4), immediately after CPB cessation (T5), and at the end of surgery (T6). Before operation, no significant differences were found between the group D and M in the levels of PaO2, PaCO2 and SPO2 (P > 0.05). The PaO2 and SPO2 levels after skin incision, sternotomy, before suspension of CPB and at the end of surgery were significantly lower in group M than in group D (P < 0.05), while the le- vels of PaCO2 after skin incision, sternotomy, before suspension of CPB and at the end of surgery, and HR after skin incision, sternotomy, before suspension of CPB, after heart re-beating,after CPB cessation and at the end of surgery in group M were considerably higher than those in group D (P < 0.05). In addition, the time of spontaneous breathing recovery of group M was significantly later than that of group D (P < 0.05). No significant differences were found between the two groups in MAP levels at the 6 time-points during surgery, in the PaO2, PaCO2 and SPO2 levels at the time-points of post-cardiac re-beating, and after CPB cessation (P > 0.05). It suggested that the respiration and circulation states in group D were more smoothly than those in group M. There was no significant difference between the two groups in the time of resuscitation (P > 0.05). Dexmedetomidine is superior to Midazolam in analgesia, and improving respiration and circulation functions for open heart surgery patients under acupuncture-assisted general anesthesia.

Dexmedetomidine, Ketamine, and Midazolam for Oral Rehabilitation: A Case Report

PubMed Central

Kim, Bill W. S.; Peskin, Robert M.

2015-01-01

Intravenous sedation is frequently provided by anesthesiologists for phobic patients undergoing elective dental treatment in outpatient settings. Propofol is one of the most commonly used anesthetic agents that can result in apnea and respiratory depression, thereby posing potential difficulties with perioperative airway management. Dexmedetomidine has been utilized successfully in intravenous sedation for a wide variety of procedures and holds potential as an alternative to propofol in outpatient dental settings. However, as a single agent, it may not provide adequate depth of sedation and analgesia for oral rehabilitation. In this case report we demonstrate an effective alternative intravenous deep-sedation technique for an adult phobic patient undergoing oral rehabilitation utilizing 3 agents in combination: dexmedetomidine, ketamine, and midazolam. This combination of agents may be especially useful for those patients with a history of substance abuse, where administration of opioids may be undesirable or contraindicated. PMID:25849472

Dexmedetomidine, ketamine, and midazolam for oral rehabilitation: a case report.

PubMed

Kim, Bill W S; Peskin, Robert M

2015-01-01

Intravenous sedation is frequently provided by anesthesiologists for phobic patients undergoing elective dental treatment in outpatient settings. Propofol is one of the most commonly used anesthetic agents that can result in apnea and respiratory depression, thereby posing potential difficulties with perioperative airway management. Dexmedetomidine has been utilized successfully in intravenous sedation for a wide variety of procedures and holds potential as an alternative to propofol in outpatient dental settings. However, as a single agent, it may not provide adequate depth of sedation and analgesia for oral rehabilitation. In this case report we demonstrate an effective alternative intravenous deep-sedation technique for an adult phobic patient undergoing oral rehabilitation utilizing 3 agents in combination: dexmedetomidine, ketamine, and midazolam. This combination of agents may be especially useful for those patients with a history of substance abuse, where administration of opioids may be undesirable or contraindicated.

Comparative evaluation of bispectral index system after sedation with midazolam and propofol combined with remifentanil versus ketamine in uncooperative during dental procedures

PubMed Central

Eshghi, Alireza; Mohammadpour, Mehrnaz; Kaviani, Nasser; Tahririan, Dana; Akhlaghi, Najmeh

2016-01-01

Background: Proper analgesic agents should be used in combination with sedative agents. Remifentanil is a synthetic narcotic/analgesic agent with a short duration effect and decreases the risk of apnea during recovery. Bispectral index system (BIS) is a new noninvasive technique for the evaluation of the depth of sedation. The aim of present clinical trial was to evaluate and compare the efficacy of intravenous sedation with propofol/midazolam/remifentanil (PMR) in comparison to propofol/midazolam/ketamine (PMK) for dental procedures in children 3-7 years of age. Materials and Methods: In this clinical trial, 32 healthy uncooperative children who were candidates for dental treatments under sedation were randomly divided into two groups. Intravenous sedation was induced with PMR in one group and with PMK in the other group. After injection and during procedure BIS index, heart rate and respiratory rate, blood pressure, and oxygen saturation was evaluated every 5 min. After the procedure, recovery time was measured. Data were analyzed with ANOVA, Friedman, Wilcoxon, and t-test. Results: The BIS value was significantly low in ketamin group (P = 0.003) but respiratory rates and heart rates were same in both groups with no statistical difference (P = 0.884, P = 0.775). The recovery time was significantly shorter in remifentanil group (P = 0.008 and P = 0.003). Conclusion: It can be concluded that intravenous sedation technique with PMR combination induces effective and safe sedation, with less pain and more forgetfulness and a shorter recovery time for children 3-7 years of age during dental procedures. PMID:26962308

The effect of play distraction on anxiety before premedication administration: a randomized trial.

PubMed

Bumin Aydın, Gözde; Yüksel, Serhat; Ergil, Jülide; Polat, Reyhan; Akelma, Fatma Kavak; Ekici, Musa; Sayın, Murat; Odabaş, Öner

2017-02-01

The majority of children scheduled to undergo surgery experience substantial anxiety in the preoperative holding area before induction of anesthesia. Pharmacological interventions aimed at reducing perioperative anxiety are paradoxically a source of stress for children themselves. Midazolam is frequently used as premedication, and the formula of this drug in Turkey is bitter. We aimed to assess the role of distraction in the form of playing with play dough (Play-Doh) on reducing premedication anxiety in children. Prospective randomized clinical trial. Preoperative holding area. One hundred four healthy children aged 3 to 7 years scheduled to undergo elective surgery were enrolled into the study. All children routinely receive sedative premedication (oral midazolam) before anesthesia. Children were randomized to 2 groups to receive either play dough (group PD) (n=52) or not (group C) (n=52) before administration of oral premedication. Children's premedication anxiety was determined by the modified Yale Preoperative Anxiety Scale (mYPAS). The difference in mYPAS scores between groups at T 0 (immediately after entering the preoperative holding area) was not significant (P=.876). Compared with group C, group PD was associated with lower mYPAS scores at T 1 and T 2 (P<.001). In group PD, mYPAS scores were significantly lower at both T 1 and T 2 as compared with the scores at T 0 (P<.001); they were similar between T 1 and T 2 (P>.001). This study showed that distraction in the form of playing with play dough facilitated administration of oral midazolam in young children. Copyright © 2016. Published by Elsevier Inc.

Sedation or Inhalant Anesthesia before Euthanasia with CO2 Does Not Reduce Behavioral or Physiologic Signs of Pain and Stress in Mice

PubMed Central

Valentine, Helen; Williams, Wendy O; Maurer, Kirk J

2012-01-01

CO2 administration is a common euthanasia method for research mice, yet questions remain regarding whether CO2 euthanasia is associated with pain and stress. Here we assessed whether premedication with acepromazine, midazolam, or anesthetic induction with isoflurane altered behavioral and physiologic parameters that may reflect pain or stress during CO2 euthanasia. Mice were assigned to 1 of 6 euthanasia groups: CO2 only at a flow rate of 1.2 L/min which displaces 20% of the cage volume per minute (V/min; control group); premedication with acepromazine (5 mg/kg), midazolam (5 mg/kg), or saline followed by 20% V/min CO2; induction with 5% isoflurane followed by greater than 100% V/min CO2 (>6L/min); and 100% V/min CO2 only (6 L/min). Measures included ultrasonic sound recordings, behavioral analysis of video recordings, plasma ACTH and corticosterone levels immediately after euthanasia, and quantification of c-fos from brain tissue. Compared with 20% V/min CO2 alone, premedication with acepromazine or midazolam did not significantly alter behavior but did induce significantly higher c-fos expression in the brain. Furthermore, the use of isoflurane induction prior to CO2 euthanasia significantly increased both behavioral and neuromolecular signs of stress. The data indicate that compared with other modalities, 20% V/min CO2 alone resulted in the least evidence of stress in mice and therefore was the most humane euthanasia method identified in the current study. PMID:22330868

Sedation or inhalant anesthesia before euthanasia with CO2 does not reduce behavioral or physiologic signs of pain and stress in mice.

PubMed

Valentine, Helen; Williams, Wendy O; Maurer, Kirk J

2012-01-01

CO(2) administration is a common euthanasia method for research mice, yet questions remain regarding whether CO(2) euthanasia is associated with pain and stress. Here we assessed whether premedication with acepromazine, midazolam, or anesthetic induction with isoflurane altered behavioral and physiologic parameters that may reflect pain or stress during CO(2) euthanasia. Mice were assigned to 1 of 6 euthanasia groups: CO(2) only at a flow rate of 1.2 L/min which displaces 20% of the cage volume per minute (V/min; control group); premedication with acepromazine (5 mg/kg), midazolam (5 mg/kg), or saline followed by 20% V/min CO(2); induction with 5% isoflurane followed by greater than 100% V/min CO(2) (>6L/min); and 100% V/min CO(2) only (6 L/min). Measures included ultrasonic sound recordings, behavioral analysis of video record- ings, plasma ACTH and corticosterone levels immediately after euthanasia, and quantification of c-fos from brain tissue. Compared with 20% V/min CO(2) alone, premedication with acepromazine or midazolam did not significantly alter behavior but did induce significantly higher c-fos expression in the brain. Furthermore, the use of isoflurane induction prior to CO(2) euthanasia significantly increased both behavioral and neuromolecular signs of stress. The data indicate that compared with other modalities, 20% V/min CO(2) alone resulted in the least evidence of stress in mice and therefore was the most humane euthanasia method identified in the current study.

The effects of nitric oxide synthase inhibitors on the sedative effect of clonidine.

PubMed

Soares de Moura, R; Rios, A A; de Oliveira, L F; Resende, A C; de Lemos Neto, M; Santos, E J; Correia, M L; Tano, T

2001-11-01

The mechanism underlying the Niteroi, Rio de Janeiro sedative effect of clonidine, an alpha2-adrenoceptor agonist, remains uncertain. Because activation of alpha2-adrenoceptors induces release of nitric oxide (NO), we tested the hypothesis that the sedative effect of clonidine depends on NO-related mechanisms. The effect of 7-nitro indazole on the sleeping time induced by clonidine was studied in Wistar rats. In addition, we examined the effect of clonidine, alpha-methyldopa, and midazolam on the thiopental-induced sleeping time in rats pretreated with N(G)-nitro-L-arginine-methyl-ester (L-NAME). The sleeping time induced by clonidine was significantly decreased by 7-nitro indazole. Thiopental sleeping time was increased by clonidine, alpha-methyldopa, and midazolam. L-NAME reduced the prolongation effect of clonidine and alpha-methyldopa, but did not alter the effect of midazolam on the thiopental-induced sleeping time. The inhibitory effect of L-NAME on clonidine-dependent prolongation of thiopental-induced sleeping time was reversed by L-arginine. These results suggest that NO-dependent mechanisms are involved in the sedative effect of clonidine. In addition, this effect seems to be specific for the sedative action of alpha2-adrenoceptors agonists. Clonidine, an antihypertensive drug, is also a sedative. This sedative effect, although an adverse event in the treatment of hypertensive patients, can be helpful for sedation of surgical patients. The mechanism of this effect, however, is unknown. In this study, we show that the sedative effect of clonidine is mediated by nitric oxide, because it could be prevented by pretreatment with nitric oxide synthase inhibitors.

Haloperidol plus promethazine for psychosis-induced aggression.

PubMed

Huf, Gisele; Alexander, Jacob; Gandhi, Pinky; Allen, Michael H

2016-11-25

Health services often manage agitated or violent people, and such behaviour is particularly prevalent in emergency psychiatric services (10%). The drugs used in such situations should ensure that the person becomes calm swiftly and safely. To examine whether haloperidol plus promethazine is an effective treatment for psychosis-induced aggression. On 6 May 2015 we searched the Cochrane Schizophrenia Group's Register of Trials, which is compiled by systematic searches of major resources (including MEDLINE, EMBASE, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. All randomised clinical trials with useable data focusing on haloperidol plus promethazine for psychosis-induced aggression. We independently extracted data. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. We found two new randomised controlled trials (RCTs) from the 2015 update searching. The review now includes six studies, randomising 1367 participants and presenting data relevant to six comparisons.When haloperidol plus promethazine was compared with haloperidol alone for psychosis-induced aggression for the outcome not tranquil or asleep at 30 minutes, the combination treatment was clearly more effective (n=316, 1 RCT, RR 0.65, 95% CI 0.49 to 0.87, high-quality evidence). There were 10 occurrences of acute dystonia in the haloperidol alone arm and none in the combination group. The trial was stopped early as haloperidol alone was considered to be too toxic.When haloperidol plus promethazine was compared with olanzapine, high-quality data showed both approaches to be tranquillising. It was suggested that the combination of haloperidol plus promethazine was more effective, but the difference between the two approaches did not reach conventional levels of statistical significance (n=300, 1 RCT, RR 0.60, 95% CI 0.22 to 1.61, high-quality evidence). Lower-quality data suggested that the risk of unwanted excessive sedation was less with the combination approach (n=116, 2 RCTs, RR 0.67, 95% CI 0.12 to 3.84).When haloperidol plus promethazine was compared with ziprasidone all data were of lesser quality. We identified no binary data for the outcome tranquil or asleep. The average sedation score (Ramsay Sedation Scale) was lower for the combination approach but not to conventional levels of statistical significance (n=60, 1 RCT, MD -0.1, 95% CI - 0.58 to 0.38). These data were of low quality and it is unclear what they mean in clinical terms. The haloperidol plus promethazine combination appeared to cause less excessive sedation but again the difference did not reach conventional levels of statistical significance (n=111, 2 RCTs, RR 0.30, 95% CI 0.06 to 1.43).We found few data for the comparison of haloperidol plus promethazine versus haloperidol plus midazolam. Average Ramsay Sedation Scale scores suggest the combination of haloperidol plus midazolam to be the most sedating (n=60, 1 RCT, MD - 0.6, 95% CI -1.13 to -0.07, low-quality evidence). The risk of excessive sedation was considerably less with haloperidol plus promethazine (n=117, 2 RCTs, RR 0.12, 95% CI 0.03 to 0.49, low-quality evidence). Haloperidol plus promethazine seemed to decrease the risk of needing restraints by around 12 hours (n=60, 1 RCT, RR 0.24, 95% CI 0.10 to 0.55, low-quality evidence). It may be that use of midazolam with haloperidol sedates swiftly, but this effect does not last long.When haloperidol plus promethazine was compared with lorazepam, haloperidol plus promethazine seemed to more effectively cause sedation or tranquillisation by 30 minutes (n=200, 1 RCT, RR 0.26, 95% CI 0.10 to 0.68, high-quality evidence). The secondary outcome of needing restraints or seclusion by 12 hours was not clearly different between groups, with about 10% in each group needing this intrusive intervention (moderate-quality evidence). Sedation data were not reported, however, the combination group did have less 'any serious adverse event' in 24-hour follow-up, but there were not clear differences between the groups and we are unsure exactly what the adverse effect was. There were no deaths.When haloperidol plus promethazine was compared with midazolam, there was clear evidence that midazolam is more swiftly tranquillising of an aggressive situation than haloperidol plus promethazine (n=301, 1 RCT, RR 2.90, 95% CI 1.75 to 4.8, high-quality evidence). On its own, midazolam seems to be swift and effective in tranquillising people who are aggressive due to psychosis. There was no difference in risk of serious adverse event overall (n=301, 1 RCT, RR 1.01, 95% CI 0.06 to 15.95, high-quality evidence). However, 1 in 150 participants allocated haloperidol plus promethazine had a swiftly reversed seizure, and 1 in 151 given midazolam had swiftly reversed respiratory arrest. Haloperidol plus promethazine is effective and safe, and its use is based on good evidence. Benzodiazepines work, with midazolam being particularly swift, but both midazolam and lorazepam cause respiratory depression. Olanzapine intramuscular and ziprasidone intramuscular do seem to be viable options and their action is swift, but resumption of aggression with subsequent need to re-inject was more likely than with haloperidol plus promethazine. Haloperidol used on its own without something to offset its frequent and serious adverse effects does seem difficult to justify.

Midazolam Injection

MedlinePlus

... few months of their pregnancy may affect the child's brain development. Other studies in infants and toddlers show that a single, short exposure to anesthetic and sedation drugs is unlikely to have negative effects on behavior or learning. However, further research is needed to ...

Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects.

PubMed

Dresser, George K; Schwarz, Ute I; Wilkinson, Grant R; Kim, Richard B

2003-01-01

Many drugs are cosubstrates of cytochrome P450 (CYP) 3A and MDR1; furthermore, their disposition is markedly affected by pretreatment with inducing agents, including St John's wort. Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor. However, the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown. The effects of 12 days' pretreatment with St John's wort on the disposition of selected in vivo probe drugs were determined in 21 young healthy subjects. Midazolam after oral and intravenous administration was used to assess CYP3A activity in both the intestinal epithelium and the liver, whereas the disposition of fexofenadine after an oral dose was assumed to be a measure of MDR1 function, and the oral plasma concentration-time profile of cyclosporine (INN, ciclosporin) was considered to reflect both CYP3A and MDR1 activities. St John's wort markedly affected the plasma concentration-time profiles of all of the drugs, with associated increases in their clearance. With midazolam, the enhancement was considerably less after intravenous administration (approximately 1.5-fold) than after oral administration (approximately 2.7-fold), and estimated intestinal and hepatic extraction ratios were higher by approximately 1.2- to 1.4-fold. By contrast, the oral clearances of fexofenadine and cyclosporine were equally increased by approximately 1.6-fold and 1.9-fold, respectively; these changes were both statistically less than for midazolam's oral clearance and greater than its estimated intestinal extraction. Although the disposition of all 3 drugs was altered by St John's wort, the extent of induction measured by oral clearance was different with CYP3A activity (midazolam), apparently increasing more than MDR1 function (fexofenadine), whereas with cyclosporine the change in oral clearance appeared to be more closely associated with the increase in MDR1 rather than CYP3A, despite the fact that both proteins are importantly involved in its disposition. These discordances indicate that, although a common molecular mechanism may be involved, the quantitative aspects of induction are complex and depend on the particular drug and the relative contributions of CYP3A and MDR1 in its disposition.

Continuous palliative sedation for patients with advanced cancer at a tertiary care cancer center.

PubMed

Prado, Bernard Lobato; Gomes, Diogo Bugano Diniz; Usón Júnior, Pedro Luiz Serrano; Taranto, Patricia; França, Monique Sedlmaier; Eiger, Daniel; Mariano, Rodrigo Coutinho; Hui, David; Del Giglio, Auro

2018-01-04

Palliative sedation (PS) is an intervention to treat refractory symptoms and to relieve suffering at the end of life. Its prevalence and practice patterns vary widely worldwide. The aim of our study was to evaluate the frequency, clinical indications and outcomes of PS in advanced cancer patients admitted to our tertiary comprehensive cancer center. We retrospectively studied the use of PS in advanced cancer patients who died between March 1st, 2012 and December 31st, 2014. PS was defined as the use of continuous infusion of midazolam or neuroleptics for refractory symptoms in the end of life. This study was approved by the Research Ethics Committee of our institution (project number 2481-15). During the study period, 552 cancer patients died at the institution and 374 met the inclusion criteria for this study. Main reason for exclusion was death in the Intensive Care Unit. Among all included patients, 54.2% (n = 203) received PS. Patients who received PS as compared to those not sedated were younger (67.8 vs. 76.4 years-old, p < 0.001) and more likely to have a diagnosis of lung cancer (23% vs. 14%, p = 0.028). The most common indications for sedation were dyspnea (55%) and delirium (19.7%) and the most common drugs used were midazolam (52.7%) or midazolam and a neuroleptic (39.4%). Median initial midazolam infusion rate was 0.75 mg/h (interquartile range - IQR - 0.6-1.5) and final rate was 1.5 mg/h (IQR 0.9-3.0). Patient survival (length of hospital stay from admission to death) of those who had PS was more than the double of those who did not (33.6 days vs 16 days, p < 0.001). The palliative care team was involved in the care of 12% (n = 25) of sedated patients. PS is a relatively common practice in the end-of-life of cancer patients at our hospital and it is not associated with shortening of hospital stay. Involvement of a dedicated palliative care team is strongly recommended if this procedure is being considered. Further research is needed to identify factors that may affect the frequency and outcomes associated with PS.

Antiemetic effects of midazolam added to fentanyl-ropivacaine patient-controlled epidural analgesia after subtotal gastrectomy: A prospective, randomized, double-blind, controlled trial

PubMed Central

Kim, Sioh; Seo, Jeongwon; Jeon, Younghoon

2010-01-01

Background: Nausea and vomiting are frequent adverse effects of patient-controlled epidural analgesia (PCEA) with opioids. Objective: This study was designed to assess the antiemetic effect of midazolam added to fentanyl—ropivacaine PCEA. Methods: In a prospective, randomized, double-blind, controlled trial, smoking patients with gastric cancer undergoing elective subtotal gastrectomy were evenly allocated to 1 of 2 treatment groups to manage postoperative pain: 0.2% ropivacaine mixed with fentanyl 4 μg/mL and midazolam 0.2 mg/mL (test group) or 0.2% ropivacaine mixed with fentanyl 4 μg/mL (control group). The PCEA infusion was set to deliver 4 μL/h of the study solution, with a bolus of 2 mL per demand and a 15-minute lockout time. The incidence of postoperative nausea and vomiting (PONV), pain intensity, sedation score, usage of rescue analgesia and rescue antiemetic, respiratory depression, urinary retention, and pruritus were recorded at 2, 6, 12, 24, 48, and 72 hours after surgery. Total infused volume of PCEA at 72 hours after surgery was measured. Results: A total of 60 patients were approached and randomized to treatment. No patients were excluded by exclusion criteria and all enrolled patients completed this study. Incidence of nausea (7% vs 33%; P = 0.02) in the test group was significantly lower than in the control group. The overall frequency of PONV in the test group was significantly less than that of the control group (7% vs 40%; P = 0.006). In addition, the mean (SD) infused volume of PCEA in the test group was significantly lower than that in the control group (392.3 [68.9] vs 351.2 [49.8] mL; P = 0.01). However, there were no significant differences in pain intensity, usage of rescue antiemetics and rescue analgesics, and mild pruritus between groups. No patient reported moderate or severe sedation, respiratory depression, or hypoxemia. In addition, there were no severe adverse events. Conclusions: Midazolam added to fentanyl-ropivacaine PCEA was associated with a significant reduction in the incidence of PONV compared with fentanyl-ropivacaine alone, and a significant decrease in the amount of PCEA administered without a significant increase in adverse events in these patients who underwent subtotal gastrectomy. PMID:24688151

78 FR 17895 - Schedules of Controlled Substances: Placement of Alfaxalone into Schedule IV

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-25

... (Schedule IV under consideration), and midazolam. Since alfaxalone is a new veterinary product and has not...[alpha]-ol-11, 20-dione. Alfaxalone has a molecular formula of C 21 H 32 O 3 and a molecular weight of...

A cost-effectiveness analysis of propofol versus midazolam for procedural sedation in the emergency department.

PubMed

Hohl, Corinne Michèle; Nosyk, Bohdan; Sadatsafavi, Mohsen; Anis, Aslam Hayat

2008-01-01

To determine the incremental cost-effectiveness of using propofol versus midazolam for procedural sedation (PS) in adults in the emergency department (ED). The authors conducted a cost-effectiveness analysis from the perspective of the health care provider. The primary outcome was the incremental cost (or savings) to achieve one additional successful sedation with propofol compared to midazolam. A decision model was developed in which the clinical effectiveness and cost of a PS strategy using either agent was estimated. The authors derived estimates of clinical effectiveness and risk of adverse events (AEs) from a systematic review. The cost of each clinical outcome was determined by incorporating the baseline cost of the ED visit, the cost of the drug, the cost of labor of physicians and nurses, the cost and probability of an AE, and the cost and probability of a PS failure. A standard meta-analytic technique was used to calculate the weighted mean difference in recovery times and obtain mean drug doses from patient-level data from a randomized controlled trial. Probabilistic sensitivity analyses were conducted to examine the uncertainty around the estimated incremental cost-effectiveness ratio using Monte Carlo simulation. Choosing a sedation strategy with propofol resulted in average savings of $17.33 (95% confidence interval [CI] = $24.13 to $10.44) per sedation performed. This resulted in an incremental cost-effectiveness ratio of -$597.03 (95% credibility interval -$6,434.03 to $6,113.57) indicating savings of $597.03 per additional successful sedation performed with propofol. This result was driven by shorter recovery times and was robust to all sensitivity analyses performed. These results indicate that using propofol for PS in the ED is a cost-saving strategy.

Viability of single balloon enteroscopy performed under endoscopist-directed sedation.

PubMed

López Rosés, Leopoldo; Álvarez, Beatriz; González Ramírez, Abel; López Baz, Alina; Fernández López, Alexia; Alonso, Sara; Dacal, Andrés; Martí, Eva; Albines, Gino; Fernández Molina, Julieta; Lancho, Ángel

2018-04-01

there is a lot of controversy with regard to who should be responsible for sedation during digestive endoscopy, particularly in advanced procedures that require deep sedation such as enteroscopy. The aim of this study was to evaluate the endoscopist-directed sedation viability during single balloon enteroscopy. this was a prospective, observational study of a series of consecutive enteroscopies. The clinical staff included an endoscopist, scrub nurse and a nurse in charge of monitoring and sedative administration. The following parameters were monitored: pulse oximetry, blood pressure (every five minutes), electrocardiogram and respiratory rate. There was continuous supplemental oxygen and CO2 insufflation. The patient was in the left lateral decubitus position and a fluoroscopic control was used. forty-four explorations were performed in 39 patients, 24 were male and 15 female. The median age was 74 (18-89) and the ASA score was I in 12 cases, II in 23 cases and III in nine cases. Comorbidities were present in 68% of cases. The drugs used included propofol in 23 cases, propofol and midazolam in ten cases, propofol/midazolam/fentanyl in two cases, propofol and fentanyl in two cases, and midazolam/fentanyl in seven cases. All procedures were complete. The length of the procedure was 52 minutes (20-120). There were diagnostic findings in 65.9% of cases and therapeutic measures in 47.7%. There were no severe complications and the rate of complications derived from sedation was 22.7%. endoscopist-directed sedation is effective and safe for single balloon enteroscopy. Multi-center and wider studies are needed in order to better assess the efficacy, safety and efficiency of sedation controlled by a non-anesthetist during advanced endoscopy in this field.

Comparison of propofol with pentobarbital/midazolam/fentanyl sedation for magnetic resonance imaging of the brain in children.

PubMed

Pershad, Jay; Wan, Jim; Anghelescu, Doralina L

2007-09-01

Propofol and pentobarbital, alone or combined with other agents, are frequently used to induce deep sedation in children for MRI. However, we are unaware of a previous comparison of these 2 agents as part of a randomized, controlled trial. We compared the recovery time of children after deep sedation with single-agent propofol with a pentobarbital-based regimen for MRI and considered additional variables of safety and efficacy. This prospective, randomized trial at a tertiary children's hospital enrolled 60 patients 1 to 17 years old who required intravenous sedation for elective cranial MRI. Patients were assigned randomly to receive a loading dose of propofol followed by continuous intravenous infusion of propofol or to receive sequential doses of midazolam, pentobarbital, and fentanyl until a modified Ramsay score of >4 was attained. A nurse who was blind to group assignment assessed discharge readiness (Aldrete score > 8) and administered a follow-up questionnaire. We compared recovery time, time to induction of sedation, total sedation time, quality of imaging, number of repeat-image sequences, adverse events, caregiver satisfaction, and time to return to presedation functional status. The groups were similar in age, gender, race, American Society of Anesthesiology physical status class, and frequency of cognitive impairment. No sedation failure or significant adverse events were observed. Propofol offered significantly shorter sedation induction time, recovery time, total sedation time, and time to return to baseline functional status. Caregiver satisfaction scores were also significantly higher in the patients in the propofol group. Propofol permits faster onset and recovery than, and comparable efficacy to, a pentobarbital/midazolam/fentanyl regimen for sedation of children for MRI.

Metabolite formation kinetics and intrinsic clearance of phenacetin, tolbutamide, alprazolam, and midazolam in adenoviral cytochrome P450-transfected HepG2 cells and comparison with hepatocytes and in vivo.

PubMed

Donato, M Teresa; Hallifax, David; Picazo, Laura; Castell, José V; Houston, J Brian; Gomez-Lechón, M José; Lahoz, Agustin

2010-09-01

Cryopreserved human hepatocytes and other in vitro systems often underpredict in vivo intrinsic clearance (CL(int)). The aim of this study was to explore the potential utility of HepG2 cells transduced with adenovirus vectors expressing a single cytochrome P450 enzyme (Ad-CYP1A2, Ad-CYP2C9, or Ad-CYP3A4) for metabolic clearance predictions. The kinetics of metabolite formation from phenacetin, tolbutamide, and alprazolam and midazolam, selected as substrates probes for CYP1A2, CYP2C9, and CYP3A4, respectively, were characterized in this in vitro system. The magnitude of the K(m) or S(50) values observed in Ad-P450 cells was similar to those found in the literature for other human liver-derived systems. For each substrate, CL(int) (or CL(max)), values from Ad-P450 systems were scaled to human hepatocytes in primary culture using the relative activity factor (RAF) approach. Scaled Ad-P450 CL(int) values were approximately 3- to 6-fold higher (for phenacetin O-deethylation, tolbutamide 4-hydroxylation, and alprazolam 4-hydroxyaltion) or lower (midazolam 1'-hydroxylation) than those reported for human cryopreserved hepatocytes in suspension. Comparison with the in vivo data reveals that Ad-P450 cells provide a favorable prediction of CL(int) for the substrates studied (in a range of 20-200% in vivo observed CL(int)). This is an improvement compared with the consistent underpredictions (<10-50% in in vivo observed CL(int)) found in cryopreserved hepatocyte studies with the same substrates. These results suggest that the Ad-P450 cell is a promising in vitro system for clearance predictions of P450-metabolized drugs.

Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects.

PubMed

Edwards, Jeffrey E; Eliot, Lise; Parkinson, Andrew; Karan, Sharon; MacConell, Leigh

2017-09-01

Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max ) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). Intercept Pharmaceuticals, Inc.

In vitro characterization of the inhibitory effects of ketoconazole on metabolic activities of cytochrome P-450 in canine hepatic microsomes.

PubMed

Kuroha, Masanori; Kuze, Yoji; Shimoda, Minoru; Kokue, Eiichi

2002-06-01

To evaluate the inhibitory potency of ketoconazole (KTZ) on the metabolic activities of isozymes of cytochrome P-450 (CYP) in dogs. 4 healthy 1-year-old male Beagles. Hepatic microsomes were harvested from 4 dogs after euthanasia. To investigate the effects of KTZ on CYP metabolic activities, 7-ethoxyresorufin, tolbutamide, bufuralol, and midazolam hydrochloride were used as specific substrates for CYP1A1/2, CYP2C21, CYP2D15, and CYP3A12, respectively. The concentrations of metabolites formed by CYP were measured by high-performance liquid chromatography, except for the resorufin concentrations that were measured by a fluorometric method. The reaction velocity-substrate concentration data were analyzed to obtain kinetic variables, including maximum reaction velocity, Michaelis-Menten constant, and inhibitory constant (Ki). KTZ competitively inhibited 7-ethoxyresorufin O-deethylation and midazolam 4-hydroxylation; it noncompetitively inhibited tolbutamide methylhydroxylation. Bufuralol 1'-hydroxylation was inhibited slightly by KTZ. The mean Ki values of KTZ were 10.6+/-6.0, 170+/-2.5, and 0.180+/-0.131 microM for 7-ethoxyresorufin O-deethylation, tolbutamide methylhydroxylation, and midazolam 4-hydroxylation, respectively. In dogs, KTZ at a therapeutic dose may change the pharmacokinetics of CYP3A12 substrates as a result of inhibition of their biotransformation. Furthermore, no influence of KTZ on the pharmacokinetics of CYP1A1/2, CYP2C21, and CYP2D15 substrates are likely. In clinical practice, adverse drug effects may develop when KTZ is administered concomitantly with a drug that is primarily metabolized by CYP3A12.

Effect of GABA agonists and GABA-A receptor modulators on cocaine- and food-maintained responding and cocaine discrimination in rats.

PubMed

Barrett, Andrew C; Negus, S Stevens; Mello, Nancy K; Caine, S Barak

2005-11-01

Recent studies indicate that GABAergic ligands modulate abuse-related effects of cocaine. The goal of this study was to evaluate the effects of a mechanistically diverse group of GABAergic ligands on the discriminative stimulus and reinforcing effects of cocaine in rats. One group of rats was trained to discriminate 5.6 mg/kg cocaine from saline in a two-lever, food-reinforced, drug discrimination procedure. In two other groups, responding was maintained by cocaine (0-3.2 mg/kg/injection) or liquid food (0-100%) under a fixed ratio 5 schedule. Six GABA agonists were tested: the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), and three GABA-A receptor modulators (the barbiturate pentobarbital, the high-efficacy benzodiazepine midazolam, and the low-efficacy benzodiazepine enazenil). When tested alone, none of the compounds substituted fully for the discriminative stimulus effects of cocaine. As acute pretreatments, select doses of midazolam and pentobarbital produced 2.2- to 3.6-fold rightward shifts in the cocaine dose-effect function. In contrast, muscimol, baclofen, GVG, and enazenil failed to alter the discriminative stimulus effects of cocaine. In assays of cocaine- and food-maintained responding, midazolam and pentobarbital decreased cocaine self-administration at doses 9.6- and 3.3-fold lower, respectively, than those that decreased food-maintained responding. In contrast, muscimol, baclofen, and GVG decreased cocaine self-administration at doses that also decreased food-maintained responding. Enazenil failed to alter cocaine self-administration. Together with previous studies, these data suggest that among mechanistically diverse GABA agonists, high-efficacy GABA-A modulators may be the most effective for modifying the abuse-related effects of cocaine.

High dose phenobarbitone coma in pediatric refractory status epilepticus; a retrospective case record analysis, a proposed protocol and review of literature.

PubMed

Gulati, Sheffali; Sondhi, Vishal; Chakrabarty, Biswaroop; Jauhari, Prashant; Lodha, Rakesh; Sankar, Jhuma

2018-04-01

Ongoing refractory status epilepticus is associated with significant morbidity and mortality. Therapeutic coma induction with midazolam, thiopentone, phenobarbitone or propofol is indicated when conventional antiepileptics fail to abort seizure. Of these, the most extensively studied is midazolam. Amongst the remaining three, phenobarbitone has the most favourable pharmacological profile, but has not been studied adequately, more so in the pediatric age group. The current retrospective case records analysis is an attempt to describe use of phenobarbitone coma in pediatric refractory status epilepticus. Case records of patients, admitted with status epilepticus to the pediatric inpatient services of a tertiary care teaching hospital of North India between January 2014 and December 2016 were reviewed. Those with refractory status epilepticus who failed to respond to midaolam infusion and phenobarbitone coma was used were included for analysis. Overall, 108 children presented in status, of which 34 developed refractory status epilepticus. Of these 34, 21 responded to midazolam infusion and in 13 high dose phenobarbitone coma following a standardised protocol was used. Amongst these 13 (8 males and 5 females, median age 6 years, IQR: 2.5-9.5), 12 responded and 1 succumbed. The median time to clinical seizure resolution and desired electroencephalographic changes post phenobarbitone initiation were 16 (IQR: 12-25) and 72 h (IQR: 48-120) respectively. High dose phenobarbitone appears to be an effective therapeutic modality in pediatric refractory status epilepticus. The current study provides a protocol for its use which can be validated in future studies with larger sample size. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women

PubMed Central

Edelman, Alison; Munar, Myrna; Elman, Miriam R; Koop, Dennis; Cherala, Ganesh

2012-01-01

AIM(S) While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women. METHODS Thirty-four, obese (body mass index, BMI > 30 kg m−2) women of reproductive age (18–35 years old) were placed on a COC pill containing 20 µg ethinylestradiol/100 µg levonorgestrel for 21 days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21 days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method. RESULTS Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3 l h−1vs. 53.9 l h−1, P < 0.05). A median decrease of 5.6 l h−1 (95% CI −4.1, 13.3 l h−1) was observed. However, the magnitude of change was similar to that reported in women with normal BMI. CONCLUSIONS Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug−drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs. PMID:22299599

Palliative sedation at home for terminally ill children with cancer.

PubMed

Korzeniewska-Eksterowicz, Aleksandra; Przysło, Łukasz; Fendler, Wojciech; Stolarska, Małgorzata; Młynarski, Wojciech

2014-11-01

The presence of symptoms that are difficult to control always requires adjustment of treatment, and palliative sedation (PS) should be considered. We analyzed our experience in conducting PS at home for terminally ill children with cancer during a seven-year period. We performed a retrospective analysis of medical records of children with cancer treated at home between the years 2005 and 2011. We analyzed the data of 42 cancer patients (18% of all patients); in 21 cases, PS was initiated (solid tumors n = 11, brain tumors [5], bone tumors [4], leukemia [1]). Sedation was introduced because of pain (n = 13), dyspnea (9), anxiety (5), or two of those symptoms (6). The main drug used for sedation was midazolam; all patients received morphine. There were no significant differences in the dose of morphine or midazolam depending on the patient's sex; age was correlated with an increase of midazolam dose (R = 0.68; P = 0.005). Duration of sedation (R = 0.61; P = 0.003) and its later initiation (R = 0.43; P = 0.05) were correlated with an increase of the morphine dose. All patients received adjuvant treatment; in patients who required a morphine dose increase, metoclopramide was used more often (P = 0.0002). Patients did not experience any adverse reactions. Later introduction of sedation was associated with a marginally higher number of intervention visits and a significantly higher number of planned visits (R = 0.53; P = 0.013). Sedation may be safely used at home. It requires close monitoring and full cooperation between the family and hospice team. Because of the limited data on home PS in pediatric populations, further studies are needed. Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Intramuscular midazolam versus intravenous diazepam for treatment of seizures in the pediatric emergency department: a randomized clinical trial.

PubMed

Portela, J L; Garcia, P C R; Piva, J P; Barcelos, A; Bruno, F; Branco, R; Tasker, R C

2015-04-01

To compare the therapeutic efficacy of intramuscular midazolam (MDZ-IM) with that of intravenous diazepam (DZP-IV) for seizures in children. Randomized clinical trial. Pediatric emergency department. Children aged 2 months to 14 years admitted to the study facility with seizures. Patients were randomized to receive DZP-IV or MDZ-IM. Groups were compared with respect to time to treatment start (min), time from drug administration to seizure cessation (min), time to seizure cessation (min), and rate of treatment failure. Treatment was considered successful when seizure cessation was achieved within 5min of drug administration. Overall, 32 children (16 per group) completed the study. Intravenous access could not be obtained within 5min in four patients (25%) in the DZP-IV group. Time from admission to active treatment and time to seizure cessation was shorter in the MDZ-IM group (2.8 versus 7.4min; p<0.001 and 7.3 versus 10.6min; p=0.006, respectively). In two children per group (12.5%), seizures continued after 10min of treatment, and additional medications were required. There were no between-group differences in physiological parameters or adverse events (p=0.171); one child (6.3%) developed hypotension in the MDZ-IM group and five (31%) developed hyperactivity or vomiting in the DZP-IV group. Given its efficacy and ease and speed of administration, intramuscular midazolam is an excellent option for treatment of childhood seizures, enabling earlier treatment and shortening overall seizure duration. There were no differences in complications when applying MDZ-IM or DZP-IV. Copyright © 2013 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial

PubMed Central

Neubert, Antje; Baarslag, Manuel Alberto; van Dijk, Monique; van Rosmalen, Joost; Standing, Joseph F; Sheng, Yucheng; Rascher, Wolfgang; Roberts, Deborah; Winslade, Jackie; Rawcliffe, Louise; Hanning, Sara M; Metsvaht, Tuuli; Giannuzzi, Viviana; Larsson, Peter; Pokorná, Pavla; Simonetti, Alessandra; Tibboel, Dick

2017-01-01

Introduction Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. Methods and analysis The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2–18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. Ethics Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. Trial Registration EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results. PMID:28637741

Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats.

PubMed

Eppolito, Amy K; Kodeih, Hanna R; Gerak, Lisa R

2014-10-01

Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone. Copyright © 2014 Elsevier Inc. All rights reserved.

Identification of Polymorphisms in the 3′-Untranslated Region of the Human Pregnane X Receptor (PXR) Gene Associated with Variability in Cytochrome P450 3A (CYP3A) Metabolism

PubMed Central

Oleson, Lauren; von Moltke, Lisa L.; Greenblatt, David J.; Court, Michael H.

2013-01-01

Single nucleotide polymorphisms (SNPs) in the 3′untranslated region (3′UTR) of human pregnane X receptor (PXR) gene may contribute to interindividual variability in cytochrome P450 3A (CYP3A) activity. Genotype-phenotype associations involving PXR-3′UTR SNPs were investigated through in vitro (53 human livers from primarily white donors) and in vivo (26 white or African-American volunteers) studies using midazolam 1′-hydroxylation and midazolam apparent oral clearance (CL/F), respectively, as CYP3A-specific probes. PXR-3′UTR resequencing identified 12 SNPs, including 2 that were novel. Although none of the SNPs evaluated were associated with altered midazolam 1′-hydroxylation in the liver bank, both rs3732359 homozygotes and rs3732360 carriers showed 80% higher (P<0.05) CL/F compared with homozygous reference individuals. These differences in CL/F were even larger (100 and 120% higher, respectively; P<0.01) when only African-American subjects (n=14) were considered. Five major haplotypes were identified containing the PXR-3′UTR SNPs and previously identified intron SNPs. Although CL/F differences were not statistically significant within the entire study cohort, African-American carriers of Haplotype-1 (which includes both rs3732359 and rs3732360 variants) exhibited 70% higher median CL/F compared with African-American non-carriers (P=0.036). Our results identify rs3732359 and rs3732360 as PXR-3′UTR SNPs associated with higher CYP3A activity in vivo in African-Americans. PMID:20082578

Interactions of the hepatitis C virus protease inhibitor faldaprevir with cytochrome P450 enzymes: in vitro and in vivo correlation.

PubMed

Sabo, John P; Kort, Jens; Ballow, Charles; Kashuba, Angela D M; Haschke, Manuel; Battegay, Manuel; Girlich, Birgit; Ting, Naitee; Lang, Benjamin; Zhang, Wei; Cooper, Curtis; O'Brien, Drané; Seibert, Eleanore; Chan, Tom S; Tweedie, Donald; Li, Yongmei

2015-04-01

The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-∞)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms. © 2015, The American College of Clinical Pharmacology.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Vol. 47/No. RR-4.

DTIC Science & Technology

1998-04-17

antihista- mines (e.g., astemizole or terfenadine); sedative-hypnotics (e.g., alprazolam , midazolam, or triazolam); calcium channel blockers (e.g...acetate, propafenone, or quinidine); ergot alkaloid derivatives; cisapride; sedative-hypnotics (e.g., alprazolam , clorazepate, diazepam, estazo- lam

A randomized controlled trial of intranasal ketamine in migraine with prolonged aura.

PubMed

Afridi, Shazia K; Giffin, Nicola J; Kaube, Holger; Goadsby, Peter J

2013-02-12

The aim of our study was to test the hypothesis that ketamine would affect aura in a randomized controlled double-blind trial, and thus to provide direct evidence for the role of glutamatergic transmission in human aura. We performed a double-blinded, randomized parallel-group controlled study investigating the effect of 25 mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active control. Each subject recorded data from 3 episodes of migraine. Eighteen subjects completed the study. Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect. These data provide translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem. This study provides class III evidence that intranasal ketamine is effective in reducing aura severity in patients with migraine with prolonged aura.

Barriers to Seizure Management in Schools: Perceptions of School Nurses.

PubMed

Terry, Debbie; Patel, Anup D; Cohen, Daniel M; Scherzer, Daniel; Kline, Jennifer

2016-12-01

The purpose of this study was to assess school nurses' perceptions of barriers to optimal management of seizures in schools. Eighty-three school nurses completed an electronic survey. Most agreed they felt confident they could identify a seizure (97.6%), give rectal diazepam (83.8%), and handle cluster seizures (67.1%), but fewer were confident they could give intranasal midazolam (63.3%), had specific information about a student's seizures (56.6%), or could swipe a vagus nerve stimulator magnet (47.4%). Nurses were more likely to be available at the time of a seizure in rural (17/20) (85%) versus suburban (21/34) (62%) or urban (8/25) (32%) schools (P = .001). School nurses are comfortable managing seizures in the school setting. However, a specific seizure plan for each child and education on intranasal midazolam and vagus nerve stimulator magnet use are needed. A barrier in urban schools is decreased availability of a nurse to identify seizures and administer treatment. © The Author(s) 2016.

[Sedation with midazolam for ambulatory pediatric dentistry].

PubMed

Shavlokhova, E A; Ostreĭkov, I F; Korolenkova, M V

2014-01-01

To improve the quality of dental treatment in children by using combined anaesthesia technique including local anaesthesia and conscious sedation, and to assess the effectiveness of conscious sedation for younger children undergoing dental treatment. The study included 208 children aged 14-88 months who received dental treatment for tooth decay and its complication under combined anaesthesia. Midazolam was used as sedative medication. Sedation level was assessed by visual scale and BIS-monitoring. ANI-monitoring was also used for pain sensitiveness evaluation. Results All 208 children were successfully treated under combined anaesthesia which showed satisfactory sedation rates both by visual scale and and BIS-monitoring values. While mean patient age was 39 months 20.6% were younger than 24 months. These data are extremely valuable as according to literature review conscious sedation in early infancy remains controversial. Our results proved conscious sedation to be effective in younger children undergoing dental treatment thus representing important alternative for general anaesthesia and providing a basis for later behavior management.

Midazolam: An Improved Anticonvulsant Treatment for Nerve Agent-Induced Seizures

DTIC Science & Technology

2002-01-01

variety of compounds that different authors had championed as being capable of stopping or moderating nerve agent seizures (e.g., memantine , clonidine...e.g., memantine , neuroactive steroids; EEG seizures were still evident) or required such a narrow dose range or specific treatment conditions that

Induction of Three-Dimensional Growth of Human Liver Cells in Simulated Microgravity

NASA Technical Reports Server (NTRS)

Pellis, Neal R.; Khaoustov, V. I.; Yoffe, B.; Murry, D. J.; Soriano, H. E.; Risin, D.; Dawson, David L. (Technical Monitor)

1999-01-01

We previously reported that a NASA-developed bioreactor that simulates microgravity environment and creates the unique environment of low shear force and high-mass transfer is conducive for maintaining long term 3-D cell cultures of functional hepatocytes (60 days). However, significant further expansion of liver mass, or the remodeling of liver in vitro was jeopardized by the appearance of apoptotic zones in the center of large cell aggregates. To optimize oxygenation and nutritional uptake within growing cellular aggregates we cultured primary human liver cells (HLC) in a bioreactor in the presence or absence of microcarriers and biodegradable scaffolds. Also, to promote angiogenesis, HLC were cultured with or without microvascular endothelial cells. HLC were harvested from human livers by collagenase perfusion. While microcarriers did not affect cell growth, HLC cultured with biodegradable scaffolds made from polyglycolic acid (PGA) formed aggregates up to 3 cm in length. Culturing cells with PGA scaffolds increased the efficiency of cell self-assembly and the formation of larger cell aggregates. Based on histological evaluation it appears that the degree of apoptotic cells was diminished as compared to cultures without scaffolds. Histology of HLC with PGA-scaffolds revealed cell distribution between the fibers of the scaffolds, and cell-cell and cell-fiber interactions. Analyses of HLC spheroids revealed tissue-like structures comprised of hepatocytes, biliary epithelial cells and/or progenitor liver cells that were arranged as bile duct-like structures along nascent vascular sprouts. Electron microscopy revealed groups of cohesive hepatocytes and bile canaliculi with multiple microvilli and tight cellular junctions. Hepatocytes were further organized into tight clusters surrounded by complex stromal structures and reticulin fibers. Also, we observed higher levels of albumin mRNA expression when hepatocytes were co-cultured with endothelial cells. To evaluate viability and microsomal deethylation activity of hepatocytes we assessed the metabolism of midazolam by gas chromatography. Samples that were collected from HLC cultured in the bioreactor contained higher levels of midazolam metabolites (1-OH-midazolam and 4-OH-midazolam) than samples collected from conventional cultures. In summary, we have shown that co-culture of HLC with endothelial cells and/or culturing in the presence of PGA scaffolds provides additional advantages in maintaining functional activity of 3-D hepatocyte cultures that resemble liver tissue. This cell culture system may facilitate studies of liver regeneration and cell-to-cell interactions that occur in vivo and suggest the feasibility of using this approach for pre-clinical metabolic screening of novel drug candidates.

Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo.

PubMed

Malizia, A L; Gunn, R N; Wilson, S J; Waters, S H; Bloomfield, P M; Cunningham, V J; Nutt, D J

1996-01-01

To date, the study of the relationship between drug occupancy and action in the brain has had to rely on the use of either animal models or of indirect kinetic measures in man, e.g. serum concentrations of unbound drug (as a measure of "free" drug in brain). We describe the first set of experiments which directly measure agonist-induced changes in both pharmacodynamic effects and pharmacokinetic parameters simultaneously and which demonstrate the feasibility of these studies in man. Five healthy volunteers each had two PET scans using [11C]flumazenil (a radiolabelled benzodiazepine site antagonist) as part of a study investigating kinetic models and the relationship between occupancy and effect of benzodiazepine site ligands. In both studies the [11C]flumazenil was displaced from the brain by infusion of midazolam administered i.v. 30 min into the scan. In one study a higher dose of midazolam was administered than in the other (range 12.5-50 micrograms/kg). Time-activity curves of the concentration of radioligand were derived in 17 different brain regions using a stereotactic automatic method of region selection. We demonstrated that there are significant differences in an index of occupancy, induced by the two different doses of midazolam, both across brain regions and within subjects. There was a significant correlation between measured occupancy index change and pharmacodynamic effects as measured by the peak change in beta 1 spectral power on EEG. There was no significant correlation between dose administered and EEG changes; plasma concentrations of midazolam were correlated with the occupancy index and with the EEG measures. In addition, we have demonstrated that a non-regional total index of brain occupancy can be obtained by analysing the non-tomographic data obtained with the PET scanner (total radioactivity counts head curve) and that this index shows significant correlations both with the dose administered and with the pharmacodynamic measure. This last finding validates the use of other non-tomographic counting techniques (Malizia et al., 1995a) where an index of displacement can be obtained after the administration of less than 1% of the dose of radiation needed for a PET study. These studies are likely to be useful in human psychopharmacology, in particular in the assessment of tolerance and of putative changes in benzodiazepine sensitivity in anxiety disorders. The same principles can be applied to other ligand studies and will be useful to validate current PK/PD models.

The Effect of the Protease Inhibitors Ritonavir on the Rate of Metabolism of Midazolam

DTIC Science & Technology

1999-10-01

demonstrated that the antifungal drug ketoconazole decreased the rate at which saquinavir metabolites were formed, thus slowing metabolism and...Kempf, D. J., Thomas, S. B. & Surber, B. W. (1997). Metabolism and disposition of the HIV-1 protease inhibitor ritonavir (AB-538) in rats, dogs , and

Effects of Post-Training Hippocampal Injections of Midazolam on Fear Conditioning

ERIC Educational Resources Information Center

Gafford, Georgette M.; Parsons, Ryan G.; Helmstetter, Fred J.

2005-01-01

Benzodiazepines have been useful tools for investigating mechanisms underlying learning and memory. The present set of experiments investigates the role of hippocampal GABA[subscript A]/benzodiazepine receptors in memory consolidation using Pavlovian fear conditioning. Rats were prepared with cannulae aimed at the dorsal hippocampus and trained…

Prehospital Use of Plasma for Traumatic Hemorrhage

DTIC Science & Technology

2013-06-01

Treatment Trials Network which h as trialed pre-hospital use of midazolam autoinjection for status epilepticus and is tria ling the use of in travenous...history and current status . J Trauma 2011; 70:811-12. 48. Ogilvie MP, Ryan ML, Proctor KG. Hetastarch during initial resuscitation from trauma. J

Effectiveness of preoperative intranasal dexmedetomidine, compared with oral midazolam, for the prevention of emergence delirium in the pediatric patient undergoing general anesthesia: a systematic review.

PubMed

FitzSimons, James; Bonanno, Laura S; Pierce, Stephanie; Badeaux, Jennifer

2017-07-01

Emergence delirium is defined as a cognitive disturbance during emergence from general anesthesia resulting in hallucinations, delusions and confusion manifested by agitation, restlessness, involuntary physical movement and extreme flailing in bed. Postoperative emergence delirium develops in 12% to 18% of all children undergoing general anesthesia for surgery. This post-anesthetic phenomenon changes cognitive and psychomotor behavior, and puts pediatric patients and health care personnel at risk of injury. A newer drug, dexmedetomidine, is a selective alpha-2 agonist, which works in the brain and spinal cord that has sedative, analgesic and anxiolytic properties. Dexmedetomidine also has the ability to lower the overall anesthetic requirements by reducing sympathetic outflow in response to painful surgical stimulation. In current literature, there is not a systematic review that compares the effectiveness of preoperative intranasal dexmedetomidine administration against oral midazolam for the prevention of emergence delirium. The objective of this review was to identify the effectiveness of preoperative intranasal dexmedetomidine compared to oral midazolam for the prevention of emergence delirium in the pediatric patient undergoing general anesthesia. This review considered studies that included pediatric patients aged three to seven years, with an American Society of Anesthesiologists (ASA) classification of I or II, and undergoing general anesthesia for elective/ambulatory surgery. This review excluded studies that included patients who had special needs including: developmental delay, chronic pain issues, and/or any preexisting mental or physical health disorders which categorized them above an ASA II. This review considered studies that compared preoperative intranasal administration of dexmedetomidine with preoperative oral administration of midazolam for the prevention of emergence delirium. This review considered both experimental and non-experimental study designs including randomized-controlled trials (RCTs), non-randomized control trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies, and analytical cross-sectional studies for inclusion. This review considered studies that included the presence of postoperative emergence delirium. Only studies that used the Pediatric Anesthesia Emergence Delirium Scale to quantify the degree of emergence delirium were included in the review. Adverse events other than emergence delirium were not considered as part of the outcomes inclusion criteria but were to be included in the discussion if any articles were identified. The search strategy aimed to discover both published as well as unpublished studies. A three-step search strategy was utilized in eight databases. Studies published in English or with an English translation after 1999 were considered for inclusion in this review. Assessment of methodological quality was not conducted as no studies were identified which met the inclusion criteria. Data extraction and synthesis was not performed since no studies were included in this systematic review. Following the three-step search strategy as previously described, 117 articles were identified: six in Clinical Trials, one in ProQuest, 14 in Ovid MEDLINE, 10 in CINAHL, 16 in the Cochrane Library, 13 in Scopus, 36 in Embase, and 21 in Web of Science. There were 43 duplicates which were identified and removed in Refworks by the primary reviewer. The primary and secondary reviewers independently retrieved 10 potentially relevant studies (from the initial 74) through title and abstract screening as described in the inclusion criteria. All of the retrieved studies were excluded, after assessment of full text, with reasons based on the inclusion criteria. There is no scientific evidence identifying the effectiveness of preoperative intranasal dexmedetomidine, compared with oral midazolam, for the prevention of emergence delirium in the pediatric patient population.

Identification of factors associated with sedation tolerance in 5000 patients undergoing outpatient colonoscopy: Canadian tertiary center experience.

PubMed

Shingina, Alexandra; Ou, George; Takach, Oliver; Svarta, Sigrid; Kwok, Ricky; Tong, Jessica; Donaldson, Kieran; Lam, Eric; Enns, Robert

2016-12-16

To develop a prediction model aimed at identifying patients that may require higher than usual sedation doses during colonoscopy. A retrospective chart review on 5000 patients who underwent an outpatient colonoscopy at St. Paul's Hospital from 2009 to 2010 was conducted in order to develop a model for identifying patients who will require increased doses of sedatives. Potential predictor variables including age, gender, endoscopy indication, high sedation requirements during previous endoscopies, difficulty of the procedure, bowel preparation quality, interventions, findings as well as current use of benzodiazepines, opioids and alcohol were analyzed. The outcome of study was the use of high dose of sedation agents for the procedure. In particular, the high dose of sedation was defined as fentanyl greater than 50 mcg and midazolam greater than 3 mg. Analysis of 5282 patients (mean age 57 ± 12, 49% female) was performed. Most common indication for the procedure was screening colonoscopy (57%). Almost half of our patients received doses exceeding Fentanyl 50 mcg and Midazolam 3 mg. Logistic regression models identified the following variables associated with high sedation: Younger age (OR = 0.95 95%CI: 0.94-0.95; P < 0.0001); abdominal pain (OR = 1.45, 95%CI: 1.08-1.96); P = 0.01) and Inflammatory Bowel Disease (OR = 1.45, 95%CI: 1.04-2.03; P = 0.02) as indications for the procedure; difficult procedure as defined by gastroenterologist (OR = 1.73, 95%CI: 1.48-2.03; P < 0.0001); past history of abdominal surgery (OR = 1.33, 95%CI: 1.17-1.52; P <0.0001) and previous colonoscopy (OR = 1.39, 95%CI: 1.21-1.60; P = 0.0001) and alcohol use (OR = 1.26, 95%CI: 1.03-1.54; P = 0.02). Age and gender adjusted analysis yielded inflammatory bowel disease as an indication (OR = 3.17, 95%CI: 1.58-6.37; P = 0.002); difficult procedure as defined by an endoscopist (OR = 5.13 95%CI: 2.97-8.85; P = 0.0001) and current use of opioids, benzodiazepines or antidepressants (OR = 2.88, 95%CI: 1.74-4.77; P = 0.001) having the highest predictive value of high sedation requirements. Our prediction model using the following pre-procedural variables including age, gender, indication for the procedure, medication/substance use, previous surgeries, previous high sedation requirements for colonoscopy yielded an area under the curve of 0.76 for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg. Pre-procedural planning is the key in conducting successful, efficient colonoscopy. Logistic regression analysis of 5000 patients who underwent out-patient colonoscopy revealed the following factors associated with increased sedation requirement: Younger age, female gender, difficult endoscopy, specific indications as well as cardiopulmonary complications and current use of opioids/benzodiazepines. Age and gender adjusted analysis yielded similar results. These patients are more likely to need a longer recovery periods post-endoscopy, which could result in additional time and personnel requirements. The final predictive model has good predictive ability for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg and fair predictive ability for Fentanyl ≥ 50 mcg and Midazolam ≥ 2 mg. The external validity of this model is planned to be tested in another center.

Community Use of Intranasal Midazolam for Managing Prolonged Seizures

ERIC Educational Resources Information Center

Kyrkou, Margaret; Harbord, Michael; Kyrkou, Nicole; Kay, Debra; Coulthard, Kingsley

2006-01-01

Background: Until a few years ago, rectal diazepam (RD) was the only option available to parents and carers managing prolonged seizures. However, its use in the community was limited due to the requirement for privacy, and because education staff in South Australia are not permitted to carry out invasive procedures. Method: Following a literature…

[Modifications in treatment of tetanus and prognosis--observations from the Cracow Department of Infectious Diseases].

PubMed

Garlicki, A; Caban, J; Bociaga-Jasik, M; Kluba-Wojewoda, U; Krukowiecki, J

1999-01-01

The assessment of modifications in the tetanus treatment, which included using metronidazol and midazolam instead penicillin and diazepam, was presented. According to our own observations and previous investigations, mentioned above changes in the tetanus therapy improve survival rate, reduce psychiatric disturbances and shorten hospitalisation time.

Hippocampal Structural Plasticity Accompanies the Resulting Contextual Fear Memory Following Stress and Fear Conditioning

ERIC Educational Resources Information Center

Giachero, Marcelo; Calfa, Gaston D.; Molina, Victor A.

2013-01-01

The present research investigated the resulting contextual fear memory and structural plasticity changes in the dorsal hippocampus (DH) following stress and fear conditioning. This combination enhanced fear retention and increased the number of total and mature dendritic spines in DH. Intra-basolateral amygdala (BLA) infusion of midazolam prior to…

[Comparison of epidural anesthesia and general anesthesia for patients with bronchial asthma].

PubMed

Kasaba, T; Suga, R; Matsuoka, H; Iwasaki, T; Hidaka, N; Takasaki, M

2000-10-01

We prospectively investigated the incidence of asthmatic attacks in 94 patients (1.5%) who were diagnosed as definite asthma. We separated the patients into three groups: epidural anesthesia (n = 10) including combined spinal/epidural anesthesia (n = 7), combined epidural and general anesthesia (n = 23), and general anesthesia (n = 54). General anesthesia was induced with propofol or midazolam and maintained with N2O and O2 with sevoflurane in adults. Patients who underwent epidural anesthesia and combined spinal and epidural anesthesia showed no asthmatic attacks. The incidence of bronchospasm with combined epidural and general anesthesia was 2/23. The incidence of bronchospasm with general anesthesia was 4/54. Bronchoconstriction occurred after tracheal intubation in 5 patients except in one patient, in whom it occurred after induction of anesthesia with midazolam. All episodes of bronchospasm in the operative period were treated successfully. The frequency of bronchospasm did not depend on the severity of asthmatic symptoms or the chronic use of bronchodilators before operation. These findings suggest that tracheal intubation, not the choice of anesthetic, plays an important role in the pathogenesis of bronchospasm.

Reversible postoperative blindness caused by bilateral status epilepticus amauroticus following thoracolumbar deformity correction: case report.

PubMed

Ibrahim, Tarik F; Sweis, Rochelle T; Nockels, Russ P

2017-07-01

Postoperative vision loss (POVL) is a devastating complication and has been reported after complex spine procedures. Anterior ischemic optic neuropathy and posterior optic neuropathy are the 2 most common causes of POVL. Bilateral occipital lobe seizures causing complete blindness are rare and have not been reported as a cause of POVL after spine surgery with the patient prone. The authors report the case of a 67-year-old man without a history of seizures who underwent a staged thoracolumbar deformity correction and developed POVL 6 hours after surgery. Imaging, laboratory, and ophthalmological examination results were nonrevealing. Routine electroencephalography study results were negative, but continuous electroencephalography captured bilateral occipital lobe seizures. The patient developed nonconvulsive status epilepticus despite initial treatment with benzodiazepines and loading doses of levetiracetam and lacosamide. He was therefore intubated for status epilepticus amauroticus and received a midazolam infusion. After electrographic seizure cessation for 48 hours, the patient was weaned off midazolam. The patient was maintained on levetiracetam and lacosamide without seizure recurrence and returned to his preoperative visual baseline status.

Total intravenous anesthesia with midazolam, ketamine, and xylazine or detomidine following induction with tiletamine, zolazepam, and xylazine in red deer (Cervus elaphus hippelaphus) undergoing surgery.

PubMed

Auer, Ulrike; Wenger, Sandra; Beigelböck, Christoph; Zenker, Wolfgang; Mosing, Martina

2010-10-01

Sixteen captive female red deer were successfully anesthetized to surgically implant a telemetry system. The deer were immobilized with (mean±SD) 1.79±0.29 mg/kg xylazine and 1.79±0.29 mg/kg tiletamine/zolazepam given intramuscularly with a dart gun. Anesthesia was maintained for 69±2 min using a total intravenous protocol with a catheter placed in the jugular vein. Group X received xylazine (0.5±0.055 mg/kg/hr) and group D, detomidine (2±0.22 μg/kg/hr), both in combination with ketamine (2±0.02 mg/kg/hr) and midazolam (0.03±0.0033 mg/kg/hr), as a constant rate infusion. Anesthesia was reversed with 0.09±0.01 mg/kg atipamezole and 8.7±1.21 μg/kg sarmazenil given intravenously in both groups. These drug combinations provided smooth induction, stable anesthesia for surgery, and rapid recovery. Respiratory depression and mild hypoxemia were seen, and we, therefore, recommend using supplemental intranasal oxygen.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Capacio, B.R.; Harris, L.W.; Anderson, D.R.

The accelerating rotarod was used to assess motor performance decrement in rats after administration of candidate anticonvulsant compounds (acetazolamide, amitriptyline, chlordiazepoxide, diazepan, diazepam-lysine, lorazepam, loprazolam, midazolam, phenobarbital and scopolamine) against nerve agent poisoning. AH compounds were tested as the commercially available injectable preparation except for diazepam-lysine and loprazolam, which are not FDA approved. A peak effect time, as well as a dose to decrease performance time by 50% from control (PDD50), was determined. The calculated PDD50 (micrometer ol/kg) values and peak effect tunes were midazolam, 1.16 at 15 min; loprazolam, 1.17 at 15 min; diazepam-lysine, 4.17 at 30 min; lorazepwn,more » 4.98 at 15 min; diazepam, 5.27 at 15 min; phenobarbital, 101.49 at 45 min; chlordiazepoxide, 159.21 at 30 min; scopolamine, amitriptyline and acetazolamide did not demonstrate a performance decrement at any of the doses tested. The PDD50 values were compared with doses which have been utilized against nerve agent-induced convulsions or published ED50 values from standard anticonvulsant screening tests (maximal electroshock MES and subcutaneous pentylenetetrazol (scMET)). I serve agents, anticonvulsants, diazepam, accelerating rotarod, motor performance.« less

Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit.

PubMed

Venn, R M; Bradshaw, C J; Spencer, R; Brealey, D; Caudwell, E; Naughton, C; Vedio, A; Singer, M; Feneck, R; Treacher, D; Willatts, S M; Grounds, R M

1999-12-01

Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p = 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation.

Pharmacodynamic and pharmacokinetic effects of the intravenous CB1 receptor agonist Org 26828 in healthy male volunteers.

PubMed

Zuurman, Lineke; Passier, Paul C C M; de Kam, Marieke L; Kleijn, Huub J; Cohen, Adam F; van Gerven, Joop M A

2010-11-01

An ideal drug for outpatient treatments under conscious sedation would have both sedative and analgesic properties. CB1/CB2 agonists are expected to have sedative, amnestic, analgesic and anti-emetic properties. The main objective of this first study in humans was to assess the sedative properties of intravenous Org 26828. In addition, pharmacokinetics, amnestic properties, postural stability, and behavioural and cardiovascular effects were studied. Midazolam intravenous 0.1 mg/kg and placebo were used as controls. The pharmacokinetic parameters (Cmax and AUC0-inf) of the main metabolite Org 26761 were proportional to dose. No effects were observed after doses up to 0.3 μg/kg of Org 26828. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 26828 at 3 and 6 μg/kg, the observed sedation was considerably less than after midazolam. Doses higher than the maximum tolerated dose of 1 μg/kg of Org 26828 caused unpleasant central nervous system effects (anxiety, paranoia, hallucinations). Therefore, Org 26828 is not suitable for providing sedation for outpatient surgical procedures.

Cardiovascular effects of a continuous rate infusion of lidocaine in calves anesthetized with xylazine, midazolam, ketamine and isoflurane.

PubMed

Araújo, Marcelo A; Dias, Bianca P; Bovino, Fernanda; Deschk, Maurício; Abimussi, Caio Jx; Oliva, Valéria Nls; Rodrigues, Celso A; Santos, Paulo Sp

2014-03-01

To assess the cardiovascular changes of a continuous rate infusion of lidocaine in calves anesthetized with xylazine, midazolam, ketamine and isoflurane during mechanical ventilation. Prospective, randomized, cross-over, experimental trial. A total of eight, healthy, male Holstein calves, aged 10 ± 1 months and weighing 114 ± 11 kg were included in the study. Calves were administered xylazine followed by ketamine and midazolam, orotracheal intubation and maintenance on isoflurane (1.3%) using mechanical ventilation. Forty minutes after induction, lidocaine (2 mg kg⁻¹ bolus) or an equivalent volume of saline (0.9%) was administered IV followed by a continuous rate infusion (100 μg kg⁻¹ minute⁻¹) of lidocaine (treatment L) or saline (treatment C). Heart rate (HR), systolic, diastolic and mean arterial pressures (SAP, DAP and MAP), central venous pressure (CVP), mean pulmonary arterial pressure (mPAP), pulmonary arterial occlusion pressure (PAOP), cardiac output, end-tidal carbon dioxide (Pe'CO2 ) and core temperature (CT) were recorded before lidocaine or saline administration (Baseline) and at 20-minute intervals (T20-T80). Plasma concentrations of lidocaine were measured in treatment L. The HR was significantly lower in treatment L compared with treatment C. There was no difference between the treatments with regards to SAP, DAP, MAP and SVRI. CI was significantly lower at T60 in treatment L when compared with treatment C. PAOP and CVP increased significantly at all times compared with Baseline in treatment L. There was no significant difference between times within each treatment and between treatments with regards to other measured variables. Plasma concentrations of lidocaine ranged from 1.85 to 2.06 μg mL⁻¹ during the CRI. At the studied rate, lidocaine causes a decrease in heart rate which is unlikely to be of clinical significance in healthy animals, but could be a concern in compromised animals. © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Therapeutic protein-drug interaction assessment for daclizumab high-yield process in patients with multiple sclerosis using a cocktail approach.

PubMed

Tran, Jonathan Q; Othman, Ahmed A; Wolstencroft, Paul; Elkins, Jacob

2016-07-01

To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes. Twenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixed-effects model. The 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity. DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity. © 2016 The British Pharmacological Society.

Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study

PubMed Central

2014-01-01

Background We performed a prospective, randomized, placebo-controlled study aimed to evaluate the efficacy and safety of a sedation protocol based on intranasal Ketamine and Midazolam (INKM) administered by a mucosal atomizer device in uncooperative children undergoing gastric aspirates for suspected tuberculosis. Primary outcome: evaluation of Modified Objective Pain Score (MOPS) reduction in children undergoing INKM compared to the placebo group. Secondary outcomes: evaluation of safety of INKM protocol, start time sedation effect, duration of sedation and evaluation of parents and doctors’ satisfaction about the procedure. Methods In the sedation group, 19 children, mean age 41.5 months, received intranasal Midazolam (0.5 mg/kg) and Ketamine (2 mg/kg). In the placebo group, 17 children received normal saline solution twice in each nostril. The child’s degree of sedation was scored using the MOPS. A questionnaire was designed to evaluate the parents’ and doctors’ opinions on the procedures of both groups. Results Fifty-seven gastric washings were performed in the sedation-group, while in the placebo-group we performed 51 gastric aspirates. The degree of sedation achieved by INMK enabled all procedures to be completed without additional drugs. The mean duration of sedation was 71.5 min. Mean MOPS was 3.5 (range 1-8) in the sedation-group, 7.2 (range 4-9) in the placebo-group (p <0.0001). The questionnaire revealed high levels of satisfaction by both doctors and parents in the sedation-group compared to the placebo-group. The only side effect registered was post-sedation agitation in 6 procedures in the sedation group (10.5%). Conclusions Our experience suggests that atomized INKM makes gastric aspirates more acceptable and easy to perform in children. Trial registration Unique trial Number: UMIN000010623; Receipt Number: R000012422. PMID:24598046

The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial.

PubMed

Neubert, Antje; Baarslag, Manuel Alberto; Dijk, Monique van; Rosmalen, Joost van; Standing, Joseph F; Sheng, Yucheng; Rascher, Wolfgang; Roberts, Deborah; Winslade, Jackie; Rawcliffe, Louise; Hanning, Sara M; Metsvaht, Tuuli; Giannuzzi, Viviana; Larsson, Peter; Pokorná, Pavla; Simonetti, Alessandra; Tibboel, Dick

2017-06-21

Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Quantitative study of controlled substance bedside wasting, disposal and evaluation of potential ecologic effects.

PubMed

Mankes, Russell F; Silver, Charles D

2013-02-01

Drugs in wastewater arise from many sources. For health care, these include excretion and direct disposal (bedside wasting). The present study reports on the dispensing and wasting of 15 controlled substances (CS) at two health care facilities in Albany, NY over a nearly two year period. The study considered measures of ecotoxicity, drug metabolism, excretion and disposal of these CS. Potential alternatives to flushing of CS into wastewaters from healthcare facilities are discussed. Drug medication and waste collection records (12,345) included: numbers of drugs dispensed, returned and wasted. Overall, 8528 g of 15 CS were wasted. Three (midazolam, acetaminophen-codeine and fentanyl) accounted for 87.5% of the total wasted. Wasting varied by hospital, 14 CS at the academic medical center hospital and 8 at the surgical care center were wasted. Liquids were more frequently wasted than tablets or pills. Some combination drugs (acetaminophen (APAP)-codeine) were frequently (50% of drug dispensed) wasted while others were less wasted (APAP-hydrocodone-6.3%; APAP-oxycodone-1.3%). The 8 CS judged more hazardous to aquatic life were: APAP-codeine, APAP-hydrocodone, APAP-oxycodone, alprazolam, diazepam, fentanyl, midazolam, and testosterone. Ketamine, morphine, oxycodone and zolpidem were of lesser acute toxicity based on available LC50 values. These CS might provide a therapeutically equivalent alternative to the more environmentally harmful drugs. In health care facilities, professionals dispose of CS by bedside wasting into water or other receptacles. This can be avoided by returning CS to the hospital's pharmacy department, thence to a licensed distributor. Study of this process of drug wasting can identify opportunities for process improvements. We found 3 CS (APAP-codeine, midazolam and testosterone) where ½ to 1/3 of the drug was wasted and 5 others with 30 to 13% wasted. Knowledge of the adverse impacts from the release of highly toxic drugs into the environment might influence CS selection and disposal alternatives. Copyright © 2012 Elsevier B.V. All rights reserved.

Evaluation of a butorphanol, detomidine, and midazolam combination for immobilization of captive Nile lechwe antelopes (Kobus magaceros).

PubMed

Laricchiuta, Pietro; De Monte, Valentina; Campolo, Marco; Grano, Fabio; Iarussi, Fabrizio; Crovace, Antonio; Staffieri, Francesco

2012-07-01

Field immobilization of captive antelope may be required for medical examination, blood sample collection, and animal identification. The aim of this study was to evaluate the effects of a combination of butorphanol, detomidine, and midazolam (BDM) and its partial reversibility in Nile lechwe antelope (Kobus megaceros). Nine captive lechwes, weighing 28-64 kg, were immobilized, in February 2011, with butorphanol 0.20 ± 0.05 (mean ± SD) mg/kg, detomidine 0.20 ± 0.05 mg/kg, and midazolam 0.31 ± 0.08 mg/kg administered intramuscularly (IM) with a blowpipe. Physiologic parameters and depth of anesthesia were recorded when the animals became recumbent at 19.55 ± 8.36 min after darting (T0) and after 10 (T10), 20 (T20), and 30 (T30) min. An arterial blood sample was collected at T20. At the end of the procedures, immobilization was partially reversed with atipamezole 0.25 mg/kg IM. Quality of induction, immobilization, and recovery was scored. The BDM combination induced immobilization and lateral recumbency in 13.44 ± 5.61 min. Median induction score (scored 1 [excellent] to 4 [poor]) was 1 (range 1-2). Heart rate varied 40-104 beats/min, respiratory rate 16-108 breaths/min, and rectal temperature 36.5-40.3 C. Hyperthermia was observed and rapidly treated in three animals that demonstrated insufficient immobilization after darting. Arterial blood gas analyses revealed a mean pH of 7.43 ± 0.07, partial arterial pressure of CO(2) of 44.1 ± 6.0 mmHg, partial arterial pressure of O(2) of 74.0 ± 13.5 mmHg, and an arterial O(2) saturation of 94.77 ± 3.96%. Recovery was smooth and animals were walking in 13.44 ± 7.85 min. Median recovery score (1 = excellent to 4 = poor) was 1 (range 1-2). The BDM was effective in immobilizing captive healthy lechwes with minimal cardiorespiratory changes.

Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes.

PubMed

RamaRao, Golime; Afley, Prachiti; Acharya, Jyothiranjan; Bhattacharya, Bijoy Krishna

2014-04-04

Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2×LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents.

In vitro-in vivo extrapolation of zolpidem as a perpetrator of metabolic interactions involving CYP3A.

PubMed

Polasek, Thomas M; Sadagopal, Janani S; Elliot, David J; Miners, John O

2010-03-01

To evaluate zolpidem as a mechanism-based inactivator of human CYP3A in vitro, and to assess its metabolic interaction potential with CYP3A drugs (in vitro-in vivo extrapolation; IV-IVE). A co- vs. pre-incubation strategy was used to quantify time-dependent inhibition of human liver microsomal (HLM) and recombinant CYP3A4 (rCYP3A4) by zolpidem. Experiments involving a 10-fold dilution step were employed to determine the kinetic constants of inactivation (K (I) and k (inact)) and to assess the in vitro mechanism-based inactivation (MBI) criteria. Inactivation data were entered into the Simcyp population-based ADME simulator to predict the increase in the area under the plasma concentration-time curve (AUC) for orally administered midazolam. Consistent with MBI, the inhibitory potency of zolpidem toward CYP3A was increased following pre-incubation. In HLMs, the concentration required for half maximal inactivation (K (I)) was 122 microM and the maximal rate of inactivation (k (inact)) was 0.094 min(-1). In comparison, K (I) and k (inact) values with rCYP3A4 were 50 microM and 0.229 min(-1), respectively. Zolpidem fulfilled all other in vitro MBI criteria, including irreversible inhibition. The mean oral AUC for midazolam in healthy volunteers was predicted to increase 1.1- to 1.7-fold due to the inhibition of metabolic clearance by zolpidem. Elderly subjects were more sensitive to the interaction, with mean increases in midazolam AUC of 1.2- and 2.2-fold for HLM IV-IVE and rCYP3A4 IV-IVE, respectively. Zolpidem is a relatively weak mechanism-based inactivator of human CYP3A in vitro. Zolpidem is unlikely to act as a significant perpetrator of metabolic interactions involving CYP3A.

A Systematic Approach to Evaluate Herb-Drug Interaction Mechanisms: Investigation of Milk Thistle Extracts and Eight Isolated Constituents as CYP3A Inhibitors

PubMed Central

Brantley, Scott J.; Graf, Tyler N.; Oberlies, Nicholas H.

2013-01-01

Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1′-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 μM demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC50 determination. The IC50s for isosilybin B and silychristin were ∼60 and 90 μM, respectively, whereas those for the remaining constituents were >100 μM. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a >1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI, ∼100 μM; kinact, ∼0.20 min−1) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation. PMID:23801821

A systematic approach to evaluate herb-drug interaction mechanisms: investigation of milk thistle extracts and eight isolated constituents as CYP3A inhibitors.

PubMed

Brantley, Scott J; Graf, Tyler N; Oberlies, Nicholas H; Paine, Mary F

2013-09-01

Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1'-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 μM demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC50 determination. The IC50s for isosilybin B and silychristin were ∼60 and 90 μM, respectively, whereas those for the remaining constituents were >100 μM. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a >1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI, ∼100 μM; kinact, ∼0.20 min(-1)) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation.

Benzodiazepine Use in Pilots of Civil Aviation Accidents: 1990-2008 Toxicology and Autopsy Findings

DTIC Science & Technology

2011-02-01

are.analyzed.for.a.number.of.benzodi- azepines,.including.diazepam,.nordiazepam,.triazolam,. alprazolam ,.temazepam,.α-hydroxyalprazolam,.oxazepam...hydroxyalprazolam.(13),.midazolam.(12),. alprazolam . (9),.and.chlordiazepoxide.(4) ..Along.with.the.detected. benzodiazepines,.ethanol.was.found.in.21.(~22...in.which.it. was.determined.that.diazepam,.nordiazepam,. alprazolam ,. temazepam,. and. chlordiazepoxide. were. the. most. fre

Glossopharyngeal Nerve Block versus Lidocaine Spray to Improve Tolerance in Upper Gastrointestinal Endoscopy.

PubMed

Ortega Ramírez, Moisés; Linares Segovia, Benigno; García Cuevas, Marco Antonio; Sánchez Romero, Jorge Luis; Botello Buenrostro, Illich; Amador Licona, Norma; Guízar Mendoza, Juan Manuel; Guerrero Romero, Jesús Francisco; Vázquez Zárate, Víctor Manuel

2013-01-01

Aim of the Study. To compare the effect of glossopharyngeal nerve block with topical anesthesia on the tolerance of patients to upper gastrointestinal endoscopy. Methods. We performed a clinical trial in one hundred patients undergoing upper gastrointestinal endoscopy. Subjects were randomly assigned to one of the following two groups: (1) treatment with bilateral glossopharyngeal nerve block (GFNB) and intravenous midazolam or (2) treatment with topical anesthetic (TASS) and intravenous midazolam. We evaluated sedation, tolerance to the procedure, hemodynamic stability, and adverse symptoms. Results. We studied 46 men and 54 women, from 17 to 78 years of age. The procedure was reported without discomfort in 48 patients (88%) in the GFNB group and 32 (64%) in the TAAS group; 6 patients (12%) in GFNB group and 18 (36%) in TAAS group reported the procedure as little discomfort (χ (2) = 3.95, P = 0.04). There was no difference in frequency of nausea (4% in both groups) and retching, 4% versus 8% for GFNB and TASS group, respectively (P = 0.55). Conclusions. The use of glossopharyngeal nerve block provides greater comfort and tolerance to the patient undergoing upper gastrointestinal endoscopy. It also reduces the need for sedation.

Glossopharyngeal Nerve Block versus Lidocaine Spray to Improve Tolerance in Upper Gastrointestinal Endoscopy

PubMed Central

Ortega Ramírez, Moisés; Linares Segovia, Benigno; García Cuevas, Marco Antonio; Sánchez Romero, Jorge Luis; Botello Buenrostro, Illich; Amador Licona, Norma; Guízar Mendoza, Juan Manuel; Guerrero Romero, Jesús Francisco; Vázquez Zárate, Víctor Manuel

2013-01-01

Aim of the Study. To compare the effect of glossopharyngeal nerve block with topical anesthesia on the tolerance of patients to upper gastrointestinal endoscopy. Methods. We performed a clinical trial in one hundred patients undergoing upper gastrointestinal endoscopy. Subjects were randomly assigned to one of the following two groups: (1) treatment with bilateral glossopharyngeal nerve block (GFNB) and intravenous midazolam or (2) treatment with topical anesthetic (TASS) and intravenous midazolam. We evaluated sedation, tolerance to the procedure, hemodynamic stability, and adverse symptoms. Results. We studied 46 men and 54 women, from 17 to 78 years of age. The procedure was reported without discomfort in 48 patients (88%) in the GFNB group and 32 (64%) in the TAAS group; 6 patients (12%) in GFNB group and 18 (36%) in TAAS group reported the procedure as little discomfort (χ 2 = 3.95, P = 0.04). There was no difference in frequency of nausea (4% in both groups) and retching, 4% versus 8% for GFNB and TASS group, respectively (P = 0.55). Conclusions. The use of glossopharyngeal nerve block provides greater comfort and tolerance to the patient undergoing upper gastrointestinal endoscopy. It also reduces the need for sedation. PMID:23533386

Pediatric status epilepticus: improved management with new drug therapies?

PubMed

Verrotti, Alberto; Ambrosi, Michela; Pavone, Piero; Striano, Pasquale

2017-06-01

Status Epilepticus (SE) is the most common neurological emergency of childhood. It requires prompt administration of appropriately selected anti-seizure medications. Areas covered: Following a distinction between estabilished and emergent drugs, we present pharmacological treatment options and their clinical utility in children, with a short mention on alternatives to drug treatment. We also propose an algorithm for the management of pediatric SE. For this review a Pubmed, Medline and Embase search was performed. Expert opinion: In early SE in children, in the prehospital setting, rectal diazepam or buccal midazolam are efficacious drugs; whereas in the hospital setting, intravenous lorazepam or diazepam are indicated. As regard estabilished stage of SE, in addition to the 'classic' compounds, such as phenytoin and phenobarbital, other drugs such as valproic acid, levetiracetam and lacosamide have been demonstrated efficacious. Treatment recommendations of refractory SE depend on retrospective case series and uncontrolled studies. We reported experiences about the use of midazolam, propofol, ketamine and lidocaine. They could be a valid option, but further prospective studies are necessary. Over the last few decades, important advances in basic mechanisms underlying refractory SE have been achieved, but few data are available regarding management of these stages.

Comparison of dexmedetomidine and midazolam for monitored anesthesia care combined with tramadol via patient-controlled analgesia in endoscopic nasal surgery: A prospective, randomized, double-blind, clinical study

PubMed Central

Karaaslan, Kazim; Yilmaz, Fahrettin; Gulcu, Nebahat; Colak, Cemil; Sereflican, Murat; Kocoglu, Hasan

2007-01-01

Abstract Background Monitored anesthesia care (MAC) may be applied for septoplasty or endoscopic sinus surgery in which an adequate sedation and analgesia without respiratory depression are desired for comfort of both the patient and the surgeon. Several combinations with different agents have been used for this purpose in these patients. However, analgesic properties for these agents have not been reported. Objective The aim of this study was to investigate the analgesic and sedative effects of dexmedetomidine or midazolam infusion combined with tramadol that was used via patient-controlled analgesia (PCA), and to document the effects of these drugs on early cognitive functions. Methods This prospective, randomized, double-blind, clinical study enrolled patients undergoing septoplasty or endoscopic sinus surgery at the Abant Izzet Baysal University Hospital, Bolu, Turkey, between February and September 2006. Patients were randomly allocated in a 1:1 ratio into 1 of 2 groups: the dexmedetomidine group (group D) patients received IV dexmedetomidine 1 μg/kg for 10 minutes followed by continuous infusion of 0.5 μg/kg · h−1; and the midazolam group (group M) patients were administered a loading dose of IV midazolam 40 μg/kg for 10 minutes followed by infusion at the rate of 50 μg/kg · h−1. A 1-minute bolus dose of IV tramadol (1.5 mg/kg) was administered in both groups 10 minutes after the administration of the primary drug, and continued via infusion using a PCA device. After baseline measurements, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), heart rate (HR), oxygen saturation, and rate of respiration were recorded after the loading dose of study drug, after the bolus tramadol dose, at 10-minute intervals during the operation, and twice in the recovery rooms; 5 minutes after arrival and 5 minutes before discharge. Verbal rating score (VRS) and Ramsay sedation score were determined at baseline (after surgery was started), every 10 minutes thereafter until the end of the operation, and 2 times during recovery. All patients were assessed with the Wechsler Memory Scale-Revised at baseline (preoperatively) and 4 hours after the operation. Results Seventy patients were enrolled in the study and randomly assigned to 1 of 2 groups: group D (sex, male/female, 23/12; mean [SEM] age, 32.53 [2.07] years; mean [SEM] weight, 73.03 [2.41] kg) or group M (sex, male/female, 21/14; mean [SEM] age, 34.43 [1.83] years; mean [SEM] weight, 67.90 [2.32] kg). All hemodynamic parameters (SAP, DAP, MAP, HR) were significantly higher in group M compared with group D from the onset of the surgery to discharge time (P < 0.05). Pain and sedation scores were similar in both groups, but the amount of PCA-administered rescue tramadol was significantly higher in group M (P = 0.001). A higher, though not statistically significant, prevalence of adverse events (ie, hypotension, bradycardia, and perioperative nausea and vomiting) were observed in group D. Postoperative logical verbal memory and digit span values were significantly higher in group D when compared with group M (P < 0.05). Postoperative digit span and visual reproduction scores were significantly higher than preoperative values in group D (P < 0.05). Postoperative personality functioning scores were significantly higher than preoperative values in group M (P < 0.05). Conclusions Based on VRS, Ramsay sedation scores, and surgeon and anesthesiologist satisfaction scores, dexmedetomidine or midazolam combined with tramadol PCA provided adequate analgesia and sedation in these adult patients undergoing septoplasty or endoscopic sinus surgery with MAC. A significantly larger amount of rescue tramadol was used by group M, suggesting that a better analgesic effect was achieved with dexmedetomidine. PMID:24678121

A study comparing the hypnotic efficacies and residual effects on actual driving performance of midazolam 15 mg, triazolam 0.5 mg, temazepam 20 mg and placebo in shiftworkers on night duty

DOT National Transportation Integrated Search

1988-11-01

The purpose of the study was to determine the hypnotic efficacy and residual effects of three hypnotics administered for the treatment of transient insomnia in the day-sleep of rotating shift workers. The average duration of day-sleep in rotating shi...

A BDNF Sensitive Mechanism Is Involved in the Fear Memory Resulting from the Interaction between Stress and the Retrieval of an Established Trace

ERIC Educational Resources Information Center

Giachero, Marcelo; Bustos, Silvia G.; Calfa, Gaston; Molina, Victor A.

2013-01-01

The present study investigates the fear memory resulting from the interaction of a stressful experience and the retrieval of an established fear memory trace. Such a combination enhanced both fear expression and fear retention in adult Wistar rats. Likewise, midazolam intra-basolateral amygdala (BLA) infusion prior to stress attenuated the…

Impact of visceral leishmaniasis and curative chemotherapy on cytochrome P450 activity in Brazilian patients.

PubMed

Lanchote, Vera Lucia; Almeida, Roque; Barral, Aldina; Barral-Netto, Manoel; Marques, Maria Paula; Moraes, Natália V; da Silva, Angela M; Souza, Tania M V; Suarez-Kurtz, Guilherme

2015-11-01

The aim of the present study was to investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil. Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2-3 days (phase 2) and 3-6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5-hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9). Mean values (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10-1.31), 1.45 (1.32-1.57) and 1.35 (1.26-1.44) ml min(-1)  kg(-1) ; omeprazole/5-hydroxyomeprazole ratio, 0.78 (0.61-0.94), 0.45 (0.27-0.63) and 0.37 (0.20-0.55); losartan/E3174 ratio, 0.66 (0.39-0.92), 0.35 (0.20-0.50) and 0.35 (0.16-0.53). Analysis of variance revealed significant differences in CYP3A (P = 0.018) and CYP2C19 (P = 0.008), but not CYP2C9 (P = 0.11) phenotypic activity, across the three study phases. The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared with post-chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for the suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on the expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed. © 2015 The British Pharmacological Society.

Impact of visceral leishmaniasis and curative chemotherapy on cytochrome P450 activity in Brazilian patients

PubMed Central

Lanchote, Vera Lucia; Almeida, Roque; Barral, Aldina; Barral-Netto, Manoel; Marques, Maria Paula; Moraes, Natália V; da Silva, Angela M; Souza, Tania M V; Suarez-Kurtz, Guilherme

2015-01-01

Aims The aim of the present study was to investigate the impact of human visceral leishmaniasis (VL) and curative chemotherapy on the activity of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 in patients from an endemic region in Brazil. Methods Adult patients with parasitologically confirmed VL were given a CYP phenotyping cocktail, comprising midazolam, omeprazole and losartan, immediately before (Study phase 1), 2–3 days (phase 2) and 3–6 months (phase 3) after curative VL chemotherapy. CYP activity was assessed by the apparent clearance of midazolam (CYP3A), omeprazole/5-hydroxyomeprazol ratio in plasma (CYP2C19) and losartan/E3174 ratio in urine (CYP2C9). Results Mean values (95% confidence interval) in phases 1, 2 and 3 were, respectively: log apparent midazolam clearance, 1.21 (1.10–1.31), 1.45 (1.32–1.57) and 1.35 (1.26–1.44) ml min–1 kg–1; omeprazole/5-hydroxyomeprazole ratio, 0.78 (0.61–0.94), 0.45 (0.27–0.63) and 0.37 (0.20-0.55); losartan/E3174 ratio, 0.66 (0.39–0.92), 0.35 (0.20–0.50) and 0.35 (0.16–0.53). Analysis of variance revealed significant differences in CYP3A (P = 0.018) and CYP2C19 (P = 0.008), but not CYP2C9 (P = 0.11) phenotypic activity, across the three study phases. Conclusion The phenotypic activities of CYP3A4 and CYP2C19 were significantly reduced during acute VL compared with post-chemotherapy. We propose that increased plasma concentrations of proinflammatory cytokines during active disease account for the suppression of CYP activity. The failure to detect significant changes in CYP2C9 activity in the overall cohort may reflect differential effects of the inflammatory process on the expression of CYP isoforms, although the possibility of insufficient statistical power cannot be dismissed. PMID:25940755

Effects of Rolapitant Administered Intravenously on the Pharmacokinetics of a Modified Cooperstown Cocktail (Midazolam, Omeprazole, Warfarin, Caffeine, and Dextromethorphan) in Healthy Subjects.

PubMed

Wang, Xiaodong; Zhang, Zhi-Yi; Arora, Sujata; Wang, Jing; Lu, Sharon; Powers, Dan; Kansra, Vikram

2018-04-25

Rolapitant is a selective, long-acting neurokinin-1 receptor antagonist, approved in the United States and Europe for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This open-label study evaluated the effects of a new intravenous formulation of rolapitant on cytochrome P450 (CYP) enzyme (CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6) activity. On days 1 and 14, 36 healthy volunteers received a modified Cooperstown cocktail (midazolam 3 mg [CYP3A substrate], caffeine 200 mg [CYP1A2 substrate], S-warfarin 10 mg [CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19 substrate], and dextromethorphan 30 mg [CYP2D6 substrate]). On day 7, subjects received the modified Cooperstown cocktail after 166.5-mg rolapitant infusion. On days 21, 28, and 35, subjects received oral dextromethorphan. Maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC 0-last ) of probe drugs post- vs pre-rolapitant administration were assessed using geometric least-squares mean ratios (GMRs) with 90%CIs. The 90%CIs of the GMRs were within the 0.80-1.25 no-effect limits for caffeine and S-warfarin C max and AUC 0-last . For midazolam C max and AUC 0-last and omeprazole C max , the 90%CIs of the GMRs were marginally outside these limits. Intravenous rolapitant coadministration increased dextromethorphan exposure, peaking 14 days post-rolapitant administration (GMRs: C max , 2.74, 90%CI 2.21-3.40; AUC 0-last , 3.36, 90%CI 2.74-4.13). Intravenous rolapitant 166.5 mg and probe drugs were well tolerated when coadministered. These data suggest that intravenous rolapitant is not an inhibitor of CYP3A, CYP2C9, CYP2C19, or CYP1A2 but is a moderate inhibitor of CYP2D6. © 2018, The American College of Clinical Pharmacology.

The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice.

PubMed

de Moura, Fernando B; McMahon, Lance R

2017-03-01

The extent to which non-α4β2 versus α4β2* nAChRs contribute to the behavioral effects of varenicline and other nAChR agonists is unclear. The purpose of this study was to characterize the discriminative stimulus effects of varenicline and nicotine using various nAChR agonists and antagonists to elucidate possible non-α4β2 nAChR mechanisms. Separate groups of male C57BL/6J mice were trained to discriminate varenicline (3.2 mg/kg) or nicotine (1 mg/kg). Test drugs included mecamylamine; the nAChR agonists epibatidine, nicotine, cytisine, varenicline, and RTI-102; the β2-containing nAChR antagonist dihydro-β-erythroidine (DHβE); the α7 nAChR agonist PNU-282987; the α7 antagonist methyllycaconitine (MLA); the α3β4 antagonist 18-methoxycoronaridine (18-MC); and the non-nAChR drugs midazolam and cocaine. In nicotine-trained mice, maximum nicotine-appropriate responding was 95% nicotine, 94% epibatidine, 63% varenicline, 58% cytisine, and less than 50% for RTI-102, PNU-282987, midazolam, and cocaine. In varenicline-trained mice, maximum varenicline-appropriate responding was 90% varenicline, 86% epibatidine, 74% cytisine, 80% RTI-102, 50% cocaine, and 50% or less for nicotine, PNU-282987, and midazolam. Drugs were studied to doses that abolished operant responding. Mecamylamine antagonized the discriminative stimulus effects, but not the rate-decreasing effects, of nicotine and varenicline. DHβE antagonized the discriminative stimulus and rate-decreasing effects of nicotine but not varenicline in either the nicotine or varenicline discrimination assays. The discriminative stimulus, but not the rate-decreasing, effects of epibatidine were antagonized by DHβE regardless of the training drug. These results suggest that α4β2* nAChRs differentially mediate the discriminative stimulus effects of nicotine and varenicline, and suggest that varenicline has substantial non-α4β2 nAChR activity.

Evaluation of butorphanol, medetomidine and midazolam as a reversible narcotic combination in free-ranging African lions (Panthera leo).

PubMed

Wenger, Sandra; Buss, Peter; Joubert, Jenny; Steenkamp, Johan; Shikwambana, Purvance; Hatt, Jean-Michel

2010-11-01

To evaluate the effects of the combination butorphanol, medetomidine and midazolam (BMM) and its reversibility in lions. Prospective clinical trial. Thirty free-ranging lions, 10 male and 20 female, weighing 81-210 kg. Lions were immobilised with butorphanol mean 0.31 ± SD 0.034 mg kg(-1), medetomidine 0.052 ± 0.006 mg kg(-1), midazolam 0.21 ± 0.024 mg kg(-1) and hyaluronidase 1250 IU administered intramuscularly with a dart gun. Upon recumbency, physiological parameters and anaesthetic depth were monitored 10-15 minutes after darting (T1) and repeated every 10 minutes for a further 30 minutes (T2, T3, T4). Arterial blood gas analyses were performed at T1 and T4. At the end of the procedure, 45-60 minutes after initial darting, immobilisation was reversed with naltrexone 0.68 ± 0.082 mg kg(-1), atipamezole 0.26 ± 0.031 mg kg(-1), and flumazenil 0.0032 ± 0.0007 mg kg(-1) administered intravenously and subcutaneously. The BMM combination rapidly induced immobilisation and lateral recumbency was reached within 7.25 ± 2.3 minutes. Median induction score [scored 1 (excellent) to 4 (poor)] was 1.4 (range 1-2). Cardio-respiratory parameters were stable. Heart rate varied from 32 to 72 beats per minute, respiratory rate from 14 to 32 breaths minute(-1) and rectal temperature from 36.6 to 40.3 °C. No sudden arousals were observed. Arterial blood gas analyses revealed a mean pH of 7.33, PaCO(2) of 33 mmHg and PaO(2) of 87 mmHg. Mild to moderate hypoxemia was seen in four lions. Recovery was smooth and lions were walking within 4.4 ± 4.25 minutes. Median recovery score [scored 1 (excellent) to 4 (poor)] was 1.3 (range 1-2). The drug combination proved to be effective in immobilising free-ranging healthy lions of both sexes with minimal cardio-respiratory changes. © 2010 The Authors. Veterinary Anaesthesia and Analgesia © 2010 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

Optimum Drug Combinations for the Sedation of Growing Boars Prior to Castration

PubMed Central

Lehmann, Heidi S.; Blache, Dominique; Drynan, Eleanor; Tshewang, Pema; Blignaut, David J. C.; Musk, Gabrielle C.

2017-01-01

Simple Summary Pigs are notoriously challenging patients. They are difficult to handle so the use of predictable and safe sedation techniques is required for husbandry and surgical procedures. Various combinations of sedative and analgesic drugs have been previously investigated in this species, though the combination of midazolam and detomidine with either butorphanol or morphine has not been reported for sedation in pigs. The use of these combinations was investigated in the context of adequate sedation to allow castration of boars with the aid of local anaesthetic infiltration. The combination of midazolam, detomidine with butorphanol provided a more reliable sedation combination than that including morphine. It is proposed that this combination of drugs would be useful for sedation during painful husbandry procedures in pigs. Abstract Juvenile male pigs were sedated for castration. Eight five-month old boars were sedated twice (two weeks apart) with a combination of detomidine (0.1 mg/kg), midazolam (0.2 mg/kg) and either butorphanol (0.2 mg/kg) (Group MDB, n = 8) or morphine (0.2 mg/kg) (Group MDM, n = 8) intramuscularly. The boars were positioned in lateral recumbency and lidocaine (200 mg total) was injected into the testicle and scrotal skin. Castration of a single testicle was performed on two occasions. Sedation and reaction (to positioning and surgery) scores, pulse rate, respiratory rate, haemoglobin oxygen saturation, body temperature, arterial blood gas parameters and the times to immobility and then recovery were recorded. Atipamezole was administered if spontaneous recovery was not evident within 60 min of sedative administration. Data were compared with either a paired-sample t-test or a Wilcoxon-Signed Rank Test. There was no difference in sedation score, body temperature, respiratory rate and haemoglobin oxygen saturation between MDB and MDM. Mild hypoxaemia was noted in both groups. There was less reaction to castration after MDB. The pulse rate was higher after MDM sedation. The times to immobility and then recovery were similar. The combination of MDB provided more reliable sedation than MDM. MDB may be useful for sedation for short procedures in pigs, though oxygen supplementation is recommended to avoid hypoxaemia. PMID:28796153

Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse transcriptase inhibitor, after single and multiple doses in healthy subjects.

PubMed

Anderson, Matt S; Gilmartin, Jocelyn; Cilissen, Caroline; De Lepeleire, Inge; Van Bortel, Luc; Dockendorf, Marissa F; Tetteh, Ernestina; Ancona, June K; Liu, Rachael; Guo, Ying; Wagner, John A; Butterton, Joan R

2015-01-01

Doravirine is a novel non-nucleoside inhibitor of HIV-1 reverse transcriptase with potent activity against wild-type virus (95% inhibitory concentration 19 nM, 50% human serum). Doravirine has low potential to cause drug-drug interactions since it is primarily eliminated by oxidative metabolism and does not inhibit or significantly induce drug-metabolizing enzymes. The pharmacokinetics and safety of doravirine were investigated in two double-blind, dose-escalation studies in healthy males. Thirty-two subjects received single doses of doravirine (6-1,200 mg) or matching placebo tablets; 40 subjects received doravirine (30-750 mg) or matching placebo tablets once daily for 10 days. In addition, the effect of doravirine (120 mg for 14 days) on single-dose pharmacokinetics of the CYP3A substrate midazolam was evaluated (10 subjects). The maximum plasma concentration (Cmax) of doravirine was achieved within 1-5 h with an apparent terminal half-life of 12-21 h. Consistent with single-dose pharmacokinetics, steady state was achieved after approximately 7 days of once daily administration, with accumulation ratios (day 10/day 1) of 1.1-1.5 in the area under the plasma concentration-time curve during the dosing interval (AUC0-24 h), Cmax and trough plasma concentration (C24 h). All dose levels produced C24 h>19 nM. Administration of 50 mg doravirine with a high-fat meal was associated with slight elevations in AUC time zero to infinity (AUC0-∞) and C24 h with no change in Cmax. Midazolam AUC0-∞ was slightly reduced by coadministration of doravirine (geometric mean ratio 0.82, 90% CI 0.70, 0.97). There was no apparent relationship between adverse event frequency or intensity and doravirine dose. No rash or significant central nervous system events other than headache were reported. Doravirine is generally well tolerated in single doses up to 1,200 mg and multiple doses up to 750 mg once daily for up to 10 days, with a pharmacokinetic profile supportive of once-daily dosing. Doravirine at steady state slightly reduced the exposure of coadministered midazolam, to a clinically unimportant extent.

Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes

PubMed Central

2014-01-01

Background Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. Results Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2 × LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Conclusion Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents. PMID:24708580

Prehospital Care for the Adult and Pediatric Seizure Patient: Current Evidence-based Recommendations.

PubMed

Silverman, Eric C; Sporer, Karl A; Lemieux, Justin M; Brown, John F; Koenig, Kristi L; Gausche-Hill, Marianne; Rudnick, Eric M; Salvucci, Angelo A; Gilbert, Greg H

2017-04-01

We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of adult and pediatric patients with a seizure and to compare these recommendations against the current protocol used by the 33 emergency medical services (EMS) agencies in California. We performed a review of the evidence in the prehospital treatment of patients with a seizure, and then compared the seizure protocols of each of the 33 EMS agencies for consistency with these recommendations. We analyzed the type and route of medication administered, number of additional rescue doses permitted, and requirements for glucose testing prior to medication. The treatment for eclampsia and seizures in pediatric patients were analyzed separately. Protocols across EMS Agencies in California varied widely. We identified multiple drugs, dosages, routes of administration, re-dosing instructions, and requirement for blood glucose testing prior to medication delivery. Blood glucose testing prior to benzodiazepine administration is required by 61% (20/33) of agencies for adult patients and 76% (25/33) for pediatric patients. All agencies have protocols for giving intramuscular benzodiazepines and 76% (25/33) have protocols for intranasal benzodiazepines. Intramuscular midazolam dosages ranged from 2 to 10 mg per single adult dose, 2 to 8 mg per single pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intranasal midazolam dosages ranged from 2 to 10 mg per single adult or pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intravenous/intrasosseous midazolam dosages ranged from 1 to 6 mg per single adult dose, 1 to 5 mg per single pediatric dose, and 0.05 to 0.1 mg/kg as a weight-based dose. Eclampsia is specifically addressed by 85% (28/33) of agencies. Forty-two percent (14/33) have a protocol for administering magnesium sulfate, with intravenous dosages ranging from 2 to 6 mg, and 58% (19/33) allow benzodiazepines to be administered. Protocols for a patient with a seizure, including eclampsia and febrile seizures, vary widely across California. These recommendations for the prehospital diagnosis and treatment of seizures may be useful for EMS medical directors tasked with creating and revising these protocols.

Management of background pain and anxiety in critically burned children requiring protracted mechanical ventilation.

PubMed

Sheridan, R; Stoddard, F; Querzoli, E

2001-01-01

Optimal control of pain and anxiety is an elusive but important goal in children with protracted critical illness. This review represents an effort to document the doses of background medication required to achieve this goal in a group of children managed under a pain and anxiety protocol that adjusts background infusions to comfort. The course of children with wounds involving at least 10% of the body surface and coincident respiratory failure requiring mechanical ventilation for more than 7 days managed 1 Jan 97 to 31 Dec 98 was reviewed. A pain and anxiety protocol was used, including background infusions of morphine and midazolam adjusted to comfort. These 28 children had a mean (+/- standard deviation) age of 5.3 +/- 4.6 years, wound size of 48.3 +/- 28.4%, and were intubated for 25.0 +/- 23.9 days. Neuromuscular blocking drugs were administered for 65 of 447 (14.5%) ventilator days. To maintain comfort, drugs were required at doses substantially above standard dosing schemes. The highest daily background infusion of morphine sulfate averaged 0.40 mg/kg/hr +/- 0.24 mg/kg/hr (usual starting dose was 0.05 to 0.1 mg/kg/hr) and was reached 14.1 +/- 12.8 days after admission. The highest daily background infusion of midazolam averaged 0.15 +/- 0.07 mg/kg/hr (usual starting dose was 0.04 mg/kg/hr) and was reached 14.0 +/- 3.8 days after admission. Morphine infusions at extubation averaged 0.22 +/- 0.17 mg/kg/hr and midazolam infusions 0.10 +/- 0.12 mg/kg/hr. All children survived to discharge and there was no perceived morbidity related to these high doses of medication. Children with serious burns and respiratory failure will require high doses of background opiates and benzodiazepines to remain comfortable, because they develop drug tolerance during protracted critical illness. Infusions can be continued at a reduced dose through extubation, do not result in addiction or other apparent morbidity if adjusted to desired level of comfort, and may contribute to a reduced incidence of treatment-related stress disorders.

Intravenous sedation as an adjunct to advanced comprehensive dental implantology: the patient's perspective and operator satisfaction.

PubMed

McCrea, S J J

2015-03-13

The aim of this three-year study was to evaluate whether elective comprehensive dental implant procedures involving guided bone and soft tissue regeneration carried out under intravenous sedation (midazolam) would be influenced by patient self-reported pre-operative anxiety levels; age and gender; effect the level of sedation with respect to the amount of sedative administered and the time taken in the procedures; effect patient intra-operative cooperation, and post-operative levels of patient satisfaction; influence further acceptance of dental implant surgical procedures; effect intra-operative surgeon satisfaction and consequently his/her post-operative sense of achievement.Design Single centre general dental practice, open study as a clinical audit. One hundred and seventy-three consecutive patients undergoing prolonged surgical procedures involving dental implantology with the adjunctive facility of intravenous sedation were monitored with respect to self-reported levels of anxiety. Vital signs of heart rate, mean systolic and diastolic blood pressure and arterial oxygen saturation were recorded and monitored pre-intra- and post-surgery. A post-operative questionnaire was completed as to the perceptions of the level of sedation. A distinct relationship between self-reported pre-operative anxiety levels, age and gender were recorded - the younger the age, the higher the anxiety, with females dominating. Females required more midazolam than males. However, the analysis of the data as a whole, incorporating both genders, revealed a non-significant correlation result. The correlation between the midazolam dosage and the Corah anxiety score produced a p value result of: r (161) = 0.008, p <0.01. Forty-four percent of the patients described themselves as having 'high anxiety and fear of the dentist', however, 99.4% of the patients answered 'yes' to having sedation again in the future. For the purpose of this study, detailed consideration was given to the gender specific results in order to reveal a wider understanding of who poses as a 'cooperative patient'. The results should prompt a rethink as to who a cooperative patient is, and whether the self-assessed level of anxiety will influence further acceptance of dental implant surgical procedures under intravenous sedation.

The effects of music on the cardiovascular system and cardiovascular health.

PubMed

Trappe, Hans-Joachim

2010-12-01

Music may not only improve quality of life but may also effect changes in heart rate and heart rate variability. It has been shown that cerebral flow was significantly lower when listening to 'Va pensiero' from Verdi's 'Nabucco' (70.4±3.3 cm/s) compared with 'Libiam nei lieti calici' from Verdi's 'La Traviata' (70.2±3.1 cm/s) (p<0.02) or Bach's Cantata No. 169 'Gott soll allein mein Herze haben' (70.9±2.9 cm/s) (p<0.02). There was no significant difference in cerebral flow during rest (67.6±3.3 cm/s) or when listening to Beethoven's Ninth Symphony (69.4±3.1 cm/s). It was reported that relaxing music significantly decreases the level of anxiety of patients in a preoperative setting (State-Trait Anxiety Inventory (STAI)-X-1 score 34)-to a greater extent even than orally administered midazolam (STAI-X-1 score 36) (p<0.001). In addition the score was better after surgery in the music group (STAI-X-1 score 30) compared with the midazolam group (STAI-X-1 score 34) (p<0.001). Higher effectiveness and absence of apparent adverse effects make relaxing, preoperative music a useful alternative to midazolam for premedication. In addition, there is sufficient practical evidence of stress reduction suggesting that a proposed regimen of listening to music while resting in bed after open-heart surgery is important in clinical use. After 30 min of bed rest, there was a significant difference in cortisol levels between the music (484.4 mmol/l) and the non-music group (618.8 mmol/l) (p<0.02). Vocal and orchestral music produce significantly better correlations between cardiovascular or respiratory signals compared with music with a more uniform emphasis (p<0.05). The greatest benefit on health is visible with classical music and meditation music, whereas heavy metal music or techno are not only ineffective but possibly dangerous and can lead to stress and/or life-threatening arrhythmias. The music of many composers most effectively improves quality of life, will increase health and probably prolong life, particularly music by Bach, Mozart or Italian composers.

Annual Research Progress Report (William Beaumont Army Medical Center) FY 1983

DTIC Science & Technology

1994-03-23

Algeo, Dept of Radiology) .............................................. 58 Pacheco, EJ: 93/53 (0) Phase II Study of Interferon-Modulated Indium- Il 1 ...76 Lutz, P: 92/68 ( 1 ) Nursing Effects on Mastectomy Patients’ Perception of Self Esteem ............................ 77 Nufer, E: 93/08 (C) Cardiac...15 1 Kravitz, MB: 93/49 (0) A Comparison Study of Midazolam and Pentobarbital Versus Pentobarbital A),=e in the Effective Sedation of

Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

PubMed

Haile, C N; Murrough, J W; Iosifescu, D V; Chang, L C; Al Jurdi, R K; Foulkes, A; Iqbal, S; Mahoney, J J; De La Garza, R; Charney, D S; Newton, T F; Mathew, S J

2014-02-01

Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

Clinical Drug-Drug Interaction Potential of BFE1224, Prodrug of Antifungal Ravuconazole, Using Two Types of Cocktails in Healthy Subjects.

PubMed

Ishii, Yasuyuki; Ito, Yuko; Matsuki, Shunji; Sanpei, Kasumi; Ogawa, Osamu; Takeda, Kenji; Schuck, Edgar L; Uemura, Naoto

2018-05-16

BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2. In addition, repaglinide was separately administered to the same subjects in study 2. There were no major effects on the pharmacokinetics of CYP and transporter substrates, except for an approximate threefold increase in midazolam exposure after oral administration of BFE1224. The clinical DDIs of BFE1224 were mild for CYP3A and minor for other major CYPs (CYP1A2/2C8/2C9/2C19/2D6) as well as those of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Effect of ketamine dose on self-rated dissociation in patients with treatment refractory anxiety disorders.

PubMed

Castle, Cameron; Gray, Andrew; Neehoff, Shona; Glue, Paul

2017-10-01

Patients receiving ketamine for refractory depression and anxiety report dissociative symptoms in the first 60 min post-dose. The most commonly used instrument to assess this is the Clinician-Administered Dissociative States Scale (CADSS), developed based on the assessment of patients with dissociative symptoms. Its psychometric properties for ketamine-induced dissociation have not been reported. We evaluated these from a study using 0.25-1 mg/kg ketamine and midazolam (as an active control) in 18 patients with treatment-resistant anxiety. Dissociation ratings were increased by ketamine in a dose-dependent manner. In contrast, midazolam showed no effect on ratings of dissociation. For individual CADSS items, the magnitude of change and the ketamine dose at which changes were observed were not homogenous. The Cronbach alpha for the total scale was high (0.937), with acceptable item-rest correlations for almost all individual items. Purposefully removing items to maximise alpha did not lead to meaningful improvements. Acceptable internal consistency was still observed after removing items which lacked evidence of responsiveness at lower doses. The high Cronbach alpha values identified in this study suggests that the CADSS is an internally consistent instrument for evaluating ketamine-induced dissociation in clinical trials in anxiety, although it does not capture symptoms such as thought disorder.

PubMed Central

Dupras, J; Vachon, P; Cuvelliez, S; Blais, D

2001-01-01

In this study, anesthesia levels obtained with tiletamine-zolazepam (TZ) and ketamine-midazolam (KM) with or without xylazine (X) were compared in rabbits. Reflexes (corneal, palpebral and withdrawal), blood parameters (PaO2, PaCO2, pH and ions HCO3-), cardiovascular function (heart rate and mean arterial blood pressure) and body temperature were evaluated before and after the injections of the anesthetic combination in the same rabbits (n = 10). With KM and TZ, no suppression of reflexes occurred. The body temperature and pH decreased and HCO3- increased similarly to KMX et TZX. Some physiological and blood parameters were less (PAM, PaCO2) and not (PaO2) affected comparatively to KMX et TZX. These protocols were of short duration of action and did not offer any anesthesia or analgesia. Therefore, their utilization should be restricted to short procedures where no painful manipulations are performed. Ketamine-midazolam-xylazine and tiletamine-zolazepam-xylazine on the other hand are indicated for interventions that require anesthesia. With these combinations, all reflexes were absent for 30-45 and 60-90 min following injections of KMX et TZX, respectively. However, these combinations induce cardiac depression, as well as a decrease of all measured blood parameters and body temperature and a reduction of PaO2. Supplementation with oxygen is recommended with the introduction of xylazine in the protocol. PMID:11424577

Central neuraxial anaesthesia presenting with spinal myoclonus in the perioperative period: a case series

PubMed Central

2009-01-01

Introduction Perioperative spinal myoclonus is extremely rare. Many anaesthetists and perioperative practitioners may not diagnose or manage this complication appropriately when it occurs. This case report of unusual acute spinal myoclonus following regional anaesthesia highlights certain aspects of this rare complication that have not previously been published. Case presentations A series of four consecutive patients who developed acute lower-limb myoclonus following spinal or epidural anaesthesia are described. The case series occurred at three different hospitals and involved four anaesthetists over a 3-year period. Two Caucasian men, aged 90-years-old and 67-years-old, manifested unilateral myoclonus. Two Caucasian women, aged 64-years-old and 53-years-old, developed bilateral myoclonus. Myoclonus was self-limiting in one patient, treated with further regional anaesthesia in one patient and treated with intravenous midazolam in two patients. The overall outcome was good in all patients, with no recurrence or sequelae in any of the patients. Conclusion This case series emphasizes that spinal myoclonus following regional anaesthesia is rare, has diverse pathophysiology and can have diverse presentations. The treatment of perioperative spinal myoclonus should be directed at the aetiology. Anaesthetists and perioperative practitioners who are unfamiliar with this rare complication should be reassured that it may be treated successfully with midazolam. PMID:19830168

High Mortality Among Non–HIV-Infected People Who Inject Drugs in Bangkok, Thailand, 2005–2012

PubMed Central

Vanichseni, Suphak; Suntharasamai, Pravan; Sangkum, Udomsak; Mock, Philip A.; Gvetadze, Roman J.; Curlin, Marcel E.; Leethochawalit, Manoj; Chiamwongpaet, Sithisat; Chaipung, Benjamaporn; McNicholl, Janet M.; Paxton, Lynn A.; Kittimunkong, Somyot; Choopanya, Kachit

2015-01-01

Objectives. We examined the causes of hospitalization and death of people who inject drugs participating in the Bangkok Tenofovir Study, an HIV preexposure prophylaxis trial. Methods. The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial conducted during 2005 to 2012 among 2413 people who inject drugs. We reviewed medical records to define the causes of hospitalization and death, examined participant characteristics and risk behaviors to determine predictors of death, and compared the participant mortality rate with the rate of the general population of Bangkok, Thailand. Results. Participants were followed an average of 4 years; 107 died: 22 (20.6%) from overdose, 13 (12.2%) from traffic accidents, and 12 (11.2%) from sepsis. In multivariable analysis, older age (40–59 years; P = .001), injecting drugs (P = .03), and injecting midazolam (P < .001) were associated with death. The standardized mortality ratio was 2.9. Conclusions. People who injected drugs were nearly 3 times as likely to die as were those in the general population of Bangkok and injecting midazolam was independently associated with death. Drug overdose and traffic accidents were the most common causes of death, and their prevention should be public health priorities. PMID:25880964

Investigation of the Anxiolytic and Antidepressant Effects of Curcumin, a Compound From Turmeric (Curcuma longa), in the Adult Male Sprague-Dawley Rat.

PubMed

Ceremuga, Tomás Eduardo; Helmrick, Katie; Kufahl, Zachary; Kelley, Jesse; Keller, Brian; Philippe, Fabiola; Golder, James; Padrón, Gina

As the use of herbal medications continues to increase in America, the potential interaction between herbal and prescription medications necessitates the discovery of their mechanisms of action. The purpose of this study was to investigate the anxiolytic and antidepressant effects of curcumin, a compound from turmeric (Curcuma longa), and its effects on the benzodiazepine site of the γ-aminobutyric acid receptor A (GABAA) receptor. Utilizing a prospective, between-subjects group design, 55 male Sprague-Dawley rats were randomly assigned to 1 of the 5 intraperitoneally injected treatment groups: vehicle, curcumin, curcumin + flumazenil, midazolam, and midazolam + curcumin. Behavioral testing was performed using the elevated plus maze, open field test, and forced swim test. A 2-tailed multivariate analysis of variance and least significant difference post hoc tests were used for data analysis. In our models, curcumin did not demonstrate anxiolytic effects or changes in behavioral despair. An interaction of curcumin at the benzodiazepine site of the GABAA receptor was also not observed. Additional studies are recommended that examine the anxiolytic and antidepressant effects of curcumin through alternate dosing regimens, modulation of other subunits on the GABAA receptor, and interactions with other central nervous system neurotransmitter systems.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review.

PubMed

Cruickshank, Moira; Henderson, Lorna; MacLennan, Graeme; Fraser, Cynthia; Campbell, Marion; Blackwood, Bronagh; Gordon, Anthony; Brazzelli, Miriam

2016-03-01

Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis. Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001). Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors. Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine. This study is registered as PROSPERO CRD42014014101. The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Assessment of recovery in patients undergoing intravenous conscious sedation using bispectral analysis.

PubMed

Sandler, N A; Hodges, J; Sabino, M

2001-06-01

The Bispectral Index (BIS) has been recently shown to objectively predict the level of sedation in patients undergoing conscious sedation. It was the goal of this study to directly compare the recovery profile of patients where the BIS was used to monitor sedation with a control group where the monitor was not used. Forty patients undergoing third molar extractions under intravenous conscious sedation were randomly assigned to 2 groups. In both groups, induction of sedation was performed using a standard dose of fentanyl (1.5 microg/kg) and midazolam (0.05 mg/kg). Propofol was then given in 10 to 20 mg boluses until a clinically desirable sedation level was achieved. In 1 group, the BIS was then monitored continually during surgery using a microcomputer (Aspect-1050 Monitor, Aspect Co, Natick, MA) and recorded at 5-minute intervals. The anesthetist (N.A.S.) provided additional propofol boluses to maintain a BIS level of 70 to 80. In the other group, the BIS sensor was applied, but the monitor was not used. In this group, the sedation was modified, and additional propofol was given based solely on the anesthetist's subjective assessment of the desired level of sedation (Observer's Assessment of Alertness/Sedation [OAA/S] scale level 2 to 3). Additional boluses of 1 mg of midazolam were given during the procedure if patients required repeated boluses of propofol at less than 5-minute intervals to maintain the desired sedation level (BIS level of 70 to 80 or OAA/S level of 2 to 3). These additional midazolam boluses, as well as the time of the last sedative dose (propofol or midazolam) were recorded to study the effect of these factors on recovery. Of the 40 patients initially included in the study, 1 subject in the BIS-monitored group was excluded due to the loss of intravenous access at initiation of the case. For the remaining 39 subjects, 19 were assessed objectively using the BIS monitor, whereas 20 were assessed subjectively using the OAA/S scale. The BIS cases were slightly longer in duration than the OAA/S cases, lasting an average of 26 minutes versus 22 minutes. This difference was statistically nonsignificant (P =.19). Less propofol was used in the BIS cases, with an average of 98 mg for BIS cases versus 106 mg for OAA/S cases (P =.59). The total dose in mg/kg/min was significantly less in the BIS group (0.054 mg/kg/min) than in the OAA/S group (0.074 mg/kg/min; P =.0082). There was no significant difference in the amount of midazolam administered after induction between the 2 groups (P =.60). The surgeon, who was blinded to whether the monitor was used, ranked the third molar extractions more difficult in the BIS group (P =.05). However, patients in the BIS group were on average more cooperative, with better maintenance of muscle tone. The difference in these parameters were nonsignificant (P =.15 and .092, respectively). A positive Romberg test was obtained earlier in BIS patients, although this difference was nonsignificant (P =.097). The straight-line test was completed significantly sooner in BIS patients (P =.013). There was no significant difference between the BIS and OAA/S groups in perceptual speed (P =.55) or computation (P =.32). There was essentially no difference between groups in patient-assessed comfort or recall of the procedure. There were also no notable differences in anesthesia complications, return to activities of daily life, or pain medication use between the 2 groups. The BIS provides additional information for standard monitoring techniques that helps guide the administration of sedative-hypnotic agents. It appears that use of the BIS monitor can help to titrate the level of sedation so that less drugs are used to maintain the desired level. The trend toward an earlier return of motor function in BIS-monitored patients warrants further investigation. Copyright 2001 American Association of Oral and Maxillofacial Surgeons.

Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulton, Emma Jane; Department of Environmental and Occupational Health Sciences, University of Washington; Levy, Lisa

2013-01-01

Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand — rifampicin (300 mg/d) was givenmore » alone for 7 days in arm 1, or in daily combination with 450 μmol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology. -- Highlights: ► The effects of SFN on PXR mediated CYP3A4 induction in humanized PXR mice and humans were examined. ► SFN had no effect on rifampicin mediated CYP3A4 induction in humans or humanized mice. ► SFN had a modest effect on basal CYP3A4 activity among subjects with higher baseline activity. ► Humanized PXR mice were generally predictive of the in vivo human response.« less

Preventing Emergence Agitation Using Ancillary Drugs with Sevoflurane for Pediatric Anesthesia: A Network Meta-Analysis.

PubMed

Wang, Xin; Deng, Qi; Liu, Bin; Yu, Xiangdi

2017-11-01

Using sevoflurane for pediatric anesthesia plays a pivotal role in surgeries. Emergence agitation (EA) is a major adverse event accompanied with pediatric anesthesia. Other anesthetic adjuvants can be combined with sevoflurane in clinical practices for different purposes. However, it is uncertain that such a practice may have substantial influence on the risk of EA. We conducted a literature search in online databases, including PubMed, Embase, Cochrane Library, and Clinical Trials. Key data were extracted from eligible randomized control trials (RCTs). Both pairwise and network meta-analysis (NMA) were conducted for synthesizing data from eligible studies. The relative risk of EA was assessed using the odds ratios (ORs) and their corresponding 95 % confidence intervals (CI) or credible intervals (CrI). Ranking scheme based on the surface under the cumulative ranking curve (SUCRA) values was produced. Several key assumptions of NMA such as heterogeneity, degree of consistence, and publication bias were validated by different statistical or graphical approaches. Evidence from 67 randomized control trials was synthesized. The relative risk of EA associated with eight anesthetic adjuvants was analyzed, including ketamine, propofol, dexmedetomidine, clonidine, midazolam, fentanyl, remifentanil, and sufentanil. Patients with the following anesthetic adjuvants appeared to have significantly reduced risk of EA in relation to those with placebo: dexmedetomidine (OR = 0.18, 95 % CrI 0.12-0.25), fentanyl (OR = 0.19, 95 % CrI 0.12-0.30), sufentanil (OR = 0.20, 95 % CrI 0.08-0.50), ketamine (OR = 0.21, 95 % CrI 0.13-0.34), clonidine (OR = 0.25, 95 % CrI 0.14-0.46), propofol (OR = 0.32, 95 % CrI 0.18-0.56), midazolam (OR = 0.46, 95 % CrI 0.27-0.77), and remifentanil (OR = 0.29, 95 % CrI 0.13-0.68). The SUCRA values for each anesthetic adjuvant were: dexmedetomidine (73.65 %), fentanyl (68.04 %), sufentanil (60.81 %), ketamine (59.99 %), clonidine (47.74 %), remifentanil (40.15 %), propofol (33.23 %), midazolam (16.33 %), and placebo (0.06 %). Incorporating anesthetic adjuvants particularly dexmedetomidine into sevoflurane appeared to be significantly associated with a decreased risk of EA in pediatric anesthesia.

Clinical Mimics: An Emergency Medicine Focused Review of Anxiety Mimics: Journal of Emergency Medicine

DTIC Science & Technology

2017-12-09

acutely agitated or moderately anxious patient, therapies that possess quick onset of action are the most useful. Benzodiazepines are the recommended...lorazepam 0.50mg or diazepam and midazolam in 1-2 mg increments.7 These medications should be used for acute treatment in the ED, with few pills provided...http://www.epilepsy.com/ learn/types-epilepsy- syndromes /temporal-lobe-epilepsy 13. Johns Hopkins Medicine. Myasthenia Gravis. Available from: http

The Effect of Gender on the Rate of Metabolism of Midazolam in Humans Using Liver Microsomes

DTIC Science & Technology

1997-05-01

of this study disprove the null hypothesis, in that the metabolic capacity of females of reproductive age to degrade MDZ to 1’-hydroxymidazolam was...demonstrate an increase in formation of 1’-hydroxymidazolam in females of reproductive age over males, corresponding with an increase in substrate...compared to males. The higher metabolic capacity of women 58 during their reproductive years might be a mechanism that developed through evolution

Inhibitory effects of kale ingestion on metabolism by cytochrome P450 enzymes in rats.

PubMed

Yamasaki, Izumi; Yamada, Masayoshi; Uotsu, Nobuo; Teramoto, Sachiyuki; Takayanagi, Risa; Yamada, Yasuhiko

2012-01-01

Kale (Brassica oleracea L. var acephala DC) is a leafy green vegetable belonging to the cabbage family (Brassicaceae) that contains a large amount of health-promoting phytochemicals. There are any reports about the effects of kale ingestion on the chemoprevention function and mechanism, but the interactions between kale and drugs have not been researched. We investigated the effects of kale intake on cytochrome P450 (CYP) metabolism by using cocktail probe drugs, including midazolam (for CYP3A4), caffeine (for CYP1A2), dextromethorphan (for CYP2D6), tolbutamide (for CYP2C9), omeprazole (for CYP2C19), and chlorzoxazone (for CYP2E1). Cocktail drugs were administered into rats treated with kale and cabbage (2000 mg/kg) for a week. The results showed that kale intake induced a significant increase in plasma levels and the AUC of midazolam, caffeine, and dextromethorphan. In addition, the plasma concentration and AUC of omeprazole tended to increase. Additionally, no almost differences in the mRNA expression levels of CYP enzymes in the liver were observed. In conclusion, kale ingestion was considered to have an inhibitory effect on the activities of CYP3A4, 1A2, 2D6, and 2C19 for a reason competitive inhibition than inhibitory changes in the mRNA expressions.

Cardiopulmonary effects of medetomidine or midazolam in combination with ketamine or tiletamine/zolazepam for the immobilisation of captive cheetahs (Acinonyx jubatus).

PubMed

Stegmann, G F; Jago, M

2006-12-01

Captive cheetah (Acinonyx jubatus) scheduled for either general health examination or dental surgery were immobilised with combinations of medetomidine-ketamine (K/DET, n = 19), midazolam-ketamine (K/MID, n = 4) or medetomidine-tiletamine-zolazepam (Z/DET, n = 5). Induction time and arterial blood pressure was not statistically significantly (P > 0.05) different between treatment groups. Transient seizures were observed in the K/DET treated animals during induction. Hypertension was present in all groups during anaesthesia with mean (+/- SD) systolic pressure of 30.7 +/- 5.0 kPa for the K/DET group, 27.7 +/- 2.7 kPa for the K/MID group, and 33.1 +/- 4.6 kPa for the Z/DET group. Heart rate was statistically significantly (P < 0.05) lower in the K/DET group (69 +/- 13.2 beats/min) compared to the K/MID group (97 +/- 22.6 beats/min), and ventilation rate was statistically significantly (P < 0.05) lower in the K/MID group (15 +/- 0.0 breaths/min) compared with the K/DET group (21 +/- 4.6). A metabolic acidosis and hypoxia were observed during anaesthesia when breathing air. Oxygen (O2) administration resulted in a statistically significant (P < 0.05) increase in the arterial partial pressure of carbon dioxide (hypercapnoea), arterial partial pressure of O2, and % oxyhaemoglobin saturation.

Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity.

PubMed

Hidaka, Muneaki; Fujita, Ken-ichi; Ogikubo, Tetsuya; Yamasaki, Keishi; Iwakiri, Tomomi; Okumura, Manabu; Kodama, Hirofumi; Arimori, Kazuhiko

2004-06-01

There has been very limited information on the capacities of tropical fruits to inhibit human cytochrome P450 3A (CYP3A) activity. Thus, the inhibitory effects of tropical fruits on midazolam 1'-hydroxylase activity of CYP3A in human liver microsomes were evaluated. Eight tropical fruits such as common papaw, dragon fruit, kiwi fruit, mango, passion fruit, pomegranate, rambutan, and star fruit were tested. We also examined the inhibition of CYP3A activity by grapefruit (white) and Valencia orange as controls. The juice of star fruit showed the most potent inhibition of CYP3A. The addition of a star fruit juice (5.0%, v/v) resulted in the almost complete inhibition of midazolam 1'-hydroxylase activity (residual activity of 0.1%). In the case of grape-fruit, the residual activity was 14.7%. The inhibition depended on the amount of fruit juice added to the incubation mixture (0.2-6.0%, v/v). The elongation of the preincubation period of a juice from star fruit (1.25 or 2.5%, v/v) with the microsomal fraction did not alter the CYP3A inhibition, suggesting that the star fruit did not contain a mechanism-based inhibitor. Thus, we discovered filtered extracts of star fruit juice to be inhibitors of human CYP3A activity in vitro.

Comparison of thiopentone/guaifenesin, ketamine/guaifenesin and ketamine/midazolam for the induction of horses to be anaesthetised with isoflurane.

PubMed

Gangl, M; Grulke, S; Detilleux, J; Caudron, I; Serteyn, D

2001-08-04

Forty-eight horses subjected to elective surgery were randomly assigned to three groups of 16 horses. After premedication with 0.1 mg/kg acepromazine intramuscularly and 0.6 mg/kg xylazine intravenously, anaesthesia was induced either with 2 g thiopentone in 500 ml of a 10 per cent guaifenesin solution, given intravenously at a dose of 1 ml/kg (group TG), or with 100 mg/kg guaifenesin and 2.2 mg/kg ketamine given intravenously (group KG), or with 0.06 mg/kg midazolam, and 2.2 mg/kg ketamine given intravenously (group KM). Anaesthesia was maintained with isoflurane. The mean (sd) end tidal isoflurane concentration (per cent) needed to maintain a light surgical anaesthesia (stage III, plane 2) was significantly lower in group KM (0.91 [0.03]) than in groups TG (1.11 [0.03]) and KG (1.14 [0.03]). The mean (sd) arterial pressure (mmHg) was significantly lower in group KG (67.4 [2.07]) than in groups TC (75.6 [2.23]) and KM (81.0 [2.16]). There were no significant differences in the logarithm of the heart rate, recovery time or quality of recovery between the three induction groups. However, pronounced ataxia was observed in the horses of group KM, especially after periods of anaesthesia lasting less than 75 minutes.

Nitrendipine decreases benzodiazepine withdrawal seizures but not the development of benzodiazepine tolerance or withdrawal signs.

PubMed Central

Dolin, S. J.; Patch, T. L.; Rabbani, M.; Siarey, R. J.; Bowhay, A. R.; Little, H. J.

1990-01-01

1. The effects of the calcium channel blocking agent, nitrendipine, were studied on seizures in mice produced during withdrawal from chronic benzodiazepine treatment and on the development of tolerance to benzodiazepines. 2. Nitrendipine produced a dose-dependent decrease in seizure incidence, when seizures were produced by the partial inverse agonist FG7142 during withdrawal from seven days treatment with flurazepam. 3. Nitrendipine did not raise the seizure thresholds in naïve mice to the full inverse agonist methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), or to the gamma-aminobutyric acid (GABA) antagonist, bicuculline. 4. When given concurrently with flurazepam for seven days, nitrendipine did not affect the incidence of seizures during flurazepam withdrawal. 5. When given concurrently with the benzodiazepines, nitrendipine did not prevent the development of tolerance to midazolam general anaesthesia or tolerance to the ataxic actions of flurazepam or midazolam. 6. Chronic treatment with flurazepam for seven days did not affect the Kd or Bmax of [3H]-nimodipine binding in mouse whole brain or cerebral cortex. 7. These results with benzodiazepines are partially in contrast with those for ethanol, where nitrendipine not only decreased ethanol withdrawal seizures when given acutely, but also prevented the development of tolerance and withdrawal signs when given concurrently with ethanol. However, they do confirm the selectivity of nitrendipine for withdrawal-induced seizures. PMID:1963805

The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model.

PubMed

Musther, Helen; Harwood, Matthew D; Yang, Jiansong; Turner, David B; Rostami-Hodjegan, Amin; Jamei, Masoud

2017-09-01

The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within physiologically based pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250 g, male Sprague-Dawley) IVIVE-linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological, and relevant IVIVE scaling factors) collated from literature and analyzed. Overall, 178 system parameter values for the model are provided. This study also highlights gaps in available system data required for strain-specific rat PBPK model development. The model's functionality and performance were assessed using previous literature-sourced in vitro properties for diazepam, metoprolol, and midazolam. The results of simulations were compared against observed pharmacokinetic rat data. Predicted and observed concentration profiles in 10 tissues for diazepam after a single intravenous (i.v.) dose making use of either observed i.v. clearance (CL iv ) or in vitro hepatocyte intrinsic clearance (CL int ) for simulations generally led to good predictions in various tissue compartments. Overall, all i.v. plasma concentration profiles were successfully predicted. However, there were challenges in predicting oral plasma concentration profiles for metoprolol and midazolam, and the potential reasons and according solutions are discussed. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Water-soluble benzodiazepine prodrug/enzyme combinations for intranasal rescue therapies.

PubMed

Siegel, Ronald A; Kapoor, Mamta; Cheryala, Narsihmulu; Georg, Gunda I; Cloyd, James C

2015-08-01

Benzodiazepines (BZDs), including diazepam (DZP) and midazolam (MDZ), are drugs of choice for rapid treatment of seizure emergencies. Current approved use of these drugs involves administration via either intravenous or rectal routes. The former requires trained medical personnel, while the latter is socially unacceptable for many patients and caregivers. In recent years, efforts have been made to formulate BZDs for nasal administration. Because of the low solubility of these molecules, organic vehicles have been used to solubilize the drugs in the nasal products under development. However, organic solvents are irritating, potentially resulting in injury to nasal tissue. Here we report preliminary studies supporting a strategy in which water-soluble BZD prodrugs and a suitable converting enzyme are coadministered in an aqueous vehicle. Diazepam and midazolam prodrugs were synthesized and were readily converted to their active forms by a protease from Aspergillus oryzae. Using a permeation assay based on monolayers of Madin-Darby canine kidney II-wild type cells, we found that enzymatically produced BZDs could be maintained at high degrees of supersaturation, enabling faster transport across the membrane than can be achieved using saturated solutions. This strategy not only obviates the need for organic solvents, but it also suggests more rapid absorption and earlier peak concentrations than can be otherwise achieved. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.

[Sedation in the terminal phase of life].

PubMed

Verhagen, E H; Eliel, M R; de Graeff, A; Teunissen, S C

1999-12-25

In 2 patients, a woman aged 38 years and a man aged 48 years, in the terminal phase of life due to metastasized+ malignancy, palliative care failed. They suffered seriously from pain, delirium, restlessness, nausea, and fear. Deep sedation was given to induce almost continuous sleep without the intention of causing death. After one and five quiet days respectively the patients died. Deep sedation is an option when palliative care fails to diminish serious suffering. Midazolam, given by continuous subcutaneous infusion is the drug of choice.

A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate, and midazolam.

PubMed

Cifani, Carlo; Polidori, Carlo; Melotto, Sergio; Ciccocioppo, Roberto; Massi, Maurizio

2009-05-01

Preclinical models are needed to investigate the neurobiology and psychobiology of binge eating and to identify innovative pharmacotherapeutic strategies. A modification of the model based on the combination of cyclic caloric restrictions and acute stress was developed to further increase its face validity and reliability and, for the first time, to assess its predictive value. Four groups of female rats were employed: group 1 was normally fed and not stressed on the test day (25th); group 2 was fed normally but was exposed to an acute stress on day 25; group 3 was exposed to three cycles (4 days 66% of chow intake + 4 days food ad libitum) of yo-yo dieting but not stressed; and group 4 was exposed to cyclic yo-yo dieting and then stressed. All groups were fed highly palatable food (HPF) for 2 h on days 5-6 and 13-14. Acute stress was elicited by exposing rats to HPF, but preventing them from access to it for 15 min. The combination of cyclic food restriction and stressful exposure to food markedly increased HPF intake. Sibutramine and fluoxetine inhibited food intake in all conditions. Topiramate selectively inhibited compulsive HPF intake in rats submitted to caloric restriction and stress. Midazolam increased HPF intake. Pharmacological results suggest that this model, in addition to face validity as an isomorphic model of human binge eating, is endowed with good predictive validity.

Defining the in Vivo Role for cytochrome b5 in cytochrome P450 function through the conditional hepatic deletion of microsomal cytochrome b5.

PubMed

Finn, Robert D; McLaughlin, Lesley A; Ronseaux, Sebastien; Rosewell, Ian; Houston, J Brian; Henderson, Colin J; Wolf, C Roland

2008-11-14

In vitro, cytochrome b5 modulates the rate of cytochrome P450-dependent mono-oxygenation reactions. However, the role of this enzyme in determining drug pharmacokinetics in vivo and the consequential effects on drug absorption distribution, metabolism, excretion, and toxicity are unclear. In order to resolve this issue, we have carried out the conditional deletion of microsomal cytochrome b5 in the liver to create the hepatic microsomal cytochrome b5 null mouse. These mice develop and breed normally and have no overt phenotype. In vitro studies using a range of substrates for different P450 enzymes showed that in hepatic microsomal cytochrome b5 null NADH-mediated metabolism was essentially abolished for most substrates, and the NADPH-dependent metabolism of many substrates was reduced by 50-90%. This reduction in metabolism was also reflected in the in vivo elimination profiles of several drugs, including midazolam, metoprolol, and tolbutamide. In the case of chlorzoxazone, elimination was essentially unchanged. For some drugs, the pharmacokinetics were also markedly altered; for example, when administered orally, the maximum plasma concentration for midazolam was increased by 2.5-fold, and the clearance decreased by 3.6-fold in hepatic microsomal cytochrome b5 null mice. These data indicate that microsomal cytochrome b5 can play a major role in the in vivo metabolism of certain drugs and chemicals but in a P450- and substrate-dependent manner.

Parental presence during induction of anesthesia: physiological effects on parents.

PubMed

Kain, Zeev N; Caldwell-Andrews, Alison A; Mayes, Linda C; Wang, Shu-Ming; Krivutza, Dawn M; LoDolce, Megan E

2003-01-01

The authors conducted a randomized controlled trial to determine whether parental presence during induction of anesthesia (PPIA) is associated with parental physiologic and behavioral manifestations of stress. Children and their parents (N = 80) were randomly assigned to one of three groups: (1) PPIA; (2) PPIA plus 0.5 mg/kg oral midazolam; and (3) control (no PPIA or midazolam). The effect of the group assignment on parental heart rate (HR), parental blood pressure, and parental skin conductance level (SCL) were assessed. Both parental HR and parental SCL were monitored continually. Anxiety of the parent and child was also assessed. Parental HR increased from baseline until the induction of anesthesia (P = 0.001). A group-by-time effect ( P= 0.005) was also found. That is, throughout the induction period there were several time points at which parents in the two PPIA groups had a significantly higher HR than did parents in the control group (P < 0.05). Similarly, SCL was found to increase in all parents from baseline until induction of anesthesia (P = 0.001). Significant group differences in SCL changes over time were found as well (P = 0.009). State anxiety and blood pressure following induction of anesthesia did not differ significantly between groups ( P= nonsignificant). Examination of parental Holter data revealed no rhythm abnormalities and no electrocardiogram changes indicating ischemia. The authors found that PPIA is associated with increased parental HR and SCL. However, no increased incidence of electrocardiogram abnormalities were found in parents present during induction of anesthesia.

Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids.

PubMed

Cunningham, Colin S; McMahon, Lance R

2013-07-01

Receptor mechanisms underlying the behavioral effects of clinically used nicotinic acetylcholine receptor agonists have not been fully established. Drug discrimination was used to compare receptor mechanisms underlying the effects of smoking cessation aids. Separate groups of male C57BL/6J mice discriminated 0.56, 1, or 1.78 mg/kg of nicotine base. Nicotine, varenicline, and cytisine were administered alone, in combination with each other, and in combination with mecamylamine and dihydro-β-erythroidine (DHβE). Midazolam and morphine were tested to examine sensitivity to non-nicotinics. The ED50 value of nicotine to produce discriminative stimulus effects systematically increased as training dose increased. Varenicline and cytisine did not fully substitute for nicotine and, as compared with nicotine, their ED50 values varied less systematically as a function of nicotine training dose. Morphine did not substitute for nicotine, whereas midazolam substituted for the low and not the higher training doses of nicotine. As training dose increased, the dose of mecamylamine needed to produce a significant rightward shift in the nicotine dose-effect function also increased. DHβE antagonized nicotine in animals discriminating the smallest dose of nicotine. Varenicline did not antagonize the effects of nicotine, whereas cytisine produced a modest though significant antagonism of nicotine. These results suggest that differences in pharmacologic mechanism between nicotine, varenicline, and cytisine include not only differences in efficacy at a common subtype of nicotinic acetylcholine receptor, but also differential affinity and/or efficacy at multiple receptor subtypes.

CRISPR/Cas9 Genetic Modification of CYP3A5 *3 in HuH-7 Human Hepatocyte Cell Line Leads to Cell Lines with Increased Midazolam and Tacrolimus Metabolism.

PubMed

Dorr, Casey R; Remmel, Rory P; Muthusamy, Amutha; Fisher, James; Moriarity, Branden S; Yasuda, Kazuto; Wu, Baolin; Guan, Weihua; Schuetz, Erin G; Oetting, William S; Jacobson, Pamala A; Israni, Ajay K

2017-08-01

Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 engineering of the CYP3A5 *3 locus (rs776746) in human liver cell line HuH-7 ( CYP3A5 *3/*3 ) has led to three CYP3A5 *1 cell lines by deletion of the exon 3B splice junction or point mutation. Cell lines CYP3A5 *1/*3 sd (single deletion), CYP3A5 *1/*1 dd (double deletion), or CYP3A5 *1/*3 pm (point mutation) expressed the CYP3A5 *1 mRNA and had elevated CYP3A5 mRNA ( P < 0.0005 for all engineered cell lines) and protein expression compared with HuH-7. In metabolism assays, HuH-7 had less tacrolimus (all P < 0.05) or midazolam (MDZ) (all P < 0.005) disappearance than all engineered cell lines. HuH-7 had less 1-OH MDZ (all P < 0.0005) or 4-OH (all P < 0.005) production in metabolism assays than all bioengineered cell lines. We confirmed CYP3A5 metabolic activity with the CYP3A4 selective inhibitor CYP3CIDE. This is the first report of genomic CYP3A5 bioengineering in human cell lines with drug metabolism analysis. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Adjuvant Agents in Regional Anesthesia in the Ambulatory Setting.

PubMed

Koyyalamudi, Veerandra; Sen, Sudipta; Patil, Shilpadevi; Creel, Justin B; Cornett, Elyse M; Fox, Charles J; Kaye, Alan D

2017-01-01

A majority of surgical practice has involved ambulatory centers with the number of outpatient operations in the USA doubling to 26.8 million per year. Local anesthesia delivery provides numerous benefits, including increased satisfaction, earlier discharge, and reduction in unplanned hospital admission. Further, with the epidemic of opioid mediated overdoses, local anesthesia can be a key tool in providing an opportunity to reduce the need for other analgesics postoperatively. Adjuvants such as epinephrine and clonidine enhance local anesthetic clinical utility. Further, dexmedetomidine prolongs regional blockade duration effects. There has also been a significant interest recently in the use of dexamethasone. Studies have demonstrated a significant prolongation in motor and sensory block with perineural dexamethasone. Findings are conflicting as to whether intravenous dexamethasone has similar beneficial effects. However, considering the possible neurotoxicity effects, which perineural dexamethasone may present, it would be prudent not to consider intravenously administered dexamethasone to prolong regional block duration. Many studies have also demonstrated neurotoxicity from intrathecally administered midazolam. Therefore, midazolam as an adjuvant is not recommended. Magnesium prolongs regional block duration but related to paucity of studies as of yet, cannot be recommended. Tramadol yields inconsistent results and ketamine is associated with psychotomimetic adverse effects. Buprenorphine consistently increases regional block duration and reduce opioid requirements by a significant amount. Future studies are warranted to define best practice strategies for these adjuvant agents. The present review focuses on the many roles of local anesthetics in current ambulatory practice.

Alpha1- and alpha2-containing GABAA receptor modulation is not necessary for benzodiazepine-induced hyperphagia.

PubMed

Morris, H V; Nilsson, S; Dixon, C I; Stephens, D N; Clifton, P G

2009-06-01

Benzodiazepines increase food intake, an effect attributed to their ability to enhance palatability. We investigated which GABA(A) receptor subtypes may be involved in mediating benzodiazepine-induced hyperphagia. The role of the alpha2 subtype was investigated by observing the effects of midazolam, on the behavioural satiety sequence in mice with targeted deletion of the alpha2 gene (alpha2 knockout). Midazolam (0.125, 0.25 and 0.5mg/kg) increased food intake and the amount of time spent feeding in alpha2 knockout mice, suggesting that BZ-induced hyperphagia does not involve alpha2-containing GABA(A) receptors. We further investigated the roles of alpha1- and alpha3-containing GABA(A) receptors in mediating BZ-induced hyperphagia. We treated alpha2(H101R) mice, in which alpha2-containing receptors are rendered benzodiazepine insensitive, with L-838417, a compound which acts as a partial agonist at alpha2-, alpha3- and alpha5-receptors but is inactive at alpha1-containing receptors. L-838417 (10 and 30 mg/kg) increased food intake and the time spent feeding in both wildtype and alpha2(H101R) mice, demonstrating that benzodiazepine-induced hyperphagia does not require alpha1- and alpha2-containing GABA(A) receptors. These observations, together with evidence against the involvement of alpha5-containing GABA(A) receptors, suggest that alpha3-containing receptors mediate BZ-induced hyperphagia in the mouse.

Monitoring of anesthetic depth during surgical correction of acquired valvular disorders: single center, randomized trial.

PubMed

Lenkin, Andrey I; Zaharov, Viktor I; Lenkin, Pavel I; Smetkin, Alexey A; Bjertnaes, Lars J; Kirov, Mikhail Y

2014-04-01

The authors' primary objective was to test the hypothesis that Cerebral State Index (CSI)-guided control of anesthetic depth might reduce the consumption of anesthetics and shorten the duration of ICU and hospital stays after surgical correction of combined valve disorders. Single center, randomized trial. City Hospital Number 1 of Arkhangelsk, Russian Federation. Fifty adult patients with combined valve disorders requiring surgical correction. The patients were randomized into 2 groups. In the CSI group, anesthetic depth was monitored, and the rate of infusion of propofol was titrated to maintain the depth of anesthesia corresponding to a CSI of 40-60. In the control group, the depth of anesthesia was monitored clinically, and the dosage of propofol was administered according to the recommendations of the manufacturer. All patients received standard perioperative monitoring. Consumption of anesthetics and length of ICU and hospital stays were recorded. Preoperative patient characteristics did not differ significantly between the groups. In the CSI group, average intraoperative doses of midazolam and propofol were reduced by 41% and 19%, respectively (p<0.01). Maintenance of anesthesia guided by CSI shortened the time until fit for ICU discharge by 50% and reduced the lengths of ICU and postoperative hospital stays by 35% and 25%, respectively (p< 0.05). Monitoring of anesthetic depth reduces the requirements for midazolam and propofol, resulting in a faster recovery and a shorter postoperative ICU and hospital stay after surgical correction of combined valve disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

Clinical Drug-Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib.

PubMed

Morcos, Peter N; Cleary, Yumi; Guerini, Elena; Dall, Georgina; Bogman, Katrijn; De Petris, Luigi; Viteri, Santiago; Bordogna, Walter; Yu, Li; Martin-Facklam, Meret; Phipps, Alex

2017-05-01

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates. © 2016, The American College of Clinical Pharmacology.

Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation.

PubMed

Fulton, B; Sorkin, E M

1995-10-01

Propofol is a phenolic derivative that is structurally unrelated to other sedative hypnotic agents. It has been used extensively as an anaesthetic agent, particularly in procedures of short duration. More recently it has been investigated as a sedative in the intensive care unit (ICU) where it produces sedation and hypnosis in a dose-dependent manner. Propofol also provides control of stress responses and has anticonvulsant and amnesic properties. Importantly, its pharmacokinetic properties are characterised by a rapid onset and short duration of action. Noncomparative and comparative trials have evaluated the use of propofol for the sedation of mechanically ventilated patients in the ICU (postsurgical, general medical, trauma). Overall, propofol provides satisfactory sedation and is associated with good haemodynamic stability. It produces results similar to or better than those seen with midazolam or other comparator agents when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation are measured. Patients sedated with propofol also tend to have a faster recovery (time to spontaneous ventilation or extubation) than patients sedated with midazolam. Although most studies did not measure time to discharge from the ICU, propofol tended to be superior to midazolam in this respect. In a few small trials in patients with head trauma or following neurosurgery, propofol was associated with adequate sedation and control of cerebral haemodynamics. The rapid recovery of patients after stopping propofol makes it an attractive option in the ICU, particularly for patients requiring only short term sedation. In short term sedation, propofol, despite its generally higher acquisition costs, has the potential to reduce overall medical costs if patients are able to be extubated and discharged from the ICU sooner. Because of the potential for hyperlipidaemia and the development of tolerance to its sedative effects, and because of the reduced need for rapid reversal of drug effects in long term sedation, the usefulness of propofol in long term situations is less well established. While experience with propofol for the sedation of patients in the ICU is extensive, there are still areas requiring further investigation. These include studies in children, trials examining cerebral and haemodynamic outcomes following long term administration and in patients with head trauma and, importantly, pharmacoeconomic investigations to determine those situations where propofol is cost effective. In the meantime, propofol is a well established treatment native to benzodiazepines and/or other hypnotics or analgesics when sedation of patients in the ICU is required. In particular, propofol possesses unique advantages over these agents in patients requiring only short term sedation.

Pediatric intensive care treatment of uncontrolled status epilepticus.

PubMed

Wilkes, Ryan; Tasker, Robert C

2013-04-01

The critically ill mechanically ventilated child with ongoing seizures that are refractory to any treatment presents a distinct challenge in pediatric neurocritical care. The evidence base from randomized controlled trials on which anti-epileptic drug (AED) strategy should be used is inadequate. This review of refractory and super-refractory status epilepticus summarizes recent pediatric case series regarding definitions, the second-tier AED therapies once initial anticonvulsants have failed, and the experience of high-dose midazolam, barbiturate anesthesia, and volatile anesthetics for uncontrolled status epilepticus. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison of the Direct Costs, Length of Recovery, and Incidence of Post Operative Anti-Emetic use After Anesthesia Induction with Propofol or a 1:1 Mixture of Thiopental and Propofol

DTIC Science & Technology

1999-10-01

other agent. The net result was enhanced GABA function. Further experiments need to be done to confirm this. Propofol and midazolam (a...REFERENCES Amrein, R., Hetzel, W., & Allen, S. R. (1995). Co-induction of anaesthesia: The rationale. European Journal of Anaesthesiology Supplement...alfentanil for a short gynecological procedure. Acta Anaesthesiology Scandinavia, 40(4), 416-420. 1:1 Mixture 47 Gan, T.J., Ginsberg, B., Grant, A.P

KETAMINE-MEDETOMIDINE AND KETAMINE-MEDETOMIDINE-MIDAZOLAM ANESTHESIA IN CAPTIVE CHEETAHS (ACINONYX JUBATUS)-COMPARISON OF BLOOD PRESSURE AND KIDNEY BLOOD FLOW.

PubMed

Stagegaard, Julia; Hørlyck, Arne; Hydeskov, Helle B; Bertelsen, Mads F

2017-06-01

Six clinically healthy captive cheetahs ( Acinonyx jubatus ) were anesthetized twice using two different drug combinations to investigate if blood pressure and kidney blood flow are affected by medetomidine dosage. Protocol KM (2.0 mg/kg ketamine and 0.05 mg/kg medetomidine) was compared with protocol KMM (2.0 mg/kg ketamine, 0.02 mg/kg medetomidine, and 0.1 mg/kg midazolam). Heart rate (HR), respiratory rate (RR), body temperature, end-tidal carbon dioxide pressure (ETCO 2 ), and anesthetic depth were monitored every 10 min. Noninvasive mean (MAP), systolic (SAP), and diastolic (DAP) arterial blood pressure were measured, and Duplex Doppler ultrasonography was performed on the kidneys. The mean arterial resistive index (RI) was determined and the pulse pressure index (PPI) was calculated, as indicators for kidney blood flow. There were no significant differences in induction and recovery times. MAP was significantly higher with KM than KMM at 35 min, and in both protocols decreased significantly after atipamezole administration. DAP was significantly higher at 25 and 35 min in animals anesthetized with KM; it also decreased significantly with both protocols after atipamezole administration. The PPI was significantly lower throughout the procedure with KM, and with both protocols increased significantly after atipamezole administration. Both the higher blood pressure and the reduced PPI with KM were likely a direct effect of the higher medetomidine dosage, and these findings indicate that lower medetomidine dosages might reduce hypertension and lead to a better PPI in cheetah immobilization.

In vitro metabolism of brucine by human liver microsomes and its interactions with CYP substrates.

PubMed

Li, Xin; Wang, Kai; Wei, Wei; Liu, Yong-yu; Gong, Lu

2013-08-25

Brucine, one of the main active ingredients in semen Strychni, has been included in many oral prescriptions of traditional Chinese medicine. In this study, we investigated the in vitro metabolism of brucine by human liver microsomes (HLMs) and the metabolic interactions of brucine with the substrates of cytochrome P450 (CYP450). Brucine was incubated with HLMs or CYP3A4 and then analysed by Liquid chromatography/mass spectrometry. The Km and Vmax values for HLMs were 30.53±3.14μM and 0.08±0.0029nmol/mg protein/min, respectively, while the corresponding values for CYP3A4 were 20.12±3.05μM and 6.40±0.21nmol/nmol P450/min. CYP3A4 may be the major enzyme responsible for brucine metabolism in HLMs, other human isoforms of CYP showed minimal or no effect on brucine metabolism. The inhibitory action of brucine was observed in CYP3A4 for the 1'-hydroxylation of midazolam, with inhibitory concentration 50 (IC50) of 8.4-fold higher than specific inhibitors in HLMs. Furthermore, brucine significantly inhibited the CYP3A4-catalyzed midazolam 1'-hydroxylation (Ki=2.14μM) at a concentration lower than 10μM, but no obvious inhibitory effects were observed on other CYP substrates (IC50>50μM). These results suggest that brucine has the potential to interact with a wide range of xenobiotics and endogenous chemicals especially CYP3A4 substrates. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Sedation in gastrointestinal endoscopy: current issues.

PubMed

Triantafillidis, John K; Merikas, Emmanuel; Nikolakis, Dimitrios; Papalois, Apostolos E

2013-01-28

Diagnostic and therapeutic endoscopy can successfully be performed by applying moderate (conscious) sedation. Moderate sedation, using midazolam and an opioid, is the standard method of sedation, although propofol is increasingly being used in many countries because the satisfaction of endoscopists with propofol sedation is greater compared with their satisfaction with conventional sedation. Moreover, the use of propofol is currently preferred for the endoscopic sedation of patients with advanced liver disease due to its short biologic half-life and, consequently, its low risk of inducing hepatic encephalopathy. In the future, propofol could become the preferred sedation agent, especially for routine colonoscopy. Midazolam is the benzodiazepine of choice because of its shorter duration of action and better pharmacokinetic profile compared with diazepam. Among opioids, pethidine and fentanyl are the most popular. A number of other substances have been tested in several clinical trials with promising results. Among them, newer opioids, such as remifentanil, enable a faster recovery. The controversy regarding the administration of sedation by an endoscopist or an experienced nurse, as well as the optimal staffing of endoscopy units, continues to be a matter of discussion. Safe sedation in special clinical circumstances, such as in the cases of obese, pregnant, and elderly individuals, as well as patients with chronic lung, renal or liver disease, requires modification of the dose of the drugs used for sedation. In the great majority of patients, sedation under the supervision of a properly trained endoscopist remains the standard practice worldwide. In this review, an overview of the current knowledge concerning sedation during digestive endoscopy will be provided based on the data in the current literature.

Sedation in gastrointestinal endoscopy: Current issues

PubMed Central

Triantafillidis, John K; Merikas, Emmanuel; Nikolakis, Dimitrios; Papalois, Apostolos E

2013-01-01

Diagnostic and therapeutic endoscopy can successfully be performed by applying moderate (conscious) sedation. Moderate sedation, using midazolam and an opioid, is the standard method of sedation, although propofol is increasingly being used in many countries because the satisfaction of endoscopists with propofol sedation is greater compared with their satisfaction with conventional sedation. Moreover, the use of propofol is currently preferred for the endoscopic sedation of patients with advanced liver disease due to its short biologic half-life and, consequently, its low risk of inducing hepatic encephalopathy. In the future, propofol could become the preferred sedation agent, especially for routine colonoscopy. Midazolam is the benzodiazepine of choice because of its shorter duration of action and better pharmacokinetic profile compared with diazepam. Among opioids, pethidine and fentanyl are the most popular. A number of other substances have been tested in several clinical trials with promising results. Among them, newer opioids, such as remifentanil, enable a faster recovery. The controversy regarding the administration of sedation by an endoscopist or an experienced nurse, as well as the optimal staffing of endoscopy units, continues to be a matter of discussion. Safe sedation in special clinical circumstances, such as in the cases of obese, pregnant, and elderly individuals, as well as patients with chronic lung, renal or liver disease, requires modification of the dose of the drugs used for sedation. In the great majority of patients, sedation under the supervision of a properly trained endoscopist remains the standard practice worldwide. In this review, an overview of the current knowledge concerning sedation during digestive endoscopy will be provided based on the data in the current literature. PMID:23382625

Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression.

PubMed

George, Duncan; Gálvez, Verònica; Martin, Donel; Kumar, Divya; Leyden, John; Hadzi-Pavlovic, Dusan; Harper, Simon; Brodaty, Henry; Glue, Paul; Taylor, Rohan; Mitchell, Philip B; Loo, Colleen K

2017-11-01

To assess the efficacy and safety of subcutaneous ketamine for geriatric treatment-resistant depression. Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment. In this double-blind, controlled, multiple-crossover study with a 6-month follow-up (randomized controlled trial [RCT] phase), 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted (RCT phase). Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months. Seven of 14 RCT-phase completers remitted with ketamine treatment. Five remitted at doses below 0.5 mg/kg. Doses ≥ 0.2 mg/kg were significantly more effective than midazolam. Ketamine was well tolerated. Repeated treatments resulted in higher likelihood of remission or longer time to relapse. Results provide preliminary evidence for the efficacy and safety of ketamine in treating elderly depressed. Dose titration is recommended for optimizing antidepressant and safety outcomes on an individual basis. Subcutaneous injection is a practical method for giving ketamine. Repeated treatments may improve remission rates (clinicaltrials.gov; NCT01441505). Copyright © 2017 American Association for Geriatric Psychiatry. All rights reserved.

Dose requirements for propofol anaesthesia for dental treatment for autistic patients compared with intellectually impaired patients.

PubMed

Asahi, Y; Kubota, K; Omichi, S

2009-01-01

We had clinical grounds to suspect that patients with autism had greater propofol requirements during dental procedures than patients with intellectual impairment without autism. This hypothesis was tested by an audit of a standard anaesthetic technique. The audit was approved by our Hospital Ethics Committee. We compared the propofol requirements and effect using a standardised protocol during dental treatment in 56 autistic patients (age range three to 35 years) and 56 intellectually impaired patients (age range four to 42 years). Patients in each disability group were divided into three subgroups by age: six years or younger, seven to 19 years and 20 years or older. Combative patients received oral midazolam premedication, other patients received a single intravenous bolus of midazolam at induction. Otherwise, standardised propofol boluses and infusion were the only anaesthetic agents used. The propofol infusion rates of the intellectually impaired group showed significant decline with age (propofol rate of requirement mg x kg(-1) x h(-1), mean [SD]): < six years 13.6 (3.6), seven to 19 years 9.5 (3.0) (P = 0.008 cf < six years group), > 19 years group 8.5 (2.4) (P = 0.001 cf < six years group). The propofol requirement was greater in the autism group than in the intellectual disability group, and the proportion of the cases where bolus propofol administration was needed after induction was significantly higher in the autistic patient group than in the intellectually impaired patients (P < 0.002). This suggests that autistic patients have greater propofol requirements for anaesthesia during ordinary dental treatment compared with intellectually impaired patients.

Face Memory: Implications for theories of binding items to context

PubMed Central

Reder, L. M.; Victoria, L. W.; Manelis, A.; Oates, J. M.; Dutcher, J. M.; Bates, J. T.; Cook, S.; Aizenstein, H. A.; Quinlan, J.; Gyulai, F.

2014-01-01

Two experiments tested the hypothesis that it is easier to bind a stimulus to context when the stimulus already has a stable (i.e., pre-existing) memory representation by comparing episodic memory of faces of celebrities vs. unknown individuals. Each face was superimposed on a picture of a well-known location (e.g., Eiffel Tower) during encoding and at a later unexpected recognition test but the background could change from encoding to test. Although recognition was to be based on the face, irrespective of background, performance was better when encoding context was reinstated. Further, a given background could be shown with many faces ("high fan") or only a few ("low fan") and this variable modulated the value added of context reinstatement. Importantly, manipulations of context only mattered for famous faces. As predicted, these effects were observed in recollection ("Remember") responses not in familiarity (“Know”) responses. Experiment 2 used the same design except that half of the subjects were administered midazolam, a drug that produces temporary anterograde amnesia, prior to encoding faces and backgrounds. Subjects injected with saline (control condition) showed the same pattern as Experiment 1; however subjects injected with midazolam showed a large decrease in the use of the "Remember" responses for famous faces and neither context reinstatement nor background fan affected performance. These results support the view that it is easier to bind stimuli to context when stimuli have a pre-existing, stable memory representation (e.g., faces of people whose identity we know) than when stimuli do not have pre-existing, stable memory representations. PMID:23395827

Benzodiazepine-site pharmacology on GABAA receptors in histaminergic neurons.

PubMed

May, A C; Fleischer, W; Kletke, O; Haas, H L; Sergeeva, O A

2013-09-01

The histaminergic tuberomamillary nucleus (TMN) of the posterior hypothalamus controls the cognitive aspects of vigilance which is reduced by common sedatives and anxiolytics. The receptors targeted by these drugs in histaminergic neurons are unknown. TMN neurons express nine different subunits of the GABAA receptor (GABAA R) with three α- (α1, α2 and α5) and two γ- (γ1, γ 2) subunits, which confer different pharmacologies of the benzodiazepine-binding site. We investigated the actions of zolpidem, midazolam, diazepam, chlordiazepoxide, flumazenil (Ro15-1788) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM) in TMN neurons using mouse genetics, electrophysiological and molecular biological methods. We find the sensitivity of GABAA R to zolpidem, midazolam and DMCM significantly reduced in TMN neurons from γ2F77I mice, but modulatory activities of diazepam, chlordiazepoxide and flumazenil not affected. Potencies and efficacies of these compounds are in line with the dominance of α2- and α1-subunit containing receptors associated with γ2- or γ1-subunits. Functional expression of the γ1-subunit is supported by siRNA-based knock-down experiments in γ2F77I mice. GABAA R of TMN neurons respond to a variety of common sedatives with a high affinity binding site (γ2F77I) involved. The γ1-subunit likely contributes to the action of common sedatives in TMN neurons. This study is relevant for understanding the role of neuronal histamine and benzodiazepines in disorders of sleep and metabolism. © 2013 The British Pharmacological Society.

Physical compatibility of various drugs with neonatal total parenteral nutrient solution during simulated Y-site administration.

PubMed

Fox, Laura M; Wilder, Alyson G; Foushee, Jaime A

2013-03-15

The physical compatibility of various drugs with neonatal total parenteral nutrient (TPN) solution during simulated Y-site administration was evaluated. Study drugs were selected based on the lack of compatibility data with them and neonatal TPN solution and the frequency of use in a local neonatal unit. These drugs included amiodarone, caffeine citrate, clindamycin, enalaprilat, epinephrine, fluconazole, fosphenytoin sodium, hydrocortisone, metoclopramide, midazolam, pentobarbital, phenobarbital, and rifampin. Equal volumes of neonatal TPN solution or sterile water for injection were combined with study drugs or sterile water for injection at concentrations used clinically in neonates. Each test was performed in triplicate. The samples were examined via turbidimetric analysis and visually against light and dark backgrounds immediately after mixing and at 0.25, 0.5, 1, 2, and 3 hours after mixing. Analysis of variance was used to determine statistically significant differences between the test and control solutions. Many of the drugs studied exhibited no visual or turbidimetric evidence of incompatibility when combined with neonatal TPN solution for up to three hours in a simulated Y-site injection. Pentobarbital, phenobarbital, and rifampin formed visible precipitation immediately after mixing with the neonatal TPN solution. Caffeine citrate, clindamycin, enalaprilat, epinephrine, fluconazole, fosphenytoin sodium, hydrocortisone, metoclopramide, and midazolam exhibited no visual or turbidimetric evidence of incompatibility when combined with a neonatal TPN solution for up to three hours in a simulated Y-site injection. Amiodarone, pentobarbital, phenobarbital, and rifampin were not compatible with the neonatal TPN solution and should not be coadministered via Y-site injection.

Drug Residues after Intravenous Anesthesia and Intrathecal Lidocaine Hydrochloride Euthanasia in Horses.

PubMed

Aleman, M; Davis, E; Knych, H; Guedes, A; Smith, F; Madigan, J E

2016-07-01

Intrathecal lidocaine hydrochloride under general anesthesia has been used as an alternative method of euthanasia in equids. Carnivore, scavenger, and even human consumption of horse meat from carcasses have been anecdotally reported in rural areas after this method of euthanasia. The presence of drug residues in horse meat has not been investigated. To investigate if drug residues are found in horse tissues and determine their concentrations. Of 11 horses requiring euthanasia for medical reasons. Prospective descriptive study. Horses were anesthetized with total IV dose of xylazine (mean, 2.5 mg/kg), midazolam (0.1 mg/kg), and ketamine hydrochloride (mean, 5.8 mg/kg). An atlanto-occipital cisterna centesis for the collection of cerebrospinal fluid (CSF) and administration of lidocaine hydrochloride (4 mg/kg) was performed. Blood samples for both serum and plasma, skeletal muscle (triceps brachii, gluteus medius), and CSF were collected for the determination of drug residues. Frozen skeletal muscle available from 5 additional horses that received standard dosages of drugs for short-term anesthesia (xylazine 1.1 mg/kg, midazolam 0.1 mg/kg, and ketamine 2.2 mg/kg) also were analyzed. Drug residues were found in the tissues of all horses, but at extremely low concentrations. Euthanasia by administration of lidocaine intrathecally to horses under IV anesthesia poses a low risk of toxicity to carnivores and scavengers that might consume muscle tissue from a carcass in which this protocol has been used. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis.

PubMed

Aoyama, T; Hirata, K; Yamamoto, Y; Yokota, H; Hayashi, H; Aoyama, Y; Matsumoto, Y

2016-08-01

Midazolam (MDZ) is commonly used for sedating critically ill patients. The daily dose required for adequate sedation increases in increments over 100 h after administration. The objectives of this study were to characterize the MDZ pharmacokinetics in critically ill patients and to describe the phenomenon of increasing daily dose by means of population pharmacokinetic analysis. Data were obtained from 30 patients treated in an intensive care unit. The patients received MDZ intravenously as a combination of bolus and continuous infusion. Serum MDZ concentration was assayed by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using the NONMEM software package. The alteration of clearance unexplained by demographic factors and clinical laboratory data was described as an autoinduction of MDZ clearance using a semi-mechanistic pharmacokinetic-enzyme turnover model. The final population pharmacokinetic model was a one-compartment model estimated by incorporating a semi-mechanistic pharmacokinetic-enzyme turnover model for clearance, taking autoinduction into account. A significant covariate for MDZ clearance was total bilirubin. An increase in total bilirubin indicated a reduction in MDZ clearance. From simulation using the population pharmacokinetic parameters obtained in this study, MDZ clearance increased 2·3 times compared with pre-induced clearance 100 h after the start of 12·5 mg/h continuous infusion. Autoinduction and total bilirubin were significant predictors of the clearance of MDZ in this population. Step-by-step dosage adjustment using this population pharmacokinetic model may be useful for establishing a MDZ dosage regimen in critically ill patients. © 2016 John Wiley & Sons Ltd.

Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial.

PubMed

Gálvez, Verònica; Nikolin, Stevan; Ho, Kerrie-Anne; Alonzo, Angelo; Somogyi, Andrew A; Loo, Colleen K

2017-02-01

Animal studies suggest that neural plasticity may play a role in the antidepressant effects of a single ketamine dose. However, the potential effects of repeated ketamine treatments on human neuroplasticity are unknown. This pilot RCT study measured plasticity-induced changes before and after a ketamine course, in three treatment-resistant depressed subjects, who were randomized to receive 8 intranasal treatments of 100mg ketamine or 4.5mg midazolam. Mood ratings were performed by a trained blinded rater at baseline and 24h-48h after the ketamine course, using the Montgomery Asberg Depression Rating Scale (MADRS). Neuroplasticity was assessed in the motor cortex using a paired associative stimulation (PAS) paradigm at baseline and 24h-48h after the treatment course. No changes in current psychotropic medication or dosage were permitted for 4weeks prior to trial entry and throughout the trial. The subject receiving ketamine, but not those receiving midazolam, presented a marked increase in neural plasticity after the treatment course. However, mood changes were not associated with changes in neural plasticity. Pilot study with small sample size. Concomitant antidepressant medications taken. Plasticity was tested in the motor cortex only, thus the generalizability of these findings to other brain areas cannot be assumed. These results suggest that a course of intranasal ketamine may enhance synaptic plasticity in subjects with depression, but this was not associated with antidepressant effects. Further research on this topic is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS

PubMed Central

Birbeck, G.L.; French, J.A.; Perucca, E.; Simpson, D.M.; Fraimow, H.; George, J.M.; Okulicz, J.F.; Clifford, D.B.; Hachad, H.; Levy, R.H.

2012-01-01

Objective: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. Methods: The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Results and Recommendations: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ∼50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). PMID:22218281

A highly sensitive method for the simultaneous UHPLC-MS/MS analysis of clonidine, morphine, midazolam and their metabolites in blood plasma using HFIP as the eluent additive.

PubMed

Veigure, Rūta; Aro, Rudolf; Metsvaht, Tuuli; Standing, Joseph F; Lutsar, Irja; Herodes, Koit; Kipper, Karin

2017-05-01

In intensive care units, the precise administration of sedatives and analgesics is crucial in order to avoid under- or over sedation and for appropriate pain control. Both can be harmful to the patient, causing side effects or pain and suffering. This is especially important in the case of pediatric patients, and dose-response relationships require studies using pharmacokinetic-pharmacodynamic modeling. The aim of this work was to develop and validate a rapid ultra-high performance liquid chromatographic-tandem mass spectrometric method for the analysis of three common sedative and analgesic agents: morphine, clonidine and midazolam, and their metabolites (morphine-3-glucuronide, morphine-6-glucuronide and 1'-hydroxymidazolam) in blood plasma at trace level concentrations. Low concentrations and low sampling volumes may be expected in pediatric patients; we report the lowest limit of quantification for all analytes as 0.05ng/mL using only 100μL of blood plasma. The analytes were separated chromatographically using the C18 column with the weak ion-pairing additive 1,1,1,3,3,3-hexafluoro-2-propanol and methanol. The method was fully validated and a matrix matched calibration range of 0.05-250ng/mL was attained for all analytes In addition, between-day accuracy for all analytes remained within 93-108%, and precision remained within 1.5-9.6% for all analytes at all concentration levels over the calibration range. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Anaesthesia of three young grey seals (Halichoerus grypus) for fracture repair

PubMed Central

2011-01-01

Three young grey seals (Halichoerus grypus) were presented separately for fracture repair to the veterinary teaching hospital of University College Dublin. The seals were premedicated with a combination of pethidine, midazolam and atropine; anaesthesia was induced with propofol via the front flipper vein and maintained with sevoflurane or isoflurane in oxygen. One of the seals did not breathe spontaneously after anaesthesia; a cardiac arrest, resulting in death, occurred after several hours of mechanical ventilation. Post-mortem examination revealed a severe lungworm infestation and parasitic pneumonia in this animal. The two other seals recovered uneventfully from anaesthesia. PMID:21777490

Suicide by Intentional Air embolism.

PubMed

Simon, Gábor; Rácz, Evelin; Mayer, Mátyás; Heckmann, Veronika; Tóth, Dénes; Kozma, Zsolt

2017-05-01

Venous air embolism occurs when air enters the venous system. The main causes of venous air embolism include medical procedures, neck and head trauma, and injuries of the genitals. Self-induced suicidal (and intentional) air embolism is extremely rare. The authors report a rare case of a suicidal air embolism committed using a self-made tool composed of a plastic bottle and an infusion set, injecting nearly 2000 mL of air into the cubital vein. The toxicological analysis suggested that midazolam, together with air, was also injected into the circulation using the same bottle and infusion set. © 2016 American Academy of Forensic Sciences.

Intramuscular Fentanyl and Ketorolac Associated with Superior Pain Control After Pediatric Bilateral Myringotomy and Tube Placement Surgery: A Retrospective Cohort Study.

PubMed

Stricker, Paul A; Muhly, Wallis T; Jantzen, Ellen C; Li, Yue; Jawad, Abbas F; Long, Alexander S; Polansky, Marcia; Cook-Sather, Scott D

2017-01-01

Bilateral myringotomy and pressure equalization tube insertion (BMT) is the most common surgery in children. Multiple anesthetic techniques for BMT have been proposed, but that which reliably promotes ideal recovery remains unclear. We sought to assess associations between anesthetic regimens that included single-agent (fentanyl or ketorolac) or dual-agent (fentanyl and ketorolac) analgesic therapy and the primary outcome of maximal postanesthesia care unit (PACU) pain score. Secondary outcomes included in-hospital rescue analgesic administration, recovery time, and emesis incidence. Principal analysis was conducted on a retrospective cohort of 3669 children aged 6 months to <7 years who underwent BMT over a 16-month period and received intraoperative fentanyl and/or ketorolac. Routine anesthetic care included preoperative oral midazolam, general anesthesia via a mask maintained with sevoflurane and N2O or air in O2, and intramuscular analgesic administration. Multivariable analyses were performed examining relationships between analgesic regimen with the following outcomes: maximum PACU Face, Legs, Activity, Cry, and Consolability (FLACC) score = 0 or 7 to 10, oxycodone administration, and time to discharge readiness. Demographic variables, midazolam exposure, and location (main hospital vs ambulatory surgery center) were included in the multivariable analyses as potential confounders. Associations with postoperative vomiting were studied separately in 2725 children from a subsequent, nonoverlapping 12-month period using similar inclusion criteria. Fentanyl and ketorolac dose-response relationships were evaluated for selected outcome variables. Maximum FLACC = 0, maximum FLACC score of 7 to 10, and oxycodone rescue were most strongly associated with dual-agent therapy versus single-agent ketorolac: odds ratios 4.89 (95% confidence interval [CI], 4.04-5.93), 0.13 (95% CI, 0.10-0.16), and 0.11 (98.3% CI, 0.09-0.14), respectively, P < .001 for each). Minor associations were found for age, Hispanic ethnicity, midazolam, and location, and none for sex or race. For subjects managed with higher dose fentanyl (≥1.5 µg/kg) and ketorolac (≥0.75 mg/kg), 90% had no demonstrable pain, agitation, or distress. Mean discharge readiness times were 21 ± 11 minutes (ketorolac), 26 ± 16 minutes (fentanyl), and 24 ± 14 minutes (dual) (P < .0001). Postoperative emesis incidences associated with ketorolac (2.7%) versus dual therapy (4.5%) were not different (P = .08). In this large retrospective pediatric BMT study, combination intramuscular fentanyl/ketorolac was strongly associated with superior PACU analgesia and reduced need for oxycodone rescue without clinically significant increases in recovery time or emesis incidence. Combination fentanyl at 1.5 to 2 µg/kg and 1 mg/kg ketorolac was associated with optimal outcomes. Dual therapy appears similarly effective in children of either European Caucasian or African ancestry or of Hispanic ethnicity.

Activation of ERK2 in basolateral amygdala underlies the promoting influence of stress on fear memory and anxiety: influence of midazolam pretreatment.

PubMed

Maldonado, N M; Espejo, P J; Martijena, I D; Molina, V A

2014-02-01

Exposure to emotionally arousing experiences elicits a robust and persistent memory and enhances anxiety. The amygdala complex plays a key role in stress-induced emotional processing and in the fear memory formation. It is well known that ERK activation in the amygdala is a prerequisite for fear memory consolidation. Moreover, stress elevates p-ERK2 levels in several areas of the brain stress circuitry. Therefore, given that the ERK1/2 cascade is activated following stress and that the role of this cascade is critical in the formation of fear memory, the present study investigated the potential involvement of p-ERK2 in amygdala subnuclei in the promoting influence of stress on fear memory formation and on anxiety-like behavior. A robust and persistent ERK2 activation was noted in the Basolateral amygdala (BLA), which was evident at 5min after restraint and lasted at least one day after the stressful experience. Midazolam, a short-acting benzodiazepine ligand, administered prior to stress prevented the increase in the p-ERK2 level in the BLA. Pretreatment with intra-BLA infusion of U0126 (MEK inhibitor), but not into the adjacent central nucleus of the amygdala, attenuated the stress-induced promoting influence on fear memory formation. Finally, U0126 intra-BLA infusion prevented the enhancement of anxiety-like behavior in stressed animals. These findings suggest that the selective ERK2 activation in BLA following stress exposure is an important mechanism for the occurrence of the promoting influence of stress on fear memory and on anxiety-like behavior. © 2013 Published by Elsevier B.V. and ECNP.

Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions.

PubMed

Palmgrén, Joni J; Mönkkönen, Jukka; Korjamo, Timo; Hassinen, Anssi; Auriola, Seppo

2006-11-01

Loss of drug content during cell culture transport experiment can lead to misinterpretations in permeability analysis. This study analyses drug adsorption to various plastic containers and drug retention in cultured cells under in vitro conditions. The loss of various drugs to polystyrene tubes and well plates was compared to polypropylene and glass tubes both in deionised water and buffer solution. In cellular uptake experiments, administered drugs were obtained from cultured cells by liquid extraction. Samples were collected at various time points and drug concentrations were measured by a new HPLC-MS/MS method. Acidic drugs (hydrochlorothiazide, naproxen, probenicid, and indomethacin) showed little if any sorption to all tested materials in either water or buffer. In the case of basic drugs, substantial loss to polystyrene tubes and well plates was observed. After 4.5 h, the relative amount remaining in aqueous test solution stored in polystyrene tubes was 64.7 +/- 6.8%, 38.4 +/- 9.1%, 31.9 +/- 6.7%, and 23.5 +/- 6.1% for metoprolol, medetomidine, propranolol, and midazolam, respectively. Interestingly, there was no significant loss of drugs dissolved in buffer to any of the tested materials indicating that buffer reduced surficial interaction. The effect of drug concentration to sorption was also tested. Results indicated that the higher the concentration in the test solution the lower the proportional drug loss, suggesting that the polystyrene contained a limited amount of binding sites. Cellular uptake studies showed considerable retention of drugs in cultured cells. The amounts of absorbed drugs in cellular structures were 0.45%, 4.88%, 13.15%, 43.80%, 23.57% and 11.22% for atenolol, metoprolol, medetomidine, propranolol, midazolam, and diazepam, respectively. Overall, these findings will benefit development and validation of further in vitro drug permeation experiments.

Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.

PubMed

Kuroha, Masanori; Azumano, Akinori; Kuze, Yoji; Shimoda, Minoru; Kokue, Eiichi

2002-01-01

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.

Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects

PubMed Central

Mueck, Wolfgang; Kubitza, Dagmar; Becka, Michael

2013-01-01

Aims The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2). Methods The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers. Results Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]). Conclusions Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination. PMID:23305158

Efficacy of nonvenous medications for acute convulsive seizures

PubMed Central

Kothari, Harsh; Zhang, Zongjun; Han, Baoguang; Horn, Paul S.; Glauser, Tracy A.

2015-01-01

Objective: This is a network meta-analysis of nonvenous drugs used in randomized controlled trials (RCTs) for treatment of acute convulsive seizures and convulsive status epilepticus. Methods: Literature was searched according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for RCTs examining treatment of acute convulsive seizures or status epilepticus with at least one of the study arms being a nonvenous medication. After demographic and outcome data extraction, a Bayesian network meta-analysis was performed and efficacy results were summarized using treatment effects and their credible intervals (CrI). We also calculated the probability of each route–drug combination being the most clinically effective for a given outcome, and provided their Bayesian hierarchical ranking. Results: This meta-analysis of 16 studies found that intramuscular midazolam (IM-MDZ) is superior to other nonvenous medications regarding time to seizure termination after administration (2.145 minutes, 95% CrI 1.308–3.489), time to seizure cessation after arrival in the hospital (3.841 minutes, 95% CrI 2.697–5.416), and time to initiate treatment (0.779 minutes, 95% CrI 0.495–1.221). Additionally, intranasal midazolam (IN-MDZ) was adjudged most efficacious for seizure cessation within 10 minutes of administration (90.4% of participants, 95% CrI 79.4%–96.9%), and persistent seizure cessation for ≥1 hour (78.5% of participants, 95% CrI 59.5%–92.1%). Paucity of RCTs produced evidence gaps resulting in small networks, routes/drugs included in some networks but not others, and some trials not being connected to any network. Conclusions: Despite the evidence gaps, IM-MDZ and IN-MDZ exhibit the best efficacy data for the nonvenous treatment of acute convulsive seizures or status epilepticus. PMID:26511448

The Effect of Midazolam and Propranolol on Fear Memory Reconsolidation in Ethanol-Withdrawn Rats: Influence of D-Cycloserine

PubMed Central

Ortiz, Vanesa; Giachero, Marcelo; Espejo, Pablo Javier; Molina, Víctor Alejandro

2015-01-01

Background: Withdrawal from chronic ethanol facilitates the formation of contextual fear memory and delays the onset to extinction, with its retrieval promoting an increase in ethanol consumption. Consequently, manipulations aimed to reduce these aversive memories, may be beneficial in the treatment of alcohol discontinuation symptoms. Related to this, pharmacological memory reconsolidation blockade has received greater attention due to its therapeutic potential. Methods: Here, we examined the effect of post-reactivation amnestic treatments such as Midazolam (MDZ, 3 mg/kg i.p) and Propranolol (PROP, 5 mg/kg i.p) on contextual fear memory reconsolidation in ethanol- withdrawn (ETOH) rats. Next, we examined whether the activation of N-methyl-D-aspartate (NMDA) receptors induced by d-cycloserine (DCS, 5 mg/kg i.p., a NMDA partial agonist) before memory reactivation can facilitate the disruptive effect of PROP and MDZ on fear memory in ETOH rats. Results: We observed a resistance to the disruptive effect of both MDZ and PROP following memory reactivation. Although intra-basolateral amygdala (BLA; 1.25 ug/side) and systemic PROP administration attenuated fear memory in DCS pre-treated ETOH rats, DCS/MDZ treatment did not affect memory in these animals. Finally, a decrease of both total and surface protein expression of the α1 GABAA receptor (GABAA-R) subunit in BLA was found in the ETOH rats. Conclusions: Ethanol withdrawal facilitated the formation of fear memory resistant to labilization post-reactivation. DCS administration promoted the disruptive effect of PROP on memory reconsolidation in ETOH rats. The resistance to MDZ’s disruptive effect on fear memory reconsolidation may be, at least in part, associated with changes in the GABAA-R composition induced by chronic ethanol administration/withdrawal. PMID:25617327

Thermoablation of Liver Metastases: Efficacy of Temporary Celiac Plexus Block

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beck, A.N., E-mail: alexander.beck@charite.de; Schaefer, M.; Werk, M.

Purpose. To determine the efficacy of celiac plexus block during thermoablation of liver metastases. Methods. Fifty-five consecutive patients underwent thermoablation therapy of liver tumors by laser-induced thermotherapy. Twenty-nine patients received a temporary celiac plexus block, 26 patients acted as control group. In both groups fentanyl and midazolam were administered intravenously upon request of the patient. The duration of the intervention, consumption of opiates, and individual pain sensations were documented. Results. No complications resulting from the celiac plexus block were recorded. Celiac plexus block significantly reduced the amount of pain medication used during thermoablation therapy of liver tumors (with block, 2.45more » {mu}g fentanyl per kg body weight; without block, 3.58 {mu}g fentanyl per kg body weight, p < 0.05; midazolam consumption was not reduced) in patients with metastases {<=}5 mm from the liver capsule. For metastases farther away from the capsule no significant differences in opiate consumption were seen. Celiac plexus block reduced the time for thermoablation significantly (178 min versus 147 min, p < 0.05) no matter how far the metastases were from the liver capsule. Average time needed to set the block was 12 min (range 9-15 min); additional costs for the block were marginal. As expected (as pain medications were given according to individual patients' needs) pain indices did not differ significantly between the two groups. Conclusion. In patients with liver metastases {<=}5 mm from the liver capsule, celiac plexus block reduces the amount of opiates necessary, simplifying patient monitoring. In addition celiac plexus block reduces intervention time, with positive effects on overall workflow for all patients.« less

Repeated anaesthesia with isoflurane and medetomidine-midazolam-fentanyl in guinea pigs and its influence on physiological parameters

PubMed Central

Tacke, Sabine; Guth, Brian; Henke, Julia

2017-01-01

Repeated anaesthesia may be required in experimental protocols and in daily veterinary practice, but anaesthesia is known to alter physiological parameters in GPs (Cavia porcellus, GPs). This study investigated the effects of repeated anaesthesia with either medetomidine-midazolam-fentanyl (MMF) or isoflurane (Iso) on physiological parameters in the GP. Twelve GPs were repeatedly administered with MMF or Iso in two anaesthesia sets. One set consisted of six 40-min anaesthesias, performed over 3 weeks (2 per week); the anaesthetic used first was randomized. Prior to Iso anaesthesia, atropine was injected. MMF anaesthesia was antagonized with AFN (atipamezole-flumazenil-naloxone). Abdominally implanted radio-telemetry devices recorded the mean arterial blood pressure (MAP), heart rate (HR) and core body temperature continuously. Additionally, respiratory rate, blood glucose and body weight were assessed. An operable state could be achieved and maintained for 40 min in all GPs. During the surgical tolerance with MMF, the GPs showed a large MAP range between the individuals. In the MMF wake- up phase, the time was shortened until the righting reflex (RR) returned and that occurred at lower MAP and HR values. Repeated Iso anaesthesia led to an increasing HR during induction (anaesthesias 2–6), non-surgical tolerance (anaesthesias 3–6) and surgical tolerance (anaesthesias 4, 6). Both anaesthetics may be used repeatedly, as repeating the anaesthesias resulted in only slightly different physiological parameters, compared to those seen with single anaesthesias. The regular atropine premedication induced HR increases and repeated MMF anaesthesia resulted in a metabolism increase which led to the faster return of RR. Nevertheless, Iso’s anaesthesia effects of strong respiratory depression and severe hypotension remained. Based on this increased anaesthesia risk with Iso, MMF anaesthesia is preferable for repeated use in GPs. PMID:28328950

Intranasal Midazolam versus Rectal Diazepam for the Management of Canine Status Epilepticus: A Multicenter Randomized Parallel-Group Clinical Trial.

PubMed

Charalambous, M; Bhatti, S F M; Van Ham, L; Platt, S; Jeffery, N D; Tipold, A; Siedenburg, J; Volk, H A; Hasegawa, D; Gallucci, A; Gandini, G; Musteata, M; Ives, E; Vanhaesebrouck, A E

2017-07-01

Intranasal administration of benzodiazepines has shown superiority over rectal administration for terminating emergency epileptic seizures in human trials. No such clinical trials have been performed in dogs. To evaluate the clinical efficacy of intranasal midazolam (IN-MDZ), via a mucosal atomization device, as a first-line management option for canine status epilepticus and compare it to rectal administration of diazepam (R-DZP) for controlling status epilepticus before intravenous access is available. Client-owned dogs with idiopathic or structural epilepsy manifesting status epilepticus within a hospital environment were used. Dogs were randomly allocated to treatment with IN-MDZ (n = 20) or R-DZP (n = 15). Randomized parallel-group clinical trial. Seizure cessation time and adverse effects were recorded. For each dog, treatment was considered successful if the seizure ceased within 5 minutes and did not recur within 10 minutes after administration. The 95% confidence interval was used to detect the true population of dogs that were successfully treated. The Fisher's 2-tailed exact test was used to compare the 2 groups, and the results were considered statistically significant if P < .05. IN-MDZ and R-DZP terminated status epilepticus in 70% (14/20) and 20% (3/15) of cases, respectively (P = .0059). All dogs showed sedation and ataxia. IN-MDZ is a quick, safe and effective first-line medication for controlling status epilepticus in dogs and appears superior to R-DZP. IN-MDZ might be a valuable treatment option when intravenous access is not available and for treatment of status epilepticus in dogs at home. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN.

PubMed

Birbeck, Gretchen L; French, Jacqueline A; Perucca, Emilio; Simpson, David M; Fraimow, Henry; George, Jomy M; Okulicz, Jason F; Clifford, David B; Hachad, Houda; Levy, René H

2012-01-01

A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C). Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal.

PubMed

Darrouj, Jamil; Puri, Nitin; Prince, Erin; Lomonaco, Anthony; Spevetz, Antoinette; Gerber, David R

2008-11-01

To report a case of alcohol withdrawal and delirium tremens successfully treated with adjunctive dexmedetomidine. A 30-year-old man with a history of alcohol abuse was admitted to the general medical unit because of altered mental status and agitation. He was initially treated for alcohol withdrawal with benzodiazepines; his condition then deteriorated and he was transferred to the intensive care unit. Because of the patient's poor response to benzodiazepines (oxazepam and lorazepam, with midazolam the last one used), intravenous dexmedetomidine was started at an initial dose of 0.2 microg/kg/h and titrated to 0.7 microg/kg/h to the patient's comfort. Midazolam was subsequently tapered to discontinuation due to excessive sedation. In the intensive care unit, the patient's symptoms remained controlled with use of dexmedetomidine alone. He remained in the intensive care unit for 40 hours; dexmedetomidine was then tapered to discontinuation and the patient was transferred back to the general medical unit on oral oxazepam and thiamine, which had been started in the emergency department. He was discharged after 5 days. A review of the PubMed database (1989-2007) failed to identify any other instances of dexmedetomidine having been used as the principal agent to treat alcohol withdrawal. The use of sedative to treat delirium tremens is well documented, with benzodiazepines being the agents of choice. The clinical utility of benzodiazepines is limited by their stimulation of the gamma-aminobutyric acid receptors, an effect not shared by dexmedetomidine, a central alpha(2)-receptor agonist that induces a state of cooperative sedation and does not suppress respiratory drive. In patients with delirium tremens, dexmedetomidine should be considered as an option for primary treatment. This case illustrates the need for further studies to investigate other potential uses for dexmedetomidine.

CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions.

PubMed

Galetin, Aleksandra; Ito, Kiyomi; Hallifax, David; Houston, J Brian

2005-07-01

The complexity of in vitro kinetic phenomena observed for CYP3A4 substrates (homo- or heterotropic cooperativity) confounds the prediction of drug-drug interactions, and an evaluation of alternative and/or pragmatic approaches and substrates is needed. The current study focused on the utility of the three most commonly used CYP3A4 in vitro probes for the prediction of 26 reported in vivo interactions with azole inhibitors (increase in area under the curve ranged from 1.2 to 24, 50% in the range of potent inhibition). In addition to midazolam, testosterone, and nifedipine, quinidine was explored as a more "pragmatic" substrate due to its kinetic properties and specificity toward CYP3A4 in comparison with CYP3A5. Ki estimates obtained in human liver microsomes under standardized in vitro conditions for each of the four probes were used to determine the validity of substrate substitution in CYP3A4 drug-drug interaction prediction. Detailed inhibitor-related (microsomal binding, depletion over incubation time) and substrate-related factors (cooperativity, contribution of other metabolic pathways, or renal excretion) were incorporated in the assessment of the interaction potential. All four CYP3A4 probes predicted 69 to 81% of the interactions with azoles within 2-fold of the mean in vivo value. Comparison of simple and multisite mechanistic models and interaction prediction accuracy for each of the in vitro probes indicated that midazolam and quinidine in vitro data provided the best assessment of a potential interaction, with the lowest bias and the highest precision of the prediction. Further investigations with a wider range of inhibitors are required to substantiate these findings.

Detection of Respiratory Adverse Events in Pediatric Dental Patients Sedated With 0.75mg/Kg of Midazolam and Oxygen by Continuous Pretracheal Auscultation: A Prospective Randomized Controlled Trial.

PubMed

Somri, Mostafa; Matter, Ibrahim; Hadjittofi, Christopher; Hoash, Naser; Moaddi, Bian; Kharouba, Johnny; Parisinos, Constantinos A; Peretz, Benjamin

Sedation is becoming more commonplace for pediatric patients undergoing minor procedures. Fortunately, electronic monitors have contributed to a reduction in the associated respiratory adverse events (RAEs). To test the hypothesis that adding the pretracheal stethoscope (PTS) to standard monitoring methods (SMMs) may improve RAE detection in sedated pediatric dental patients, the frequency of RAEs detected by SMMs (i.e. visual observation, capnography, and pulse oximetry) was compared to that detected by SMMs alongside continuous PTS auscultation. A prospective, randomised, controlled trial was performed with 100 pediatric patient participants of ASA≤2, who were scheduled to receive dental treatment under 0.75 mg/kg and oxygen. Patients were randomised into Groups A (n=50; SMMs) and B (n=50; SMMs+PTS). Inclusion criteria were behavioral management problems and intolerance to dental treatment despite behavioral management techniques or nitrous oxide administration. Exclusion criteria were high-risk conditions for RAEs, altered mental status, gastrointestinal disorders, parental refusal of conscious sedation and failure of previous conscious sedation. An anesthesist was present throughout the dental treatments. RAEs were detected in 10 (20%) and 22(44%) Group A and B patients respectively (p=0.01). The majority of RAEs within Group B were detected by PTS auscultation (n=19). Capnography produced 13 and 15 false-positive results in Groups A and B respectively, whereas the PTS produced 4(8%) false-positive results in Group B (p=0.009). PTS was found to be useful for detecting RAEs during pediatric dental sedation with 0.75mg/kg midazolam and oxygen, in the presence of an anesthesist.

Magnesium sulphate has beneficial effects as an adjuvant during general anaesthesia for Caesarean section.

PubMed

Lee, D H; Kwon, I C

2009-12-01

The use of low concentrations of volatile anaesthetics with avoidance of opioids may induce intraoperative awareness and adverse haemodynamic responses during Caesarean section. Magnesium is well known to reduce anaesthetic requirements and to block noxious stimuli. We investigated whether i.v. magnesium sulphate modulates anaesthetic depth and analgesic efficacy during Caesarean section. Seventy-two patients undergoing Caesarean section were randomly assigned to receive i.v. saline (control group) or magnesium sulphate 30 mg kg(-1) bolus+10 mg kg(-1) h(-1) continuous infusion (Mg 30 group) or 45 mg kg(-1) bolus+15 mg kg(-1) h(-1) continuous infusion (Mg 45 group) after induction. Bispectral index (BIS) value, mean arterial pressure (MAP), and midazolam, fentanyl, and atracurium consumptions were recorded. BIS values [mean (sd)] at 7.5 and 10 min after surgery and before delivery in the control [64 (9), 66 (8), 67 (8), P<0.001] and the Mg 30 groups [62 (8), P<0.01; 64 (7), 63 (9), P<0.001] were higher than in the Mg 45 group [56 (8), 55 (8), 55 (7)]. MAP was greater in the control group (P<0.05) than in the Mg 30 and Mg 45 groups during the pre-delivery period. The magnesium groups required less midazolam (P<0.05), fentanyl (Mg 30, P<0.05; Mg 45, P<0.01), and atracurium (P<0.001) vs the control group. Preoperative i.v. magnesium sulphate attenuated BIS and arterial pressure increases during the pre-delivery period. Magnesium sulphate can be recommended as an adjuvant during general anaesthesia for Caesarean section to avoid perioperative awareness and pressor response resulting from inadequate anaesthesia, analgesia, or both.

Evaluation of injectable anaesthesia with five medetomidine-midazolam based combinations in Egyptian fruit bats ( Rousettus aegyptiacus).

PubMed

Tuval, Avishag; Las, Liora; Shilo-Benjamini, Yael

2018-01-01

Egyptian fruit bats are increasingly used as model animals in neuroscience research. Our aim was to characterize suitable injectable anaesthesia for this species, possibly replacing inhalant anaesthesia, thus minimizing occupational health hazards. Eight bats were randomly assigned by a crossover design for subcutaneously administered combinations of medetomidine-midazolam with: saline (MM-Sal), ketamine (MM-Ket), fentanyl (MM-Fen), morphine (MM-Mor), or butorphanol (MM-But). The anaesthetic depth and vital signs were monitored at baseline and every 10 min until bats recovered. If after 180 min the bats did not recover, atipamezole was administered. Mean induction times were 7-11.5 min with all combinations. Twitching during induction was common. All combinations produced anaesthesia, with significantly decreased heart rate (from 400 to 200 bpm) and respiratory rate (from 120-140 to 36-65 rpm). Arrhythmia and irregular breathing patterns occurred. MM-Fen, MM-Mor, and MM-But depressed respiration significantly more than MM-Sal. Time to first movement with MM-Ket and MM-But lasted significantly longer than with MM-Sal. Recovery time was significantly shorter in the MM-Sal (88 min) in comparison to all other treatments, and it was significantly longer in the MM-But (159 min), with atipamezole administered to four of the eight bats. In conclusion, all five anaesthetic protocols are suitable for Egyptian fruit bats; MM-Ket produces long anaesthesia and minimal respiratory depression, but cannot be antagonized completely. MM-Fen, MM-Mor, and MM-But depress respiration, but are known to produce good analgesia, and can be fully antagonized. Administration of atipamezole following the use of MM-But in Egyptian fruit bats is recommended.

Practice and documentation of palliative sedation: a quality improvement initiative

PubMed Central

McKinnon, M.; Azevedo, C.; Bush, S.H.; Lawlor, P.; Pereira, J.

2014-01-01

Background Palliative sedation (ps), the continuous use of sedating doses of medication to intentionally reduce consciousness and relieve refractory symptoms at end of life, is ethically acceptable if administered according to standards of best practice. Procedural guidelines outlining the appropriate use of ps and the need for rigorous documentation have been developed. As a quality improvement strategy, we audited the practice and documentation of ps on our palliative care unit (pcu). Methods A pharmacy database search of admissions in 2008 identified, for a subsequent chart review, patients who had received either a continuous infusion of midazolam (≥10 mg/24 h), regular parenteral dosing of methotrimeprazine (≥75 mg daily), or regular phenobarbital. Documentation of the decision-making process, consent, and medication use was collected using a data extraction form based on current international ps standards. Results Interpretation and comparison of data were difficult because of an apparent lack of a consistent operational definition of ps. Patient records had no specific documentation in relation to ps initiation, to clearly identified refractory symptoms, and to informed consent in 60 (64.5%), 43 (46.2%), and 38 (40.9%) charts respectively. Variation in the medications used was marked: 54 patients (58%) were started on a single agent and 39 (42%), on multiple agents. The 40 patients (43%) started on midazolam alone received a mean daily dose of 21.4 mg (standard deviation: 24.6 mg). Conclusions The lack of documentation and standardized practice of ps on our pcu has resulted in a quality improvement program to address those gaps. They also highlight the importance of conducting research and developing clinical guidelines in this area. PMID:24764700

A rare cause of status epilepticus; alpha lipoic acid intoxication, case report and review of the literature.

PubMed

Tolunay, Orkun; Çelik, Tamer; Kömür, Mustafa; Gezgin, Ali Emre; Kaya, Musa Soner; Çelik, Ümit

2015-11-01

Alpha lipoic acid is a powerful antioxidant widely used for the supplementary treatment of diabetic neuropathy. Intoxication with alpha lipoic acid is very rare. There is no reported dose of safety in children. A 14-month-old previously healthy girl was referred to our hospital with the diagnosis of drug intoxication. She was admitted to the emergency department with lethargy and continuing involuntary movements for several hours after she had ingested an unknown amount of alpha lipoic acid. On admission she was lethargic and had myoclonic seizures involving all extremities. She had no fever and laboratory examinations were normal except for mild metabolic acidosis. The seizures were unresponsive to bolus midazolam, phenytoin infusion and levetiracetam infusion. She was taken to the pediatric intensive care unit with the diagnosis of status epilepticus. After failure of the treatment with midazolam infusion she was intubated and thiopental sodium infusion was started. Her myoclonic seizures were controlled with thiopental sodium infusion. After 48 h intubation and mechanical ventilation thiopental sodium was gradually reduced and then stopped. Following the withdraw of thiopental sodium, she was seizure free on her discharge on the 8th day. Alpha lipoic acid and derivatives cause side effects in children like refractory convulsions. They are frequently rendered as vitamins by diabetic patients and are left at places where children can easily access them. Therefore, when faced with refractory convulsions in children who have had no disease before, intoxication by medicaments with alpha lipoic acid should be taken into consideration. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Evaluation of heat hyperalgesia and anxiety like-behaviors in a rat model of orofacial cancer.

PubMed

Gambeta, Eder; Kopruszinski, Caroline Machado; Dos Reis, Renata Cristiane; Zanoveli, Janaina Menezes; Chichorro, Juliana Geremias

2016-04-21

Pain and anxiety are commonly experienced by cancer patients and both significantly impair their quality of life. Some authors claim that there is a relationship between pain and anxiety, while others suggest that there is not a direct association. In any case, there is indeed a consensus that anxiety impairs the pain condition beyond be under diagnosed and undertreated in cancer pain patients. Herein we investigated if rats presenting heat hyperalgesia induced by orofacial cancer cell inoculation would display anxiety-like behaviors. In addition, we evaluated if pain blockade would result in alleviation of anxiety behaviors, as well as, if blockade of anxiety would result in pain relief. Orofacial cancer was induced in male Wistar rats by inoculation of Walker-256 cells into the right vibrissal pad. Heat facial hyperalgesia was assessed on day 6 after the inoculation, and on this time point rats were submitted to the elevated plus maze and the light-dark transition tests. The influence of lidocaine and midazolam on heat hyperalgesia and anxiety-like behaviors was assessed. The peak of facial heat hyperalgesia was detected 6 days after cancer cells inoculation, and at this time point, rats exhibited increased anxiety-like behaviors. Local treatment with lidocaine (2%/50μL) caused a marked reduction of heat hyperalgesia, but failed to affect the anxiety-like behaviors, while midazolam (0.5mg/kg, i.p.) treatment failed to change the heat threshold, but induced an anxiolytic-like effect. Altogether, our data demonstrated that rats with orofacial cancer present pain- and anxiety-like behaviors, but brief heat hyperalgesia relief does not affect the anxiety-like behaviors, and vice-versa, in our experimental conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Anesthetic effects of a combination of medetomidine, midazolam and butorphanol on the production of offspring in Japanese field vole, Microtus montebelli.

PubMed

Kageyama, Atsuko; Tohei, Atsushi; Ushijima, Hitoshi; Okada, Konosuke

2016-09-01

Pentobarbital sodium (Somnopentyl) can induce surgical anesthesia with a strong hypnotic effect that causes loss of consciousness. Animals have been known to die during experimental surgery under anesthesia with Somnopentyl, causing it to be declared inadequate as a general anesthetic for single treatment. An anesthetic combination of 0.3 mg/kg medetomidine, 4.0 mg/kg midazolam and 5.0 mg/kg butorphanol (M/M/B:0.3/4/5) was reported to induce anesthesia for a duration of around 40 min in ICR mice; similar anesthetic effects were reported in both male and female BALB/c and C57BL/6J strains of mice. However, the anesthetic effects of this combination in Japanese field vole, Microtus montebelli, remain to be evaluated. In the present study, we assessed the effects of Somnopentyl and different concentrations of anesthetic combination (M/M/B:0.3/4/5, 0.23/3/3.75 or 0.15/2/2.5) in Japanese field voles, by means of anesthetic scores. We also examined effect of these anesthetics on production of offspring. Death of the animals was observed only with Somnopentyl. The anesthetic score of Somnopentyl was lower than those of the other anesthetics, although there were no significant differences in duration, body weight and frequency of respiratory among the evaluated anesthetics. Abortion rate with Somnopentyl was significantly higher than that with the M/M/B:0.23/3/3.75 combination, although there was no significant difference in the number of offspring between two. In conclusion, results of this study provide basic information for achieving appropriate anesthetic concentrations in addition to indicating a new, safe and effective surgical anesthetic for Japanese field voles.

Effects of an anesthetic mixture of medetomidine, midazolam, and butorphanol in rats-strain difference and antagonism by atipamezole.

PubMed

Kirihara, Yumiko; Takechi, Mayumi; Kurosaki, Kaoru; Kobayashi, Yuta; Saito, Yoji; Takeuchi, Takashi

2016-01-01

An anesthetic mixture of medetomidine (MED), midazolam (MID), and butorphanol (BUT) has been used in laboratory animals. We previously reported that this anesthetic mixture produced closely similar anesthetic effects in BALB/c and C57BL/6J strains. We also demonstrated the efficacy of atipamezole (ATI), an antagonist of MED that produced quick recovery from anesthesia in mice. Anesthetics have various anesthetic effects among animal strains. However, the differences in the effects of anesthetic mixtures in rats are unclear. In the present study, we first examined effects of the abovementioned anesthetic mixture using three different rat strains: Wistar (WST), Sprague-Dawley (SD), and Fischer 344 (F344). Second, we examined how different dosages and optimum injection timing of ATI affected recovery from anesthesia in rats. We used the anesthetic score to measure anesthetic duration and a pulse oximeter to monitor vital signs. We found no significant differences in anesthetic duration among the three different strains. However, recovery from anesthesia in the SD strain took significantly longer than in the other strains. The antagonistic effects of ATI (0.15 mg/kg and 0.75 mg/kg) were equivalent when administered at 30 min after anesthetic mixture administration. The antagonistic effects of ATI 0.75 mg/kg were stronger than those of ATI 0.15 mg/kg at 10 min after anesthetic mixture administration. This anesthetic mixture is a useful drug that can induce similar anesthetic effects in three different strains and has an antagonist, ATI, that makes rats quickly recover from anesthesia. These results may contribute to the welfare of laboratory animals.

Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial.

PubMed

Gálvez, Verònica; Li, Adrienne; Huggins, Christina; Glue, Paul; Martin, Donel; Somogyi, Andrew A; Alonzo, Angelo; Rodgers, Anthony; Mitchell, Philip B; Loo, Colleen K

2018-04-01

Ketamine research in depression has mostly used intravenous, weight-based approaches, which are difficult to translate clinically. Intranasal (IN) ketamine is a promising alternative but no controlled data has been published on the feasibility, safety and potential efficacy of repeated IN ketamine treatments. This randomised, double-blind, placebo-controlled pilot study compared a 4-week course of eight treatments of 100 mg ketamine or 4.5 mg midazolam. Each treatment was given as 10 separate IN sprays, self-administered 5 min apart. The study was stopped early due to poor tolerability after five treatment-resistant depressed participants were included. Feasibility, safety (acute and cumulative), cognitive and efficacy outcomes were assessed. Plasma ketamine and norketamine concentrations were assayed after the first treatment. Significant acute cardiovascular, psychotomimetic and neurological side effects occurred at doses < 100 mg ketamine. No participants were able to self-administer all 10 ketamine sprays due to incoordination; treatment time occasionally had to be extended (>45 min) due to acute side effects. No hepatic, cognitive or urinary changes were observed after the treatment course in either group. There was an approximately two-fold variation in ketamine and norketamine plasma concentrations between ketamine participants. At course end, one participant had remitted in each of the ketamine and midazolam groups. IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.

Music during interventional radiological procedures, effect on sedation, pain and anxiety: a randomised controlled trial

PubMed Central

Kulkarni, S; Johnson, P C D; Kettles, S; Kasthuri, R S

2012-01-01

Objective : To assess the effects of playing patient-selected music during interventional procedures on (1) the doses of sedation and analgesia and (2) anxiety levels. Methods : Patients undergoing interventional radiological procedures were randomised to either the intervention (music) or the control (no music) group. Patients in the intervention group had music of their choice played via headphones during the procedure. The primary outcomes were reductions in the doses of drugs for sedation (midazolam) and analgesia (fentanyl). Anxiety levels were assessed both before and after the procedure using the validated State Anxiety Inventory. Mean pulse rate and average of mean blood pressures were also recorded before and during the procedures as surrogate indicators of anxiety levels. Results : 100 patients were randomised in a 1:1 ratio. There were 58 males and 42 females, with a mean age of 58 years. Sedation was required in 21 (42%) patients in the music group compared with 30 (60%) patients in the control group (p=0.046). The mean [standard deviation (SD)] midazolam dose was 2.1 mg (2.3 mg) in the control group and 1.3 mg (2.2 mg) in the music group (p=0.027). The mean (SD) fentanyl dose was 29 mg (40 mg) in the control group and 18 mg (34 mg) in the music group (p=0.055). There was no significant effect of music on the change from baseline in anxiety levels (p=0.74), pulse rate (p=0.56) or blood pressure (p=0.34). Conclusion : Sedation requirements are significantly reduced by playing self-selected music to the patient during interventional radiology procedures. By lowering sedation during interventional radiology, music makes the procedure safer. It also contributes favourably to the overall patient experience. PMID:22422386

Repeated anaesthesia with isoflurane and medetomidine-midazolam-fentanyl in guinea pigs and its influence on physiological parameters.

PubMed

Schmitz, Sabrina; Tacke, Sabine; Guth, Brian; Henke, Julia

2017-01-01

Repeated anaesthesia may be required in experimental protocols and in daily veterinary practice, but anaesthesia is known to alter physiological parameters in GPs (Cavia porcellus, GPs). This study investigated the effects of repeated anaesthesia with either medetomidine-midazolam-fentanyl (MMF) or isoflurane (Iso) on physiological parameters in the GP. Twelve GPs were repeatedly administered with MMF or Iso in two anaesthesia sets. One set consisted of six 40-min anaesthesias, performed over 3 weeks (2 per week); the anaesthetic used first was randomized. Prior to Iso anaesthesia, atropine was injected. MMF anaesthesia was antagonized with AFN (atipamezole-flumazenil-naloxone). Abdominally implanted radio-telemetry devices recorded the mean arterial blood pressure (MAP), heart rate (HR) and core body temperature continuously. Additionally, respiratory rate, blood glucose and body weight were assessed. An operable state could be achieved and maintained for 40 min in all GPs. During the surgical tolerance with MMF, the GPs showed a large MAP range between the individuals. In the MMF wake- up phase, the time was shortened until the righting reflex (RR) returned and that occurred at lower MAP and HR values. Repeated Iso anaesthesia led to an increasing HR during induction (anaesthesias 2-6), non-surgical tolerance (anaesthesias 3-6) and surgical tolerance (anaesthesias 4, 6). Both anaesthetics may be used repeatedly, as repeating the anaesthesias resulted in only slightly different physiological parameters, compared to those seen with single anaesthesias. The regular atropine premedication induced HR increases and repeated MMF anaesthesia resulted in a metabolism increase which led to the faster return of RR. Nevertheless, Iso's anaesthesia effects of strong respiratory depression and severe hypotension remained. Based on this increased anaesthesia risk with Iso, MMF anaesthesia is preferable for repeated use in GPs.

A developed determination of midazolam and 1'-hydroxymidazolam in plasma by liquid chromatography-mass spectrometry: application of human pharmacokinetic study for measurement of CYP3A activity.

PubMed

Shimizu, Mikiko; Uno, Tsukasa; Tamura, Hiro-omi; Kanazawa, Hideko; Murakami, Isao; Sugawara, Kazunobu; Tateishi, Tomonori

2007-03-01

This paper describes sensitive and reliable determination of midazolam (MDZ) and its major metabolite 1'-hydroxymidazolam (1-OHMDZ) in human plasma by liquid chromatography-mass spectrometry (LC-MS) with a sonic spray ionization (SSI) interface. MDZ, 1-OHMDZ and diazepam as an internal standard were extracted from 1ml of alkalinized plasma using n-hexane-chloroform (70:30, v/v). The extract was injected into an analytical column (YMC-Pak Pro C(18), 50mmx2.0mmi.d.). The mobile phase for separation consisted of 10mM ammonium acetate and methanol (50:50, v/v) and was delivered at a flow-rate of 0.2ml/min. The drift voltage was 100V. The sampling aperture was heated at 120 degrees C and the shield temperature was 260 degrees C. The total time for chromatographic separation was less than 16min. The validated concentration ranges of this method were 0.25-50ng/ml for both MDZ and 1-OHMDZ. Mean recoveries were 93.6% for MDZ and 86.6% for 1-OHMDZ. Intra- and inter-day coefficient variations were less than 6.5 and 5.5% for MDZ, and 6.1 and 5.7% for 1-OHMDZ at 0.3, 4, 20 and 40ng/ml. The limits of quantification were 0.25ng/ml for both MDZ and 1-OHMDZ. This method was sensitive and reliable enough for pharmacokinetic studies on healthy volunteers, and was applied for the measurement of CYP3A activity in humans after an intravenous (1mg) and a single-oral administration (2mg) of subtherapeutic MDZ dose.

[Strychnine poisoning].

PubMed

Scheffold, N; Heinz, B; Albrecht, H; Pickert, A; Cyran, J

2004-10-15

A 46-year-old man presented two hours after ingestion of about 250 mg strychnine with severe violent, generalized convulsions, triggered by external stimuli. During the convulsion-free periods there were no abnormal signs in the physical examination. The presence of strychnine was confirmed by urine analysis with gas chromatography-mass spectrometry. Because diazepam as anticonvulsant of choice was not effective in abating the convulsions the patient was intubated. A combination with midazolam, fentanyl and pancuronium was effective in controlling the convulsions. The patient was discharged from ICU on day three. Fatal outcome of strychnine poisoning demands an aggressive management with early intubation, control of muscle tremors and prevention of rhabdomyolisis and renal failure.

The efficacy of dexmedetomidine-remifentanil versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy

PubMed Central

Zhang, Hongquan; Fang, Baojun; Zhou, Wenjing

2017-01-01

Abstract Flexible bronchoscopy has been more and more used for diagnosis and management diseases of respiratory system in pediatrics. Previous studies have reported that remifentanil (RF) and propofol are safe and effective for flexible bronchoscopy in adults, however, there have no trials evaluate the efficacy of DEX-RF versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy. We divided 123 children undergoing flexible bronchoscopy with DEX-RF or dexmedetomidine-propofol into 2 groups: Group DR (n = 63, DEX infusion at 1.0 μg kg−1 for 10 minutes, then adjusted to 0.5–0.7 μg kg−1 h−1; RF infusion at 1.0 μg kg−1 for 5 minutes, then adjusted to 0.05–0.2 μg kg−1 min−1), Group DP (n = 60, DEX infusion at 1.0 μg kg−1 for 10 minutes, then adjusted to 0.5–0.7 μg kg−1 h−1; propofol infusion at 10 μg kg−1 for 5 minutes, then adjusted to 0.05–0.1 μg kg−1 min−1). Ramsay sedation scale of the 2 groups was maintained at 3. Anesthesia onset time; total number of intraoperative patient movements; hemodynamics; total cumulative dose of DEX; amount of and time to first-dose rescue midazolam and lidocaine; postoperative recovery time; adverse events; and bronchoscopist satisfaction score were recorded. Anesthesia onset time was significantly shorter in DP (8.22 ± 2.48 vs 12.25 ± 6.43 minutes, respectively, for DP, DR, P = 0.015). The perioperative hemodynamic profile was more stable in DR than DP group. More children moved during flexible bronchoscopy in DP group (P = 0.009). Total dose of rescue midazolam and lidocaine was significantly higher in DR than in DP (P < 0.001). Similarly, the time to first dose of rescue midazolam and lidocaine was significantly longer in DP than in DR (P < 0.001). Total cumulative dose of DEX was more in DR than DP group (P < 0.001). The time to recovery for discharge from the postanesthesia care unit (PACU) was significantly shorter in DP than in DR group (P < 0.001). The bronchoscopist-satisfaction scores were higher for DR than DP (P = 0.036). There were significant differences between the 2 groups in terms of the overall incidence of hypertension, tachycardia, and hypoxemia (P < 0.05). Although underwent longer recovery time and more incidence of rescue scheme, DEX-RF resulted in more stable hemodynamic profiles and bronchoscopist-satisfaction scores, lesser patient movements, and can hence be more effectively used in children undergoing flexible bronchoscopy than dexmedetomidine-propofol. PMID:28072737

Sedative techniques for endoscopic retrograde cholangiopancreatography.

PubMed

Garewal, Davinder; Powell, Steve; Milan, Stephen J; Nordmeyer, Jonas; Waikar, Pallavi

2012-06-13

Endoscopic retrograde cholangiopancreatography (ERCP) is an uncomfortable therapeutic procedure that cannot be performed without adequate sedation or general anaesthesia. A considerable number of ERCPs are performed annually in the UK (at least 48,000) and many more worldwide. The primary objective of our review was to evaluate and compare the efficacy and safety of sedative or anaesthetic techniques used to facilitate the procedure of ERCP in adult (age > 18 years) patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 8); MEDLINE (1950 to September 2011); EMBASE (1950 to September 2011); CINAHL, Web of Science and LILACS (all to September 2011). We searched for additional studies drawn from reference lists of retrieved trial materials and review articles and conference proceedings. We considered all randomized or quasi-randomized controlled studies where the main procedures performed were ERCPs. The three interventions we searched for were (1) conscious sedation (using midazolam plus opioid) versus deep sedation (using propofol); (2) conscious sedation versus general anaesthesia; and (3) deep sedation versus general anaesthesia. We considered all studies regardless of which healthcare professional administered the sedation. We reviewed 124 papers and identified four randomized trials (with a total of 510 participants) that compared the use of conscious sedation using midazolam and meperidine with deep sedation using propofol in patients undergoing ERCP procedures. All sedation was administered by non-anaesthetic personnel. Due to the clinical heterogeneity of the studies we decided to review the papers from a narrative perspective as opposed to a full meta-analysis. Our primary outcome measures included mortality, major complications and inability to complete the procedure due to sedation-related problems. Secondary outcomes encompassed sedation efficacy and recovery. No immediate mortality was reported. There was no significant difference in serious cardio-respiratory complications suffered by patients in either sedation group. Failure to complete the procedure due to sedation-related problems was reported in one study. Three studies found faster and better recovery in patients receiving propofol for their ERCP procedures. Study protocols regarding use of supplemental oxygen, intravenous fluid administration and capnography monitoring varied considerably. The studies showed either moderate or high risk of bias. Results from individual studies suggested that patients have a better recovery profile after propofol sedation for ERCP procedures than after midazolam and meperidine sedation. As there was no difference between the two sedation techniques as regards safety, propofol sedation is probably preferred for patients undergoing ERCP procedures. However, in all of the studies that were identified only non-anaesthesia personnel were involved in administering the sedation. It would be helpful if further research was conducted where anaesthesia personnel were involved in the administration of sedation for ERCP procedures. This would clarify the extent to which anaesthesia personnel should be involved in the administration of propofol sedation.

The safety and efficacy of dexmedetomidine-remifentanil in children undergoing flexible bronchoscopy

PubMed Central

Li, Xia; Wang, Xue; Jin, Shuguang; Zhang, Dongsheng; Li, Yanuo

2017-01-01

Abstract Flexible bronchoscopy is more and more used for diagnosis and management of various pulmonary diseases in pediatrics. As poor coordination of children, the procedure is usually performed under general anesthesia with spontaneous or controlled ventilation to increase children and bronchoscopists’ safety and comfort. Previous studies have reported that dexmedetomidine (DEX) could be safely and effectively used for flexible bronchoscopy in both adulate and children. However, there is no trial to evaluate the dose-finding of safety and efficacy of dexmedetomidine-remifentanil (DEX-RF) in children undergoing flexible bronchoscopy. The objective of this study is to evaluate the dose-finding of safety and efficacy of DEX-RF in children undergoing flexible bronchoscopy. One hundred thirty-five children undergoing flexible bronchoscopy with DEX-RF were divided into 3 groups: Group DR1 (n = 47, DEX infusion at 0.5 μg·kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 0.5 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR2 (n = 43, DEX infusion at 1 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR3 (n = 45, DEX infusion at 1.5 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1). Ramsay sedation scale of the 3 groups was maintained 3. Anesthesia onset time, total number of intraoperative children movements, hemodynamics (heart rate, arterial pressure, pulse oxygen saturation (SpO2), respiratory rate), total cumulative dose of dexmedetomidine and remifentanil, the amount of midazolam and lidocaine, time to first dose of rescue midazolam and lidocaine, postoperative recovery time, adverse events, bronchoscopist satisfaction score were recorded. Anesthesia onset time was significantly shorter in DR3 group (14.23 ± 5.45 vs 14.45 ± 5.12 vs 11.13 ± 4.51 minutes, respectively, of DR1, DR2, DR3, P = 0.003). Additionally, the perioperative hemodynamic profile was more stable in group DR3 than that in the other 2 groups. Total number of children movements during flexible bronchoscopy was higher in DR1 group than the other 2 groups (46.81% 22/47 vs 34.88% 15/43 vs 17.78% 8/45, respectively, of DR1, DR2, DR3, P = 0.012). Total doses of rescue midazolam and lidocaine were significantly higher in DR1 and DR2 groups than that of DR3 group (P = 0.000). The time to first dose of rescue midazolam and lidocaine was significantly longer in DR3 group than DR1 and DR2 groups (P = 0.000). Total cumulative dose of dexmedetomidine was more in DR2 and DR3 groups (P = 0.000), while the amount of remifentanil was more in DR1 and DR2 groups (P = 0.000). The time to recovery for discharge from the PACU was significantly shorter in DR1 group compared with the other 2 groups (P = 0.000). Results from bronchoscopist satisfaction score showed significantly higher in DR2 and DR3 groups than that of DR1 group (P = 0.025). There were significant differences among the 3 groups in terms of the overall incidence of hypertension, tachycardia, hypoxemia, and cough (P < 0.05). Though it required longer recovery time, high dose of DEX-RF, which provided better stable hemodynamic profiles and bronchoscopist satisfaction score, less amount of rescue scheme, and children movements, could be safely and efficacy used in children undergoing flexible bronchoscopy. PMID:28296782

[Analysis of inadvertent epidural injection of drugs].

PubMed

Kasaba, T; Uehara, K; Katsuki, H; Ono, Y; Takasaki, M

2000-12-01

We asked 31 anesthesiologists, who were on the Japanese Board of Anesthesiology, about inadvertent injection of drugs into the epidural space, and received answers from 28 (90%). Fifteen (54%) had an experience of inadvertent epidural injection, and five of them had two experiences. Injected drugs were ephedrine (6 times), a mixture of neostigmine and atropine (3), thiopental (2), etilefrine (2), vecuronium (1), suxamethonium (1), bicarbonate (1), midazolam (1), lactated Ringer's solution (1), nicardipine (1), and pentazocine (1). The inadvertent injection of thiopental or bicarbonate was noticed by back pain during injection. No treatment was added after the inadvertent injections, except a patient with an epidural steroid injection following thiopental. No neurological complications were found in any patients.

Status Epilepticus and Refractory Status Epilepticus Management

PubMed Central

Abend, Nicholas S.; Bearden, David; Helbig, Ingo; McGuire, Jennifer; Narula, Sona; Panzer, Jessica A.; Topjian, Alexis; Dlugos, Dennis J.

2014-01-01

Status epilepticus (SE) describes persistent or recurring seizures without a return to baseline mental status, and is a common neurologic emergency. SE can occur in the context of epilepsy or may be symptomatic of a wide range of underlying etiologies. The clinician’s aim is to rapidly institute care that simultaneously stabilizes the patient medically, identifies and manages any precipitant conditions, and terminates seizures. Seizure management involves “emergent” treatment with benzodiazepines followed by “urgent” therapy with other anti-seizure medications. If seizures persist then refractory SE is diagnosed and management options include additional anti-seizure medications or infusions of midazolam or pentobarbital. This paper reviews the management of pediatric SE and RSE. PMID:25727508

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children.

PubMed

Fong, Choong Yi; Tay, Chee Geap; Ong, Lai Choo; Lai, Nai Ming

2017-11-03

Paediatric neurodiagnostic investigations, including brain neuroimaging and electroencephalography (EEG), play an important role in the assessment of neurodevelopmental disorders. The use of an appropriate sedative agent is important to ensure the successful completion of the neurodiagnostic procedures, particularly in children, who are usually unable to remain still throughout the procedure. To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non-invasive neurodiagnostic procedures in children. We used the standard search strategy of the Cochrane Epilepsy Group. We searched MEDLINE (OVID SP) (1950 to July 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 7, 2017), Embase (1980 to July 2017), and the Cochrane Epilepsy Group Specialized Register (via CENTRAL) using a combination of keywords and MeSH headings. We included randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non-drug agent(s), or placebo for children undergoing non-invasive neurodiagnostic procedures. Two review authors independently assessed the studies for their eligibility, extracted data, and assessed risk of bias. Results were expressed in terms of risk ratio (RR) for dichotomous data, mean difference (MD) for continuous data, with 95% confidence intervals (CIs). We included 13 studies with a total of 2390 children. The studies were all conducted in hospitals that provided neurodiagnostic services. Most studies assessed the proportion of sedation failure during the neurodiagnostic procedure, time for adequate sedation, and potential adverse effects associated with the sedative agent.The methodological quality of the included studies was mixed, as reflected by a wide variation in their 'Risk of bias' profiles. Blinding of the participants and personnel was not achieved in most of the included studies, and three of the 13 studies had high risk of bias for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in single small studies.Children who received oral chloral hydrate had lower sedation failure when compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 1 study, moderate-quality evidence). Children who received oral chloral hydrate had a higher risk of sedation failure after one dose compared to those who received intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study, low-quality evidence), but after two doses there was no evidence of a significant difference between the two groups (RR 3.00, 95% CI 0.33 to 27.46; 1 study, very low-quality evidence). Children who received oral chloral hydrate appeared to have more sedation failure when compared with music therapy, but the quality of evidence was very low for this outcome (RR 17.00, 95% CI 2.37 to 122.14; 1 study). Sedation failure rates were similar between oral chloral hydrate, oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam.Children who received oral chloral hydrate had a shorter time to achieve adequate sedation when compared with those who received oral dexmedetomidine (MD -3.86, 95% CI -5.12 to -2.6; 1 study, moderate-quality evidence), oral hydroxyzine hydrochloride (MD -7.5, 95% CI -7.85 to -7.15; 1 study, moderate-quality evidence), oral promethazine (MD -12.11, 95% CI -18.48 to -5.74; 1 study, moderate-quality evidence), and rectal midazolam (MD -95.70, 95% CI -114.51 to -76.89; 1 study). However, children with oral chloral hydrate took longer to achieve adequate sedation when compared with intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 1 study, low-quality evidence) and intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study, moderate-quality evidence).No data were available to assess the proportion of children with successful completion of neurodiagnostic procedure without interruption by the child awakening. Most trials did not assess adequate sedation as measured by specific validated scales, except in the comparison of chloral hydrate versus intranasal midazolam and oral promethazine.Compared to dexmedetomidine, chloral hydrate was associated with a higher risk of nausea and vomiting (RR 12.04 95% CI 1.58 to 91.96). No other adverse events were significantly associated with chloral hydrate (including behavioural change, oxygen desaturation) although there was an increased risk of adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study, low-quality evidence). The quality of evidence for the comparisons of oral chloral hydrate against several other methods of sedation was very variable. Oral chloral hydrate appears to have a lower sedation failure rate when compared with oral promethazine for children undergoing paediatric neurodiagnostic procedures. The sedation failure was similar for other comparisons such as oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam. When compared with intravenous pentobarbital and music therapy, oral chloral hydrate had a higher sedation failure rate. However, it must be noted that the evidence for the outcomes for the comparisons of oral chloral hydrate against intravenous pentobarbital and music therapy was of very low to low quality, therefore the corresponding findings should be interpreted with caution.Further research should determine the effects of oral chloral hydrate on major clinical outcomes such as successful completion of procedures, requirements for additional sedative agent, and degree of sedation measured using validated scales, which were rarely assessed in the studies included in this review. The safety profile of chloral hydrate should be studied further, especially the risk of major adverse effects such as bradycardia, hypotension, and oxygen desaturation.

Regio- and Stereo-Selective Oxidation of a Cardiovascular Drug, Metoprolol, Mediated by Cytochrome P450 2D and 3A Enzymes in Marmoset Livers.

PubMed

Uehara, Shotaro; Ishii, Sakura; Uno, Yasuhiro; Inoue, Takashi; Sasaki, Erika; Yamazaki, Hiroshi

2017-08-01

A β -blocker, metoprolol, is one of the in vivo probes for human cytochrome P450 (P450) 2D6. Investigation of nonhuman primate P450 enzymes helps to improve the accuracy of the extrapolation of pharmacokinetic data from animals into humans. Common marmosets ( Callithrix jacchus ) are a potential primate model for preclinical research, but the detailed roles of marmoset P450 enzymes in metoprolol oxidation remain unknown. In this study, regio- and stereo-selectivity of metoprolol oxidations by a variety of P450 enzymes in marmoset and human livers were investigated in vitro. Although liver microsomes from cynomolgus monkeys and rats preferentially mediated S -metoprolol O -demethylation and R -metoprolol α -hydroxylation, respectively, those from humans, marmosets, minipigs, and dogs preferentially mediated R -metoprolol O -demethylation, in contrast to the slow rates of R - and S -metoprolol oxidation in mouse liver microsomes. R - and S -metoprolol O -demethylation activities in marmoset livers were strongly inhibited by quinidine and ketoconazole, and were significantly correlated with bufuralol 1'-hydroxylation and midazolam 1'-hydroxylation activities and also with P450 2D and 3A4 contents, which is different from the case in human livers that did not have any correlations with P450 3A-mediated midazolam 1'-hydroxylation. Recombinant human P450 2D6 enzyme and marmoset P450 2D6/3A4 enzymes effectively catalyzed R -metoprolol O -demethylation, comparable to the activities of human and marmoset liver microsomes, respectively. These results indicated that the major roles of P450 2D enzymes for the regio- and stereo-selectivity of metoprolol oxidation were similar between human and marmoset livers, but the minor roles of P450 3A enzymes were unique to marmosets. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

[Electroacupuncture intervention combined with general anesthesia for 80 cases of heart valve replacement surgery under cardiopulmonary bypass].

PubMed

Chi, Hao; Zhou, Wen-Xiong; Wu, Yao-Yao; Chen, Tong-Yu; Ge, Wen; Yuan, Lan; Shen, Wei-Dong; Zhou, Jia

2014-02-01

To determine whether electroacupuncture (EA) intervention combined with general anesthesia (GA) strategy can reduce early post-operative morbidity and medical costs in patients undergoing heart valve replacement operation under cardiopulmonary bypass. A total of 160 heart valve replacement surgery patients undergoing cardiopulmonary bypass were randomly divided into GA and EA + GA groups (n = 80 in each group). Patients of the GA group were given with intravenous injection of Fentanyl, Midazolam, Vecuronium Bromide, etc. and routine tracheal intubation. EA (3-4 Hz, 2.0-2.2 mA) was applied to bilateral Zhongfu (LU 1), Chize (LU 5) and Ximen (PC 4) beginning about 20 mm before the surgery in the EA + GA group. Endotracheal intubation was not employed but only prepared as a standby for patients of the EA + GA group. The dosage of narcotic drugs, duration of surgery, duration of aertic blockage, rate of cardiac re-beating, volumes of post-operative blood transfusion, discharge volume, cases of post-operative pulmonary infection, vocal cord injury, and the time of first bed-off, first eating and duration in intensive care unit (IOU) residence. etc. were recorded. The successful rates of heart valve replacement surgery were similar in both GA and EA + GA groups. Compared with the GA group, the dosages of Fentanyl, Midazolam and Vecuronium of the EA + GA group were significantly lower (P < 0.05, P < 0.01), the numbers of patients needing blood-transfusion, antibiotics treatment, and suffering from pulmonary infection were fewer, the time of first bed-off and duration of hospitalizetion and IOU residence were considerably shorter (P < 0.05, P < 0.01) and the total medical cost was obviously lower (P < 0.05) in the EA + GA group. EA combined with general anesthesia strategy for heart valve replacement surgery without endotracheal intubation is safe and can reduce post-operative morbidity and medical costs in patients undergoing heart valve replacement surgery under cardiopulmonary bypass.

Spatio-temporal dynamics of multimodal EEG-fNIRS signals in the loss and recovery of consciousness under sedation using midazolam and propofol

PubMed Central

Won, Dong-Ok; Chi, Seong In; Seo, Kwang-Suk; Kim, Hyun Jeong; Müller, Klaus-Robert; Lee, Seong-Whan

2017-01-01

On sedation motivated by the clinical needs for safety and reliability, recent studies have attempted to identify brain-specific signatures for tracking patient transition into and out of consciousness, but the differences in neurophysiological effects between 1) the sedative types and 2) the presence/absence of surgical stimulations still remain unclear. Here we used multimodal electroencephalography–functional near-infrared spectroscopy (EEG–fNIRS) measurements to observe electrical and hemodynamic responses during sedation simultaneously. Forty healthy volunteers were instructed to push the button to administer sedatives in response to auditory stimuli every 9–11 s. To generally illustrate brain activity at repetitive transition points at the loss of consciousness (LOC) and the recovery of consciousness (ROC), patient-controlled sedation was performed using two different sedatives (midazolam (MDZ) and propofol (PPF)) under two surgical conditions. Once consciousness was lost via sedatives, we observed gradually increasing EEG power at lower frequencies (<15 Hz) and decreasing power at higher frequencies (>15 Hz), as well as spatially increased EEG powers in the delta and lower alpha bands, and particularly also in the upper alpha rhythm, at the frontal and parieto-occipital areas over time. During ROC from unconsciousness, these spatio-temporal changes were reversed. Interestingly, the level of consciousness was switched on/off at significantly higher effect-site concentrations of sedatives in the brain according to the use of surgical stimuli, but the spatio-temporal EEG patterns were similar, regardless of the sedative used. We also observed sudden phase shifts in fronto-parietal connectivity at the LOC and the ROC as critical points. fNIRS measurement also revealed mild hemodynamic fluctuations. Compared with general anesthesia, our results provide insights into critical hallmarks of sedative-induced (un)consciousness, which have similar spatio-temporal EEG-fNIRS patterns regardless of the stage and the sedative used. PMID:29121108

Spatio-temporal dynamics of multimodal EEG-fNIRS signals in the loss and recovery of consciousness under sedation using midazolam and propofol.

PubMed

Yeom, Seul-Ki; Won, Dong-Ok; Chi, Seong In; Seo, Kwang-Suk; Kim, Hyun Jeong; Müller, Klaus-Robert; Lee, Seong-Whan

2017-01-01

On sedation motivated by the clinical needs for safety and reliability, recent studies have attempted to identify brain-specific signatures for tracking patient transition into and out of consciousness, but the differences in neurophysiological effects between 1) the sedative types and 2) the presence/absence of surgical stimulations still remain unclear. Here we used multimodal electroencephalography-functional near-infrared spectroscopy (EEG-fNIRS) measurements to observe electrical and hemodynamic responses during sedation simultaneously. Forty healthy volunteers were instructed to push the button to administer sedatives in response to auditory stimuli every 9-11 s. To generally illustrate brain activity at repetitive transition points at the loss of consciousness (LOC) and the recovery of consciousness (ROC), patient-controlled sedation was performed using two different sedatives (midazolam (MDZ) and propofol (PPF)) under two surgical conditions. Once consciousness was lost via sedatives, we observed gradually increasing EEG power at lower frequencies (<15 Hz) and decreasing power at higher frequencies (>15 Hz), as well as spatially increased EEG powers in the delta and lower alpha bands, and particularly also in the upper alpha rhythm, at the frontal and parieto-occipital areas over time. During ROC from unconsciousness, these spatio-temporal changes were reversed. Interestingly, the level of consciousness was switched on/off at significantly higher effect-site concentrations of sedatives in the brain according to the use of surgical stimuli, but the spatio-temporal EEG patterns were similar, regardless of the sedative used. We also observed sudden phase shifts in fronto-parietal connectivity at the LOC and the ROC as critical points. fNIRS measurement also revealed mild hemodynamic fluctuations. Compared with general anesthesia, our results provide insights into critical hallmarks of sedative-induced (un)consciousness, which have similar spatio-temporal EEG-fNIRS patterns regardless of the stage and the sedative used.

Intratesticular and incisional line infiltration with ropivacaine for castration in medetomidine-butorphanol-midazolam sedated dogs.

PubMed

Kushnir, Yishai; Toledano, Noa; Cohen, Liat; Bdolah-Abram, Tali; Shilo-Benjamini, Yael

2017-03-01

To evaluate whether intratesticular and incisional ropivacaine infiltration produces sufficient intra- and postoperative analgesia for castrating dogs under sedation. Randomized, blinded, controlled clinical study. Twenty-three healthy dogs weighing 5.8-35.6 kg admitted for castration. Dogs were sedated with medetomidine (0.01 mg kg -1 ), butorphanol (0.2 mg kg -1 ) and midazolam (0.2 mg kg -1 ) intramuscularly, and were randomly assigned to group R, 0.2-0.4 mL kg -1 of ropivacaine 0.5%, or group S, an equivalent volume of saline injected intratesticularly and along the incision line. If persistent motion was observed during surgery, sedation was considered to be insufficient and general anaesthesia was induced. Carprofen 2.2 mg kg -1 was administered postoperatively. Pain was evaluated in all dogs before sedation and postoperatively following atipamezole administration at 1, 2, 4, 8 and 24 hours using an interactive visual analogue scale (IVAS; 0-100), the Glasgow composite pain scale-short form (CMPS-SF; 0-24), and a mechanical algometer. Methadone 0.3 mg kg -1 was administered intravenously to dogs if IVAS >30 or CMPS-SF >4. There was no significant difference between groups for the number of dogs administered general anaesthesia. The time from the beginning of surgery to induction of general anaesthesia was significantly shorter [median (range)] in group S [6 (3-25) minutes] than in group R [56 (36-76) minutes]. At 8 hours IVAS was significantly higher in group S (14 ± 10) than in group R (6 ± 4). Intratesticular and incisional ropivacaine infiltration delayed the time to anaesthesia induction, and provided analgesia after castration performed under deep sedation in dogs. Intratesticular local anaesthesia can be an important part of the anaesthetic plan for castration. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Comparison of Physiological Parameters and Anaesthesia Specific Observations during Isoflurane, Ketamine-Xylazine or Medetomidine-Midazolam-Fentanyl Anaesthesia in Male Guinea Pigs

PubMed Central

Tacke, Sabine; Guth, Brian; Henke, Julia

2016-01-01

Guinea pigs (GPs) are difficult to anaesthetize successfully, the choices for anaesthesia are limited and physiological parameters are likely to be influenced substantially under anaesthesia. We implanted blood pressure radio-telemetry devices into 16 male GPs and subjected them to anaesthesia with ketamine-xylazine (KX), medetomidine-midazolam-fentanyl (MMF) or isoflurane (Iso, plus atropine premedication) in a randomized order with a 7 day interval between anaesthesias. Each anaesthesia lasted 40min, after which Iso was discontinued, MMF was fully antagonized with atipamezole-flumazenil-naloxone and KX was partially antagonized with atipamezole. Hemodynamics were recorded continuously for at least 240min after induction and the GPs were monitored for respiratory rate, reflex responses and specific observations until regaining of their righting reflex (RR). Blood for glucose testing was taken from the ear at 7.5, 20 and 40min during anaesthesia. Recovery time was short with MMF and Iso but long for KX. MMF induced only a transient blood pressure drop after antagonization, whereas Iso caused a marked hypotension during maintenance and KX led to moderate hypotension after antagonization. MMF and Iso produced tolerable heart rate changes, but KX led to long term post-anaesthetic bradycardia. Hypothermia occurred with all anaesthesias, but the GPs returned to normothermia the fastest under MMF, followed shortly by Iso. KX, however, caused a profound and prolonged hypothermia. The respiration was depressed with all anaesthesias, substantially with MMF (-41%) and KX (-52%) and severe during Iso maintenance (-71%). Blood glucose with MMF and KX increased throughout the anaesthesia, but the values remained within reference values with all anaesthetics. The reflex responses character and strength varied between the anaesthetics. In conclusion, MMF is the anaesthetic of choice and Iso may be used for short, non-painful procedures. We advise against the use of KX in GPs. PMID:27658033

Comparison of two sedation regimens during targeted temperature management after cardiac arrest.

PubMed

Paul, Marine; Bougouin, Wulfran; Dumas, Florence; Geri, Guillaume; Champigneulle, Benoit; Guillemet, Lucie; Ben Hadj Salem, Omar; Legriel, Stéphane; Chiche, Jean-Daniel; Charpentier, Julien; Mira, Jean-Paul; Sandroni, Claudio; Cariou, Alain

2018-07-01

Although guidelines on post-resuscitation care recommend the use of short-acting agents for sedation during targeted temperature management (TTM) after cardiac arrest (CA), the potential advantages of this strategy have not been clinically demonstrated. We compared two sedation regimens (propofol-remifentanil, period P2, vs midazolam-fentanyl, period P1) among comatose TTM-treated CA survivors. Management protocol, apart from sedation and neuromuscular blockers use, did not change between the two periods. Baseline severity was assessed with Cardiac-Arrest-Hospital-Prognosis (CAHP) score. Time to awakening was measured starting from discontinuation of sedation at the end of rewarming. Awakening was defined as delayed when it occurred after more than 48 h. 460 patients (134 in P2, 326 in P1) were included. CAHP score did not significantly differ between P2 and P1 (P = 0.93). Sixty percent of patients awoke in both periods (81/134 vs. 194/326, P = 0.85). Median time to awakening was 2.5 (IQR 1-9) hours in P2 vs. 17 (IQR 7-60) hours in P1. Awakening was delayed in 6% of patients in P2 vs. 29% in P1 (p < 0.001). After adjustment, P2 was associated with significantly lower odds of delayed awakening (OR 0.08, 95% CI 0.03-0.2; P < 0.001). Patients in P2 had significantly more ventilator-free days (25 vs. 24 days; P = 0.007), and lower catecholamine-free days within day 28. Survival and favorable neurologic outcome at discharge did not differ across periods. During TTM following resuscitation from CA, sedation with propofol-remifentanil was associated with significantly earlier awakening and more ventilator-free days as compared with midazolam-fentanyl. Copyright © 2018 Elsevier B.V. All rights reserved.

Non-anesthesiologist-administered Propofol is not Related to an Increase in Transcutaneous CO2 Pressure During Flexible Bronchoscopy Compared to Guideline-based Sedation: A Randomized Controlled Trial.

PubMed

Mercado-Longoría, Roberto; Armeaga-Azoños, Carolina; Tapia-Orozco, Jasel; González-Aguirre, Julio E

2017-09-01

Evidence for the use of non-anesthesiologist-administered propofol for sedation during flexible bronchoscopy is scarce. The main objective of this study was to determine whether non-anesthesiologist-administered propofol balanced sedation was related to higher transcutaneous CO 2 pressure compared with current guideline-based sedation (combination midazolam and opioid). Secondary outcomes were post-procedural recuperation time, patient satisfaction and frequency of adverse events. In this randomized controlled trial we included data from outpatients aged 18 years or older with an indication for flexible bronchoscopy in a university hospital in northern Mexico. Ninety-one patients were included: 42 in the midazolam group and 49 in the propofol group. During 60min of transcutaneous capnometry monitoring, mean transcutaneous CO 2 pressure values did not differ significantly between groups (43.6 [7.5] vs. 45.6 [9.6]mmHg, P=.281). Propofol was related with a high Aldrete score at 5, 10, and 15min after flexible bronchoscopy (9 [IQR 6-10] vs. 10 [9,10], P=.006; 9 [8-10] vs. 10 [IQR 10-10], P<.001 and 10 [IQR 9-10] vs. 10 [10], respectively) and with high patient satisfaction on a visual analogue scale of 1 (not satisfied) to 10 (very satisfied) (8.41 [1.25] vs. 8.97 [0.98], P=.03). Frequency of adverse events was similar among groups (30.9% vs. 22.4%, P=.47). Compared with guideline-recommended sedation, non-anesthesiologist-administered propofol balanced sedation is not associated with higher transcutaneous CO 2 pressure or with more frequent adverse effects. Propofol use is associated with faster sedation recovery and with high patient satisfaction. NCT02820051. Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.

[Music and health--what kind of music is helpful for whom? What music not?].

PubMed

Trappe, H-J

2009-12-01

It is well known that music not only may improve quality of life (QoL) but also have different effects on heart rate (HR) and its variability (HRV). Music emphasis and rhythmic phrases are tracked consistently by physiological variables. Autonomic responses are synchronized with music, which might therefore convey emotions through autonomic arousal during crescendos or rhythmic phrases. A greater modulation of HR, HRV and modulations in cardiac autonomic nerve activity was revealed with a greater effect for music performance than music perception. Reactions to music are considered subjective, but studies suggested that cardiorespiratory variables are influenced under different circumstances. It has been shown that relaxing music decreases significantly the level of anxiety in a preoperative setting to a greater extent than orally administered midazolam (p < 0,001). Higher effectiveness and absence of apparent adverse effects make preoperative relaxing music a useful alternative to midazolam for premedication. In addition, there is sufficient practical evidence of stress reduction to suggest that a proposed regimen of listening to music while resting in bed after open heart surgery. Music intervention should be offered as an integral part of the multimodal regime administered to the patients that have undergone cardiovascular surgery. It is a supportive source that increases relaxation. Music is also effective in under conditions and music can be utilized as an effective intervention for patients with depressive symptoms, geriatrics and in pain, intensive care or palliative medicine. However, careful selected music that incorporates a patient's own preferences may offer an effective method to reduce anxiety and to improve quality of life. The most benefit on health is visible in classic music, meditation music whereas heavy metal music or technosounds are even ineffective or dangerous and will lead to stress and/or life threatening arrhythmias. There are many composers most effectively to improve QoL, particularly Bach, Mozart and Italian composers are "ideal". Georg Thieme Verlag KG Stuttgart, New York.

[Assessment of the use of racemic ketamine and its S(+) isomer, associated or not with low doses of fentanyl, in balneotherapy for major burn patients].

PubMed

Cantinho, Fernando Antônio de Freitas; Silva, Antonio Carlos Pereira da

2009-01-01

The care of the wounds of major burn patients triggers severe painful stimuli. The objective of this study was to assess the safety and efficacy of different drug combinations in anesthesia for balneotherapy. After approval by the Ethics Commission, 200 procedures of balneotherapy in 87 major burn adult patients were evaluated. Midazolam was used in all cases. The vials of ketamine were numbered and, therefore, at the time of the use, one did not know whether racemic or S(+)ketamine was being used. Each morning it was decided by drawing lots whether fentanyl would be used or not in the procedures of that day. Patients were included in one of four groups: ISO/sf (S(+) isomer without fentanyl), ISO/cf (S(+) isomer with fentanyl), RAC/sf (racemic ketamine without fentanyl), and RAC/cf (racemic ketamine with fentanyl). The initial doses proposed were as follows: midazolam, 0.06 mg.kg-1; ketamine, 1.0 to 1.1 mg.kg-1; and fentanyl, 0.8 (1/4)g.kg1-1; additional doses were administered as needed. Only one patient recalled the pain of balneotherapy. In the group that received S(+)ketamine, the use of fentanyl did not bring additional advantages; however, when associated with racemic ketamine, fentanyl reduced the total dose and the number of ketamine boluses. The extension of body surface burned was the main determinant of the severity of post-procedure pain. Reduced pain severity was the main factor considered by patients when grading their satisfaction with the anesthesia. The four different drug combinations proved to be safe and guaranteed the absence of pain during balneotherapy. Characteristics not directly related to the anesthetics proved to be more important in the incidence of post-procedure pain, which was the main factor considered by major burn patient to define their satisfaction with the anesthesia used.

Use of high doses of quetiapine in bipolar disorder episodes are not linked to high activity of cytochrome P4503A4 and/or cytochrome P4502D6.

PubMed

Khazaal, Yasser; Preisig, Martin; Chatton, Anne; Kaufmann, Nadine; Bilancioni, Romain; Eap, Chin B

2013-09-01

The use of quetiapine for treatment of bipolar disorders at a higher dosage than the licensed range is not unusual in clinical practice. Quetiapine is predominantly metabolised by cytochrome P450 3A4 (CYP3A4) and to a lesser extent by CYP2D6. The large interindividual variability of those isozyme activities could contribute to the variability observed in quetiapine dosage. The aim of the present study is to evaluate if the use of high dosages of quetiapine in some patients, as compared to patients treated with a dosage in the licensed range (up to 800 mg/day), could be explained by a high activity of CYP3A4 and/or of CYP2D6. CYP3A4 activities were determined using the midazolam metabolic ratio in 21 bipolar and schizoaffective bipolar patients genotyped for CYP2D6. 9 patients were treated with a high quetiapine dosage (mean ± SD, median; range: 1467 ± 625, 1200; 1000-3000 mg/day) and 11 with a normal quetiapine dosage (433 ± 274, 350; 100-800 mg/day). One patient in the high dose and one patient in the normal dose groups were genotyped as CYP2D6 ultrarapid metabolizers. CYP3A4 activities were not significantly different between the two groups (midazolam metabolic ratio: 9.4 ± 8.2; 6.2; 1.7-26.8 vs 3.9 ± 2.3; 3.8; 1.5-7.6, in the normal dose group as compared to the high dose group, respectively, NS). The use of high quetiapine dosage for the patients included in the present study cannot be explained by variations in pharmacokinetics parameters such as a high activity of CYP3A4 and/or of CYP2D6.

A Comparison Between the Hemodynamic Effects of Cisatracurium and Atracurium in Patient with Low Function of Left Ventricle who are Candidate for Open Heart Surgery.

PubMed

Ghorbanlo, Masoud; Mohaghegh, Mahmoud Reza; Yazdanian, Forozan; Mesbah, Mehrdad; Totonchi, Ziya

2016-07-27

The need for muscle relaxants in general anesthesia in different surgeries including cardiac surgeries, and the type of relaxant to be used considering its different hemodynamic effects on patients with heart disease can be of considerable importance. In this study, the hemodynamic effects of two muscle relaxants, Cisatracurium and Atracurium in patients whit low function of left ventricle who are candidate for open heart surgery have been considered. This study has been designed as a randomized prospective double-blind clinical trial. The target population included all adult patients with heart disease whose ejection fraction reported by echocardiography or cardiac catheterization was 35% or less before the surgery, and were candidate for open heart surgery in Shahid Rajaei Heart Center. Taking into account the inclusion and exclusion criteria, the patients were randomly placed in two groups of 30 people each. In the induction stage, all the patients received midazolam, etomidate, and one of the considered muscle relaxant, either 0.2 mg/kg of cisatracurium or 0.5mg/kg of Atracurium within one minute. In the maintenance stage of anesthesia, the patients were administered by infusion of midazolam, sufentanil and the same muscle relaxant used in the induction stage. The hemodynamic indexes were recorded and evaluated in different stages of anesthesia and surgery as well as prior to transfer to ICU. In regard with descriptive indexes (age and sex distributions, premedication with cardiac drugs, ejection fraction before surgery, basic disease) there was no statistically significant difference between the groups. The significant difference of hemodynamic indexes between the two groups of this study, and the need for hemodynamic stability in all stages of surgery for patients with low function of left ventricle who are candidate for open heart surgery, proves that administering Cisatracurium as the muscle relaxant is advantageous and better.

Anesthetics inhibit extracellular signal-regulated Kinase1/2 phosphorylation via NMDA receptor, phospholipase C and protein kinase C in mouse hippocampal slices.

PubMed

Haiying, Gao; Mingjie, Han; Lingyu, Zhang; Qingxiang, Wang; Haisong, Wang; Bingxi, Zhang

2017-02-01

Extracellular signal-regulated kinase 1/2 (ERK1/2) has been implicated in learning and memory; however, whether intravenous anesthetics modulate ERK1/2 remains unknown. The aim of this study was to examine the effect of several intravenous anesthetics on the phosphorylation of ERK1/2 in the hippocampus of adult mice. Western blotting was used to examine cellular levels of phosphorylated and unphosphorylated ERK1/2 in mouse hippocampus slices, which were incubated with or without anesthetics including propofol, etomidate, ketamine and midazolam, a protein kinase C (PKC) activator or inhibitor, or phospholipase C (PLC) activator or inhibitor. Propofol, etomidate, ketamine and midazolam reduced phosphorylation of ERK1/2 in a time-dependent manner. Washing out propofol after 5 min increased ERK1/2 phosphorylation. The anesthetic-induced depression of ERK1/2 phosphorylation was blocked by 0.1 μM phorbol-12-myristate 13-acetate (an activator of PKC), 50 μM U73122 (an inhibitor of PLC). The anesthetic-induced depression of ERK1 phosphorylation was blocked by 1 mMN-methyl-d-aspartate (NMDA). Whereas 100 μM chelerythrine (an inhibitor of PKC) and 100 μM carbachol (an activator of PLC) and 20 μM PD-98059 (an inhibitor of MEK) had additive effects on propofol-induced inhibition of ERK1/2 phosphorylation. In contrast, 10 μM MK801 (a NMDA receptor antagonist) did not block anesthetic-induced inhibition of ERK1/2 phosphorylation. Intravenous anesthetics markedly decreased phosphorylation of ERK1/2 in mouse hippocampal slices, most likely via the NMDA receptor, and PLC- and PKC-dependent pathways. Thus, ERK1/2 represents a target for anesthetics in the brain. Copyright © 2016. Published by Elsevier Ltd.

In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto.

PubMed

Gurley, Bill J; Gardner, Stephanie F; Hubbard, Martha A; Williams, D Keith; Gentry, W Brooks; Carrier, Julie; Khan, Ikhlas A; Edwards, David J; Shah, Amit

2004-11-01

Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Single-time point phenotypic metabolic ratios were used to determine whether long-term supplementation of Citrus aurantium , Echinacea purpurea , milk thistle (Silybum marianum), or saw palmetto (Serenoa repens) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Twelve healthy volunteers (6 women, 6 men) were randomly assigned to receive C aurantium , E purpurea , milk thistle, or saw palmetto for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 by use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively. The content of purported "active" phytochemicals was determined for each supplement. Comparisons of presupplementation and postsupplementation phenotypic ratios suggested that these particular supplements had no significant effect on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Phytochemical profiles indicated that C aurantium was devoid of the CYP3A4 inhibitor 6',7'-dihydroxybergamottin. Quantities of fatty acids, flavonolignans, and cichoric acid were consistent with label claims for saw palmetto, milk thistle, and E purpurea , respectively. Botanical supplements containing C aurantium , milk thistle, or saw palmetto extracts appear to pose a minimal risk for CYP-mediated herb-drug interactions in humans. Although the effects of E purpurea on CYP activity were minor, further study into the interaction potential of this botanical is merited.

Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P450 3A Activity and Single-Time-Point Oral Midazolam Microdose Phenotype in Healthy Subjects.

PubMed

Woolsey, Sarah J; Beaton, Melanie D; Choi, Yun-Hee; Dresser, George K; Gryn, Steven E; Kim, Richard B; Tirona, Rommel G

2016-04-01

Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4β-hydroxycholesterol (4βHC) and 6β-hydroxycortisol (6βHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4βHC and 6βHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4βHC and 6βHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 μg). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4βHC and 6βHCL MRs ranged 6.5-, 10- and 13-fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4βHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4βHC nor 6βHCL MRs were associated with MDZ oral clearance. Plasma 4βHC and 6βHCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

N-acetylcysteine for neuropsychiatric symptoms in a woman with Williams syndrome.

PubMed

Pineiro, Mildred Lopez; Roberts, Antoinette M; Waxler, Jessica L; Mullett, Jennifer E; Pober, Barbara R; McDougle, Christopher J

2014-11-01

Williams syndrome is a relatively rare genetic disorder caused by the hemizygous microdeletion of a region in chromosome 7q11.23. Individuals with Williams syndrome typically present with a highly social, overfriendly, and empathic personality. Comorbid medical and neuropsychiatric disorders are common. Reports of effective pharmacological treatment of associated neuropsychiatric disorders are limited. The authors describe the successful treatment of interfering anger, aggression, and hair-pulling with N-acetylcysteine in a 19-year-old woman with Williams syndrome. The neuropsychiatric symptoms emerged 1 week following an upper gastrointestinal endoscopy, for which fentanyl, midazolam, and propofol were used as anesthetics. The patient's treatment course and hypothesized mechanisms underlying the clinical presentation and symptom resolution are described. © The Author(s) 2014.

The use of phenobarbital and other anti-seizure drugs in newborns.

PubMed

El-Dib, Mohamed; Soul, Janet S

2017-10-01

Neonatal seizures constitute the most frequent presenting neurologic sign encountered in the neonatal intensive care unit. Despite limited efficacy and safety data, phenobarbital continues to be used near-universally as the first-line anti-seizure drug (ASD) in neonates. The choice of second-line ASDs varies by provider and institution, and is still not supported by sufficient scientific evidence. In this review, we discuss the available evidence supporting the efficacy, mechanism of action, potential adverse effects, key pharmacokinetic characteristics such as interaction with therapeutic hypothermia, logistical issues, and rationale for use of neonatal ASDs. We describe the widely used neonatal ASDs, namely phenobarbital, phenytoin, midazolam, and levetiracetam, in addition to potential ASDs, including lidocaine, topiramate, and bumetanide. Copyright © 2017. Published by Elsevier Ltd.

Pulmonary atelectasis manifested after induction of anesthesia: a contribution of sinobronchial syndrome?

PubMed

Igarashi, Ayuko; Amagasa, Sumio; Oda, Shinya; Yokoo, Noriko

2007-01-01

A 31-year-old man underwent general anesthesia for sinus surgery. Anesthesia was induced with midazolam and butorphanol, and an endotracheal tube was orally placed with a bronchoscope, due to difficulty with temporomandibular joint opening. Ventilation difficulty and increased peak inspiratory pressure were noticed shortly after tracheal intubation, and bronchoscopy was performed for diagnosis. The bronchi were filled with a clear mucous secretion. Removal of the secretion improved respiration and decreased the peak inspiratory pressure. A chest roentgenogram taken prior to extubation showed right upper lobe atelectasis. A diagnosis of sinobronchial syndrome was made postoperatively. The etiology of the acutely developed atelectasis was unclear. However, the latent syndrome may have induced excessive airway secretion with stimuli such as endotracheal intubation.

Role of levetiracetam in refractory seizures due to a rare progressive myoclonic epilepsy: Lafora body disease

PubMed Central

Hashmi, Mubashira; Saleem, Feroza; Mustafa, Muhammad Shahid; Sheerani, Mughis; Ehtesham, Zeeshan; Siddiqui, Khurram

2010-01-01

Lafora disease is one of the rare, most fatal progressive myoclonic epilepsies reported. We present a case of a teenager with intractable seizures and progressive mental decline, diagnosed as Lafora body disease on axillary skin biopsy. He was admitted with status epilepticus with refractory myoclonic and generalised tonic clonic seizures. Despite on maximum doses of multiple antiepileptic drugs and infusions of propofol and midazolam, his seizures were refractory to all forms of medical therapy tried. Levetiracetam (LEV), a pyrrolidine derivative, was introduced; he showed a prompt response and was weaned off successfully from infusions of anticonvulsants and mechanical ventilation within 48 h of introduction of LEV, followed by an almost seizure-free status. PMID:22791845

Management of a high risk epileptic patient under conscious sedation: A multidisciplinary approach

PubMed Central

Chellathurai, Burnice Nalina Kumari; Thiagarajan, Ramakrishnan; Jayakumaran, SelvaKumar; Devadoss, Pradeep; Elavazhagan

2016-01-01

Epilepsy, characterized by the risk of recurrent seizures, is a chronic disease that afflicts about 5% of the world's population. The main dental problems associated with epileptic patients include gingival hyperplasia, minor oral injuries, tooth trauma, and prosthodontic problems, which require the dental treatment. Stress and fear are the most common triggering factors for the epilepsy in dental chair. Therefore, a more appropriate method of treating such epileptic patients may be warranted. Conscious sedation is a technique of providing good anesthesia and analgesia to patients, the main advantage of which is the patient's rapid return to presentation levels. Midazolam used as a sedative agent has anticonvulsant properties. This case report highlights a case requiring multiple dental procedures carried out in a high risk epileptic patient under conscious sedation. PMID:27041847

Refractory status epilepticus complicated by drug-induced involuntary movements.

PubMed

Nair, Pradeep Pankajakshan; Wadwekar, Vaibhav; Murgai, Aditya; Narayan, Sunil K

2014-02-11

New onset refractory status epilepticus (NORSE) is a neurological emergency and difficult to treat condition. We report a case of involuntary movements resulting from thiopentone sodium infusion during the management of refractory status epilepticus. A young woman was admitted with fever and NORSE in the neurology intensive care unit. In addition to supportive measures, she was treated with intravenous lorazepam, phenytoin sodium, sodium valproate, midazolam and thiopentone sodium. While on thiopentone sodium, she developed involuntary twitches involving her upper limbs and face with EEG showing no evidence of ongoing status epilepticus. Because of the temporal relationship with thiopentone infusion, we tapered the dose of thiopentone sodium, which resulted in the disappearance of the movements. The patient recovered well with no recurrence of the seizures during the hospital stay.

Anesthetic management of a 4-month-old red fox (Vulpes vulpes) for orthopedic surgery.

PubMed

Anagnostou, Tilemahos; Flouraki, Eugenia; Kostakis, Charalampos; Komnenou, Anastasia; Prassinos, Nikitas; Raptopoulos, Dimitrios

2015-03-01

A 4-mo-old red fox (Vulpes vulpes) was found recumbent after a vehicular accident. Radiology revealed several limb fractures and the fox underwent surgery after 24 hr of initial stabilization. Premedication consisted of dexmedetomidine and morphine. Anesthesia was induced with ketamine and midazolam and maintained with isoflurane. Lidocaine, bupivacaine, and morphine were administered epidurally and further analgesia was provided with meloxicam. The heart rate and respiratory rate of the fox remained stable during surgery and, except for a mild hypothermia, the recovery from anesthesia was uneventful. The postoperative pain scores were low and the animal was transported to a rehabilitation facility and eventually released to the wild. The low pain scores postoperatively should be attributed to the successful application of epidural anesthesia and analgesia.

"Herbal seizures"--atypical symptoms after ibogaine intoxication: a case report.

PubMed

Breuer, Lorenz; Kasper, Burkhard S; Schwarze, Bernd; Gschossmann, Juergen M; Kornhuber, Johannes; Müller, Helge H

2015-10-31

Misuse of various new psychotropic substances such as ibogaine is increasing rapidly. Knowledge of their negative side effects is sparse. We present a case of intoxication with the herbal substance ibogaine in a 22-year-old white man. After taking a cumulative dose of 38 g (taken in two doses), he developed visual memories, nausea and vomiting. He developed a generalized tonic-clonic seizure with additional grand mal seizures. He was treated with midazolam and levetiracetam. Extended drug screenings and computed tomography and magnetic resonance imaging findings were all negative. Knowledge of the side effects of ibogaine has mainly come from reports of cardiovascular complications; seizures are rarely mentioned and experimental findings are inconsistent. It seems that ibogaine acts like a proconvulsive drug at high doses.

Differences in cytochrome p450-mediated pharmacokinetics between chinese and caucasian populations predicted by mechanistic physiologically based pharmacokinetic modelling.

PubMed

Barter, Zoe E; Tucker, Geoffrey T; Rowland-Yeo, Karen

2013-12-01

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval. We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized by cytochromes P450 (CYPs) relative to Caucasian populations. Such predictions should help to inform the need for duplication of in vivo pharmacokinetic studies in the two ethnic groups and the design of such studies. Demographic and physiological data for Chinese, along with information on CYP abundances and the frequencies of associated genetic polymorphisms in Chinese, were collated from literature sources and incorporated within the Simcyp Population-based Simulator(®) (v11.1). Default Simcyp parameter values for a virtual Caucasian population and for model compounds metabolized principally by specific CYPs were used as the point of reference. The drugs and the main CYPs involved in their metabolism were phenacetin (CYP1A2), desipramine (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), and alprazolam and midazolam (CYP3A). Hydroxy bupropion formation was used as a more sensitive marker of CYP2B6 activity than bupropion kinetics. Observed plasma drug concentration-time profiles and pharmacokinetic parameters after oral and, where possible, intravenous dosing were obtained from published in vivo studies in both Chinese and Caucasian subjects. Virtual subjects generated within Simcyp were matched to the subjects used in the in vivo studies with respect to age, sex, dosage and, where possible, CYP phenotype frequency. Predicted and observed plasma drug concentrations and weight-normalized clearances were compared between the ethnic groups. Significant differences were identified between Chinese and Caucasian populations in the frequency of CYP2C19 poor metabolizers (PMs) [Chinese 13 %; Caucasian 2.4 %], CYP2D6 PMs and intermediate metabolizers (IMs) [Chinese PMs 0.3 %, IMs 39 %; Caucasian PMs 8 %, IMs <1 %], the hepatic abundance of CYP2C19 (mean values: Chinese 8 pmol/mg; Caucasian 14 pmol/mg) and liver weight (mean values: Chinese 1198 g; Caucasian 1603 g). The observed plasma drug concentration-time profiles and weight-normalized clearances were predicted with reasonable accuracy (100 % within twofold; 89 % within 1.5-fold) in both ethnic groups. The predicted phenacetin, tolbutamide, omeprazole, desipramine, midazolam (intravenous), midazolam (oral), alprazolam (intravenous) and alprazolam (oral) clearances were 36, 25, 51, 43, 24, 17, 21 and 22 % lower, respectively, in Chinese than in Caucasians; the observed clearances were 28, 2, 75, 42, 19, 62, 20 and 21 % lower, respectively. Predicted and observed formation of hydroxy bupropion was lower in Caucasians than in Chinese (6 and 20 %, respectively). Differences between ethnic groups were less after normalization for body weight. The results of this study indicate the value of simulation based on mechanistic physiologically based pharmacokinetic modelling (PBPK) in anticipating the likely extent of any differences in the kinetics of CYP substrates in Chinese and Caucasian populations arising from demographic, physiological and genetic differences.

Pain control requirements for percutaneous ablation of renal tumors: cryoablation versus radiofrequency ablation--initial observations.

PubMed

Allaf, Mohamad E; Varkarakis, Ioannis M; Bhayani, Sam B; Inagaki, Takeshi; Kavoussi, Louis R; Solomon, Stephen B

2005-10-01

To retrospectively compare the pain control requirements of patients undergoing computed tomography (CT)-guided percutaneous radiofrequency (RF) ablation with those of patients undergoing CT-guided percutaneous cryoablation of small (< or = 4-cm) renal tumors. The study was HIPAA compliant and received institutional review board exemption; informed consent was not required. Medical and procedure records of patients who underwent RF ablation and cryoablation of renal tumors from June 19, 2003, to February 28, 2004, were retrospectively reviewed for clinical data, tumor characteristics, and anesthesia information. During the study period, 10 men (mean age, 66.5 years) underwent cryoablation of 11 renal lesions, and 14 patients (11 men, four women; mean age, 68.1 years) underwent RF ablation of 15 renal tumors. Analgesic and sedative requirements during the procedure were compared. Standard anesthesia consisted of 5 mL of 1% lidocaine injected locally, and conscious sedation consisted of 50 microg of fentanyl and 1 mg of midazolam administered intravenously. The Fisher exact test and Student t test were used to compare clinical factors and drug requirements between the two groups. There was no difference in terms of patient demographics, tumor diameter, or distribution of central versus noncentral lesions between the two groups. Cryoablation was associated with a significantly lower dose of fentanyl (165.0 microg [RF group] vs 75.0 microg [cryoablation group]; P < .001) and midazolam (2.9 mg [RF group] vs 1.6 mg [cryoablation group]; P = .026). In the RF group, one patient required general anesthesia, one patient required supplemental narcotics (5 mg of oxycodone) and sedatives (1 mg lorezapam), and one patient became apneic for a brief interval after receiving additional narcotics for pain during the procedure. An additional RF session was terminated early in one patient because of pain, and further medication could not be administered owing to bradycardia. No patients in the cryoablation group required any additional or alternate anesthetics. Image-guided percutaneous cryoablation of small (< or = 4-cm) renal lesions appears to require less analgesia than RF ablation. Prospective trials with validated pain scales are needed to examine this further. RSNA, 2005

Investigation of the coordinated functional activities of cytochrome P450 3A4 and P-glycoprotein in limiting the absorption of xenobiotics in Caco-2 cells.

PubMed

Tran, Christine D H; Timmins, Peter; Conway, Barbara R; Irwin, William J

2002-01-01

The coordination of the functional activities of intestinal CYP3A4 and P-gp in limiting the absorption of xenobiotics in Caco-2 cells was investigated. Growing Caco-2 cells were exposed to increasing concentrations of doxorubicin (1-2 microM) in plastic flasks to encourage a subpopulation of cells, that displayed an intrinsically higher multidrug resistance (mdr) phenotype than the parent cells, to survive and grow. Doxorubicin-exposed (hereinafter referred to as type I cells) and nonexposed Caco-2 cells (parent cells) on collagen-coated inserts were also treated with either 0 (control) or 0.25 microM 1alpha,25-dihydroxyvitamin D(3) to promote cellular CYP3A4 expression. Increased P-gp protein expression, as detected by Western blotting, was noted in type I cells (213 +/- 54.35%) compared to that of parent cells (100 +/- 6.05%). Furthermore, they retained significantly less [(3)H]vincristine sulphate (p < 0.05), a P-gp substrate, after efflux (272.89 +/- 11.86 fmol/mg protein) than the parent cells (381.39 +/- 61.82 fmol/mg protein). The expression of CYP3A4 in parental cells after 1alpha,25-dihydroxyvitamin D(3) treatment was quantified to be 76.2 +/- 7.6 pmol/mg protein and comparable with that found in human jejunal enterocytes (70.0 +/- 20.0 pmol/mg protein). Type I cells, however, expressed a very low quantity of CYP3A4 both before and after the treatment that was beyond the minimum detection limit of Western blotting. Functionally, the rates of 1-hydroxylation of midazolam by CYP3A for both cell types ranged from 257.0 +/- 20.0 to 1057.0 +/- 46.0 pmol/min/mg protein. Type I cells, although having a higher P-gp expression and activity comparatively, metabolized midazolam less extensively than the parent cells. The results suggested that there were noncoordinated functional activities of intestinal CYP3A4 and P-gp in Caco-2 cells, although they both functioned independently to minimize intestinal epithelial absorption of xenobiotics. Copyright 2002 Wiley-Liss, Inc.

Intramuscular and rectal therapies of acute seizures.

PubMed

Leppik, Ilo E; Patel, Sima I

2015-08-01

The intramuscular (IM) and rectal routes are alternative routes of delivery for antiepileptic drugs (AEDs) when the intravenous route is not practical or possible. For treatment of acute seizures, the AED used should have a short time to maximum concentration (Tmax). Some AEDs have preparations that may be given intramuscularly. These include the benzodiazepines (diazepam, lorazepam, and midazolam) and others (fosphenytoin, levetiracetam). Although phenytoin and valproate have parenteral preparations, these should not be given intramuscularly. A recent study of prehospital treatment of status epilepticus evaluated a midazolam (MDZ) autoinjector delivering IM drug compared to IV lorazepam (LZP). Seizures were absent on arrival to the emergency department in 73.4% of the IM MDZ compared to a 63.4% response in LZP-treated subjects (p < 0.001 for superiority). Almost all AEDs have been evaluated for rectal administration as solutions, gels, and suppositories. In a placebo-controlled study, diazepam (DZP) was administered at home by caregivers in doses that ranged from 0.2 to 0.5 mg/kg. Diazepam was superior to placebo in reduced seizure frequency in children (p < 0.001) and in adults (p = 0.02) and time to recurrent seizures after an initial treatment (p < 0.001). Thus, at this time, only MZD given intramuscularly and DZP given rectally appear to have the properties required for rapid enough absorption to be useful when intravenous routes are not possible. Some drugs cannot be administered rectally owing to factors such as poor absorption or poor solubility in aqueous solutions. The relative rectal bioavailability of gabapentin, oxcarbazepine, and phenytoin is so low that the current formulations are not considered to be suitable for administration by this route. When administered as a solution, diazepam is rapidly absorbed rectally, reaching the Tmax within 5-20 min in children. By contrast, rectal administration of lorazepam is relatively slow, with a Tmax of 1-2h. The dependence of gabapentin on an active transport system, and the much-reduced surface area of the rectum compared with the small intestine, may be responsible for its lack of absorption from the rectum. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.

Role of benzodiazepine and serotonergic mechanisms in conditioned freezing and antinociception using electrical stimulation of the dorsal periaqueductal gray as unconditioned stimulus in rats.

PubMed

Castilho, V M; Macedo, C E; Brandão, M L

2002-12-01

The dorsal periaqueductal gray matter (dPAG) has been implicated in the modulation of defensive behavior. Electrical stimulation of this structure can be used as an unconditioned stimulus to produce a conditioned fear reaction expressed by freezing, antinociception, and autonomic responses. This study investigated the influence of benzodiazepine, serotonergic, and opioid mechanisms on these conditioned responses. Animals implanted with an electrode and a guide cannula into the dPAG were submitted to two conditioning sessions. Each session consisted of ten pairings of the light in a distinctive chamber (CS) with the electrical stimulation of this structure at the escape threshold. On the next day, each animal was exposed only to the CS (testing) and the duration of freezing, number of rearing and grooming episodes were recorded for 5 min. Before and after the testing session, animals were submitted to the tail-flick test. Fifteen minutes before the exposure to the CS, animals received injections into the dPAG of midazolam (a positive modulator of benzodiazepine sites), alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT; an agonist of 5-HT(2) receptors), naltrexone (an opioid antagonist), or vehicle. Conditioning with dPAG electrical stimulation caused significant increases in the time of freezing and conditioned antinociception. Injections of midazolam into the dPAG significantly inhibited freezing behavior and antinociception due to conditioning. Injections of alpha-Me-5-HT inhibited the effects of conditioning on freezing without affecting conditioned antinociception. Injections of naltrexone (13 nmol/0.2 micro l) did not change any of the conditioned responses studied. (1) Conditioned freezing and antinociception are modulated by benzodiazepine mechanisms into dPAG. (2) 5-HT(2) receptors seem to regulate conditioned freezing behavior. However, conditioned antinociception was not affected by 13 nmol naltrexone. (3) Opioid mechanisms do not seem to be involved in the conditioned responses using electrical stimulation of the dPAG as unconditioned stimulus. Further studies with other opioid and 5-HT(2) receptor antagonists are still needed to confirm the conclusions drawn from the present work.

Infraslow status epilepticus: A new form of subclinical status epilepticus recorded in a child with Sturge-Weber syndrome.

PubMed

Bello-Espinosa, Luis E

2015-08-01

Analysis of infraslow EEG activity (ISA) has shown potential in the evaluation of patients with epilepsy and in the differentiation between focal and generalized epilepsies. Infraslow EEG activity analysis may also provide insights into the pathophysiology of refractory clinical and subclinical status epilepticus. The purpose of this report is to describe a girl with Sturge-Weber syndrome (SWS) who presented with a 96-h refractory encephalopathy and nonischemic hemiparesis and who was identified to have infraslow status epilepticus (ISSE), which successfully resolved after midazolam administration. The continuous EEG recording of a 5-year-old girl with known structural epilepsy due to Sturge-Weber syndrome is presented. The patient presented to the ED with acute confusion, eye deviation, and right hemiparesis similar to two previous admissions. Despite administration of lorazepam, fosphenytoin, phenobarbital, and valproic loads, the patient showed no improvement in the clinical condition after 48 h. The continuous video-EEG monitoring (VEM) showed continuous severe diffuse nonrhythmic asymmetric slowing but no apparent ictal activity on continuous conventional EEG recording settings. As brain CT, CTA, CTV, and complete MRI scans including DWI obtained within 72 h of presentation failed to demonstrate any ischemic changes, analysis of the EEG infraslow (ISA) activity was undertaken using LFF: 0.01 Hz and HFF: of 0.1 Hz, respectively. Continuous subclinical unilateral rhythmic ictal ISA was identified. This was only evident on the left hemisphere which correlated with the structural changes due to SWS. A trial of continuous 120 to 240 μg/kg/h of IV midazolam resulted in immediate resolution of the contralateral hemiparesis and encephalopathy. Continuous prolonged rhythmic ictal infraslow activity (ISA) can cause super-refractory subclinical focal status epilepticus. This has not been previously reported, and we propose that this be called infraslow status epilepticus (ISSE). Infraslow EEG activity analysis should be performed in all patients with unexplained subclinical status epilepticus. This article is part of a Special Issue entitled "Status Epilepticus". Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Palliative sedation challenging the professional competency of health care providers and staff: a qualitative focus group and personal written narrative study.

PubMed

Leboul, Danièle; Aubry, Régis; Peter, Jean-Michel; Royer, Victor; Richard, Jean-François; Guirimand, Frédéric

2017-04-11

Despite recent advances in palliative medicine, sedating a terminally ill patient is regarded as an indispensable treatment to manage unbearable suffering. With the prospect of widespread use of palliative sedation, the feelings and representations of health care providers and staff (carers) regarding sedation must be carefully explored if we are to gain a better understanding of its impact and potential pitfalls. The objective of the study was to provide a comprehensive description of the opinions of carers about the use of sedation practices in palliative care units (PCU), which have become a focus of public attention following changes in legislation. Data were collected using a qualitative study involving multi-professional focus groups with health care providers and staff as well as personal narratives written by physicians and paramedical staff. A total of 35 medical and paramedical providers volunteered to participate in focus group discussions in three Palliative Care Units in two French hospitals and to write personal narratives. Health care provider and staff opinions had to do with their professional stance and competencies when using midazolam and practicing sedation in palliative care. They expressed uncertainty regarding three aspects of the comprehensive care: biomedical rigour of diagnosis and therapeutics, quality of the patient/provider relationship and care to be provided. Focusing on the sedative effect of midazolam and continuous sedation until death, the interviewed health care providers examined the basics of their professional competency as well as the key role played by the health care team in terms of providing support and minimizing workplace suffering. Nurses were subject to the greatest misgivings about their work when they were called upon to sedate patients. The uncertainty experienced by the carers with regard to the medical, psychosocial and ethical justification for sedation is a source of psychological burden and moral distress, and it has proved to be a major source of suffering in the workplace. Lastly, the study shows the uncertainty can have the positive effect of prompting the care team to devise ways to deal with it.

Epidemiology and diagnostic and therapeutic management of febrile seizures in the Italian pediatric emergency departments: A prospective observational study.

PubMed

Vitaliti, Giovanna; Castagno, Emanuele; Ricceri, Fulvio; Urbino, Antonio; Di Pianella, Alberto Verrotti; Lubrano, Riccardo; Caramaschi, Elisa; Prota, Maurizio; Pulvirenti, Rita Maria; Ajovalasit, Patrizia; Signorile, Giuseppe; Navone, Carla; La Bianca, Maria Rosaria; Villani, Alberto; Corsello, Giovanni; Falsaperla, Raffaele

2017-01-01

Febrile seizures (FS) involve 2-5% of the paediatric population, among which Complex FS (CFS) account for one third of accesses for FS in Emergency Departments (EDs). The aim of our study was to define the epidemiology, the clinical, diagnostic and therapeutic approach to FS and CFSs in the Italian EDs. A multicenter prospective observational study was performed between April 2014 and March 2015. Patients between 1 and 60 months of age, randomly accessing to ED for ongoing FS or reported FS at home were included. Demographic features and diagnostic-therapeutic follow-up were recorded. FS were categorized in simple (<10min), prolonged (10-30min) and status epilepticus (>30min). The study population consisted of 268 children. Most of the children experienced simple FS (71.65%). Among the 68 (25.37%) patients with complex FS, 11 were 6-12 month-old, accounting for 45.83% of all the infants with FS in the younger age group. No therapy has been administered at home in 76.12% patients; 23.51% of them received endorectal diazepam and only 1 patient received buccal midazolam. At arrival at ED, no therapy was necessary for 70.52% patients; 50.63% received endorectal diazepam and 17.72% an i.v. bolus of midazolam. Blood tests and acid-base balanced were performed respectively in 82.09% of cases. An electroencephalogram at ED was performed in 21.64% of patients. Neuroimagings were done in 3.73% of cases. A neurologic consultation was asked for 36 patients (13.43%). this is the first study assessing epidemiologic characteristics of FS in the Italian pediatric population, evidencing a higher prevalence of CFSs in children younger than 12 months of age and opening a new research scenario on the blood brain barrier vulnerability. On a national level, our study showed the need for a diagnostic standardized work-up to improve the cost/benefit ratio on CFS management. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of respiratory function during TIVA and isoflurane anaesthesia in ponies Part II: breathing patterns and transdiaphragmatic pressure.

PubMed

Kowalczyk, Lidia; Steblaj, Barbara; Schauvliege, Stijn; Schramel, Johannes Peter; Pavlidou, Kiriaki; Savvas, Ioannis; Duchateau, Luc; Gasthuys, Frank; Moens, Yves

2014-11-01

To compare breathing patterns and transdiaphragmatic pressure during total intravenous (TIVA) and isoflurane anaesthesia in ponies. Experimental, cross-over study. Six healthy ponies weighing 286 (233-388) ± 61 kg, age 13 (9-16) ± 3 years. Following premedication with romifidine [80 μg kg(-1) intravenously (IV)], general anaesthesia was induced with midazolam (0.06 mg kg(-1) IV) and ketamine (2.5 mg kg(-1) IV) and maintained with either isoflurane (Fe'Iso = 1.1%) (T-ISO) or an IV combination of romifidine (120 μg kg(-1) per hour), midazolam (0.09 mg kg(-1) hour(-1)) and ketamine (3.3 mg kg(-1) hour(-1)) (T-TIVA), while breathing 60% oxygen (FIO(2)). The circumference changes of the rib cage (RC) and abdominal compartment (ABD) were recorded using respiratory ultrasonic plethysmography (RUP). Balloon tipped catheters were placed in the distal oesophagus and the stomach and maximal transdiaphragmatic pressure (Pdi max) was calculated during Mueller's manoeuvre. The breathing pattern T-ISO was more regular and respiratory rate significantly lower compared with T-TIVA. Ponies in T-TIVA showed regularly appearing sighs, which were never observed in T-ISO. Different contribution of the RC and ABD compartments to the breathing pattern was observed with a smaller participation of the RC to the total volume change during T-ISO. Transdiaphragmatic pressures (mean 13.7 ± SD 8.61 versus 23.4 ± 7.27 cmH(2) O, p < 0.0001) were lower in T-TIVA compared to T-ISO [corrected]. The sum of the RC and ABD circumferential changes was lower during T-TIVA compared to T-ISO (6.32 ± 4.42 versus 11.72 ± 4.38 units, p < 0.0001). Marked differences in breathing pattern and transdiaphragmatic pressure exist during inhalation- and TIVA and these should be taken into account for clinical estimation of anaesthetic depth. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Differential Effects of Ethanol and Midazolam upon the Devaluation of an Aversive Memory in Infant Rats

PubMed Central

Pautassi, Ricardo Marcos; Nizhnikov, Michael; Molina, Juan Carlos; Boehm, Stephen L.; Spear, Norman

2007-01-01

In infant rats, low doses of ethanol have been found to attenuate the aversive representation of an unconditioned stimulus (US) as assessed through a revaluation paradigm. This may be explained by early anxiolytic properties of EtOH. The present set of experiments was aimed at analyzing possible mechanisms of these putative anti-anxiety effects of EtOH. In a the first experiment, EtOH's effects upon the expression of citric acid-induced distress calls were compared with varying doses of midazolam (MDZ), a fast-acting GABAA agonist. Similar calming effects of 0.5 g/kg EtOH and 0.09 mg/kg MDZ were observed. Both drugs were then assessed in their capability to alter the expression of a conditioned aversion by devaluing the US. Aversive conditioning was conducted on postnatal day 14 (PD14) by pairing a lemon odor (conditioned stimulus, CS) with intraoral stimulation of citric acid (US). Control animals experienced both stimuli in an explicitly unrelated fashion. On PD 15 pups were briefly exposed to the citric acid solution under the effects of 0.5 g/kg EtOH, 0.09 mg/kg MDZ, or the respective vehicle for each drug. Pups were then tested in a two-way odor preference test (lemon vs. cineole). Both vehicle and MDZ-treated animals spent significantly less time near the lemon CS, thus expressing a citric-acid mediated odor aversion. This conditioned response was completely inhibited in pups that received 0.5 g/kg EtOH. Locomotor patterns at test were not affected by either EtOH or MDZ administration. A higher dose of MDZ (0.18 mg/kg, i.p) was also ineffective in attenuating the aversive memory. In summary, EtOH's devaluating capabilities are not shared by MDZ, indicating that these effects of EtOH may not be GABA-mediated. Appetitive motivational properties of EtOH or non-GABAA-mediated anti-anxiety effects (i.e, NMDA-related) could underlie this devaluation effect of ethanol. PMID:17936511

The anesthetic effects on vasopressor modulation of cerebral blood flow in an immature swine model.

PubMed

Bruins, Benjamin; Kilbaugh, Todd J; Margulies, Susan S; Friess, Stuart H

2013-04-01

The effect of various sedatives and anesthetics on vasopressor modulation of cerebral blood flow (CBF) in children is unclear. In adults, isoflurane has been described to decrease CBF to a lesser extent than fentanyl and midazolam. Most large-animal models of neurocritical care use inhaled anesthetics for anesthesia. Investigations involving modulations of CBF would have improved translatability within a model that more closely approximates the current practice in the pediatric intensive care unit. Fifteen 4-week-old piglets were given 1 of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/h and fentanyl 100 μg/kg/h, n = 8) or ISO (isoflurane 1.5%-2% and fentanyl 100 μg/kg/h, n = 7). Mean arterial blood pressure, intracranial pressure (ICP), CBF, and brain tissue oxygen tension were measured continuously as piglets were exposed to escalating doses of arginine vasopressin, norepinephrine (NE), and phenylephrine (PE). Baseline CBF was similar in the 2 groups (ISO 38 ± 10 vs TIVA 35 ± 26 mL/100 g/min) despite lower baseline cerebral perfusion pressure in the ISO group (45 ± 11 vs 71 ± 11 mm Hg; P < 0.0005). Piglets in the ISO group displayed increases in ICP with PE and NE (11 ± 4 vs 16 ± 4 mm Hg and 11 ± 8 vs 18 ± 5 mm Hg; P < 0.05), but in the TIVA group, only exposure to PE resulted in increases in ICP when comparing maximal dose values with baseline data (11 ± 4 vs 15 ± 5 mm Hg; P < 0.05). Normalized CBF displayed statistically significant increases regarding anesthetic group and vasopressor dose when piglets were exposed to NE and PE (P < 0.05), suggesting an impairment of autoregulation within ISO, but not TIVA. The vasopressor effect on CBF was limited when using a narcotic-benzodiazepine-based anesthetic protocol compared with volatile anesthetics, consistent with a preservation of autoregulation. Selection of anesthetic drugs is critical to investigate mechanisms of cerebrovascular hemodynamics, and in translating critical care investigations between the laboratory and bedside.

Clinically important drug interactions with zopiclone, zolpidem and zaleplon.

PubMed

Hesse, Leah M; von Moltke, Lisa L; Greenblatt, David J

2003-01-01

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.

Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol alone or a sedation protocol and daily interruption.

PubMed

Mehta, Sangeeta; Meade, Maureen; Burry, Lisa; Mallick, Ranjeeta; Katsios, Christina; Fergusson, Dean; Dodek, Peter; Burns, Karen; Herridge, Margaret; Devlin, John W; Tanios, Maged; Fowler, Robert; Jacka, Michael; Skrobik, Yoanna; Olafson, Kendiss; Cook, Deborah

2016-08-01

Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation. This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation. Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356 mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, and was at target (3.2 vs 3.3, 95 % CI -0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the night and day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were more unintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases in nighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and the decision not to extubate the patient despite successful SBT. Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses were associated with SBT failure and delayed extubation. ClinicalTrials.gov NCT00675363 . Registered 7 May 2008.

A Retrospective Observational Study of Anesthetic Induction Dosing Practices in Female Elderly Surgical Patients: Are We Overdosing Older Patients?

PubMed

Akhtar, Shamsuddin; Heng, Joseph; Dai, Feng; Schonberger, Robert B; Burg, Mathew M

2016-10-01

Despite guidelines suggesting a 25-50 % reduction in induction doses of intravenous anesthetic agents in the elderly (≥65 years), we hypothesized that practitioners were not sufficiently correcting drug administration for age, contributing to an increased incidence of hypotension in older patients undergoing general anesthesia. We conducted a retrospective, observational study in a tertiary-care academic hospital. The study included 768 female patients undergoing gynecologic surgeries who received propofol-based induction of general anesthesia. Weight-adjusted anesthetic induction dosing, age-associated differences in dosing by ASA-PS (American Society of Anesthesiology-Physical Status), and hemodynamic outcomes between younger (18-64 years, n = 537) and older (≥65 years, n = 231) female patients were analyzed. Older patients received lower doses of propofol and midazolam than younger patients (propofol: 2.037 ± 0.783 vs 2.322 ± 0.834 mg/kg, p < 0.001; midazolam: 0.013 ± 0.014 vs 0.023 ± 0.042 mg/kg, p < 0.001). However, practitioners still consistently exceeded the FDA recommended dose (1-1.5 mg/kg) of propofol for elderly patients. There was no significant difference in the doses of fentanyl administered between the two age groups (1.343 ± 0.744 vs 1.363 ± 0.763 μg/kg, p = 0.744), and doses of fentanyl in older patients exceeded the recommended dose (0.5-1.0 μg/kg). Corresponding to observed overdosing of induction agents, older patients experienced larger decreases in post-induction blood pressure and were more likely to receive vasopressor therapy. Anesthetic induction doses of fentanyl and propofol were not sufficiently corrected in older patients in accordance with recommendations. Significantly greater frequency of post-induction hypotension occurred amongst older patients. Quality improvement efforts may lead to improved outcomes in this vulnerable population.

Does intravenous induction dosing among patients undergoing gastrointestinal surgical procedures follow current recommendations: a study of contemporary practice.

PubMed

Akhtar, Shamsuddin; Liu, Jia; Heng, Joseph; Dai, Feng; Schonberger, Robert B; Burg, Matthew M

2016-09-01

It is recommended to correct intravenous induction doses by up to 50% for patients older than 65 years. The objectives were to determine (a) the degree to which anesthesia providers correct induction doses for age and (b) additionally adjust for American Society of Anesthesiologists physical status (ASA-PS) class (severity of illness) and (c) whether postinduction hypotension is more common among patients aged >65. Retrospective chart review. Academic medical center. A total of 1869 adult patients receiving general anesthesia for GI surgical procedures from February 2013 to January 2014. Patients were divided into 3 age groups (age <65, 65-79, ≥80 years) and then further stratified into ASA-PS class (I/II vs III/IV). Multiple pairwise comparisons were conducted using Welch t tests for continuous variables to determine whether dosing was different for the older groups vs the younger group; separate analyses were performed within and across ASA-PS class. This approach was also used to determine differences in mean arterial pressure change in the older groups vs the younger group, whereas the rates of hypotension among different age groups were compared by Cochran-Armitage trend test. No significant decrease in dosing between age groups was observed for fentanyl and midazolam. For propofol, there was a significantly lower dosing for older patients: 17% for patients aged 65-79 and 29% for those aged >80, which was still in less than the recommendations. An inverse relationship was observed between propofol dosing and ASA-PS class, but no consistent relationship was noted for fentanyl and midazolam. There were a significantly larger drop in mean arterial pressure and a greater likelihood of hypotension following induction in patients aged 65-79 years and >80 years as compared with those aged <65 years. This study shows that the administered dose of anesthetic induction agents is significantly higher than that recommended for patients older than 65 years. This failure to age-adjust dose may contribute to hypotensive episodes. Copyright © 2016 Elsevier Inc. All rights reserved.

The Impact of the Hepatocyte-to-Plasma pH Gradient on the Prediction of Hepatic Clearance and Drug-Drug Interactions for CYP2C9 and CYP3A4 Substrates.

PubMed

Rougée, Luc R A; Mohutsky, Michael A; Bedwell, David W; Ruterbories, Kenneth J; Hall, Stephen D

2017-09-01

Surrogate assays for drug metabolism and inhibition are traditionally performed in buffer systems at pH 7.4, despite evidence that hepatocyte intracellular pH is 7.0. This pH gradient can result in a pK a -dependent change in intracellular/extracellular concentrations for ionizable drugs that could affect predictions of clearance and P450 inhibition. The effect of microsomal incubation pH on in vitro enzyme kinetic parameters for CYP2C9 (diclofenac, (S)-warfarin) and CYP3A4 (midazolam, dextromethorphan, testosterone) substrates, enzyme specific reversible inhibitors (amiodarone, desethylamiodarone, clozapine, nicardipine, fluconazole, fluvoxamine, itraconazole) and a mechanism-based inhibitor (amiodarone) was investigated. Intrinsic clearance through CYP2C9 significantly increased (25% and 50% for diclofenac and (S)-warfarin respectively) at intracellular pH 7.0 compared with traditional pH 7.4. The CYP3A4 substrate dextromethorphan intrinsic clearance was decreased by 320% at pH 7.0, while midazolam and testosterone remained unchanged. Reversible inhibition of CYP2C9 was less potent at pH 7.0 compared with 7.4, while CYP3A4 inhibition potency was variably affected. Maximum enzyme inactivation rate of amiodarone toward CYP2C9 and CYP3A4 decreased at pH 7.0, while the irreversible inhibition constant remained unchanged for CYP2C9, but decreased for CYP3A4 at pH 7.0. Predictions of clearance and drug-drug interactions made through physiologically based pharmacokinetic models were improved with the inclusion of predicted intracellular concentrations based at pH 7.0 and in vitro parameters determined at pH 7.0. No general conclusion on the impact of pH could be made and therefore a recommendation to change buffer pH to 7.0 cannot be made at this time. It is recommended that the appropriate hepatocyte intracellular pH 7.0 be used for in vitro determinations when in vivo predictions are made. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Sleep, performance, and plasma levels in chronic insomniacs during 14-day use of flurazepam and midazolam: an introduction.

PubMed

Johnson, L C; Chernik, D A; Sateia, M J

1990-08-01

A review of the published literature reveals many unanswered questions regarding the effects of sedative-hypnotics on sleep, performance, and mood. The relationship between plasma half-life and hypnotic efficacy is also not clear. A randomized, double-blind, parallel-groups, multicenter study was designed to examine sleep, performance, and mood in patients with insomnia. A large, heterogeneous sample of patients with a history of benzodiazepine use for chronic insomnia was chosen to reflect the adult population for which sedative-hypnotics are often prescribed and to ensure statistical reliability. Although the major focus of the current study was on the effects of two benzodiazepine hypnotics on performance, this study also provided information on the following important issues: (1) effect of dose level; (2) short-versus long-term administration; and (3) significance of plasma half-life as it relates to hypnotic efficacy.

Continuous subcutaneous infusion of lidocaine for persistent hiccup in advanced cancer.

PubMed

Kaneishi, Keisuke; Kawabata, Masahiro

2013-03-01

Persistent hiccup can cause anorexia, weight loss, disabling sleep deprivation, anxiety, and depression. Therefore, relief of persistent hiccup is important for advanced cancer patients and their family. Most reports on this condition are case series reports advocating the use of baclofen, haloperidol, gabapentin, and midazolam. However, these medications are occasionally ineffective or accompanied by intolerable side effects. The sodium channel blocker lidocaine has been shown to be effective in treating a variety of disorders thought to involve neuropathic mechanisms. Intravenous administration of lidocaine is common but efficacy has also been reported for subcutaneous infusion. In advanced cancer patients, subcutaneous infusion is easy, advantageous, and accompanied by less discomfort. We report a case of severe and sustained hiccup caused by gastric cancer that was successfully treated with a continuous subcutaneous infusion of lidocaine (480 mg (24 ml)/day) without severe side effects.

[General anesthesia for a patient with pulmonary hypertension, bronchial asthma and obesity].

PubMed

Nakamura, Shinji; Nishiyama, Tomoki; Hanaoka, Kazuo

2005-10-01

The management of the patient with pulmonary hypertension is a challenge for the anesthesiologists because the risk of right-sided heart failure is markedly increased. We experienced a case of general anesthesia for a patient with pulmonary hypertension (mean pulmonary arterial pressure 39 mmHg), bronchial asthma and obesity. A 31-year-old woman was scheduled for arytenoid rotation for left recurrent nerve palsy. We applied routine monitors (noninvasive blood-pressure, five-lead electrocardiogram, pulse oximeter), and direct blood pressure monitoring through the radial artery. Anesthesia was induced with midazolam 4 mg, fentanyl 100 microg and sevoflurane 5%, and maintained with sevoflurane (1-2%) and nitrous oxide in oxygen. Surgery was completed in 100 minutes without any complications. We could successfully perform general anesthesia in a patient complicated by pulmonary hypertension, bronchial asthma and obesity, without invasive right-sided heart catheterization.

[Strychnine poisoning: uncommon, but does still happen].

PubMed

van Berlo-van de Laar, Inge R F; Arbouw, Maurits E L; Bles, Carmen M A

2015-01-01

Acute strychnine poisoning is an uncommon form of intoxication, characterized by severe tonic clonic seizures and tetanus-like contractions while the patient is fully conscious. It can result in respiratory failure, leading to death. A 47-year-old man was admitted to the casualty department 2 hours after self-poisoning with strychnine. The clinical picture consisted of persistent seizures, which were treated with midazolam and propofol. The patient went into respiratory failure and asystole, so intubation and cardiac massage were initiated. Other complications were severe metabolic acidosis, hyperthermia and rhabdomyolysis with renal failure. The treatment consisted of cooling, hyperhydration and intravenous administration of sodium bicarbonate. He was discharged to a mental care institution with no persistent symptoms 11 days later. Early aggressive treatment of a strychnine intoxication can be life-saving. Knowledge of the clinical picture and the right treatment is important. Treatment is primarily focussed on stopping the convulsions and securing the airway.

Investigation of an alternative generic model for predicting pharmacokinetic changes during physiological stress.

PubMed

Peng, Henry T; Edginton, Andrea N; Cheung, Bob

2013-10-01

Physiologically based pharmacokinetic models were developed using MATLAB Simulink® and PK-Sim®. We compared the capability and usefulness of these two models by simulating pharmacokinetic changes of midazolam under exercise and heat stress to verify the usefulness of MATLAB Simulink® as a generic PBPK modeling software. Although both models show good agreement with experimental data obtained under resting condition, their predictions of pharmacokinetics changes are less accurate in the stressful conditions. However, MATLAB Simulink® may be more flexible to include physiologically based processes such as oral absorption and simulate various stress parameters such as stress intensity, duration and timing of drug administration to improve model performance. Further work will be conducted to modify algorithms in our generic model developed using MATLAB Simulink® and to investigate pharmacokinetics under other physiological stress such as trauma. © The Author(s) 2013.

Myristicin and phenytoin toxicity in an infant

PubMed Central

Sivathanu, Shobhana; Sampath, Sowmya; David, Henry Suresh; Rajavelu, Kulandai Kasthuri

2014-01-01

A developmentally normal infant presented with repeated episodes of afebrile status epilepticus following nutmeg ingestion. He had developed two episodes of afebrile status epilepticus and had received different treatments earlier, but the details of treatment were not available. On admission, he redeveloped convulsions and loading doses of phenytoin, phenobarbitone and midazolam were administered. However, seizures persisted and extrapyramidal movements, nystagmus and visual dysfunction were noted. Iatrogenic phenytoin toxicity was considered and confirmed by drug levels. His symptoms completely disappeared after discontinuation of phenytoin therapy. The initial seizures were attributed to myristicin, an active component of nutmeg, because of the temporal association. However, the subsequent seizures were due to phenytoin toxicity caused by administration of multiple loading doses. This case highlights that nutmeg, a spice, can cause serious toxic effects like status epilepticus. Furthermore, treatment of status epilepticus with phenytoin can cause iatrogenic seizures due to its narrow therapeutic range. PMID:24903724

Atipamezole in the management of detomidine overdose in a pony.

PubMed

Di Concetto, Stefano; Michael Archer, R; Sigurdsson, Sigurdur F; Clarke, Kw

2007-01-01

A pony undergoing elective castration accidentally received an overdose of IV detomidine (200 microg kg(-1)) before anaesthesia was induced with ketamine and midazolam. A further 100 microg kg(-1) IV dose of detomidine was administered during anaesthesia. The mistake was recognized only when the animal failed to recover from anaesthesia in the expected time. The overdose (300 microg kg(-1) in total) was treated successfully with atipamezole, initially given IV and subsequently IM and titrated to effect to a total dose of 1100 microg kg(-1). The pony regained the standing position. A further injection of atipamezole (76 microg kg(-1) IM) was given 5 hours later to counteract slight signs of re-sedation. Atipamezole proved an effective antagonist for detomidine in a pony at an initial dose 3.65 x and a final total dose 3.9 x greater than the alpha2 agonist.

[Continuous subcutaneous infusion in palliative care, an undervalued method].

PubMed

van Marum, R J; de Vogel, E M; Zylicz, Z

2002-11-23

Three patients, 2 men aged 55 and 54 years and a woman aged 86 years, were admitted to hospital for treatment of symptoms resulting from terminal disease (pain, agitation, nausea etc.). In all three patients, continuous subcutaneous infusion (CSI) of medication was successfully used to control the symptoms. Compared with intravenous infusion, the technique of CSI is easy to learn and is associated with fewer complications. Its reliability and ease-of-use make it a technique that can be used not only in a hospital setting, but also in general practice and nursing homes. Medication used in palliative care (e.g. morphine, haloperidol, metoclopramide, levomepromazine, midazolam) can often be administered safely by CSI. In palliative care, where goals should be accomplished with minimal burden to the patient, CSI must be considered the technique of choice in patients who are unable to swallow their medication.

Investigation of the anxiolytic effects of linalool, a lavender extract, in the male Sprague-Dawley rat.

PubMed

Cline, Michael; Taylor, John E; Flores, Jesus; Bracken, Samuel; McCall, Suzanne; Ceremuga, Thomas E

2008-02-01

The purpose of our study was to investigate the anxiolytic effects of linalool and its potential interaction with the GABAA receptor in Sprague-Dawley rats. Lavender has been used traditionally as an herbal remedy in the treatment of many medical conditions, including anxiety. Linalool is a major component of the essential oil of lavender. Forty-four rats were divided into 4 groups: control, linalool, midazolam (positive control), and flumazenil and linalool. The behavioral and the neurohormonal/physiological components of anxiety were evaluated. The behavioral component was examined by using the elevated plus maze (open arm time/total time) and the neurohormonal/physiological component by measuring serum catecholamine and corticosterone levels. Data analysis was performed using a 2-tailed Multivariate Analysis of Variance and Sheffe post-hoc test. Our data suggest that linalool does not produce anxiolysis by modulation of the GABAA receptor; however, linalool may modulate motor movements and locomotion.

Effects of anesthetic agents on in vivo axonal HCN current in normal mice.

PubMed

Osaki, Yusuke; Nodera, Hiroyuki; Banzrai, Chimeglkham; Endo, Sachiko; Takayasu, Hirokazu; Mori, Atsuko; Shimatani, Yoshimitsu; Kaji, Ryuji

2015-10-01

The objective was to study the in vivo effects of anesthetic agents on peripheral nerve excitability. Normal male mice were anesthetized by either isoflurane inhalation or a combination of medetomidine, midazolam, and butorphanol intraperitoneal injection ("triple agents"). Immediately after induction, the tail sensory nerve action potential was recorded and its excitability was monitored. Under both anesthetic protocols, there was an interval excitability change by long hyperpolarizing currents. There was greater threshold reduction approximately 30min post induction, in comparison to immediately post induction. Other excitability parameters were stable over time. Modeling suggested interval suppression of internodal H conductance or leak current. Anesthetic agents affected responses to long hyperpolarizing currents. Axonal excitability during intraoperative monitoring may be affected by anesthetic agents. Interpretation of interval excitability changes under anesthesia requires caution, especially with long hyperpolarizing currents. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Rabies in the critical care unit: diagnostic and therapeutic approaches.

PubMed

Jackson, Alan C

2011-09-01

Worldwide, human rabies is prevalent where there is endemic dog rabies, but the disease may present unexpectedly in critical care units when suggestive clinical features have passed. In North America transmission from bats is most common and there is often no history of a bat bite or even contact with bats. Laboratory diagnostic evaluation for rabies includes serology plus skin biopsy, cerebrospinal fluid, and saliva specimens for rabies virus antigen and/or RNA detection. Rare patients have survived rabies, and most received rabies vaccine prior to the onset of illness. Therapeutic coma (midazolam and phenobarbital), ketamine, and antiviral therapies (dubbed the "Milwaukee Protocol") were given to a rabies survivor, but this therapy was likely not directly responsible for the favorable outcome. There have been many subsequent failures of similar therapeutic approaches. There is no scientific rationale for the use of therapeutic coma in human rabies. New approaches to treating human rabies need to be developed.

[Bronchoscopy in ventilated patients: full narcosis or local anesthesia?].

PubMed

Konrad, F; Wiedeck, H; Winter, H; Kilian, J

1990-04-01

In a prospective, randomised trial bronchoscopy was performed either in local anaesthesia (LA) or general anaesthesia, each on 15 ventilated patients. LA was carried out with oxybuprocain-hydrochloride 1% in repeated doses injected into the trachea and main bronchi, general anaesthesia with midazolam, piritramide and vecuronium bromide. Measurements were performed before, 3 minutes after induction of anaesthesia, immediately after bronchoscopy and 15 and 60 minutes after bronchoscopy. There was no effect on cardiocirculatory function during bronchoscopy in both groups, but we found a decrease in paO2 from 97 to 80 mmHg (median) after application of LA. Subsequent bronchoscopy did not significantly influence paO2. The present study shows that in ventilation patients undergoing fibreoptic bronchoscopy, the application of LA will usually result in a decline of arterial oxygen tension. This procedure should therefore only be performed if general anaesthesia is undesirable, as e.g. in patients being weaned from ventilation.

In vitro inhibition of cytochrome P450 3A4 by Aronia melanocarpa constituents.

PubMed

Bräunlich, Marie; Christensen, Hege; Johannesen, Siri; Slimestad, Rune; Wangensteen, Helle; Malterud, Karl E; Barsett, Hilde

2013-01-01

Extracts, subfractions, isolated anthocyanins and procyanidins, and two phenolic acids from aronia [Aronia melanocarpa] were investigated for their CYP3A4 inhibitory effects, using midazolam as the probe substrate and recombinant insect cell microsomes expressing CYP3A4 as the enzyme source. Procyanidin B5 was a considerably stronger CYP3A4 inhibitor in vitro than the isomeric procyanidin B2 and comparable to bergamottin, a known CYP3A4 inhibitor from grapefruit juice. The inhibitory activity of proanthocyanidin-containing fractions was correlated to the degree of polymerization. Among the anthocyanins, cyanidin 3-arabinoside showed stronger CYP3A4 inhibition than cyanidin 3-galactoside and cyanidin 3-glucoside. Thus, the ability to inhibit CYP3A4 in vitro seems to be influenced by the sugar unit linked to the anthocyanidin. Georg Thieme Verlag KG Stuttgart · New York.

Incidence and factors related to delirium in an intensive care unit.

PubMed

Mori, Satomi; Takeda, Juliana Rumy Tsuchihashi; Carrara, Fernanda Souza Angotti; Cohrs, Cibelli Rizzo; Zanei, Suely Sueko Viski; Whitaker, Iveth Yamaguchi

2016-01-01

To identify the incidence of delirium, compare the demographic and clinical characteristics of patients with and without delirium, and verify factors related to delirium in critical care patients. Prospective cohort with a sample made up of patients hospitalized in the Intensive Care Unit (ICU) of a university hospital. Demographic, clinical variables and evaluation with the Confusion Assessment Method for Intensive Care Unit to identify delirium were processed to the univariate analysis and logistic regression to identify factors related to the occurrence of delirium. Of the total 149 patients in the sample, 69 (46.3%) presented delirium during ICU stay, whose mean age, severity of illness and length of ICU stay were statistically higher. The factors related to delirium were: age, midazolam, morphine and propofol. Results showed high incidence of ICU delirium associated with older age, use of sedatives and analgesics, emphasizing the need for relevant nursing care to prevent and identify early, patients presenting these characteristics. Identificar a incidência de delirium, comparar as características demográficas e clínicas dos pacientes com e sem delirium e verificar os fatores relacionados ao delirium em pacientes internados em Unidade de Terapia Intensiva (UTI). Coorte prospectiva, cuja amostra foi constituída de pacientes internados em UTI de um hospital universitário. Variáveis demográficas, clínicas e da avaliação com o Confusion Assessment Method for Intensive Care Unit para identificação de delirium foram processadas para análise univariada, e regressão logística para identificar fatores relacionados à ocorrência do delirium. Do total de 149 pacientes da amostra, 69 (46,3%) apresentaram delirium durante a internação na UTI, observando-se que a média da idade, o índice de gravidade e o tempo de permanência nas UTI foram estatisticamente maiores. Os fatores relacionados ao delirium foram: idade, midazolam, morfina e propofol. Os resultados mostraram elevada incidência de delirium na UTI e sua ocorrência associada às idades mais avançadas e o uso de sedativos e analgésicos, ressaltando-se a importância da atuação do enfermeiro na prevenção e identificação precoce do quadro nos pacientes com essas características.

Treatment of Convulsive Status Epilepticus.

PubMed

Grover, Eric H; Nazzal, Yara; Hirsch, Lawrence J

2016-03-01

Convulsive status epilepticus (CSE) is a medical emergency with an associated high mortality and morbidity. It is defined as a convulsive seizure lasting more than 5 min or consecutive seizures without recovery of consciousness. Successful management of CSE depends on rapid administration of adequate doses of anti-epileptic drugs (AEDs). The exact choice of AED is less important than rapid treatment and early consideration of reversible etiologies. Current guidelines recommend the use of benzodiazepines (BNZ) as first-line treatment in CSE. Midazolam is effective and safe in the pre-hospital or home setting when administered intramuscularly (best evidence), buccally, or nasally (the latter two possibly faster acting than intramuscular (IM) but with lower levels of evidence). Regular use of home rescue medications such as nasal/buccal midazolam by patients and caregivers for prolonged seizures and seizure clusters may prevent SE, prevent emergency room visits, improve quality of life, and lower health care costs. Traditionally, phenytoin is the preferred second-line agent in treating CSE, but it is limited by hypotension, potential arrhythmias, allergies, drug interactions, and problems from extravasation. Intravenous valproate is an effective and safe alternative to phenytoin. Valproate is loaded intravenously rapidly and more safely than phenytoin, has broad-spectrum efficacy, and fewer acute side effects. Levetiracetam and lacosamide are well tolerated intravenous (IV) AEDs with fewer interactions, allergies, and contraindications, making them potentially attractive as second- or third-line agents in treating CSE. However, data are limited on their efficacy in CSE. Ketamine is probably effective in treating refractory CSE (RCSE), and may warrant earlier use; this requires further study. CSE should be treated aggressively and quickly, with confirmation of treatment success with epileptiform electroencephalographic (EEG), as a transition to non-convulsive status epilepticus is common. If the patient is not fully awake, EEG should be continued for at least 24 h. How aggressively to treat refractory non-convulsive SE (NCSE) or intermittent non-convulsive seizures is less clear and requires additional study. Refractory SE (RSE) usually requires anesthetic doses of anti-seizure medications. If an auto-immune or paraneoplastic etiology is suspected or no etiology can be identified (as with cryptogenic new onset refractory status epilepticus, known as NORSE), early treatment with immuno-modulatory agents is now recommended by many experts.

Stability of 21 Cocaine, Opioid and Benzodiazepine Drug Analytes in Spiked Meconium at Three Temperatures.

PubMed

Wu, Fang; Marin, Stephanie J; McMillin, Gwendolyn A

2017-04-01

In this study, the stability of 21 cocaine, opioid and benzodiazepine analytes in spiked meconium was investigated at three storage temperatures: 4°C, room temperature (RT), and 37°C (body temperature). The drugs/metabolites included were hydrocodone, hydromorphone, codeine, morphine, 6-acetylmorphine (6-AM), oxycodone, oxymorphone, cocaine, cocaethylene, benzoylecgonine, m-hydroxybenzoylecgonine, diazepam, oxazepam, temazepam, nordiazepam, chlordiazepoxide, lorazepam, alprazolam, alpha-hydroxyalprazolam, clonazepam, 7-aminoclonazepam, midazolam, alpha-hydroxymidazolam and zolpidem. Drug testing was performed using mass spectrometry methods that were validated for clinical use. After 2 weeks of storage, a substantial loss was observed in the concentrations of 7-aminoclonazepam (48.4% at 4°C and 71.5% at RT), and chlordiazepoxide (59.5% at RT). A slight decrease was observed in the concentrations of alprazolam (20.9% at 4°C), clonazepam (24.5% at 4°C), chlordiazepoxide (23.5% at 4°C), midazolam (20.8% at 4°C), nordiazepam (22.8% at RT), and alpha-hydroxyalprazolam (20.7% at 4°C). At 37°C, the concentrations of chlordiazepoxide, 7-aminoclonazepam, lorazepam, oxazepam, nordiazepam and temazepam decreased by 81.4%, 86.8%, 56.5%, 59.9%, 45.4% and 31.7%, respectively, after 2 weeks. 6-AM was observed to be unstable regardless of storage temperatures. For morphine, a 33.3% increase at 4°C and a 23.4% increase at RT were observed after 2 weeks, respectively, possibly due to 6-AM degradation, while no changes ≥20% were observed at 37°C. All other analytes were stable up to 2 weeks at all three storage temperatures (concentration changes <20%). The stability of select drug analytes in authentic clinical meconium specimens was consistent with that observed in spiked meconium. In conclusion, some drugs in meconium may not be stable for long periods of time. Sample storage conditions are an important consideration in the context of detection windows and interpreting drug-testing results in meconium. To the best of our knowledge, this is the first stability study of cocaine, opioids and benzodiazepines in meconium concerning the effects of storage temperatures. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Intranasal midazolam during presurgical epilepsy monitoring is well tolerated, delays seizure recurrence, and protects from generalized tonic-clonic seizures.

PubMed

Kay, Lara; Reif, Philipp S; Belke, Marcus; Bauer, Sebastian; Fründ, Detlef; Knake, Susanne; Rosenow, Felix; Strzelczyk, Adam

2015-09-01

To evaluate the tolerability and efficacy of the ictal and immediate postictal application of intranasal midazolam (in-MDZ) in adolescents and adults during video-electroencephalography (EEG) monitoring. Medical records of all patients treated with in-MDZ between 2008 and 2014 were reviewed retrospectively. For each single patient, the time span until recurrence of seizures was analyzed after an index seizure with and without in-MDZ application. To prevent potential bias, we defined the first seizure with application of in-MDZ as the in-MDZ index seizure. The control index seizure was the preceding, alternatively the next successive seizure without application of in-MDZ. In total, 75 epilepsy patients (mean age 34 ± 14.7 years; 42 male, 33 female) were treated with in-MDZ (mean dose 5.1 mg). Adverse events were observed in four patients (5.3%), and no serious adverse events occurred. The median time after EEG seizure onset before administration of in-MDZ was 2.17 min (interquartile range [IQR] 03.82; range 0.13-15.0 min). Over the next 12 h after in-MDZ, the number of seizures was significantly lower (p = 0.031). The median seizure-free interval was significantly longer following treatment with in-MDZ (5.83 h; IQR 6.83, range 0.4-23.87) than it was for those with no in-MDZ treatment (2.37 h; IQR 4.87, range 0.03-21.87; p = 0.015). Conversely, the likelihood of the patient developing a subsequent seizure was four times higher (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.30-14.47) in the first hour and decreased gradually after 12 h (OR 1.5, 95% CI 1.06-2.12). The occurrence of generalized tonic-clonic seizures was lower in the in-MDZ group in the 24-h observation period (OR 4.67, 95% CI 1.41-15.45; p = 0.009). Ictal and immediate postictal administration of in-MDZ was well tolerated and not associated with serious adverse events. We demonstrated a significant reduction of subsequent seizures (all seizure types) for a 12 h period and of generalized tonic-clonic seizures for 24 h following in-MDZ. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

The Ontogeny of Cytochrome P450 Enzyme Activity and Protein Abundance in Conventional Pigs in Support of Preclinical Pediatric Drug Research.

PubMed

Millecam, Joske; De Clerck, Laura; Govaert, Elisabeth; Devreese, Mathias; Gasthuys, Elke; Schelstraete, Wim; Deforce, Dieter; De Bock, Lies; Van Bocxlaer, Jan; Sys, Stanislas; Croubels, Siska

2018-01-01

Since the implementation of several legislations to improve pediatric drug research, more pediatric clinical trials are being performed. In order to optimize these pediatric trials, adequate preclinical data are necessary, which are usually obtained by juvenile animal models. The growing piglet has been increasingly suggested as a potential animal model due to a high degree of anatomical and physiological similarities with humans. However, physiological data in pigs on the ontogeny of major organs involved in absorption, distribution, metabolism, and excretion of drugs are largely lacking. The aim of this study was to unravel the ontogeny of porcine hepatic drug metabolizing cytochrome P450 enzyme (CYP450) activities as well as protein abundances. Liver microsomes from 16 conventional pigs (8 males and 8 females) per age group: 2 days, 4 weeks, 8 weeks, and 6-7 months were prepared. Activity measurements were performed with substrates of major human CYP450 enzymes: midazolam (CYP3A), tolbutamide (CYP2C), and chlorzoxazone (CYP2E). Next, the hepatic scaling factor, microsomal protein per gram liver (MPPGL), was determined to correct for enzyme losses during the fractionation process. Finally, protein abundance was determined using proteomics and correlated with enzyme activity. No significant sex differences within each age category were observed in enzyme activity or MPPGL. The biotransformation rate of all three substrates increased with age, comparable with human maturation of CYP450 enzymes. The MPPGL decreased from birth till 8 weeks of age followed by an increase till 6-7 months of age. Significant sex differences in protein abundance were observed for CYP1A2, CYP2A19, CYP3A22, CYP4V2, CYP2C36, CYP2E_1, and CYP2E_2. Midazolam and tolbutamide are considered good substrates to evaluate porcine CYP3A/2C enzymes, respectively. However, chlorzoxazone is not advised to evaluate porcine CYP2E enzyme activity. The increase in biotransformation rate with age can be attributed to an increase in absolute amount of CYP450 proteins. Finally, developmental changes were observed regarding the involvement of specific CYP450 enzymes in the biotransformation of the different substrates.

Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR.

PubMed

de Vries, E M; Lammers, L A; Achterbergh, R; Klümpen, H-J; Mathot, R A A; Boelen, A; Romijn, J A

2016-01-01

Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR. To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR-/-) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65). Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR-/- mice. The decrease in Cyp1a2 was diminished in CAR-/- in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR-/- compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR-/- mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR-/-. The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole. We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR.

Transient bradycardia induced by thiopentone sodium: a unique challenge in the management of refractory status epilepticus

PubMed Central

Sharma, Sushma; Nair, Pradeep P; Murgai, Aditya; Selvaraj, Raja J

2013-01-01

Thiopentone sodium is one of the important drugs in the armamentarium for terminating refractory status epilepticus, a neurological emergency. We report a case of thiopentone-related bradycardia during the management of the new onset refractory status epilepticus in a young man, which was circumvented by prophylactic insertion of temporary pacemaker while thiopentone infusion was continued. A systematic approach was employed to manage the status epilepticus, including infusion of thiamine and glucose followed by antiepileptic drugs. The patient was ventilated and infused with lorazepam, phenytoin, sodium valproate, levetiracetam and midazolam followed by thiopentone sodium. With the introduction of thiopentone the seizures could be controlled but the patient developed severe bradycardia and junctional rhythm. The bradycardia disappeared when thiopentone was withdrawn and reappeared when the drug was reintroduced. Propofol infusion was tried with no respite in seizures. Later thiopentone sodium was reintroduced after inserting temporary cardiac pacemaker. Seizure was controlled and patient was weaned off the ventilator. PMID:24130206

Transient bradycardia induced by thiopentone sodium: a unique challenge in the management of refractory status epilepticus.

PubMed

Sharma, Sushma; Nair, Pradeep P; Murgai, Aditya; Selvaraj, Raja J

2013-10-15

Thiopentone sodium is one of the important drugs in the armamentarium for terminating refractory status epilepticus, a neurological emergency. We report a case of thiopentone-related bradycardia during the management of the new onset refractory status epilepticus in a young man, which was circumvented by prophylactic insertion of temporary pacemaker while thiopentone infusion was continued. A systematic approach was employed to manage the status epilepticus, including infusion of thiamine and glucose followed by antiepileptic drugs. The patient was ventilated and infused with lorazepam, phenytoin, sodium valproate, levetiracetam and midazolam followed by thiopentone sodium. With the introduction of thiopentone the seizures could be controlled but the patient developed severe bradycardia and junctional rhythm. The bradycardia disappeared when thiopentone was withdrawn and reappeared when the drug was reintroduced. Propofol infusion was tried with no respite in seizures. Later thiopentone sodium was reintroduced after inserting temporary cardiac pacemaker. Seizure was controlled and patient was weaned off the ventilator.

Anesthesia and perioperative management of a pneumonectomized dog.

PubMed

Anagnostou, Tilemahos L; Pavlidou, Kiriaki; Savvas, Ioannis; Kazakos, George M; Papazoglou, Lysimachos G; Ververidis, Haralabos N; Raptopoulos, Dimitris

2012-01-01

Although left- or right-sided pneumonectomy is tolerated by normal dogs, complications impacting the respiratory, cardiovascular, and gastrointestinal systems are not uncommon. Pneumonectomy in dogs results in secondary changes in the remaining lung, which include: decreased compliance and vital capacity; and increased pulmonary vascular resistance potentially leading to right ventricular hypertrophy. Such alterations make the anesthetic management of an animal with one lung particularly challenging. This report describes a dog with a history of left pneumonectomy due to Aspergillus fumigatus pneumonia 3 yr before presentation. The dog presented with a vaginal wall prolapse, and surgical resection of the protruding vaginal wall, ovariectomy, and prophylactic gastropexy were performed. Anesthesia was induced with midazolam, fentanyl, and propofol and was maintained with isoflurane using intermittent positive pressure ventilation and a constant rate infusion of fentanyl. Epidural anesthesia was also used. Recovery and postoperative management were uncomplicated. Intensive hemodynamic and respiratory monitoring and appropriate response and treatment of any detected abnormalities, taking into consideration the pathophysiologic alterations occurring in a pneumonectomized animal, are required for successful perianesthetic management.

Administration of drugs by infusion pumps in palliative medicine.

PubMed

Thorsen, A B; Yung, N S; Leung, A C

1994-03-01

A retrospective study was carried out in 100 adult patients with advanced malignant disease. They were given subcutaneous continuous infusions of medication for symptom relief. The drugs were administered through a butterfly needle inserted subcutaneously in the anterior chest wall using a battery-operated infusion pump. The indications for using this technique were inability to swallow due to deteriorating general condition, oesophageal obstruction, intestinal obstruction, severe nausea and vomiting, terminal dyspnoea and poor pain control with oral opiates. All patients received morphine; other drugs administered through the syringe driver included hyoscine, metoclopramide, cyclizine, dexamethasone and midazolam. Ninety-four patients continued subcutaneous infusion until death. The mean duration of treatment was 9.1 days. The treatment was well tolerated by the patients and controlled their symptoms satisfactorily in the great majority. The use of continuous subcutaneous infusion via a syringe driver gives good symptom control. In the last days of life when the patients have difficulty tolerating oral medication, continuous subcutaneous infusion is a superior alternative to frequent intermittent parenteral injections.