Neutrophil apoptosis: a marker of disease severity in sepsis and sepsis-induced acute respiratory distress syndrome

PubMed Central

Fialkow, Léa; Fochesatto Filho, Luciano; Bozzetti, Mary C; Milani, Adriana R; Rodrigues Filho, Edison M; Ladniuk, Roberta M; Pierozan, Paula; de Moura, Rafaela M; Prolla, João C; Vachon, Eric; Downey, Gregory P

2006-01-01

Introduction Apoptosis of neutrophils (polymorphonuclear neutrophils [PMNs]) may limit inflammatory injury in sepsis and acute respiratory distress syndrome (ARDS), but the relationship between the severity of sepsis and extent of PMN apoptosis and the effect of superimposed ARDS is unknown. The objective of this study was to correlate neutrophil apoptosis with the severity of sepsis and sepsis-induced ARDS. Methods A prospective cohort study was conducted in intensive care units of three tertiary hospitals in Porto Alegre, southern Brazil. Fifty-seven patients with sepsis (uncomplicated sepsis, septic shock, and sepsis-induced ARDS) and 64 controls were enrolled. Venous peripheral blood was collected from patients with sepsis within 24 hours of diagnosis. All surgical groups, including controls, had their blood drawn 24 hours after surgery. Control patients on mechanical ventilation had blood collected within 24 hours of initiation of mechanical ventilation. Healthy controls were blood donors. Neutrophils were isolated, and incubated ex vivo, and apoptosis was determined by light microscopy on cytospun preparations. The differences among groups were assessed by analysis of variance with Tukeys. Results In medical patients, the mean percentage of neutrophil apoptosis (± standard error of the mean [SEM]) was lower in sepsis-induced ARDS (28% ± 3.3%; n = 9) when compared with uncomplicated sepsis (57% ± 3.2%; n = 8; p < 0.001), mechanical ventilation without infection, sepsis, or ARDS (53% ± 3.0%; n = 11; p < 0.001) and healthy controls (69% ± 1.1%; n = 33; p < 0.001) but did not differ from septic shock (38% ± 3.7%; n = 12; p = 0.13). In surgical patients with sepsis, the percentage of neutrophil apoptosis was lower for all groups when compared with surgical controls (52% ± 3.6%; n = 11; p < 0.001). Conclusion In medical patients with sepsis, neutrophil apoptosis is inversely proportional to the severity of sepsis and thus may be a marker of the severity of

Early detection strategy and mortality reduction in severe sepsis.

PubMed

Westphal, Glauco Adrieno; Feijó, Janaína; Andrade, Patrícia Silva de; Trindade, Louise; Suchard, Cezar; Monteiro, Márcio Andrei Gil; Martins, Sheila Fonseca; Nunes, Fernanda; Caldeira Filho, Milton

2009-06-01

To evaluate the impact of implementing an institutional policy for detection of severe sepsis and septic shock. Study before (stage I), after (stage II) with prospective data collection in a 195 bed public hospital.. Stage I: Patients with severe sepsis or septic shock were included consecutively over 15 months and treated according to the Surviving Sepsis Campaign guidelines. Stage II: In the 10 subsequent months, patients with severe sepsis or septic shock were enrolled based on an active search for signs suggesting infection (SSI) in hospitalized patients. The two stages were compared for demographic variables, time needed for recognition of at least two signs suggesting infection (SSI-Δt), compliance to the bundles of 6 and 24 hours and mortality. We identified 124 patients with severe sepsis or septic shock, 68 in stage I and 56 in stage II. The demographic variables were similar in both stages. The Δt-SSI was 34 ± 54 hours in stage I and 7 ± 8.4 hours in stage II (p <0.001). There was no difference in compliance to the bundles. In parallel there was significant reduction of mortality rates at 28 days (54.4% versus 30%, p <0.02) and hospital (67.6% versus 41%, p <0.003). The strategy used helped to identify early risk of sepsis and resulted in decreased mortality associated with severe sepsis and septic shock.

Identifying Pediatric Severe Sepsis and Septic Shock: Accuracy of Diagnosis Codes.

PubMed

Balamuth, Fran; Weiss, Scott L; Hall, Matt; Neuman, Mark I; Scott, Halden; Brady, Patrick W; Paul, Raina; Farris, Reid W D; McClead, Richard; Centkowski, Sierra; Baumer-Mouradian, Shannon; Weiser, Jason; Hayes, Katie; Shah, Samir S; Alpern, Elizabeth R

2015-12-01

To evaluate accuracy of 2 established administrative methods of identifying children with sepsis using a medical record review reference standard. Multicenter retrospective study at 6 US children's hospitals. Subjects were children >60 days to <19 years of age and identified in 4 groups based on International Classification of Diseases, Ninth Revision, Clinical Modification codes: (1) severe sepsis/septic shock (sepsis codes); (2) infection plus organ dysfunction (combination codes); (3) subjects without codes for infection, organ dysfunction, or severe sepsis; and (4) infection but not severe sepsis or organ dysfunction. Combination codes were allowed, but not required within the sepsis codes group. We determined the presence of reference standard severe sepsis according to consensus criteria. Logistic regression was performed to determine whether addition of codes for sepsis therapies improved case identification. A total of 130 out of 432 subjects met reference SD of severe sepsis. Sepsis codes had sensitivity 73% (95% CI 70-86), specificity 92% (95% CI 87-95), and positive predictive value 79% (95% CI 70-86). Combination codes had sensitivity 15% (95% CI 9-22), specificity 71% (95% CI 65-76), and positive predictive value 18% (95% CI 11-27). Slight improvements in model characteristics were observed when codes for vasoactive medications and endotracheal intubation were added to sepsis codes (c-statistic 0.83 vs 0.87, P = .008). Sepsis specific International Classification of Diseases, Ninth Revision, Clinical Modification codes identify pediatric patients with severe sepsis in administrative data more accurately than a combination of codes for infection plus organ dysfunction. Copyright © 2015 Elsevier Inc. All rights reserved.

Decreased ADAMTS 13 Activity is Associated With Disease Severity and Outcome in Pediatric Severe Sepsis

PubMed Central

Lin, Jainn-Jim; Chan, Oi-Wa; Hsiao, Hsiang-Ju; Wang, Yu; Hsia, Shao-Hsuan; Chiu, Cheng-Hsun

2016-01-01

Abstract Decreased ADAMTS 13 activity has been reported in severe sepsis and in sepsis-induced disseminated intravascular coagulation. This study aimed to investigate the role of ADAMTS 13 in different pediatric sepsis syndromes and evaluate its relationship with disease severity and outcome. We prospectively collected cases of sepsis treated in a pediatric intensive care unit, between July 2012 and June 2014 in Chang Gung Children's Hospital in Taoyuan, Taiwan. Clinical characteristics and ADAMTS-13 activity were analyzed. All sepsis syndromes had decreased ADAMTS 13 activity on days 1 and 3 of admission compared to healthy controls. Patients with septic shock had significantly decreased ADAMTS 13 activity on days 1 and 3 compared to those with sepsis and severe sepsis. There was a significant negative correlation between ADAMTS 13 activity on day 1 and day 1 PRISM-II, PELOD, P-MOD, and DIC scores. Patients with mortality had significantly decreased ADAMTS 13 activity on day 1 than survivors, but not on day 3. Different pediatric sepsis syndromes have varying degrees of decreased ADAMTS 13 activity. ADAMTS 13 activity is strongly negatively correlated with disease severity of pediatric sepsis syndrome, whereas decreased ADAMTS 13 activity on day 1 is associated with increased risk of mortality. PMID:27100422

Decreased ADAMTS 13 Activity is Associated With Disease Severity and Outcome in Pediatric Severe Sepsis.

PubMed

Lin, Jainn-Jim; Chan, Oi-Wa; Hsiao, Hsiang-Ju; Wang, Yu; Hsia, Shao-Hsuan; Chiu, Cheng-Hsun

2016-04-01

Decreased ADAMTS 13 activity has been reported in severe sepsis and in sepsis-induced disseminated intravascular coagulation. This study aimed to investigate the role of ADAMTS 13 in different pediatric sepsis syndromes and evaluate its relationship with disease severity and outcome. We prospectively collected cases of sepsis treated in a pediatric intensive care unit, between July 2012 and June 2014 in Chang Gung Children's Hospital in Taoyuan, Taiwan. Clinical characteristics and ADAMTS-13 activity were analyzed. All sepsis syndromes had decreased ADAMTS 13 activity on days 1 and 3 of admission compared to healthy controls. Patients with septic shock had significantly decreased ADAMTS 13 activity on days 1 and 3 compared to those with sepsis and severe sepsis. There was a significant negative correlation between ADAMTS 13 activity on day 1 and day 1 PRISM-II, PELOD, P-MOD, and DIC scores. Patients with mortality had significantly decreased ADAMTS 13 activity on day 1 than survivors, but not on day 3. Different pediatric sepsis syndromes have varying degrees of decreased ADAMTS 13 activity. ADAMTS 13 activity is strongly negatively correlated with disease severity of pediatric sepsis syndrome, whereas decreased ADAMTS 13 activity on day 1 is associated with increased risk of mortality.

Augmented Passive Immunotherapy with P4 Peptide Improves Phagocyte Activity in Severe Sepsis.

PubMed

Morton, Ben; Mitsi, Elena; Pennington, Shaun H; Reiné, Jesús; Wright, Angela D; Parker, Robert; Welters, Ingeborg D; Blakey, John D; Rajam, Gowrisankar; Ades, Edwin W; Ferreira, Daniela M; Wang, Duolao; Kadioglu, Aras; Gordon, Stephen B

2016-12-01

Antimicrobial resistance threatens to undermine treatment of severe infection; new therapeutic strategies are urgently needed. Preclinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. Our aim was to determine ex vivo P4 activity in a target population of patients admitted to critical care with severe infection. We prospectively recruited UK critical care unit patients with severe sepsis and observed clinical course (≥3 months postdischarge). Blood samples were taken in early (≤48 h postdiagnosis, n = 54), latent (7 days postdiagnosis, n = 39), and convalescent (3-6 months postdiagnosis, n = 18) phases of disease. The primary outcome measure was killing of opsonized Streptococcus pneumoniae by neutrophils with and without P4 peptide stimulation. We also used a flow cytometric whole blood phagocytosis assay to determine phagocyte association and oxidation of intraphagosomal reporter beads. P4 peptide increased neutrophil killing of opsonized pneumococci by 8.6% (confidence interval 6.35-10.76, P < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared with unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source. We have extended preclinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis.

Immature platelet fraction in bacterial sepsis severity assessment

NASA Astrophysics Data System (ADS)

Djuang, M. H.; Ginting, F.; Hariman, H.

2018-03-01

Sepsis is an infection-induced syndrome, mostly caused by bacteria, of organ dysfunctions that caused by host response dysregulations. One of the simplest sepsis-indicator is platelet and its indexes. A new platelet parameter called immature platelet count (IPF) became theinterest in this study. The study aims to see whether IPF could assess sepsis severity by procalcitonin (PCT).Sixty-four of seventy-one patients with increased PCT were included in this cross-sectional study and separated into three groups based on their PCT levels. IPF showed no significance among the three groups (p-value>0.05) while platelet count was significant (p-value<0.05). Mean Platelet Volume (MPV) and Platelet Distribution Width (PDW) showed a strongpositive correlation with IPF. Higher sepsis severity based on PCT showed larger platelet count, as the result of platelet destructions caused by pro-inflammatory cytokines and endotoxins.

Identifying patients with severe sepsis using administrative claims: patient-level validation of the angus implementation of the international consensus conference definition of severe sepsis.

PubMed

Iwashyna, Theodore J; Odden, Andrew; Rohde, Jeffrey; Bonham, Catherine; Kuhn, Latoya; Malani, Preeti; Chen, Lena; Flanders, Scott

2014-06-01

Severe sepsis is a common and costly problem. Although consistently defined clinically by consensus conference since 1991, there have been several different implementations of the severe sepsis definition using ICD-9-CM codes for research. We conducted a single center, patient-level validation of 1 common implementation of the severe sepsis definition, the so-called "Angus" implementation. Administrative claims for all hospitalizations for patients initially admitted to general medical services from an academic medical center in 2009-2010 were reviewed. On the basis of ICD-9-CM codes, hospitalizations were sampled for review by 3 internal medicine-trained hospitalists. Chart reviews were conducted with a structured instrument, and the gold standard was the hospitalists' summary clinical judgment on whether the patient had severe sepsis. Three thousand one hundred forty-six (13.5%) hospitalizations met ICD-9-CM criteria for severe sepsis by the Angus implementation (Angus-positive) and 20,142 (86.5%) were Angus-negative. Chart reviews were performed for 92 randomly selected Angus-positive and 19 randomly-selected Angus-negative hospitalizations. Reviewers had a κ of 0.70. The Angus implementation's positive predictive value was 70.7% [95% confidence interval (CI): 51.2%, 90.5%]. The negative predictive value was 91.5% (95% CI: 79.0%, 100%). The sensitivity was 50.4% (95% CI: 14.8%, 85.7%). Specificity was 96.3% (95% CI: 92.4%, 100%). Two alternative ICD-9-CM implementations had high positive predictive values but sensitivities of <20%. The Angus implementation of the international consensus conference definition of severe sepsis offers a reasonable but imperfect approach to identifying patients with severe sepsis when compared with a gold standard of structured review of the medical chart by trained hospitalists.

Identifying Patients with Severe Sepsis Using Administrative Claims: Patient-Level Validation of the Angus Implementation of the International Consensus Conference Definition of Severe Sepsis

PubMed Central

Iwashyna, Theodore J.; Odden, Andrew; Rohde, Jeffrey; Bonham, Catherine; Kuhn, Latoya; Malani, Preeti; Chen, Lena; Flanders, Scott

2012-01-01

Background Severe sepsis is a common and costly problem. Although consistently defined clinically by consensus conference since 1991, there have been several different implementations of the severe sepsis definition using ICD-9-CM codes for research. We conducted a single center, patient-level validation of one common implementation of the severe sepsis definition, the so-called “Angus” implementation. Methods Administrative claims for all hospitalizations for patients initially admitted to general medical services from an academic medical center in 2009–2010 were reviewed. On the basis of ICD-9-CM codes, hospitalizations were sampled for review by three internal medicine-trained hospitalists. Chart reviews were conducted with a structured instrument, and the gold standard was the hospitalists’ summary clinical judgment on whether the patient had severe sepsis. Results 3,146 (13.5%) hospitalizations met ICD-9-CM criteria for severe sepsis by the Angus implementation (“Angus-positive”) and 20,142 (86.5%) were Angus-negative. Chart reviews were performed for 92 randomly-selected Angus-positive and 19 randomly-selected Angus-negative hospitalizations. Reviewers had a kappa of 0.70. The Angus implementation’s positive predictive value (PPV) was 70.7% (95%CI: 51.2%, 90.5%). The negative predictive value was 91.5% (95%CI: 79.0%, 100%). The sensitivity was 50.4% (95%CI: 14.8%, 85.7%). Specificity was 96.3% (95%CI: 92.4%, 100%). Two alternative ICD-9-CM implementations had high PPVs but sensitivities of less than 20%. Conclusions The Angus implementation of the international consensus conference definition of severe sepsis offers a reasonable but imperfect approach to identifying patients with severe sepsis when compared with a gold standard of structured review of the medical chart by trained hospitalists. PMID:23001437

Functional outcomes in pediatric severe sepsis: further analysis of the researching severe sepsis and organ dysfunction in children: a global perspective trial.

PubMed

Farris, Reid W D; Weiss, Noel S; Zimmerman, Jerry J

2013-11-01

To evaluate risk factors for poor functional outcome in 28-day survivors after an episode of severe sepsis. Retrospective cohort study examining data from the Researching Severe Sepsis and Organ Dysfunction in Children: A Global Perspective trial (NCT00049764). One hundred and four pediatric centers in 18 countries. Children with severe sepsis who required both vasoactive-inotropic infusions and mechanical ventilation and who survived to 28 days (n = 384). None. Poor functional outcome was defined as a Pediatric Overall Performance Category score greater than or equal to 3 and an increase from baseline when measured 28 days after trial enrollment. Median Pediatric Overall Performance Category at enrollment was 1 (interquartile range, 1-2). Median Pediatric Overall Performance Category at 28 days was 2 (interquartile range, 1-4). Thirty-four percent of survivors had decline in their functional status at 28 days, and 18% were determined to have a "poor" functional outcome. Hispanic ethnicity was associated with poor functional outcome compared to the white referent group (risk ratio = 1.9; 95% CI: 1.0-3.0). Clinical factors associated with increased risk of poor outcome included CNS and intra-abdominal infection sources compared to the lung infection referent category (risk ratio = 3.3; 95% CI: 1.4-5.6 and 2.4; 95% CI: 1.0-4.5, respectively); a history of recent trauma (risk ratio = 3.9; 95% CI: 1.4-5.4); receipt of cardiopulmonary resuscitation prior to enrollment (risk ratio = 5.1; 95% CI: 2.9-5.7); and baseline Pediatric Risk of Mortality III score of 20-29 (risk ratio = 2.8; 95% CI: 1.2-5.2) and Pediatric Risk of Mortality III greater than or equal to 30 (risk ratio = 4.5; 95% CI: 1.6-8.0) compared to the referent group with Pediatric Risk of Mortality III scores of 0-9. In this sample of 28-day survivors of pediatric severe sepsis diminished functional status was common. This analysis provides evidence that particular patient characteristics and aspects of an

Getting the invite list right: a discussion of sepsis severity scoring systems in severe complicated intra-abdominal sepsis and randomized trial inclusion criteria.

PubMed

Tolonen, Matti; Coccolini, Federico; Ansaloni, Luca; Sartelli, Massimo; Roberts, Derek J; McKee, Jessica L; Leppaniemi, Ari; Doig, Christopher J; Catena, Fausto; Fabian, Timothy; Jenne, Craig N; Chiara, Osvaldo; Kubes, Paul; Kluger, Yoram; Fraga, Gustavo P; Pereira, Bruno M; Diaz, Jose J; Sugrue, Michael; Moore, Ernest E; Ren, Jianan; Ball, Chad G; Coimbra, Raul; Dixon, Elijah; Biffl, Walter; MacLean, Anthony; McBeth, Paul B; Posadas-Calleja, Juan G; Di Saverio, Salomone; Xiao, Jimmy; Kirkpatrick, Andrew W

2018-01-01

Severe complicated intra-abdominal sepsis (SCIAS) is a worldwide challenge with increasing incidence. Open abdomen management with enhanced clearance of fluid and biomediators from the peritoneum is a potential therapy requiring prospective evaluation. Given the complexity of powering multi-center trials, it is essential to recruit an inception cohort sick enough to benefit from the intervention; otherwise, no effect of a potentially beneficial therapy may be apparent. An evaluation of abilities of recognized predictive systems to recognize SCIAS patients was conducted using an existing intra-abdominal sepsis (IAS) database. All consecutive adult patients with a diffuse secondary peritonitis between 2012 and 2013 were collected from a quaternary care hospital in Finland, excluding appendicitis/cholecystitis. From this retrospectively collected database, a target population (93) of those with either ICU admission or mortality were selected. The performance metrics of the Third Consensus Definitions for Sepsis and Septic Shock based on both SOFA and quick SOFA, the World Society of Emergency Surgery Sepsis Severity Score (WSESSSS), the APACHE II score, Manheim Peritonitis Index (MPI), and the Calgary Predisposition, Infection, Response, and Organ dysfunction (CPIRO) score were all tested for their discriminant ability to identify this subgroup with SCIAS and to predict mortality. Predictive systems with an area under-the-receiving-operating characteristic (AUC) curve > 0.8 included SOFA, Sepsis-3 definitions, APACHE II, WSESSSS, and CPIRO scores with the overall best for CPIRO. The highest identification rates were SOFA score ≥ 2 (78.4%), followed by the WSESSSS score ≥ 8 (73.1%), SOFA ≥ 3 (75.2%), and APACHE II ≥ 14 (68.8%) identification. Combining the Sepsis-3 septic-shock definition and WSESSS ≥ 8 increased detection to 80%. Including CPIRO score ≥ 3 increased this to 82.8% (Sensitivity-SN; 83% Specificity-SP; 74%. Comparatively, SOFA �

Severe sepsis in pre-hospital emergency care: analysis of incidence, care, and outcome.

PubMed

Seymour, Christopher W; Rea, Thomas D; Kahn, Jeremy M; Walkey, Allan J; Yealy, Donald M; Angus, Derek C

2012-12-15

Severe sepsis is common and highly morbid, yet the epidemiology of severe sepsis at the frontier of the health care system-pre-hospital emergency care-is unknown. We examined the epidemiology of pre-hospital severe sepsis among emergency medical services (EMS) encounters, relative to acute myocardial infarction and stroke. Retrospective study using a community-based cohort of all nonarrest, nontrauma King County EMS encounters from 2000 to 2009 who were transported to a hospital. Overall incidence rate of hospitalization with severe sepsis among EMS encounters, as well as pre-hospital characteristics, admission diagnosis, and outcomes. Among 407,176 EMS encounters, we identified 13,249 hospitalizations for severe sepsis, of whom 2,596 died in the hospital (19.6%). The crude incidence rate of severe sepsis was 3.3 per 100 EMS encounters, greater than for acute myocardial infarction or stroke (2.3 per 100 and 2.2 per 100 EMS encounters, respectively). More than 40% of all severe sepsis hospitalizations arrived at the emergency department after EMS transport, and 80% of cases were diagnosed on admission. Pre-hospital care intervals, on average, exceeded 45 minutes for those hospitalized with severe sepsis. One-half or fewer of patients with severe sepsis were transported by paramedics (n = 7,114; 54%) or received pre-hospital intravenous access (n = 4,842; 37%). EMS personnel care for a substantial and increasing number of patients with severe sepsis, and spend considerable time on scene and during transport. Given the emphasis on rapid diagnosis and intervention for sepsis, the pre-hospital interval may represent an important opportunity for recognition and care of sepsis.

Development and Validation of a Disease Severity Scoring Model for Pediatric Sepsis.

PubMed

Hu, Li; Zhu, Yimin; Chen, Mengshi; Li, Xun; Lu, Xiulan; Liang, Ying; Tan, Hongzhuan

2016-07-01

Multiple severity scoring systems have been devised and evaluated in adult sepsis, but a simplified scoring model for pediatric sepsis has not yet been developed. This study aimed to develop and validate a new scoring model to stratify the severity of pediatric sepsis, thus assisting the treatment of sepsis in children. Data from 634 consecutive patients who presented with sepsis at Children's hospital of Hunan province in China in 2011-2013 were analyzed, with 476 patients placed in training group and 158 patients in validation group. Stepwise discriminant analysis was used to develop the accurate discriminate model. A simplified scoring model was generated using weightings defined by the discriminate coefficients. The discriminant ability of the model was tested by receiver operating characteristic curves (ROC). The discriminant analysis showed that prothrombin time, D-dimer, total bilirubin, serum total protein, uric acid, PaO2/FiO2 ratio, myoglobin were associated with severity of sepsis. These seven variables were assigned with values of 4, 3, 3, 4, 3, 3, 3 respectively based on the standardized discriminant coefficients. Patients with higher scores had higher risk of severe sepsis. The areas under ROC (AROC) were 0.836 for accurate discriminate model, and 0.825 for simplified scoring model in validation group. The proposed disease severity scoring model for pediatric sepsis showed adequate discriminatory capacity and sufficient accuracy, which has important clinical significance in evaluating the severity of pediatric sepsis and predicting its progress.

Pre-Sepsis Depressive Symptoms Are Associated with Incident Cognitive Impairment in Survivors of Severe Sepsis: A Prospective Cohort Study of Older Americans

PubMed Central

Davydow, Dimitry S.; Hough, Catherine L.; Langa, Kenneth M.; Iwashyna, Theodore J.

2012-01-01

Objectives To test the hypothesis that pre-sepsis depressive symptoms are associated with an increased risk of new cognitive impairment in severe sepsis survivors. Design Prospective longitudinal cohort study. Setting Population-based cohort of older U.S. adults interviewed as part of the Health and Retirement Study (1998–2006). Participants 447 patients with normal pre-sepsis cognition who survived 540 hospitalizations for severe sepsis and completed at least one follow-up interview. Measurements Severe sepsis was identified using a validated algorithm in Medicare claims. Depressive symptoms were assessed prospectively with a modified version of the Center for Epidemiologic Studies Depression Scale. Cognitive function was assessed using versions of the Telephone Interview for Cognitive Status (TICS). We used logistic regression with robust standard errors to examine associations between substantial depressive symptoms at any interview before sepsis and incident cognitive impairment (either mild or moderate-to-severe cognitive impairment) at any interview after sepsis. Results The prevalence of substantial depressive symptoms in those with normal cognition before sepsis was 38% (95%Confidence Interval [CI]: 34%, 42%). After severe sepsis, 18% (95%CI: 15%, 20%) of survivors had incident cognitive impairment. In unadjusted analyses, pre-sepsis substantial depressive symptoms were associated with post-sepsis incident cognitive impairment (Odds Ratio [OR] 2.56, 95%CI: 1.53, 4.27). After adjustment for demographics, health-risk behaviors, clinical characteristics of the sepsis episode, and pre-sepsis TICS scores, pre-sepsis substantial depressive symptoms remained the strongest factor associated with post-sepsis incident cognitive impairment (OR 2.58, 95%CI: 1.45, 4.59). Conclusion Pre-sepsis substantial depressive symptoms are independently associated with incident post-sepsis cognitive impairment. Depressed older adults may be particularly at risk for developing

Heparanase level and procoagulant activity are reduced in severe sepsis.

PubMed

Matan, Moshe; King, Daniel; Peled, Eli; Ackerman, Shanny; Bar-Lavi, Yaron; Brenner, Benjamin; Nadir, Yona

2018-02-01

During severe sepsis, levels and activity of all coagulation proteins are reduced. Heparanase is implicated in angiogenesis and tumor progression. We previously demonstrated that heparanase also affected the hemostatic system. It forms a complex and increases the activity of the blood coagulation initiator tissue factor. To evaluate heparanase levels and procoagulant activity as predictors of sepsis severity. Twenty-one patients with non-trauma, non-surgical sepsis admitted to the intensive care unit and 35 controls were recruited. Plasma samples were drawn from the study participants on days 1 and 7 following admission. Heparanase levels and procoagulant activity on day 1 were significantly reduced in patients compared to controls (P < .0001, P < .0001, respectively). Day 1 heparanase procoagulant activity ≥350 ng/mL yielded a negative predictive value for severe sepsis of 89%. Additionally, heparanase procoagulant activity on day 7 correlated with the change in the APACHE score between days 1 and 7 (r = .66, P = .007). Heparanase procoagulant activity decreases during sepsis and returns to normal levels as soon as the patient recovers. Hence, it can be potentially used to predict the risk of severe sepsis. These findings need to be further explored in large-scale studies. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Drotrecogin alfa (activated): a novel therapeutic strategy for severe sepsis

PubMed Central

Pastores, S

2003-01-01

Recent studies have highlighted the close link between activation of the coagulation system and the inflammatory response in the pathophysiology of severe sepsis. The protein C anticoagulant pathway plays an integral part in modulating the coagulation and inflammatory responses to infection. In patients with sepsis, endogenous protein C levels are decreased, shifting the balance toward greater systemic inflammation, coagulation, and cell death. On the basis of a single large randomised phase 3 trial, drotrecogin alfa (activated), a recombinant form of human activated protein C, was recently approved for the treatment of adult patients with severe sepsis and a high risk of death. Since its approval, several questions have been raised regarding the appropriate use of this agent. Given the increased risk of serious bleeding and the high cost of treatment, drotrecogin alfa (activated) should be reserved at this time for the most acutely ill patients with severe sepsis who meet the criteria that were used in the phase 3 trial. PMID:12566544

New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality.

PubMed

Lin, John C; Spinella, Philip C; Fitzgerald, Julie C; Tucci, Marisa; Bush, Jenny L; Nadkarni, Vinay M; Thomas, Neal J; Weiss, Scott L

2017-01-01

To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. Secondary analysis of a prospective, cross-sectional, point prevalence study. International, multicenter PICUs. Pediatric patients with severe sepsis identified on five separate days over a 1-year period. None. Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001). Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts

Angiopoietin-1, Angiopoietin-2 and Bicarbonate as Diagnostic Biomarkers in Children with Severe Sepsis

PubMed Central

Wang, Kun; Bhandari, Vineet; Giuliano, John S.; O′Hern, Corey S.; Shattuck, Mark D.; Kirby, Michael

2014-01-01

Severe pediatric sepsis continues to be associated with high mortality rates in children. Thus, an important area of biomedical research is to identify biomarkers that can classify sepsis severity and outcomes. The complex and heterogeneous nature of sepsis makes the prospect of the classification of sepsis severity using a single biomarker less likely. Instead, we employ machine learning techniques to validate the use of a multiple biomarkers scoring system to determine the severity of sepsis in critically ill children. The study was based on clinical data and plasma samples provided by a tertiary care center's Pediatric Intensive Care Unit (PICU) from a group of 45 patients with varying sepsis severity at the time of admission. Canonical Correlation Analysis with the Forward Selection and Random Forests methods identified a particular set of biomarkers that included Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), and Bicarbonate (HCO) as having the strongest correlations with sepsis severity. The robustness and effectiveness of these biomarkers for classifying sepsis severity were validated by constructing a linear Support Vector Machine diagnostic classifier. We also show that the concentrations of Ang-1, Ang-2, and HCO enable predictions of the time dependence of sepsis severity in children. PMID:25255212

The Effect of Hospital Volume on Mortality in Patients Admitted with Severe Sepsis

PubMed Central

Shahul, Sajid; Hacker, Michele R.; Novack, Victor; Mueller, Ariel; Shaefi, Shahzad; Mahmood, Bilal; Ali, Syed Haider; Talmor, Daniel

2014-01-01

Importance The association between hospital volume and inpatient mortality for severe sepsis is unclear. Objective To assess the effect of severe sepsis case volume and inpatient mortality. Design Setting and Participants Retrospective cohort study from 646,988 patient discharges with severe sepsis from 3,487 hospitals in the Nationwide Inpatient Sample from 2002 to 2011. Exposures The exposure of interest was the mean yearly sepsis case volume per hospital divided into tertiles. Main Outcomes and Measures Inpatient mortality. Results Compared with the highest tertile of severe sepsis volume (>60 cases per year), the odds ratio for inpatient mortality among persons admitted to hospitals in the lowest tertile (≤10 severe sepsis cases per year) was 1.188 (95% CI: 1.074–1.315), while the odds ratio was 1.090 (95% CI: 1.031–1.152) for patients admitted to hospitals in the middle tertile. Similarly, improved survival was seen across the tertiles with an adjusted inpatient mortality incidence of 35.81 (95% CI: 33.64–38.03) for hospitals with the lowest volume of severe sepsis cases and a drop to 32.07 (95% CI: 31.51–32.64) for hospitals with the highest volume. Conclusions and Relevance We demonstrate an association between a higher severe sepsis case volume and decreased mortality. The need for a systems-based approach for improved outcomes may require a high volume of severely septic patients. PMID:25264788

Designing and testing computer based screening engine for severe sepsis/septic shock.

PubMed

Herasevich, V; Afessa, B; Chute, C G; Gajic, O

2008-11-06

This study addresses the role of a sepsis "sniffer", an automatic screening tool for the timely identification of patients with severe sepsis/septic shock, based electronic medical records. During the two months prospective implementation in a medical intensive care unit, 37 of 320 consecutive patients developed severe sepsis/septic shock. The sniffer demonstrated a sensitivity of 48% and specificity of 86%, and positive predictive value 32%. Further improvements are needed prior to the implementation of sepsis sniffer in clinical practice and research.

Comparison of oxidative stress & leukocyte activation in patients with severe sepsis & burn injury

PubMed Central

Mühl, Diana; Woth, Gábor; Drenkovics, Livia; Varga, Adrienn; Ghosh, Subhamay; Csontos, Csaba; Bogár, Lajos; Wéber, György; Lantos, János

2011-01-01

Background & objectives: We evaluated pro- and anti-oxidant disturbances in sepsis and non-sepsis burn patients with systemic inflammatory response syndrome (SIRS). Adhesion molecules and inflammation markers on leukocytes were also analyzed. We hypothesized that oxidative stress and leukocyte activation markers can lead to the severity of sepsis. Methods: In 28 severe sepsis and 27 acute burn injury patients blood samples were collected at admission and 4 days consecutively. Oxidative stress markers: production of reactive oxygen species (ROS), myeloperoxidase, malondialdehyde and endogenous antioxidants: plasma protein sulphydryl groups, reduced glutathione, superoxide dismutase and catalase were measured. Flow cytometry was used to determine CD11a, CD14, CD18, CD49d and CD97 adhesion molecules on leukocytes. Procalcitonin, C-reactive protein, fibrinogen, platelet count and lactate were also analyzed. Results: Pro-oxidant parameters were significantly elevated in sepsis patients at admission, ROS intensity increased in burn patients until the 5th day. Endogenous antioxidant levels except catalase showed increased levels after burn trauma compared to sepsis. Elevated granulocyte activation and suppressed lymphocyte function were found at admission and early activation of granulocytes caused by increasing activation/migration markers in sepsis. Leukocyte adhesion molecule expression confirmed the suppressed lymphocyte and monocyte function in sepsis. Interpretation & conclusions: Severe sepsis is accompanied by oxidative stress and pathological leukocyte endothelial cell interactions. The laboratory parameters used for the evaluation of sepsis and several markers of pro- and antioxidant status were different between sepsis and non-sepsis burn patients. The tendency of changes in these parameters may refer to major oxidative stress in sepsis and developing SIRS in burns. PMID:21808137

Systemic inflammatory response syndrome criteria in defining severe sepsis.

PubMed

Kaukonen, Kirsi-Maija; Bailey, Michael; Pilcher, David; Cooper, D Jamie; Bellomo, Rinaldo

2015-04-23

The consensus definition of severe sepsis requires suspected or proven infection, organ failure, and signs that meet two or more criteria for the systemic inflammatory response syndrome (SIRS). We aimed to test the sensitivity, face validity, and construct validity of this approach. We studied data from patients from 172 intensive care units in Australia and New Zealand from 2000 through 2013. We identified patients with infection and organ failure and categorized them according to whether they had signs meeting two or more SIRS criteria (SIRS-positive severe sepsis) or less than two SIRS criteria (SIRS-negative severe sepsis). We compared their characteristics and outcomes and assessed them for the presence of a step increase in the risk of death at a threshold of two SIRS criteria. Of 1,171,797 patients, a total of 109,663 had infection and organ failure. Among these, 96,385 patients (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis. Over a period of 14 years, these groups had similar characteristics and changes in mortality (SIRS-positive group: from 36.1% [829 of 2296 patients] to 18.3% [2037 of 11,119], P<0.001; SIRS-negative group: from 27.7% [100 of 361] to 9.3% [122 of 1315], P<0.001). Moreover, this pattern remained similar after adjustment for baseline characteristics (odds ratio in the SIRS-positive group, 0.96; 95% confidence interval [CI], 0.96 to 0.97; odds ratio in the SIRS-negative group, 0.96; 95% CI, 0.94 to 0.98; P=0.12 for between-group difference). In the adjusted analysis, mortality increased linearly with each additional SIRS criterion (odds ratio for each additional criterion, 1.13; 95% CI, 1.11 to 1.15; P<0.001) without any transitional increase in risk at a threshold of two SIRS criteria. The need for two or more SIRS criteria to define severe sepsis excluded one in eight otherwise similar patients with infection, organ failure, and substantial mortality and failed to define a transition point in

A Severe Sepsis Mortality Prediction Model and Score for Use with Administrative Data

PubMed Central

Ford, Dee W.; Goodwin, Andrew J.; Simpson, Annie N.; Johnson, Emily; Nadig, Nandita; Simpson, Kit N.

2016-01-01

Objective Administrative data is used for research, quality improvement, and health policy in severe sepsis. However, there is not a sepsis-specific tool applicable to administrative data with which to adjust for illness severity. Our objective was to develop, internally validate, and externally validate a severe sepsis mortality prediction model and associated mortality prediction score. Design Retrospective cohort study using 2012 administrative data from five US states. Three cohorts of patients with severe sepsis were created: 1) ICD-9-CM codes for severe sepsis/septic shock, 2) ‘Martin’ approach, and 3) ‘Angus’ approach. The model was developed and internally validated in ICD-9-CM cohort and externally validated in other cohorts. Integer point values for each predictor variable were generated to create a sepsis severity score. Setting Acute care, non-federal hospitals in NY, MD, FL, MI, and WA Subjects Patients in one of three severe sepsis cohorts: 1) explicitly coded (n=108,448), 2) Martin cohort (n=139,094), and 3) Angus cohort (n=523,637) Interventions None Measurements and Main Results Maximum likelihood estimation logistic regression to develop a predictive model for in-hospital mortality. Model calibration and discrimination assessed via Hosmer-Lemeshow goodness-of-fit (GOF) and C-statistics respectively. Primary cohort subset into risk deciles and observed versus predicted mortality plotted. GOF demonstrated p>0.05 for each cohort demonstrating sound calibration. C-statistic ranged from low of 0.709 (sepsis severity score) to high of 0.838 (Angus cohort) suggesting good to excellent model discrimination. Comparison of observed versus expected mortality was robust although accuracy decreased in highest risk decile. Conclusions Our sepsis severity model and score is a tool that provides reliable risk adjustment for administrative data. PMID:26496452

[Peritonitis: main reason of severe sepsis in surgical intensive care].

PubMed

Weiss, G; Steffanie, W; Lippert, H

2007-04-01

Aim of the study was to determine the epidemiology of sepsis in an university surgical intensive care unit. We were mainly interested in getting information about incidence, reason and clinical course of peritonitis. The results should give more information about diagnostic and therapy of sepsis in the surgical intensive care. We analyzed our 2 676 ICU-patients from 2000 to 2002 with infection as main diagnosis. By means of medical report we analyzed the kind of infection and the clinical course of 561 (21 %) patients. For 356 (13.3 %) patients with peritonitis we observed the kind, the reason and the severity of infection and further the special events in the clinical course. The incidence of severe sepsis was 14.8 %. With 63 % the peritonitis is the main infectiological diagnosis on admission to ICU. 33.8 % of infections are hospital acquired. 71.3 % of patients with peritonitis developed a severe sepsis or septic shock during the clinical course. On average 4.7 further abdominal surgical interventions and 5.1 new occurring nosocomial infections marked a difficult surgical and infectious treatment course. Hospital acquired infections (70 %), high value of scoring and inadequate surgical treatment (23.7 %) have proved to be a good prognostic instrument for the development of tertiary peritonitis. With a share of 17 % from patients with peritonitis and a mortality of 35 % they have a strong influence on the ICU-mortality. Peritonitis is the main reason of severe sepsis on the surgical ICU. Hospital acquired infections especially the tertiary peritonitis have the highest mortality. High mortality is the consequence from the large number of difficult clinical courses and high rates of severe sepsis and septic shock. "Second hits" play a crucial role for the therapy and the prognosis of these patients. To decline the mortality future studies must more consider the problem of hospital acquired and tertiary abdominal infections.

Apoptosis-induced lymphopenia in sepsis and other severe injuries.

PubMed

Girardot, Thibaut; Rimmelé, Thomas; Venet, Fabienne; Monneret, Guillaume

2017-02-01

Sepsis and other acute injuries such as severe trauma, extensive burns, or major surgeries, are usually followed by a period of marked immunosuppression. In particular, while lymphocytes play a pivotal role in immune response, their functions and numbers are profoundly altered after severe injuries. Apoptosis plays a central role in this process by affecting immune response at various levels. Indeed, apoptosis-induced lymphopenia duration and depth have been associated with higher risk of infection and mortality in various clinical settings. Therapies modulating apoptosis represent an interesting approach to restore immune competence after acute injury, although their use in clinical practice still presents several limitations. After briefly describing the apoptosis process in physiology and during severe injuries, we will explore the immunological consequences of injury-induced lymphocyte apoptosis, and describe associations with clinically relevant outcomes in patients. Therapeutic perspectives targeting apoptosis will also be discussed.

Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study

PubMed Central

Phua, Jason; Du, Bin; Tang, Yao-Qing; Divatia, Jigeeshu V; Tan, Cheng Cheng; Gomersall, Charles D; Faruq, Mohammad Omar; Shrestha, Babu Raja; Gia Binh, Nguyen; Arabi, Yaseen M; Salahuddin, Nawal; Wahyuprajitno, Bambang; Tu, Mei-Lien; Wahab, Ahmad Yazid Haji Abd; Hameed, Akmal A; Nishimura, Masaji; Procyshyn, Mark; Chan, Yiong Huak

2011-01-01

Objectives To assess the compliance of Asian intensive care units and hospitals to the Surviving Sepsis Campaign’s resuscitation and management bundles. Secondary objectives were to evaluate the impact of compliance on mortality and the organisational characteristics of hospitals that were associated with higher compliance. Design Prospective cohort study. Setting 150 intensive care units in 16 Asian countries. Participants 1285 adult patients with severe sepsis admitted to these intensive care units in July 2009. The organisational characteristics of participating centres, the patients’ baseline characteristics, the achievement of targets within the resuscitation and management bundles, and outcome data were recorded. Main outcome measure Compliance with the Surviving Sepsis Campaign’s resuscitation (six hours) and management (24 hours) bundles. Results Hospital mortality was 44.5% (572/1285). Compliance rates for the resuscitation and management bundles were 7.6% (98/1285) and 3.5% (45/1285), respectively. On logistic regression analysis, compliance with the following bundle targets independently predicted decreased mortality: blood cultures (achieved in 803/1285; 62.5%, 95% confidence interval 59.8% to 65.1%), broad spectrum antibiotics (achieved in 821/1285; 63.9%, 61.3% to 66.5%), and central venous pressure (achieved in 345/870; 39.7%, 36.4% to 42.9%). High income countries, university hospitals, intensive care units with an accredited fellowship programme, and surgical intensive care units were more likely to be compliant with the resuscitation bundle. Conclusions While mortality from severe sepsis is high, compliance with resuscitation and management bundles is generally poor in much of Asia. As the centres included in this study might not be fully representative, achievement rates reported might overestimate the true degree of compliance with recommended care and should be interpreted with caution. Achievement of targets for blood cultures

Programmed Cell Death-1/Programmed Death-ligand 1 Pathway: A New Target for Sepsis.

PubMed

Liu, Qiang; Li, Chun-Sheng

2017-04-20

Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment. Studies of the association between PD-1/PD-L1 and sepsis published up to January 31, 2017, were obtained by searching the PubMed database. English language studies, including those based on animal models, clinical research, and reviews, with data related to PD-1/PD-L1 and sepsis, were evaluated. Immunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of the PD-1/PD-L1 pathway could reduce the exhaustion of T-cells and enhance the proliferation and activation of T-cells. The anti-PD-1/PD-L1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and future studies aimed at revaluating the efficacy and safety of this targeted approach.

Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database.

PubMed

Ruth, Amanda; McCracken, Courtney E; Fortenberry, James D; Hall, Matthew; Simon, Harold K; Hebbar, Kiran B

2014-11-01

To 1) describe the characteristics and outcomes over time of PICU patients with severe sepsis within the dedicated U.S. children's hospitals, 2) identify patient subgroups at risk for mortality from pediatric severe sepsis, and 3) describe overall pediatric severe sepsis resource utilization. Retrospective review of a prospectively collected multi-institutional children's hospital database. PICUs in 43 U.S. children's hospitals. PICU patients from birth to younger than 19 years were identified with severe sepsis by modified Angus criteria and International Classification of Diseases, 9th Revision, codes for severe sepsis and septic shock. None. Data from the Pediatric Health Information System database collected by the Children's Hospital Association from 2004 to 2012. Pediatric severe sepsis was defined by 1) International Classification of Diseases, 9th Revision, codes reflecting severe sepsis and septic shock and 2) International Classification of Diseases, 9th Revision, codes of infection and organ dysfunction as defined by modified Angus criteria. From 2004 to 2012, 636,842 patients were identified from 43 hospitals. Pediatric severe sepsis prevalence was 7.7% (49,153) with an associated mortality rate of 14.4%. Age less than 1 year (vs age 10 to < 19) (odds ratio, 1.4), underlying cardiovascular condition (odds ratio, 1.4) and multiple organ dysfunction, conferred higher odds of mortality. Resource burden was significant with median hospital length of stay of 17 days (interquartile range, 8-36 d) and PICU length of stay of 7 days (interquartile range, 2-17 d), with median cost/day of $4,516 and median total hospitalization cost of $77,446. There was a significant increase in the severe sepsis prevalence rate from 6.2% to 7.7% from 2004 to 2012 (p < 0.001) and a significant decrease in mortality from 18.9% to 12.0% (p < 0.001). Center mortality was negatively correlated with prevalence (rs = -0.48) and volume (rs = -0.39) and positively correlated with cost

Feasibility of modified surviving sepsis campaign guidelines in a resource-restricted setting based on a cohort study of severe S. aureus sepsis [corrected].

PubMed

Mahavanakul, Weera; Nickerson, Emma K; Srisomang, Pramot; Teparrukkul, Prapit; Lorvinitnun, Pichet; Wongyingsinn, Mingkwan; Chierakul, Wirongrong; Hongsuwan, Maliwan; West, T Eoin; Day, Nicholas P; Limmathurotsakul, Direk; Peacock, Sharon J

2012-01-01

The Surviving Sepsis Campaign (SSC) guidelines describe best practice for the management of severe sepsis and septic shock in developed countries, but most deaths from sepsis occur where healthcare is not sufficiently resourced to implement them. Our objective was to define the feasibility and basis for modified guidelines in a resource-restricted setting. We undertook a detailed assessment of sepsis management in a prospective cohort of patients with severe sepsis caused by a single pathogen in a 1,100-bed hospital in lower-middle income Thailand. We compared their management with the SSC guidelines to identify care bundles based on existing capabilities or additional activities that could be undertaken at zero or low cost. We identified 72 patients with severe sepsis or septic shock associated with S. aureus bacteraemia, 38 (53%) of who died within 28 days. One third of patients were treated in intensive care units (ICUs). Numerous interventions described by the SSC guidelines fell within existing capabilities, but their implementation was highly variable. Care available to patients on general wards covered the fundamental principles of sepsis management, including non-invasive patient monitoring, antimicrobial administration and intravenous fluid resuscitation. We described two additive care bundles, one for general wards and the second for ICUs, that if consistently performed would be predicted to improve outcome from severe sepsis. It is feasible to implement modified sepsis guidelines that are scaled to resource availability, and that could save lives prior to the publication of international guidelines for developing countries.

Sepsis

MedlinePlus

... its early stage, before it becomes more dangerous. Sepsis To be diagnosed with sepsis, you must exhibit ... rate higher than 20 breaths a minute Severe sepsis Your diagnosis will be upgraded to severe sepsis ...

High Levels of Morbidity and Mortality Among Pediatric Hematopoietic Cell Transplant Recipients With Severe Sepsis: Insights From the Sepsis PRevalence, OUtcomes, and Therapies International Point Prevalence Study.

PubMed

Lindell, Robert B; Gertz, Shira J; Rowan, Courtney M; McArthur, Jennifer; Beske, Florian; Plunkett, Adrian; Weiss, Scott L; Thomas, Neal J; Nadkarni, Vinay M; Fitzgerald, Julie C

2017-12-01

Pediatric severe sepsis is a major cause of morbidity and mortality worldwide, and hematopoietic cell transplant patients represent a high-risk population. We assessed the epidemiology of severe sepsis in hematopoietic cell transplant patients, describing patient outcomes compared with children with no history of hematopoietic cell transplant. Secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies point prevalence study, comparing demographics, sepsis etiology, illness severity, organ dysfunction, and sepsis-related treatments in patients with and without hematopoietic cell transplant. The primary outcome was hospital mortality. Multivariable logistic regression models were used to determine adjusted differences in mortality. International; 128 PICUs in 26 countries. Pediatric patients with severe sepsis prospectively identified over a 1-year period. None. In patients with severe sepsis, 37/567 (6.5%) had a history of hematopoietic cell transplant. Compared with patients without hematopoietic cell transplant, hematopoietic cell transplant patients had significantly higher hospital mortality (68% vs 23%; p < 0.001). Hematopoietic cell transplant patients were more likely to have hospital acquired sepsis and had more preexisting renal and hepatic dysfunction than non-hematopoietic cell transplant patients with severe sepsis. History of hematopoietic cell transplant, renal replacement therapy, admission from inpatient floor, and number of organ dysfunctions at severe sepsis recognition were independently associated with hospital mortality in multivariable analysis; hematopoietic cell transplant conferred the highest odds of mortality (odds ratio, 4.00; 95% CI, 1.78-8.98). In secondary analysis of hematopoietic cell transplant patients compared with other immunocompromised patients with severe sepsis, history of hematopoietic cell transplant remained independently associated with hospital mortality (odds ratio, 3.03; 95% CI, 1.11-8.27). In an

Comparison of Pediatric Severe Sepsis Managed in U.S. and European ICUs.

PubMed

Giuliano, John S; Markovitz, Barry P; Brierley, Joe; Levin, Richard; Williams, Gary; Lum, Lucy Chai See; Dorofaeff, Tavey; Cruces, Pablo; Bush, Jenny L; Keele, Luke; Nadkarni, Vinay M; Thomas, Neal J; Fitzgerald, Julie C; Weiss, Scott L

2016-06-01

Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies. We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality. European and U.S. PICUs. Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study. None. European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days. Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future

Comparison of Pediatric Severe Sepsis Managed in U.S. and European ICUs

PubMed Central

Giuliano, John S.; Markovitz, Barry P.; Brierley, Joe; Levin, Richard; Williams, Gary; Lum, Lucy Chai See; Dorofaeff, Tavey; Cruces, Pablo; Bush, Jenny L.; Keele, Luke; Nadkarni, Vinay M.; Thomas, Neal J.; Fitzgerald, Julie C.; Weiss, Scott L.

2017-01-01

Objectives Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies. Design We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality. Setting European and U.S. PICUs. Patients Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study. Interventions None. Measurements and Main Results European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality −3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days. Conclusions Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions

The Epidemiology of Hospital Death Following Pediatric Severe Sepsis: When, Why, and How Children With Sepsis Die.

PubMed

Weiss, Scott L; Balamuth, Fran; Hensley, Josey; Fitzgerald, Julie C; Bush, Jenny; Nadkarni, Vinay M; Thomas, Neal J; Hall, Mark; Muszynski, Jennifer

2017-09-01

The epidemiology of in-hospital death after pediatric sepsis has not been well characterized. We investigated the timing, cause, mode, and attribution of death in children with severe sepsis, hypothesizing that refractory shock leading to early death is rare in the current era. Retrospective observational study. Emergency departments and ICUs at two academic children's hospitals. Seventy-nine patients less than 18 years old treated for severe sepsis/septic shock in 2012-2013 who died prior to hospital discharge. None. Time to death from sepsis recognition, cause and mode of death, and attribution of death to sepsis were determined from medical records. Organ dysfunction was assessed via daily Pediatric Logistic Organ Dysfunction-2 scores for 7 days preceding death with an increase greater than or equal to 5 defined as worsening organ dysfunction. The median time to death was 8 days (interquartile range, 1-12 d) with 25%, 35%, and 49% of cumulative deaths within 1, 3, and 7 days of sepsis recognition, respectively. The most common cause of death was refractory shock (34%), then multiple organ dysfunction syndrome after shock recovery (27%), neurologic injury (19%), single-organ respiratory failure (9%), and nonseptic comorbidity (6%). Early deaths (≤ 3 d) were mostly due to refractory shock in young, previously healthy patients while multiple organ dysfunction syndrome predominated after 3 days. Mode of death was withdrawal in 72%, unsuccessful cardiopulmonary resuscitation in 22%, and irreversible loss of neurologic function in 6%. Ninety percent of deaths were attributable to acute or chronic manifestations of sepsis. Only 23% had a rise in Pediatric Logistic Organ Dysfunction-2 that indicated worsening organ dysfunction. Refractory shock remains a common cause of death in pediatric sepsis, especially for early deaths. Later deaths were mostly attributable to multiple organ dysfunction syndrome, neurologic, and respiratory failure after life-sustaining therapies

Symptoms of depression in survivors of severe sepsis: a prospective cohort study of older Americans.

PubMed

Davydow, Dimitry S; Hough, Catherine L; Langa, Kenneth M; Iwashyna, Theodore J

2013-09-01

To examine if incident severe sepsis is associated with increased risk of subsequent depressive symptoms and to assess which patient characteristics are associated with increased risk of depressive symptoms. Prospective longitudinal cohort study. Population-based cohort of older U.S. adults interviewed as part of the Health and Retirement Study (1998-2006). A total of 439 patients who survived 471 hospitalizations for severe sepsis and completed at least one follow-up interview. Depressive symptoms were assessed with a modified version of the Center for Epidemiologic Studies Depression Scale. Severe sepsis was identified using a validated algorithm in Medicare claims. The point prevalence of substantial depressive symptoms was 28% at a median of 1.2 years before sepsis, and remained 28% at a median of 0.9 years after sepsis. Neither incident severe sepsis (relative risk [RR]: 1.00; 95% confidence interval [CI]: 0.73, 1.34) nor severe sepsis-related clinical characteristics were significantly associated with subsequent depressive symptoms. These results were robust to potential threats from missing data or alternative outcome definitions. After adjustment, presepsis substantial depressive symptoms (RR: 2.20; 95% CI: 1.66, 2.90) and worse postsepsis functional impairment (RR: 1.08 per new limitation; 95% CI: 1.03, 1.13) were independently associated with substantial depressive symptoms after sepsis. The prevalence of substantial depressive symptoms in severe sepsis survivors is high but is not increased relative to their presepsis levels. Identifying this large subset of severe sepsis survivors at increased risk for major depression, and beginning interventions before hospital discharge, may improve outcomes. Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Hyperglycemia and glycemic variability are associated with the severity of sepsis in nondiabetic subjects.

PubMed

Preechasuk, Lukana; Suwansaksri, Nattakarn; Ipichart, Nantawan; Vannasaeng, Sathit; Permpikul, Chairat; Sriwijitkamol, Apiradee

2017-04-01

The purpose was to compare glucose variability (GV) obtained via continuous glucose monitoring between nondiabetic sepsis patients and healthy subjects and to seek associations between GV and sepsis severity in nondiabetic sepsis patients. Nondiabetic sepsis inpatients and healthy controls received a 72-hour continuous glucose monitoring (iPro2, Medtronic) postadmission and post-oral glucose tolerance test, respectively. The mean glucose level (MGL) along with GV represented by standard deviation (SD) and the mean amplitude of glycemic excursion (MAGE) were calculated at 24 and 72 hours. Sepsis severity was evaluated with the Sepsis-related Organ Failure Assessment Score (SOFA). MGL and GV in patients with SOFA ≥9 and <9 were compared. Thirty nondiabetic sepsis and 10 healthy subjects were recruited. No differences were found between groups except for higher patient age in sepsis patients. The MGL and MAGE 72h of sepsis patients were significantly higher than those of healthy subjects. MGL and GV 24h were higher in patients with SOFA ≥9 than in patients with SOFA <9 (MGL 24h 195±17 vs 139±27, P<.001; SD 24h 32 [28, 36] vs 19 [5, 58], P=.02; and MAGE 24h 94 [58, 153] vs 54 [16, 179], P=.01). Nondiabetic sepsis patients had higher MGL and GV values than healthy subjects. MGL and GV 24h were associated with sepsis severity. Copyright © 2016 Elsevier Inc. All rights reserved.

Severe Maternal Sepsis in the UK, 2011–2012: A National Case-Control Study

PubMed Central

Acosta, Colleen D.; Kurinczuk, Jennifer J.; Lucas, D. Nuala; Tuffnell, Derek J.; Sellers, Susan; Knight, Marian

2014-01-01

Background In light of increasing rates and severity of sepsis worldwide, this study aimed to estimate the incidence of, and describe the causative organisms, sources of infection, and risk factors for, severe maternal sepsis in the UK. Methods and Findings A prospective case-control study included 365 confirmed cases of severe maternal sepsis and 757 controls from all UK obstetrician-led maternity units from June 1, 2011, to May 31, 2012. Incidence of severe sepsis was 4.7 (95% CI 4.2–5.2) per 10,000 maternities; 71 (19.5%) women developed septic shock; and five (1.4%) women died. Genital tract infection (31.0%) and the organism Escherichia coli (21.1%) were most common. Women had significantly increased adjusted odds ratios (aORs) of severe sepsis if they were black or other ethnic minority (aOR = 1.82; 95% CI 1.82–2.51), were primiparous (aOR = 1.60; 95% CI 1.17–2.20), had a pre-existing medical problem (aOR = 1.40; 95% CI 1.01–1.94), had febrile illness or were taking antibiotics in the 2 wk prior to presentation (aOR = 12.07; 95% CI 8.11–17.97), or had an operative vaginal delivery (aOR = 2.49; 95% CI 1.32–4.70), pre-labour cesarean (aOR = 3.83; 95% CI 2.24–6.56), or cesarean after labour onset (aOR = 8.06; 95% CI 4.65–13.97). Median time between delivery and sepsis was 3 d (interquartile range = 1–7 d). Multiple pregnancy (aOR = 5.75; 95% CI 1.54–21.45) and infection with group A streptococcus (aOR = 4.84; 2.17–10.78) were associated with progression to septic shock; for 16 (50%) women with a group A streptococcal infection there was <2 h—and for 24 (75%) women, <9 h—between the first sign of systemic inflammatory response syndrome and a diagnosis of severe sepsis. A limitation of this study was the proportion of women with sepsis without an identified organism or infection source (16.4%). Conclusions For each maternal sepsis death, approximately 50 women have life-threatening morbidity from

Evaluation of oxidative stress and antioxidant status: Correlation with the severity of sepsis.

PubMed

Kumar, S; Gupta, E; Kaushik, S; Kumar Srivastava, V; Mehta, S K; Jyoti, A

2018-04-01

Sepsis is a condition caused by infection followed by unregulated inflammatory response which may lead to the organ dysfunction. During such condition, over-production of oxidants is one of the factors which contribute cellular toxicity and ultimately organ failure and mortality. Antioxidants having free radicals scavenging activity exert protective role in various diseases. This study has been designed to evaluate the levels of oxidative and antioxidative activity in sepsis patients and their correlation with the severity of the sepsis. A total of 100 sepsis patients and 50 healthy controls subjects were enrolled in this study from the period October 2016 to June 2017. The investigation included measurements of oxidative enzyme, myeloperoxidase (MPO), antioxidant enzymes including superoxide dismutase activity (SOD) and catalase activity (CAT) and cytokines (TNF-α, IL-8 and IFN-γ). Furthermore, the level of these activities was correlated with severity of sepsis. Augmented levels of oxidants were found in sepsis as demonstrated by DMPO nitrone adduct formation and plasma MPO level activity (1.37 ± 0.51 in sepsis vs 0.405 ± 0.16 in control subjects). Cytokines were also found to be increased in sepsis patients. However, plasma SOD and CAT activities were significantly attenuated (P < .001) in the sepsis patients compared with controls subjects. Moreover, inverse relation between antioxidant enzymes (SOD and CAT) and organ failure assessment (SOFA), physiological score (APACHE II), organ toxicity specific markers have been observed as demonstrated by Pearson's correlation coefficient. This study suggests that imbalance between oxidant and antioxidant plays key role in the severity of sepsis. © 2018 The Foundation for the Scandinavian Journal of Immunology.

Severe Sepsis and Septic Shock Cases Meeting Guidelines Among Patients in a University Hospital Setting.

PubMed

Charrier, J A; Steen, C L; Borrero, E

2017-01-01

A diagnosis of severe sepsis or septic shock has been shown to significantly increase mortality rate independent of other factors. Research has revealed all cause hospital case fatality rates have declined yet the percentage of severe sepsis cases continues to increase and age-adjusted mortality rates from severe sepsis and septic shock has significantly increased during the same time period. Patients with severe sepsis demonstrate ongoing mortality rate increases for up to 2 years following hospitalization when compared to aged matched controls of nonseptic patients. International guidelines with mortality benefit for the management of severe sepsis and septic shock have been illustrated in the latest surviving sepsis campaign. The objective of this study was to increase the percentage of patients admitted to the hospital with a diagnosis of severe sepsis or septic shock who met guidelines based on surviving sepsis campaign. A retrospective chart review was conducted for patients admitted to UHC from January 2016 to present to identify cases with a diagnosis of severe sepsis or septic shock, and whether they met guidelines set forth by surviving sepsis campaign both before and after an intervention program which included interviews with providers failing to meet protocol, educational sessions on guidelines to meet protocol, resident led quality improvement workshops to address barriers to meeting protocol, and development of an EMR power plan to assist providers on meeting protocol. 139 cases with a diagnosis, or meeting criteria for, severe sepsis or septic shock were identified during the period of 1/1/2016-9/30/2016 with an average of 43 percent of total cases which met guidelines. Trend analysis revealed increased compliance following resident lead intervention program with 31 percent and 49 percent before and after intervention, respectively. ICU data is currently being analyzed for meeting guidelines and have not been included in current data. The most

Albumin replacement in patients with severe sepsis or septic shock.

PubMed

Caironi, Pietro; Tognoni, Gianni; Masson, Serge; Fumagalli, Roberto; Pesenti, Antonio; Romero, Marilena; Fanizza, Caterina; Caspani, Luisa; Faenza, Stefano; Grasselli, Giacomo; Iapichino, Gaetano; Antonelli, Massimo; Parrini, Vieri; Fiore, Gilberto; Latini, Roberto; Gattinoni, Luciano

2014-04-10

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P=0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P=0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% confidence interval [CI], 0.87 to 1.14; P=0.94). At 90 days, 365 of 888 patients (41.1%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.29). No significant differences in other secondary outcomes were observed between the two groups. In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS ClinicalTrials.gov number, NCT00707122.).

THE EPITHELIUM AS A TARGET IN SEPSIS.

PubMed

Chawla, Lakhmir S; Fink, Mitchell; Goldstein, Stuart L; Opal, Steven; Gómez, Alonso; Murray, Patrick; Gómez, Hernando; Kellum, John A

2016-03-01

Organ dysfunction induced by sepsis has been consistently associated with worse outcome and death. Regardless of the organ compromised, epithelial dysfunction is present throughout the body, affecting those organs that contain epithelia like the skin, lungs, liver, gut, and kidneys. Despite their obvious differences, sepsis seems to alter common features of all epithelia, such as barrier function and vectorial ion transport. Such alterations in the lung, the gut, and the kidney have direct implications that may explain the profound organ functional impairments in the absence of overt cell death. Epithelial injury in this context is not only an explanatory real pathophysiologic event, but also represents a source of biomarkers that have been explored to identify organ compromise earlier, predict outcome, and even to test novel therapeutic interventions such as blood purification. However, this remains largely experimental, and despite promising results, work is still required to better understand the response of the epithelial cells to sepsis, to define their role in adaptation to insults, to comprehend the interorgan cross-talk that occurs in these circumstances, and to exploit these aspects in pursuit of targeted therapies like blood purification, which may improve outcome for these patients in the future.

Prognostic Value of Dynamic Monitoring of Cellular Immunity and HMGB1 in Severe Sepsis: Delayed Chronic Inflammation may be the Leading Cause of Death in Late Severe Sepsis.

PubMed

Yu, Han; Qi, Zhijiang; Zhao, Lianxing; Shao, Rui; Fang, Yingying; Li, Chunsheng

2016-12-01

Sepsis is a life-threatening response to infection with a high mortality rate. In order to explore the prognostic value of dynamic monitoring of cellular immunity during late severe sepsis, we assessed levels of Tlymphocyte subsets, the human leukocyte antigen D-related (HLA-DR), and the high mobility group box-1 (HMGB1) protein. Study participants included 247 consecutive severe sepsis patients who were admitted to Beijing ChaoYang Hospital's Emergency Intensive Care Unit. Patients were divided into survivors and non-survivors based on 90-day survival rates, and clinical data were collected. T-lymphocyte subsets on days 1 and 7, HLA-DR on days 1 and 12, and HMGB1 on days 1, 3, 5, 7, and 12 were analyzed. Counts of CD3+, CD3+CD4+, and CD3+CD8+ T cells on day 1 in non-survivors were lower than those in survivors. By day 7, counts of all three types of T cells had increased in both survivors and non-survivors, but CD3+ and CD3+CD8+ T cells remained lower in non-survivors than in survivors. There was no significant difference in HLA-DR levels between survivors and non-survivors on day 1, but HLA-DR levels increased in survivors and decreased in non-survivors by day 12. In contrast, over days 1 - 12, HMGB1 levels increased in non-survivors and decreased in survivors. Patients with severe sepsis present with cellular immune dysfunction and persistent chronic inflammation, both of which may lead to death in the late phase of severe sepsis. Dynamic monitoring of indicators of cellular immunity and HMGB1 is useful for evaluating the immune status, chronic inflammation processes, and prognoses of patients with severe sepsis.

Hypothermia in the sepsis syndrome and clinical outcome. The Methylprednisolone Severe Sepsis Study Group.

PubMed

Clemmer, T P; Fisher, C J; Bone, R C; Slotman, G J; Metz, C A; Thomas, F O

1992-10-01

To evaluate the consequences of clinical hypothermia associated with sepsis syndrome and septic shock. Analysis of data from a multi-institutional, randomized, placebo-controlled, prospective study with predetermined end-point analysis of development of shock, recovery from shock, hospital length of stay, and death. Multi-institutional medical and surgical ICUs. Patients meeting predetermined criteria for severe sepsis syndrome. Appropriate sepsis and shock care with 50% of patients receiving methylprednisolone and 50% receiving placebo. The occurrence rate of hypothermia (< 35.5 degrees C) is 9% in this population. When compared with febrile patients, hypothermic patients had a higher frequency of central nervous system dysfunction (88% vs. 60%), increased serum bilirubin concentration (35% vs. 15%), prolonged prothrombin times (50% vs. 23%), shock (94% vs. 61%), failure to recover from shock (66% vs. 26%), and death (62% vs. 26%). The hypothermic patients were also more likely to be classified as having a rapidly or ultimately fatal disease upon study admission. This prospective study confirms that hypothermia associated with sepsis syndrome has a significant relationship to outcome manifest by increased frequency of shock and death from shock. This finding is in sharp contrast to the protective effects of induced hypothermia in septic animals and perhaps man.

Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis.

PubMed

Weber, Stefan U; Schewe, Jens-Christian; Lehmann, Lutz E; Müller, Stefan; Book, Malte; Klaschik, Sven; Hoeft, Andreas; Stüber, Frank

2008-01-01

In transgenic animal models of sepsis, members of the Bcl-2 family of proteins regulate lymphocyte apoptosis and survival of sepsis. This study investigates the gene regulation of pro-apoptotic and anti-apoptotic members of the Bcl-2 family of proteins in patients with early stage severe sepsis. In this prospective case-control study, patients were recruited from three intensive care units (ICUs) in a university hospital. Sixteen patients were enrolled when they fulfilled the criteria of severe sepsis. Ten critically ill but non-septic patients and 11 healthy volunteers served as controls. Blood samples were immediately obtained at inclusion. To confirm the presence of accelerated apoptosis in the patient groups, caspase-3 activation and phosphatidylserine externalisation in CD4+, CD8+ and CD19+ lymphocyte subsets were assessed using flow cytometry. Specific mRNAs of Bcl-2 family members were quantified from whole blood by real-time PCR. To test for statistical significance, Kruskal-Wallis testing with Dunn's multiple comparison test for post hoc analysis was performed. In all lymphocyte populations caspase-3 (p < 0.05) was activated, which was reflected in an increased phosphatidylserine externalisation (p < 0.05). Accordingly, lymphocyte counts were decreased in early severe sepsis. In CD4+ T-cells (p < 0.05) and B-cells (p < 0.001) the Bcl-2 protein was decreased in severe sepsis. Gene expression of the BH3-only Bim was massively upregulated as compared with critically ill patients (p < 0.001) and 51.6-fold as compared with healthy controls (p < 0.05). Bid was increased 12.9-fold compared with critically ill patients (p < 0.001). In the group of mitochondrial apoptosis inducers, Bak was upregulated 5.6-fold, while the expression of Bax showed no significant variations. By contrast, the pro-survival members Bcl-2 and Bcl-xl were both downregulated in severe sepsis (p < 0.001 and p < 0.05, respectively). In early severe sepsis a gene expression pattern with

Biomarkers of sepsis

PubMed Central

2013-01-01

Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate’s effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high. PMID:23480440

Immunoparalysis: Clinical and immunological associations in SIRS and severe sepsis patients.

PubMed

Papadopoulos, Panagiotis; Pistiki, Aikaterini; Theodorakopoulou, Maria; Christodoulopoulou, Theodora; Damoraki, Georgia; Goukos, Dimitris; Briassouli, Efrossini; Dimopoulou, Ioanna; Armaganidis, Apostolos; Nanas, Serafim; Briassoulis, George; Tsiodras, Sotirios

2017-04-01

This study was designed to identify changes in the monocytic membrane marker HLA-DR and heat shock proteins (HSPs) in relation to T-regulatory cells (T-regs) and other immunological marker changes in patients with systemic inflammatory response syndrome (SIRS) or sepsis/septic shock. Healthy volunteers, intensive care unit (ICU) patients with SIRS due to head injury and ICU patients with severe sepsis/septic shock were enrolled in the current study. Determination of CD14+/HLA-DR+ cells, intracellular heat-shock proteins and other immunological parameters were performed by flow cytometry and RT-PCR techniques as appropriate. Univariate and multivariate analysis examined associations of CD14/HLA-DR, HSPs, T-regs and suppressor of cytokine signalling (SOCS) proteins with SIRS, sepsis and outcome. Fifty patients (37 with severe sepsis and 13 with SIRS) were enrolled, together with 20 healthy volunteers used as a control group. Compared to healthy individuals, patients with SIRS and severe sepsis showed progressive decline of their CD14/HLA-DR expression (0% to 7.7% to 50% within each study subpopulation, p<0.001). Mean fluorescent intensity (MFI) levels of HSP70 and HSP90 on monocytes and polymorphonuclear cells were significantly higher in SIRS patients compared to controls and fell significantly in severe sepsis/septic shock patients (p<0.05 for all comparisons). There was no statistically significant difference between subgroups for levels of T-regulatory cells or relative copies of Suppressor of Cytokine Signalling 3 (SOCS3) proteins. In univariate models percent of CD14/HLA-DR was associated with mortality (OR: 1.8 95%CI 1.02-3.2, p=0.05), while in multivariate models after adjusting for CD14/HLA-DR only younger age and lower Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were associated with increased chances of survival (beta -0.05, OR 0.9, 95% CI 0.9-0.99, p=0.038 for age and beta -0.11, OR 0.89, 95% CI 0.8-0.99, p=0.037 for APACHE II

Use of Systematic Methods to Improve Disease Identification in Administrative Data: The Case of Severe Sepsis.

PubMed

Shahraz, Saeid; Lagu, Tara; Ritter, Grant A; Liu, Xiadong; Tompkins, Christopher

2017-03-01

Selection of International Classification of Diseases (ICD)-based coded information for complex conditions such as severe sepsis is a subjective process and the results are sensitive to the codes selected. We use an innovative data exploration method to guide ICD-based case selection for severe sepsis. Using the Nationwide Inpatient Sample, we applied Latent Class Analysis (LCA) to determine if medical coders follow any uniform and sensible coding for observations with severe sepsis. We examined whether ICD-9 codes specific to sepsis (038.xx for septicemia, a subset of 995.9 codes representing Systemic Inflammatory Response syndrome, and 785.52 for septic shock) could all be members of the same latent class. Hospitalizations coded with sepsis-specific codes could be assigned to a latent class of their own. This class constituted 22.8% of all potential sepsis observations. The probability of an observation with any sepsis-specific codes being assigned to the residual class was near 0. The chance of an observation in the residual class having a sepsis-specific code as the principal diagnosis was close to 0. Validity of sepsis class assignment is supported by empirical results, which indicated that in-hospital deaths in the sepsis-specific class were around 4 times as likely as that in the residual class. The conventional methods of defining severe sepsis cases in observational data substantially misclassify sepsis cases. We suggest a methodology that helps reliable selection of ICD codes for conditions that require complex coding.

Risk factors and pathogenic significance of severe sepsis and septic shock in 2286 patients with gram-negative bacteremia.

PubMed

Kang, Cheol-In; Song, Jae-Hoon; Chung, Doo Ryeon; Peck, Kyong Ran; Ko, Kwan Soo; Yeom, Joon-Sup; Ki, Hyun Kyun; Son, Jun Seong; Lee, Seung Soon; Kim, Yeon-Sook; Jung, Sook-In; Kim, Shin-Woo; Chang, Hyun-Ha; Ryu, Seong Yeol; Kwon, Ki Tae; Lee, Hyuck; Moon, Chisook

2011-01-01

The aim of this study was to identify risk factors for development of severe sepsis or septic shock and to evaluate the clinical impact of severe sepsis on outcome in patients with gram-negative bacteremia (GNB). From the database of a nationwide surveillance for bacteremia, patients with GNB were analyzed. Data of patients with severe sepsis or septic shock were compared with those of patient with sepsis. Of 2286 patients with GNB, 506 (22.1%) fulfilled the criteria of severe sepsis or septic shock. Factors associated with severe sepsis or septic shock in the multivariate analysis included renal disease, indwelling urinary catheter, hematologic malignancy, and neutropenia. The 30-day mortality of patients with severe sepsis or septic shock was significantly higher than that of patients with sepsis (39.5% [172/435] vs. 7.4% [86/1170]; P < 0.001). Multivariable analysis revealed that solid tumor, liver disease, pulmonary disease, pneumonia, and pathogens other than Escherichia coli, which were risk factors of development of severe sepsis or septic shock, were also found to be strong predictors of mortality. Severe sepsis or septic shock was a significant factor associated with mortality (OR, 3.34; 95% CI, 2.35-4.74), after adjustment for other variables predicting poor prognosis. Severe sepsis or septic shock was a common finding in patients with GNB, predicting a higher mortality rate. Renal disease and indwelling urinary catheter were the most important risk factors significantly associated with severe sepsis or septic shock among patients with GNB. Copyright © 2010 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

The continuum of maternal sepsis severity: incidence and risk factors in a population-based cohort study.

PubMed

Acosta, Colleen D; Knight, Marian; Lee, Henry C; Kurinczuk, Jennifer J; Gould, Jeffrey B; Lyndon, Audrey

2013-01-01

To investigate the incidence and risk factors associated with uncomplicated maternal sepsis and progression to severe sepsis in a large population-based birth cohort. This retrospective cohort study used linked hospital discharge and vital statistics records data for 1,622,474 live births in California during 2005-2007. Demographic and clinical factors were adjusted using multivariable logistic regression with robust standard errors. 1598 mothers developed sepsis; incidence of all sepsis was 10 per 10,000 live births (95% CI = 9.4-10.3). Women had significantly increased adjusted odds (aOR) of developing sepsis if they were older (25-34 years: aOR = 1.29; ≥35 years: aOR = 1.41), had ≤high-school education (aOR = 1.63), public/no-insurance (aOR = 1.22) or a cesarean section (primary: aOR = 1.99; repeat: aOR = 1.25). 791 women progressed to severe sepsis; incidence of severe sepsis was 4.9 per 10,000 live births (95% CI = 4.5-5.2). Women had significantly increased adjusted odds of progressing to severe sepsis if they were Black (aOR = 2.09), Asian (aOR = 1.59), Hispanic (aOR = 1.42), had public/no-insurance (aOR = 1.52), delivered in hospitals with <1,000 births/year (aOR = 1.93), were primiparous (aOR = 2.03), had a multiple birth (aOR = 3.5), diabetes (aOR = 1.47), or chronic hypertension (aOR = 8.51). Preeclampsia and postpartum hemorrhage were also significantly associated with progression to severe sepsis (aOR = 3.72; aOR = 4.18). For every cumulative factor, risk of uncomplicated sepsis increased by 25% (95% CI = 17.4-32.3) and risk of progression to severe sepsis/septic shock increased by 57% (95% CI = 40.8-74.4). The rate of severe sepsis was approximately twice the 1991-2003 national estimate. Risk factors identified are relevant to obstetric practice given their cumulative risk effect and the apparent increase in severe sepsis incidence.

Out-of-hospital characteristics and care of patients with severe sepsis: a cohort study

PubMed Central

Seymour, Christopher W.; Band, Roger A.; Cooke, Colin R.; Mikkelsen, Mark E.; Hylton, Julie; Rea, Tom D.; Goss, Christopher H.; Gaieski, David F.

2010-01-01

Purpose Early recognition and treatment in severe sepsis improves outcomes. Yet, out-of-hospital patient characteristics and emergency medical services (EMS) care in severe sepsis is understudied. Our goal was to describe out-of-hospital characteristics and EMS care in patients with severe sepsis, and evaluate associations between out-of-hospital characteristics and severity of organ dysfunction in the emergency department (ED). Materials & Methods We performed a secondary data analysis of existing data from patients with severe sepsis transported by EMS to an academic medical center. We constructed multivariable linear regression models to determine if out-of-hospital factors are associated with serum lactate and SOFA in the ED. Results Two hundred sixteen patients with severe sepsis arrived by EMS. Median serum lactate in the ED was 3.0 mmol/L (IQR:2.0-5.0) and median SOFA score was 4 (IQR:2-6). Sixty-three percent (135) of patients were transported by advanced life support providers and 30% (62) received IV fluid. Lower out-of-hospital Glasgow coma scale (GCS) was independently associated with elevated serum lactate (p<0.01). Out-of-hospital hypotension, greater respiratory rate, and lower GCS were associated with greater SOFA (p<0.01). Conclusions Out-of-hospital fluid resuscitation occurred in less than one-third of patients with severe sepsis, and routinely measured out-of-hospital variables were associated with greater serum lactate and SOFA in the ED. PMID:20381301

May thrombopoietin be a useful marker of sepsis severity assessment in patients with SIRS entering the emergency department?

PubMed

Segre, Elisabetta; Pigozzi, Luca; Lison, Davide; Pivetta, Emanuele; Bosco, Ornella; Vizio, Barbara; Suppo, Umberto; Turvani, Fabrizio; Morello, Fulvio; Battista, Stefania; Moiraghi, Corrado; Montrucchio, Giuseppe; Lupia, Enrico

2014-10-01

Thrombopoietin (TPO), a growth factor primarily involved in regulating thrombopoiesis, has been recently implicated in the pathogenesis of sepsis. TPO levels are, indeed, greatly increased in patients with sepsis compared to control subjects, and correlate with sepsis severity. The aim of this study was to evaluate TPO as predictive biomarker of sepsis and of sepsis severity in patients entering the emergency department (ED) with systemic inflammatory response syndrome (SIRS). This was a prospective observational study. Ours is a sub-study of the 'Need-speed trial', a multi-center observational study involving six Italian centers affiliated to the GREAT Italian Network. TPO was measured by ELISA. We enrolled 13 patients with SIRS (6 with acute pancreatitis, 3 with acute heart failure, 1 with pulmonary embolism, and 3 with allergic reactions), and 40 patients with sepsis, eight of whom had severe sepsis and three septic shock. TPO was significantly higher in patients with sepsis than with SIRS. In addition, TPO was higher in patients with severe sepsis than with sepsis, and in patients with septic shock than with severe sepsis, although these differences did not reach the statistical significance. Our preliminary results suggest that TPO may have the potential to be considered a promising early biomarker for both the diagnosis of sepsis and the assessment of sepsis severity in patients with SIRS entering the ED.

[Procalcitonin as a predictor of trauma severity and post-traumatic sepsis in children].

PubMed

Liu, Shao-Feng; Yuan, Gao-Pin; Yang, Jian; He, Tao-Zhen; Feng, Hai-Huan; Liu, Min

2012-09-01

To determine the association of procalcitonin (PCT) with trauma severity and post traumatic sepsis in children. The blood samples of 30 children with acute trauma in a Pediatric unit were collected for four consecutive days. The levels of PCT, IL-6, CRP and WBC were measured. The pediatric trauma score (PTS), length of stay in hospital, incidence of sepsis and clinical outcomes of the children were recorded. The value of PCT for predicting prognosis of children with trauma was compared with other inflammatory markers. Plasma PCT levels increased significantly in the patients in our study. Sepsis occurred in 23.33% of the patients. The patients with sepsis had higher levels of PCT than those with and without systemic inflammatory response syndrome (SIRS) and the healthy controls (P < 0.05). The peak level of PCT emerged on day 2 after trauma. The plasma PCT levels were positively correlated with trauma severity. The level of PCT on day 2 was an independent predictor for post-trauma sepsis and SIRS. Plasma PCT levels increase markedly in post trauma children. Plasma PCT of day 2 after trauma is an independent predictor of post-traumatic sepsis and SIRS complications. There is a significant correlation between the severity of injury and plasma PCT.

Validation of the Sepsis Severity Score Compared with Updated Severity Scores in Predicting Hospital Mortality in Sepsis Patients.

PubMed

Khwannimit, Bodin; Bhurayanontachai, Rungsun; Vattanavanit, Veerapong

2017-06-01

Recently, the Sepsis Severity Score (SSS) was constructed to predict mortality in sepsis patients. The aim of this study was to compare performance of the SSS with the Acute Physiology and Chronic Health Evaluation (APACHE) II-IV, Simplified Acute Physiology Score (SAPS) II, and SAPS 3 scores in predicting hospital outcome in sepsis patients. A retroprospective analysis was conducted in the medical intensive care unit of a tertiary university hospital. A total of 913 patients were enrolled; 476 of these patients (52.1%) had septic shock. The median SSS was 80 (range 20-137). The SSS presented good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.892. However, the AUC of the SSS did not differ significantly from that of APACHE II (P = 0.07), SAPS II (P = 0.06), and SAPS 3 (P = 0.11). The APACHE IV score showed the best discrimination with an AUC of 0.948 and the overall performance by a Brier score of 0.096. The AUC of the APACHE IV score was statistically greater than the SSS, APACHE II, SAPS II, and SAPS 3 (P <0.0001 for all) and APACHE III (P = 0.0002). The calibration of all scores was poor with the Hosmer-Lemeshow goodness-of-fit H test <0.05. The SSS provided as good discrimination as the APACHE II, SAPS II, and SAPS 3 scores. However, the APACHE IV score had the best discrimination and overall performance in our sepsis patients. The SSS needs to be adapted and modified with new parameters to improve its performance.

Treatment outcomes after implementation of an adapted WHO protocol for severe sepsis and septic shock in Haiti.

PubMed

Papali, Alfred; Eoin West, T; Verceles, Avelino C; Augustin, Marc E; Nathalie Colas, L; Jean-Francois, Carl H; Patel, Devang M; Todd, Nevins W; McCurdy, Michael T

2017-10-01

The World Health Organization (WHO) has developed a simplified algorithm specific to resource-limited settings for the treatment of severe sepsis emphasizing early fluids and antibiotics. However, this protocol's clinical effectiveness is unknown. We describe patient outcomes before and after implementation of an adapted WHO severe sepsis protocol at a community hospital in Haiti. Using a before-and-after study design, we retrospectively enrolled 99 adult Emergency Department patients with severe sepsis from January through March 2012. After protocol implementation in January 2014, we compared outcomes to 67 patients with severe sepsis retrospectively enrolled from February to April 2014. We defined sepsis according to the WHO's Integrated Management of Adult Illness guidelines and severe sepsis as sepsis plus organ dysfunction. After protocol implementation, quantity of fluid administered increased and the physician's differential diagnoses more often included sepsis. Patients were more likely to have follow-up vital signs taken sooner, a radiograph performed, and a lactic acid tested. There were no improvements in mortality, time to fluids or antimicrobials. Use of a simplified sepsis protocol based primarily on physiologic parameters allows for substantial improvements in process measures in the care of severely septic patients in a resource-constrained setting. Copyright © 2017 Elsevier Inc. All rights reserved.

Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care

PubMed Central

Williams, Mark D; Braun, Lee Ann; Cooper, Liesl M; Johnston, Joseph; Weiss, Richard V; Qualy, Rebecca L; Linde-Zwirble, Walter

2004-01-01

Introduction Infection is an important complication in cancer patients, which frequently leads to or prolongs hospitalization, and can also lead to acute organ dysfunction (severe sepsis) and eventually death. While cancer patients are known to be at higher risk for infection and subsequent complications, there is no national estimate of the magnitude of this problem. Our objective was to identify cancer patients with severe sepsis and to project these numbers to national levels. Methods Data for all 1999 hospitalizations from six states (Florida, Massachusetts, New Jersey, New York, Virginia, and Washington) were merged with US Census data, Centers for Disease Control vital statistics and National Cancer Institute, Surveillance, Epidemiology, and End Results initiative cancer prevalence data. Malignant neoplasms were identified by International Classification of Disease (ninth revision, clinical modification) (ICD-9-CM) codes (140–208), and infection and acute organ failure were identified from ICD-9-CM codes following Angus and colleagues. Cases were identified as a function of age and were projected to national levels. Results There were 606,176 cancer hospitalizations identified, with severe sepsis present in 29,795 (4.9%). Projecting national estimates for the US population, cancer patients account for 126,209 severe sepsis cases annually, or 16.4 cases per 1000 people with cancer per year. The inhospital mortality for cancer patients with severe sepsis was 37.8%. Compared with the overall population, cancer patients are much more likely to be hospitalized (relative risk, 2.77; 95% confidence interval, 2.77–2.78) and to be hospitalized with severe sepsis (relative risk, 3.96; 95% confidence interval, 3.94–3.99). Overall, severe sepsis is associated with 8.5% (46,729) of all cancer deaths at a cost of $3.4 billion per year. Conclusion Severe sepsis is a common, deadly, and costly complication in cancer patients. PMID:15469571

Hospitalized cancer patients with severe sepsis: analysis of incidence, mortality, and associated costs of care.

PubMed

Williams, Mark D; Braun, Lee Ann; Cooper, Liesl M; Johnston, Joseph; Weiss, Richard V; Qualy, Rebecca L; Linde-Zwirble, Walter

2004-10-01

Infection is an important complication in cancer patients, which frequently leads to or prolongs hospitalization, and can also lead to acute organ dysfunction (severe sepsis) and eventually death. While cancer patients are known to be at higher risk for infection and subsequent complications, there is no national estimate of the magnitude of this problem. Our objective was to identify cancer patients with severe sepsis and to project these numbers to national levels. Data for all 1999 hospitalizations from six states (Florida, Massachusetts, New Jersey, New York, Virginia, and Washington) were merged with US Census data, Centers for Disease Control vital statistics and National Cancer Institute, Surveillance, Epidemiology, and End Results initiative cancer prevalence data. Malignant neoplasms were identified by International Classification of Disease (ninth revision, clinical modification) (ICD-9-CM) codes (140-208), and infection and acute organ failure were identified from ICD-9-CM codes following Angus and colleagues. Cases were identified as a function of age and were projected to national levels. There were 606,176 cancer hospitalizations identified, with severe sepsis present in 29,795 (4.9%). Projecting national estimates for the US population, cancer patients account for 126,209 severe sepsis cases annually, or 16.4 cases per 1000 people with cancer per year. The inhospital mortality for cancer patients with severe sepsis was 37.8%. Compared with the overall population, cancer patients are much more likely to be hospitalized (relative risk, 2.77; 95% confidence interval, 2.77-2.78) and to be hospitalized with severe sepsis (relative risk, 3.96; 95% confidence interval, 3.94-3.99). Overall, severe sepsis is associated with 8.5% (46,729) of all cancer deaths at a cost of 3.4 billion dollars per year. Severe sepsis is a common, deadly, and costly complication in cancer patients.

ACUTE DIALYSIS QUALITY INITIATIVE (ADQI) XIV SEPSIS PHENOTYPES AND TARGETS FOR BLOOD PURIFICATION IN SEPSIS: THE BOGOTÁ CONSENSUS.

PubMed

Kellum, John A; Gómez, Hernando; Gómez, Alonso; Murray, Patrick; Ronco, Claudio

2016-03-01

Despite widespread use, there is currently no consensus on how extracorporeal blood purification therapies should be applied or studied in patients with sepsis. One major obstacle has been the lack of clear descriptions of specific sepsis phenotypes tied to mechanisms that would permit the identification of molecular targets. Current evidence suggests that sepsis-related morbidity and mortality involve widely different clinical phenotypes that variably include mitochondrial dysfunction, abnormalities of vascular biology including endothelial dysfunction and coagulopathy, epithelial dysfunction, and immune suppression and dysregulation. While most cases of sepsis involve some element of all of these pathobiologic processes, the magnitude of each varies greatly from patient to patient in part as a result of the pathogen and in part related to host-specific factors. Thus, the purpose of the fourteenth international consensus conference of acute dialysis quality initiative was to develop consensus for a conceptual model of sepsis-induced organ failure that can be treated by extracorporeal blood purification and possibly also with drugs or other therapies. We assembled a group of experts from around the world and used a modified Delphi method to reach consensus. Specific findings and recommendations for future research are provided in the four accompanying papers.

Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study.

PubMed

Weiss, Scott L; Fitzgerald, Julie C; Maffei, Frank A; Kane, Jason M; Rodriguez-Nunez, Antonio; Hsing, Deyin D; Franzon, Deborah; Kee, Sze Ying; Bush, Jenny L; Roy, Jason A; Thomas, Neal J; Nadkarni, Vinay M

2015-09-16

Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients <18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen's κ. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria. Of the 706 patients, 301 (42.6%) met both definitions. The inter-rater agreement (κ ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician's diagnosis of severe sepsis, only 69% (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria

Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis

PubMed Central

2012-01-01

Background Community-acquired pneumonia (CAP) is considered the most important cause of death from infectious disease in developed countries. Severity assessment scores partially address the difficulties in identifying high-risk patients. A lack of specific and valid pathophysiologic severity markers affect early and effective sepsis therapy. HMGB-1, sRAGE and RAGE have been involved in sepsis and their potential as severity markers has been proposed. The aim of this study was to evaluate HMGB-1, RAGE and sRAGE levels in patients with CAP-associated sepsis and determine their possible association with clinical outcome. Method We evaluated 33 patients with CAP-associated sepsis admitted to the emergency room and followed in the medical wards. Severity assessment scores (CURB-65, PSI, APACHE II, SOFA) and serologic markers (HMGB-1, RAGE, sRAGE) were evaluated on admission. Results Thirty patients with a diagnosis of CAP-associated sepsis were enrolled in the study within 24 hours after admission. Fourteen (46.6%) had pandemic (H1N1) influenza A virus, 2 (6.6%) had seasonal influenza A and 14 other diagnoses. Of the patients in the study group, 16 (53.3%) had a fatal outcome. ARDS was observed in 17 (56.6%) and a total of 22 patients had severe sepsis on admission (73%). The SOFA score showed the greatest difference between surviving and non-surviving groups (P = .003) with similar results in ARDS patients (P = .005). sRAGE levels tended to be higher in non-surviving (P = .058) and ARDS patients (P = .058). Logistic regression modeling demonstrated that SOFA (P = .013) and sRAGE (P = .05) were the only variables that modified the probability of a fatal outcome. Conclusion The association of elevated sRAGE with a fatal outcome suggests that it may have an independent causal effect in CAP. SOFA scores were the only clinical factor with the ability to identify surviving and ARDS patients. PMID:22264245

Economic aspects of severe sepsis: a review of intensive care unit costs, cost of illness and cost effectiveness of therapy.

PubMed

Burchardi, Hilmar; Schneider, Heinz

2004-01-01

Severe sepsis remains both an important clinical challenge and an economic burden in intensive care. An estimated 750,000 cases occur each year in the US alone (300 cases per 100,000 population). Lower numbers are estimated for most European countries (e.g. Germany and Austria: 54-116 cases per year per 100,000). Sepsis patients are generally treated in intensive care units (ICUs) where close supervision and intensive care treatment by a competent team with adequate equipment can be provided. Staffing costs represent from 40% to >60% of the total ICU budget. Because of the high proportion of fixed costs in ICU treatment, the total cost of ICU care is mainly dependent on the length of ICU stay (ICU-LOS). The average total cost per ICU day is estimated at approximately 1200 Euro for countries with a highly developed healthcare system (based on various studies conducted between 1989 and 2001 and converted at 2003 currency rates). Patients with infections and severe sepsis require a prolonged ICU-LOS, resulting in higher costs of treatment compared with other ICU patients. US cost-of-illness studies focusing on direct costs per sepsis patient have yielded estimates of 34,000 Euro, whereas European studies have given lower cost estimates, ranging from 23,000 Euro to 29,000 Euro. Direct costs, however, make up only about 20-30% of the cost of illness of severe sepsis. Indirect costs associated with severe sepsis account for 70-80% of costs and arise mainly from productivity losses due to mortality. Because of increasing healthcare cost pressures worldwide, economic issues have become important for the introduction of new innovations. This is evident when introducing new biotechnology products, such as drotrecogin-alpha (activated protein C), into specific therapy for severe sepsis. Data so far suggest that when drotrecogin-alpha treatment is targeted to those patients most likely to achieve the greatest benefit, the drug is cost effective by the standards of other well

Developing the surveillance algorithm for detection of failure to recognize and treat severe sepsis.

PubMed

Harrison, Andrew M; Thongprayoon, Charat; Kashyap, Rahul; Chute, Christopher G; Gajic, Ognjen; Pickering, Brian W; Herasevich, Vitaly

2015-02-01

To develop and test an automated surveillance algorithm (sepsis "sniffer") for the detection of severe sepsis and monitoring failure to recognize and treat severe sepsis in a timely manner. We conducted an observational diagnostic performance study using independent derivation and validation cohorts from an electronic medical record database of the medical intensive care unit (ICU) of a tertiary referral center. All patients aged 18 years and older who were admitted to the medical ICU from January 1 through March 31, 2013 (N=587), were included. The criterion standard for severe sepsis/septic shock was manual review by 2 trained reviewers with a third superreviewer for cases of interobserver disagreement. Critical appraisal of false-positive and false-negative alerts, along with recursive data partitioning, was performed for algorithm optimization. An algorithm based on criteria for suspicion of infection, systemic inflammatory response syndrome, organ hypoperfusion and dysfunction, and shock had a sensitivity of 80% and a specificity of 96% when applied to the validation cohort. In order, low systolic blood pressure, systemic inflammatory response syndrome positivity, and suspicion of infection were determined through recursive data partitioning to be of greatest predictive value. Lastly, 117 alert-positive patients (68% of the 171 patients with severe sepsis) had a delay in recognition and treatment, defined as no lactate and central venous pressure measurement within 2 hours of the alert. The optimized sniffer accurately identified patients with severe sepsis that bedside clinicians failed to recognize and treat in a timely manner. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Delay Within the 3-Hour Surviving Sepsis Campaign Guideline on Mortality for Patients With Severe Sepsis and Septic Shock.

PubMed

Pruinelli, Lisiane; Westra, Bonnie L; Yadav, Pranjul; Hoff, Alexander; Steinbach, Michael; Kumar, Vipin; Delaney, Connie W; Simon, Gyorgy

2018-04-01

To specify when delays of specific 3-hour bundle Surviving Sepsis Campaign guideline recommendations applied to severe sepsis or septic shock become harmful and impact mortality. Retrospective cohort study. One health system composed of six hospitals and 45 clinics in a Midwest state from January 01, 2011, to July 31, 2015. All adult patients hospitalized with billing diagnosis of severe sepsis or septic shock. Four 3-hour Surviving Sepsis Campaign guideline recommendations: 1) obtain blood culture before antibiotics, 2) obtain lactate level, 3) administer broad-spectrum antibiotics, and 4) administer 30 mL/kg of crystalloid fluid for hypotension (defined as "mean arterial pressure" < 65) or lactate (> 4). To determine the effect of t minutes of delay in carrying out each intervention, propensity score matching of "baseline" characteristics compensated for differences in health status. The average treatment effect in the treated computed as the average difference in outcomes between those treated after shorter versus longer delay. To estimate the uncertainty associated with the average treatment effect in the treated metric and to construct 95% CIs, bootstrap estimation with 1,000 replications was performed. From 5,072 patients with severe sepsis or septic shock, 1,412 (27.8%) had in-hospital mortality. The majority of patients had the four 3-hour bundle recommendations initiated within 3 hours. The statistically significant time in minutes after which a delay increased the risk of death for each recommendation was as follows: lactate, 20.0 minutes; blood culture, 50.0 minutes; crystalloids, 100.0 minutes; and antibiotic therapy, 125.0 minutes. The guideline recommendations showed that shorter delays indicates better outcomes. There was no evidence that 3 hours is safe; even very short delays adversely impact outcomes. Findings demonstrated a new approach to incorporate time t when analyzing the impact on outcomes and provide new evidence for clinical practice

Acute and long-term dysphagia in critically ill patients with severe sepsis: results of a prospective controlled observational study.

PubMed

Zielske, Joerg; Bohne, Silvia; Brunkhorst, Frank M; Axer, Hubertus; Guntinas-Lichius, Orlando

2014-11-01

Dysphagia is a major risk factor for morbidity and mortality in critically ill patients treated in intensive care units (ICUs). Structured otorhinolaryngological data on dysphagia in ICU survivors with severe sepsis are missing. In a prospective study, 30 ICU patients with severe sepsis and thirty without sepsis as control group were examined using bedside fiberoptic endoscopic evaluation of swallowing after 14 days in the ICU (T1) and 4 months after onset of critical illness (T2). Swallowing dysfunction was assessed using the Penetration-Aspiration Scale (PAS). The Functional Oral Intake Scale was applied to evaluate the diet needed. Primary endpoint was the burden of dysphagia defined as PAS score >5. At T1, 19 of 30 severe sepsis patients showed aspiration with a PAS score >5, compared to 7 of 30 in critically ill patients without severe sepsis (p = 0.002). Severe sepsis and tracheostomy were independent risk factors for severe dysphagia with aspiration (PAS > 5) at T1 (p = 0.042 and 0.006, respectively). 4-month mortality (T2) was 57 % in severe sepsis patients compared to 20 % in patients without severe sepsis (p = 0.006). At T2, more severe sepsis survivors were tracheostomy-dependent and needed more often tube or parenteral feeding (p = 0.014 and p = 0.040, respectively). Multivariate analysis revealed tracheostomy at T1 as independent risk factor for severe dysphagia at T2 (p = 0.030). Severe sepsis appears to be a relevant risk factor for long-term dysphagia. An otorhinolaryngological evaluation of dysphagia at ICU discharge is mandatory for survivors of severe critical illness to plan specific swallowing rehabilitation programs.

Endothelial glycocalyx degradation is more severe in patients with non-pulmonary sepsis compared to pulmonary sepsis and associates with risk of ARDS and other organ dysfunction.

PubMed

Murphy, Laura S; Wickersham, Nancy; McNeil, J Brennan; Shaver, Ciara M; May, Addison K; Bastarache, Julie A; Ware, Lorraine B

2017-10-06

Disruption of the endothelial glycocalyx contributes to acute lung injury in experimental sepsis but has not been well studied in humans. To study glycocalyx degradation in sepsis-induced ARDS, we measured plasma levels of syndecan-1, a marker for glycocalyx degradation. The present study is a retrospective observational study of 262 ventilated medical ICU patients at risk of ARDS due to severe sepsis and APACHE II ≥ 25. Plasma syndecan-1 was measured at study enrollment. Primary analysis focused on the association between syndecan-1 levels and the development of ARDS, other organ dysfunction (Brussels criteria), or in-hospital mortality. Overall, 135 (52%) patients developed ARDS. In patients with non-pulmonary sepsis, syndecan-1 levels were associated with ARDS (p = 0.05). Regardless of etiology of sepsis, higher syndecan-1 levels were associated with hepatic (p < 0.001), renal (p = 0.003), coagulation (p = 0.001), and circulatory (p = 0.02) failure as well as in-hospital mortality (p = 0.001), and there was a significant association between syndecan-1 levels and the number of vasopressors required in the first 24 h (p < 0.001). In addition, elevated syndecan levels were independently predictive of mortality in multivariable logistic regression adjusted for age and APACHE II score (odds ratio 1.85 per log increase in syndecan-1, 95% CI 1.056-3.241, p = 0.03). The extent of endothelial glycocalyx degradation is associated with non-pulmonary organ dysfunction in subjects with sepsis and is associated with ARDS but only in the subgroup with non-pulmonary sepsis. Measurement of syndecan-1 levels in sepsis patients might be useful for identifying patients at high risk of organ dysfunction and mortality as well as those who could benefit from therapies targeted at protecting or restoring the glycocalyx.

Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study.

PubMed

Ferrer, Ricard; Artigas, Antonio; Suarez, David; Palencia, Eduardo; Levy, Mitchell M; Arenzana, Angel; Pérez, Xose Luis; Sirvent, Josep-Maria

2009-11-01

Several Surviving Sepsis Campaign Guidelines recommendations are reevaluated. To analyze the effectiveness of treatments recommended in the sepsis guidelines. In a prospective observational study, we studied all adult patients with severe sepsis from 77 intensive care units. We recorded compliance with four therapeutic goals (central venous pressure 8 mm Hg or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, central venous oxygen saturation 70% or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, blood glucose greater than or equal to the lower limit of normal but less than 150 mg/dl, and inspiratory plateau pressure less than 30 cm H(2)O for mechanically ventilated patients) and four treatments (early broad-spectrum antibiotics, fluid challenge in the event of hypotension and/or lactate greater than 36 mg/dl, low-dose steroids for septic shock, drotrecogin alfa [activated] for multiorgan failure). The primary outcome measure was hospital mortality. The effectiveness of each treatment was estimated using propensity scores. Of 2,796 patients, 41.6% died before hospital discharge. Treatments associated with lower hospital mortality were early broad-spectrum antibiotic treatment (treatment within 1 hour vs. no treatment within first 6 hours of diagnosis; odds ratio, 0.67; 95% confidence interval, 0.50-0.90; P = 0.008) and drotrecogin alfa (activated) (odds ratio, 0.59; 95% confidence interval, 0.41-0.84; P = 0.004). Fluid challenge and low-dose steroids showed no benefits. In severe sepsis, early administration of broad-spectrum antibiotics in all patients and administration of drotrecogin alfa (activated) in the most severe patients reduce mortality.

Diagnostic accuracy of a screening electronic alert tool for severe sepsis and septic shock in the emergency department.

PubMed

Alsolamy, Sami; Al Salamah, Majid; Al Thagafi, Majed; Al-Dorzi, Hasan M; Marini, Abdellatif M; Aljerian, Nawfal; Al-Enezi, Farhan; Al-Hunaidi, Fatimah; Mahmoud, Ahmed M; Alamry, Ahmed; Arabi, Yaseen M

2014-12-05

Early recognition of severe sepsis and septic shock is challenging. The aim of this study was to determine the diagnostic accuracy of an electronic alert system in detecting severe sepsis or septic shock among emergency department (ED) patients. An electronic sepsis alert system was developed as a part of a quality-improvement project for severe sepsis and septic shock. The system screened all adult ED patients for a combination of systemic inflammatory response syndrome and organ dysfunction criteria (hypotension, hypoxemia or lactic acidosis). This study included all patients older than 14 years who presented to the ED of a tertiary care academic medical center from Oct. 1, 2012 to Jan. 31, 2013. As a comparator, emergency medicine physicians or the critical care physician identified the patients with severe sepsis or septic shock. In the ED, vital signs were manually entered into the hospital electronic heath record every hour in the critical care area and every two hours in other areas. We also calculated the time from the alert to the intensive care unit (ICU) referral. Of the 49,838 patients who presented to the ED, 222 (0.4%) were identified to have severe sepsis or septic shock. The electronic sepsis alert had a sensitivity of 93.18% (95% CI, 88.78% - 96.00%), specificity of 98.44 (95% CI, 98.33% - 98.55%), positive predictive value of 20.98% (95% CI, 18.50% - 23.70%) and negative predictive value of 99.97% (95% CI, 99.95% - 99.98%) for severe sepsis and septic shock. The alert preceded ICU referral by a median of 4.02 hours (Q1 - Q3: 1.25-8.55). Our study shows that electronic sepsis alert tool has high sensitivity and specificity in recognizing severe sepsis and septic shock, which may improve early recognition and management.

Key process indicators of mortality in the implementation of protocol-driven therapy for severe sepsis.

PubMed

Wang, Jiun-Long; Chin, Chun-Shih; Chang, Ming-Chen; Yi, Chi-Yuan; Shih, Sou-Jen; Hsu, Jeng-Yuan; Wu, Chieh-Liang

2009-10-01

Severe sepsis and septic shock are life-threatening disorders. Integrating treatments into a bundle strategy has been proposed to facilitate timely resuscitation, but is difficult to implement. We implemented protocol-driven therapy for severe sepsis, and analyzed retrospectively the key process indicators of mortality in managing sepsis. Continuous quality improvement was begun to implement a tailored protocol-driven therapy for sepsis in a 24-bed respiratory intensive care unit (RICU) of Taichung Veterans General Hospital from January 2007 to February 2008. Patients, who were admitted to the RICU directly, or within 24 hours, were enrolled if they met the criteria for severe sepsis and septic shock. Disease severity [Acute Physiology and Chronic Health Evaluation (APACHE) II and lactate level], causes of sepsis, comorbidity and site of sepsis onset were recorded. Process-of-care indicators included resuscitation time (Tr-s), RICU bed availability (Ti-s) and the ratio of completing the elements of the protocol at 1, 2, 4 and 6 hours. The structure and process-of-care indicators reflated to mortality at 7 days after RICU admission and at RICU discharge were identified retrospectively. Eighty-six patients (mean age, 71 +/- 14 years, 72 men, 14 women, APACHE II, 25.0 +/- 7.0) were enrolled. APACHE II scores and lactate levels were higher for mortality than survival at 7 days after RICU admission (p < 0.01). For the process-of-care indicators, Ti-s (562.2 +/- 483.3 vs.1017.3 +/- 557.8 minutes, p = 0.03) and Tr-s (60.7 +/- 207.8 vs. 248.5 +/- 453.1 minutes, p = 0.07) were shorter for survival than mortality at 7 days after RICU admission. The logistic regression study showed that Tr-s was an important indicator. The ratio of completing the elements of protocols at 1, 2, 4 and 6 hours ranged from 70% to 90% and was not related to mortality. Protocol-driven therapy for sepsis was put into clinical practice. Early resuscitation and ICU bed availability were key process

Procalcitonin levels in patients with positive blood culture, positive body fluid culture, sepsis, and severe sepsis: a cross-sectional study.

PubMed

Yu, Ying; Li, Xia-Xi; Jiang, Ling-Xiao; Du, Meng; Liu, Zhan-Guo; Cen, Zhong-Ran; Wang, Hua; Guo, Zhen-Hui; Chang, Ping

2016-01-01

Numerous investigations on procalcitonin (PCT) have been carried out, although few with large sample size. To deal with the complexity of sepsis, an understanding of PCT in heterogeneous clinical conditions is required. Hospitalized patients aged 10-79 years were included in this retrospective and cross-sectional study. PCT tests were assayed within 2 days of blood culture. A total of 2952 cases (from 2538 patients) were enrolled in this study, including 440 cases in the 'positive BC' group, 123 cases in the 'positive body fluid culture' group, and 2389 cases in the 'negative all culture' group. Median PCT values were 4.53 ng/ml, 2.95 ng/ml, and 0.49 ng/ml, respectively. Median PCT values in the gram-negative BC group and gram-positive BC group, respectively, were 6.99 ng/ml and 2.96 ng/ml. Median PCT values in the 'positive hydrothorax culture' group, 'positive ascites culture' group, 'positive bile culture' group, and 'positive cerebrospinal fluid culture' group, respectively, were 1.39 ng/ml, 8.32 ng/ml, 5.98 ng/ml, and 0.46 ng/ml. In all, 357 cases were classified into the 'sepsis' group, 150 of them were classified into the 'severe sepsis' group. Median PCT values were 5.63 ng/ml and 11.06 ng/ml, respectively. PCT could be used in clinical algorithms to diagnose positive infections and sepsis. Different PCT levels could be related to different kinds of microbemia, different infection sites, and differing severity of sepsis.

Prediction about severity and outcome of sepsis by pro-atrial natriuretic peptide and pro-adrenomedullin.

PubMed

Wang, Rui-lan; Kang, Fu-xin

2010-06-01

Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. The aim of the present study was to evaluate the prognostic value of pro-atrial natriuretic peptide (pro-ANP) and pro-adrenomedullin (pro-ADM) levels in a cohort of medical intensive care patients and to compare it with that of other known biomarkers and physiological scores. Blood samples of 51 consecutive critically ill patients admitted to the intensive care unit and 53 age-matched healthy control people were evaluated in this prospective study. The prognostic value of pro-ANP and pro-ADM levels was compared with that of acute physiology and chronic health evaluation (APACHE) II scores and various biomarkers such as C-reactive protein, interleukin-6 and procalcitonin. Pro-ANP and pro-ADM were detected by a new sandwich immunoassay. On admission, 25 patients had systemic inflammatory response syndrome (SIRS), 12 sepsis, 9 severe sepsis and 5 septic shock. At that time, the median levels (ng/ml) of pro-ANP and pro-ADM were 87.22 and 0.34 respectively in patients with SIRS, 1533.30 and 2.23 in those with sepsis, 1098.73 and 4.57 in those with severe sepsis, and 1933.94 and 8.21 in those with septic shock. With the increasing severity of disease, the levels of pro-ANP and pro-ADM were gradually increased. On admission, the circulating levels of pro-ANP and pro-ADM in patients with sepsis, severe sepsis, or septic shock were significantly higher in non-survivors than in survivors (P less than 0.05). In a receiver operating characteristic curve analysis for the survival of patients with sepsis, the areas under the curve (AUCs) for pro-ANP and pro-ADM were 0.89 and 0.87 respectively, which was similar to the AUCs for procalcitonin and APACHE II scores. Pro-ANP and pro-ADM are valuable biomarkers for prediction of severity of septic patients.

Severe malaria vivax with sepsis bacterial: a case report

NASA Astrophysics Data System (ADS)

Tarigan, P.; Ginting, F.

2018-03-01

Malaria cases are often misdiagnosis by clinicians in tropical areas like Indonesia. Some cases show overlapping signs and symptoms of another infection that are common in the tropical areas such as typhoid, dengue, and leptospirosis. It can be misdiagnosed in practice and led to a wrong management that can end fatally. Severe malaria is usually caused by Plasmodium falciparum. P. vivax can also cause severe malaria but the cases reported are uncommon. Since infections with severe P. vivax that generally results in serious disease is quite uncommon in Indonesia, their identification and management are important. We report a case of severe malaria with sepsis, renal injury and hepatic impairment associated with malaria in a 70-year-old male. Clinical manifestations included anemia, sepsis, and elevated serum creatinine, urea, total bilirubin, and procalcitonin. The rapid diagnostic test for malaria and microscopic examination of blood smears were positive for P. vivax. The patient was treated as severe malaria with intravenous artesunate for six days, followed by oral treatment of primaquine for 14 days. Intravenous fluid therapy, antipyretic, anti-malaria and antibiotic treatment were administered. The patient was stable and then discharged from the hospital. The prognosis depends much on early diagnosis and appropriate supportive treatment.

Validation of Test Performance and Clinical Time Zero for an Electronic Health Record Embedded Severe Sepsis Alert.

PubMed

Rolnick, Joshua; Downing, N Lance; Shepard, John; Chu, Weihan; Tam, Julia; Wessels, Alexander; Li, Ron; Dietrich, Brian; Rudy, Michael; Castaneda, Leon; Shieh, Lisa

2016-01-01

Increasing use of EHRs has generated interest in the potential of computerized clinical decision support to improve treatment of sepsis. Electronic sepsis alerts have had mixed results due to poor test characteristics, the inability to detect sepsis in a timely fashion and the use of outside software limiting widespread adoption. We describe the development, evaluation and validation of an accurate and timely severe sepsis alert with the potential to impact sepsis management. To develop, evaluate, and validate an accurate and timely severe sepsis alert embedded in a commercial EHR. The sepsis alert was developed by identifying the most common severe sepsis criteria among a cohort of patients with ICD 9 codes indicating a diagnosis of sepsis. This alert requires criteria in three categories: indicators of a systemic inflammatory response, evidence of suspected infection from physician orders, and markers of organ dysfunction. Chart review was used to evaluate test performance and the ability to detect clinical time zero, the point in time when a patient develops severe sepsis. Two physicians reviewed 100 positive cases and 75 negative cases. Based on this review, sensitivity was 74.5%, specificity was 86.0%, the positive predictive value was 50.3%, and the negative predictive value was 94.7%. The most common source of end-organ dysfunction was MAP less than 70 mm/Hg (59%). The alert was triggered at clinical time zero in 41% of cases and within three hours in 53.6% of cases. 96% of alerts triggered before a manual nurse screen. We are the first to report the time between a sepsis alert and physician chart-review clinical time zero. Incorporating physician orders in the alert criteria improves specificity while maintaining sensitivity, which is important to reduce alert fatigue. By leveraging standard EHR functionality, this alert could be implemented by other healthcare systems.

Validation of Test Performance and Clinical Time Zero for an Electronic Health Record Embedded Severe Sepsis Alert

PubMed Central

Downing, N. Lance; Shepard, John; Chu, Weihan; Tam, Julia; Wessels, Alexander; Li, Ron; Dietrich, Brian; Rudy, Michael; Castaneda, Leon; Shieh, Lisa

2016-01-01

Summary Bachground Increasing use of EHRs has generated interest in the potential of computerized clinical decision support to improve treatment of sepsis. Electronic sepsis alerts have had mixed results due to poor test characteristics, the inability to detect sepsis in a timely fashion and the use of outside software limiting widespread adoption. We describe the development, evaluation and validation of an accurate and timely severe sepsis alert with the potential to impact sepsis management. Objective To develop, evaluate, and validate an accurate and timely severe sepsis alert embedded in a commercial EHR. Methods The sepsis alert was developed by identifying the most common severe sepsis criteria among a cohort of patients with ICD 9 codes indicating a diagnosis of sepsis. This alert requires criteria in three categories: indicators of a systemic inflammatory response, evidence of suspected infection from physician orders, and markers of organ dysfunction. Chart review was used to evaluate test performance and the ability to detect clinical time zero, the point in time when a patient develops severe sepsis. Results Two physicians reviewed 100 positive cases and 75 negative cases. Based on this review, sensitivity was 74.5%, specificity was 86.0%, the positive predictive value was 50.3%, and the negative predictive value was 94.7%. The most common source of end-organ dysfunction was MAP less than 70 mm/Hg (59%). The alert was triggered at clinical time zero in 41% of cases and within three hours in 53.6% of cases. 96% of alerts triggered before a manual nurse screen. Conclusion We are the first to report the time between a sepsis alert and physician chart-review clinical time zero. Incorporating physician orders in the alert criteria improves specificity while maintaining sensitivity, which is important to reduce alert fatigue. By leveraging standard EHR functionality, this alert could be implemented by other healthcare systems. PMID:27437061

Combination therapy with milrinone and esmolol for heart protection in patients with severe sepsis: a prospective, randomized trial.

PubMed

Wang, Zenggeng; Wu, Qinghua; Nie, Xiangbi; Guo, Jinghua; Yang, Chunli

2015-11-01

As a β-adrenoceptor antagonist (β-blocker), esmolol can reduce cardiac output and the phosphodiesterase III inhibitor milrinone has been shown to improve heart contractility in patients with septic shock. This study was performed to assess the effects of esmolol combined with milrinone in patients with severe sepsis. This prospective randomized study was conducted in patients with severe sepsis in the intensive care unit of the Jiangxi Provincial People's Hospital (Nanchang, Jiangsu, China) between June 2013 and June 2014. Patients were randomly divided into control (C), milrinone (M), and milrinone-esmolol (ME) groups. The primary outcome was the rate of controlling the heart rate (HR) to achieve target levels. Secondary outcomes included the 28-day survival rate and changes in hemodynamic variables, organ function variables, myocardial injury markers, and the serum levels of proinflammatory factors. A total of 90 patients with severe sepsis were included in this study (30 per group). The HR in the ME group was lower than in the M and C groups after 12 h. The rate of successful HR control during the first 96 h was significantly higher in the ME group (60.0 vs. 33.3 % in the M group, vs. 26.7 % in the C group). Also, patients in the ME group had higher 28-day overall survival compared with the M (Log rank statistic = 5.452; P = 0.020) and C groups (Log rank statistic = 10.206; P = 0.001). Additionally, several variables showed significant improvement in the ME group 96 h after treatment compared with the M and C groups (P < 0.05). Combination therapy with milrinone and esmolol could improve cardiac function and the 28-day survival rate in patients with severe sepsis.

An Unbiased Systems Genetics Approach to Mapping Genetic Loci Modulating Susceptibility to Severe Streptococcal Sepsis

PubMed Central

Abdeltawab, Nourtan F.; Aziz, Ramy K.; Kansal, Rita; Rowe, Sarah L.; Su, Yin; Gardner, Lidia; Brannen, Charity; Nooh, Mohammed M.; Attia, Ramy R.; Abdelsamed, Hossam A.; Taylor, William L.; Lu, Lu; Williams, Robert W.; Kotb, Malak

2008-01-01

Striking individual differences in severity of group A streptococcal (GAS) sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL) on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%–30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases. PMID:18421376

Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment.

PubMed

Andonegui, Graciela; Zelinski, Erin L; Schubert, Courtney L; Knight, Derrice; Craig, Laura A; Winston, Brent W; Spanswick, Simon C; Petri, Björn; Jenne, Craig N; Sutherland, Janice C; Nguyen, Rita; Jayawardena, Natalie; Kelly, Margaret M; Doig, Christopher J; Sutherland, Robert J; Kubes, Paul

2018-05-03

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

Designing a Pediatric Severe Sepsis Screening Tool

PubMed Central

Sepanski, Robert J.; Godambe, Sandip A.; Mangum, Christopher D.; Bovat, Christine S.; Zaritsky, Arno L.; Shah, Samir H.

2014-01-01

We sought to create a screening tool with improved predictive value for pediatric severe sepsis (SS) and septic shock that can be incorporated into the electronic medical record and actively screen all patients arriving at a pediatric emergency department (ED). “Gold standard” SS cases were identified using a combination of coded discharge diagnosis and physician chart review from 7,402 children who visited a pediatric ED over 2 months. The tool’s identification of SS was initially based on International Consensus Conference on Pediatric Sepsis (ICCPS) parameters that were refined by an iterative, virtual process that allowed us to propose successive changes in sepsis detection parameters in order to optimize the tool’s predictive value based on receiver operating characteristics (ROC). Age-specific normal and abnormal values for heart rate (HR) and respiratory rate (RR) were empirically derived from 143,603 children seen in a second pediatric ED over 3 years. Univariate analyses were performed for each measure in the tool to assess its association with SS and to characterize it as an “early” or “late” indicator of SS. A split-sample was used to validate the final, optimized tool. The final tool incorporated age-specific thresholds for abnormal HR and RR and employed a linear temperature correction for each category. The final tool’s positive predictive value was 48.7%, a significant, nearly threefold improvement over the original ICCPS tool. False positive systemic inflammatory response syndrome identifications were nearly sixfold lower. PMID:24982852

Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis

PubMed Central

2011-01-01

Introduction CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis. Methods This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint. Results Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03). Conclusions In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target. PMID:21406105

Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis.

PubMed

Lorente, Leonardo; Martín, María M; Varo, Nerea; Borreguero-León, Juan María; Solé-Violán, Jordi; Blanquer, José; Labarta, Lorenzo; Díaz, César; Jiménez, Alejandro; Pastor, Eduardo; Belmonte, Felipe; Orbe, Josune; Rodríguez, José A; Gómez-Melini, Eduardo; Ferrer-Agüero, José M; Ferreres, José; Llimiñana, María C; Páramo, José A

2011-03-15

CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis. This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint. Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03). In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target.

Persistent inflammation and T cell exhaustion in severe sepsis in the elderly

PubMed Central

2014-01-01

Introduction Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis. Methods Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥65 years) and adult (18–64 years) septic patients with serial measurement of serum interleukin (IL)-6. Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation. In the mouse study, young (6–8 weeks) and aged (20–22 months) C57/B6 mice were subjected to cecal ligation and puncture (CLP), and survival was compared after 7 days with serial measurement of serum IL-6. Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured. Results The survival rate in elderly sepsis patients and aged septic mice was significantly lower than that in adult patients and young septic mice (60% vs. 93% in septic patients, 0% vs. 63% in septic mice, P < 0.05). Serum IL-6 levels in elderly sepsis patients and aged septic mice were persistently higher than those in adult patients and young septic mice. Expression of negative co-stimulatory molecules in CD4+ T cells in the spleen, lymph nodes, and peripheral blood was significantly higher in aged mice than in young mice (P < 0.01). Ex vivo stimulation decreased CD25 expression, IL-2 production, and proliferation to a greater extent in CD4+ T cells from elderly patients and aged septic mice than in those from adult patients and young septic mice. Elderly patients demonstrated increased

Beneficial effects of the heme oxygenase-1/carbon monoxide system in patients with severe sepsis/septic shock.

PubMed

Takaki, Shoji; Takeyama, Naoshi; Kajita, Yuka; Yabuki, Teru; Noguchi, Hiroki; Miki, Yasuo; Inoue, Yasusuke; Nakagawa, Takashi; Noguchi, Hiroshi

2010-01-01

We evaluated the relations among the arterial carbon monoxide (CO) concentration, heme oxygenase (HO)-1 expression by monocytes, oxidative stress, plasma levels of cytokines and bilirubin, and the outcome of patients with severe sepsis or septic shock. Thirty-six patients who fulfilled the criteria for severe sepsis or septic shock and 21 other patients without sepsis during their stay in the intensive care unit were studied. HO-1 protein expression by monocytes, arterial CO, oxidative stress, bilirubin, and cytokines were measured. Arterial blood CO, cytokine, and bilirubin levels, and monocyte HO-1 protein expression were higher in patients with severe sepsis/septic shock than in non-septic patients. Increased HO-1 expression was related to the arterial CO concentration and oxidative stress. There was a positive correlation between survival and increased HO-1 protein expression or a higher CO level. Arterial CO and monocyte HO-1 protein expression were increased in critically ill patients, particularly those with severe sepsis or septic shock, suggesting that oxidative stress is closely related to HO-1 expression. The HO-1/CO system may play an important role in sepsis.

Clinical Significance of Tissue Factor and CD13 Double-Positive Microparticles in Sirs Patients with Trauma and Severe Sepsis.

PubMed

Matsumoto, Hisatake; Yamakawa, Kazuma; Ogura, Hiroshi; Koh, Taichin; Matsumoto, Naoya; Shimazu, Takeshi

2017-04-01

Activated immune cells such as monocytes are key factors in systemic inflammatory response syndrome (SIRS) following trauma and sepsis. Activated monocytes induce almost all tissue factor (TF) expression contributing to inflammation and coagulation. TF and CD13 double-positive microparticles (TF/CD13MPs) are predominantly released from these activated monocytes. This study aimed to evaluate TF/CD13MPs and assess their usefulness as a biomarker of pathogenesis in early SIRS following trauma and sepsis. This prospective study comprising 24 trauma patients, 25 severe sepsis patients, and 23 healthy controls was conducted from November 2012 to February 2015. Blood samples were collected from patients within 24 h after injury and diagnosis of severe sepsis and from healthy controls. Numbers of TF/CD13MPs were measured by flow cytometry immediately thereafter. Injury Severity Score (ISS) and Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were calculated at patient enrollment. APACHE II and SOFA scores and International Society of Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) diagnostic criteria algorithm were calculated at the time of enrollment of severe sepsis patients. Numbers of TF/CD13MPs were significantly increased in both trauma and severe sepsis patients versus controls and correlated significantly with ISS and APACHE II score in trauma patients and with APACHE II and ISTH DIC scores in severe sepsis patients. Increased numbers of TF/CD13MPs correlated significantly with severities in the acute phase in trauma and severe sepsis patients, suggesting that TF/CD13MPs are important in the pathogenesis of early SIRS following trauma and sepsis.

Plasma dia-filtration for severe sepsis.

PubMed

Eguchi, Yutaka

2010-01-01

The mortality rate in severe sepsis is 30-50%, and independent liver and renal dysfunction impacts significantly on hospital and intensive care mortality. If 4 or more organs fail, mortality is > 90%. Recently, we reported a novel plasmapheresis--plasma diafiltration (PDF)--the concept of which is plasma filtration with dialysis. PDF employs a plasma separator that has a sieving coefficient of 0.3 for albumin and which requires flowing dialysate outside the hollow fiber. For substitute liquid, 1,200 ml of fresh frozen plasma followed by 50 ml of 25% albumin solution is used for 8 h as 1 session. In a single-center study, 24 patients with septic shock were admitted to the ICU, then 37.7 +/- 30.0 h later, 7 patients received PDF. The patients' Sequential Organ Failure Assessment (SOFA) scores had increased from 14.9 +/- 3.6 on ICU admission to 17.1 +/- 3.0 before PDF procedure. PDF was performed, with an average of 7.4 +/- 4.4 sessions (range 3-15) per patient. Five patients survived after day 28, thus the 28-day mortality rate was 29%. In our multicenter study, 33 patients with severe sepsis who simultaneously suffered from liver dysfunction were enrolled and received PDF. On average, 12.0 +/- 16.4 sessions (range 2-70) per patient were performed. The 28-day mortality rate was 36.4%, while the predicted death rate was 68.0 +/- 17.7%. These findings suggest that PDF is a simple modality and may become a useful strategy for treatment of patients with septic multiple organ failure. Copyright 2010 S. Karger AG, Basel.

Infection Rate and Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis

PubMed Central

Mayr, Florian B.; Yende, Sachin; Linde-Zwirble, Walter T.; Peck-Palmer, Octavia M.; Barnato, Amber E.; Weissfeld, Lisa A.; Angus, Derek C.

2013-01-01

Context Severe sepsis, defined as infection complicated by acute organ dysfunction, occurs more frequently and leads to more deaths in black than in white individuals. The optimal approach to minimize these disparities is unclear. Objective To determine the extent to which higher severe sepsis rates in black than in white patients are due to higher infection rates or to a higher risk of acute organ dysfunction. Design, Setting, and Participants Analysis of infection-related hospitalizations from the 2005 hospital discharge data of 7 US states and infection-related emergency department visits from the 2003-2007 National Hospital Ambulatory Care Survey. Main Outcome Measure Age- and sex-standardized severe sepsis and infection hospitalization rates and the risk of acute organ dysfunction. Results Of 8 661 227 non–childbirth-related discharges, 2 261 857 were associated with an infection, and of these, 381 787 (16.8%) had severe sepsis. Black patients had a 67% higher age- and sex-standardized severe sepsis rate than did white patients (9.4; 95% confidence interval [CI], 9.3-9.5 vs 5.6; 95% CI, 5.6-5.6 per 1000 population; P<.001) and 80% higher standardized mortality (1.8, 95% CI, 1.8-1.9 vs 1.0, 95% CI, 1.0-1.1 per 1000 population; P<.001). The higher severe sepsis rate was explained by both a higher infection rate in black patients (47.3; 95% CI, 47.1-47.4 vs 34.0; 95% CI, 33.9-34.0 per 1000 population; incidence rate ratio, 1.39; P<.001) and a higher risk of developing acute organ dysfunction (age- and sex-adjusted odds ratio [OR],1.29; 95% CI, 1.27-1.30; P<.001). Differences in infection presented broadly across different sites and etiology of infection and for community- and hospital-acquired infections and occurred despite a lower likelihood of being admitted for infection from the emergency department (adjusted OR, 0.70; 95% CI, 0.64-0.76; P<.001). The higher risk of organ dysfunction persisted but was attenuated after adjusting for age, sex, comorbid

Protocolized treatment is associated with decreased organ dysfunction in pediatric severe sepsis

PubMed Central

Balamuth, Fran; Weiss, Scott L.; Fitzgerald, Julie C.; Hayes, Katie; Centkowski, Sierra; Chilutti, Marianne; Grundmeier, Robert W.; Lavelle, Jane; Alpern, Elizabeth R.

2016-01-01

Objective To determine whether treatment with a protocolized sepsis guideline in the emergency department (ED) was associated with a lower burden of organ dysfunction (OD) by hospital day 2 compared to non-protocolized usual care in pediatric patients with severe sepsis. Design Retrospective cohort study Setting Tertiary care children’s hospital from January 1, 2012–March 31, 2014. Measurements and Main Results Subjects with international consensus defined severe sepsis and pediatric intensive care unit (PICU) admission within 24 hours of ED arrival were included. The exposure was the use of a protocolized ED sepsis guideline. The primary outcome was complete resolution of OD by hospital day 2. One hundred eighty nine subjects were identified during the study period. Of these, 121 (64%) were treated with the protocolized ED guideline and 68 were not. There were no significant differences between the groups in age, sex, race, number of comorbid conditions, ED triage level, or OD on arrival to the ED. Patients treated with protocolized ED care were more likely to be free of OD on hospital day 2 after controlling for sex, comorbid condition, indwelling central venous catheter, PIM-2 score, and timing of antibiotics and intravenous fluids (adjusted OR 4.2, 95% CI 1.7, 10.4). Conclusions Use of a protocolized ED sepsis guideline was independently associated with resolution of OD by hospital day 2 compared to non-protocolized usual care. These data indicate that morbidity outcomes in children can be improved with the use of protocolized care. PMID:27455114

Protocolized Treatment Is Associated With Decreased Organ Dysfunction in Pediatric Severe Sepsis.

PubMed

Balamuth, Fran; Weiss, Scott L; Fitzgerald, Julie C; Hayes, Katie; Centkowski, Sierra; Chilutti, Marianne; Grundmeier, Robert W; Lavelle, Jane; Alpern, Elizabeth R

2016-09-01

To determine whether treatment with a protocolized sepsis guideline in the emergency department was associated with a lower burden of organ dysfunction by hospital day 2 compared to nonprotocolized usual care in pediatric patients with severe sepsis. Retrospective cohort study. Tertiary care children's hospital from January 1, 2012, to March 31, 2014. Patients older than 56 days old and younger than 18 years old with international consensus defined severe sepsis and who required PICU admission within 24 hours of emergency department arrival were included. The exposure was the use of a protocolized emergency department sepsis guideline. The primary outcome was complete resolution of organ dysfunction by hospital day 2. One hundred eighty nine subjects were identified during the study period. Of these, 121 (64%) were treated with the protocolized emergency department guideline and 68 were not. There were no significant differences between the groups in age, sex, race, number of comorbid conditions, emergency department triage level, or organ dysfunction on arrival to the emergency department. Patients treated with protocolized emergency department care were more likely to be free of organ dysfunction on hospital day 2 after controlling for sex, comorbid condition, indwelling central venous catheter, Pediatric Index of Mortality-2 score, and timing of antibiotics and IV fluids (adjusted odds ratio, 4.2; 95% CI, 1.7-10.4). Use of a protocolized emergency department sepsis guideline was independently associated with resolution of organ dysfunction by hospital day 2 compared to nonprotocolized usual care. These data indicate that morbidity outcomes in children can be improved with the use of protocolized care.

The Ratio of Arginine to Dimethylarginines is Reduced and Predicts Outcomes in Patients with Severe Sepsis

PubMed Central

Gough, Michael S.; Morgan, Mary Anne M.; Mack, Cynthia M.; Darling, Denise C.; Frasier, Lauren M.; Doolin, Kathleen P.; Apostolakos, Michael J.; Stewart, Judith C.; Graves, Brian T.; Arning, Erland; Bottiglieri, Teodoro; Mooney, Robert A.; Frampton, Mark W.; Pietropaoli, Anthony P.

2011-01-01

Objective Arginine deficiency may contribute to microvascular dysfunction, but previous studies suggest that arginine supplementation may be harmful in sepsis. Systemic arginine availability can be estimated by measuring the ratio of arginine to its endogenous inhibitors, asymmetric and symmetric dimethylarginine. We hypothesized that the arginine to dimethylarginine (Arg/DMA) ratio is reduced in patients with severe sepsis and associated with severity of illness and outcomes. Design Case-control and prospective cohort study Setting Medical and surgical intensive care units of an academic medical center Patients and Subjects 109 severe sepsis and 50 control subjects Measurements and Main Results Plasma and urine were obtained in control subjects and within 48 hours of diagnosis in severe sepsis patients. The Arg/DMA ratio was higher in control subjects vs. sepsis patients ((median = 95 [inter-quartile range = 85 – 114]) vs. 34 [24 – 48], p < 0.001), and in hospital survivors vs. non-survivors ((39 [26 – 52]) vs. 27 [19 – 32], p = 0.004). The Arg/DMA ratio was correlated with Acute Physiology and Chronic Health Evaluation II score (Spearman’s correlation coefficient [rho] = − 0.40, p < 0.001) and organ-failure free days (rho = 0.30, p = 0.001). A declining Arg/DMA ratio was independently associated with hospital mortality (odds ratio =1.63 per quartile, 95% confidence interval [CI] = 1.00 – 2.65, p = 0.048) and risk of death over 6 months (hazard ratio = 1.41 per quartile, 95% CI = 1.01 – 1.98, p = 0.043). The Arg/DMA ratio was correlated with the urinary nitrate to creatinine ratio (rho = 0.46, p < 0.001). Conclusions The Arg/DMA ratio is associated with severe sepsis, severity of illness, and clinical outcomes. The Arg/DMA ratio may be a useful biomarker, and interventions designed to augment systemic arginine availability in severe sepsis may still be worthy of investigation. PMID:21378552

Resuscitation With Balanced Fluids Is Associated With Improved Survival in Pediatric Severe Sepsis.

PubMed

Emrath, Elizabeth T; Fortenberry, James D; Travers, Curtis; McCracken, Courtney E; Hebbar, Kiran B

2017-07-01

To evaluate outcomes in patients receiving balanced fluids for resuscitation in pediatric severe sepsis. Observational cohort review of prospectively collected data from a large administrative database. PICUs from 43 children's hospitals. PICU patients diagnosed with severe sepsis. None. We reviewed data from the Pediatric Health Information System database from 2004 to 2012. Children with pediatric severe sepsis receiving balanced fluids for resuscitation in the first 24 and 72 hours of treatment were compared to those receiving unbalanced fluids. Thirty-six thousand nine hundred eight patients met entry criteria for analysis. Two thousand three hundred ninety-eight patients received exclusively balanced fluids at 24 hours and 1,641 at 72 hours. After propensity matching, the 72-hour balanced fluids group had lower mortality (12.5% vs 15.9%; p = 0.007; odds ratio, 0.76; 95% CI, 0.62-0.93), lower prevalence of acute kidney injury (16.0% vs 19.2%; p = 0.028; odds ratio, 0.82; 95% CI, 0.68-0.98), and fewer vasoactive infusion days (3.0 vs 3.3 d; p < 0.001) when compared with the unbalanced fluids group. In this retrospective analysis carried out by propensity matching, exclusive use of balanced fluids in pediatric severe sepsis patients for the first 72 hours of resuscitation was associated with improved survival, decreased prevalence of acute kidney injury, and shorter duration of vasoactive infusions when compared with exclusive use of unbalanced fluids.

Epidemiology and Outcome of Severe Sepsis and Septic Shock in Intensive Care Units in Mainland China

PubMed Central

Zhou, Jianfang; Qian, Chuanyun; Zhao, Mingyan; Yu, Xiangyou; Kang, Yan; Ma, Xiaochun; Ai, Yuhang; Xu, Yuan; Liu, Dexin; An, Youzhong; Wu, Dawei; Sun, Renhua; Li, Shusheng; Hu, Zhenjie; Cao, Xiangyuan; Zhou, Fachun; Jiang, Li; Lin, Jiandong; Mao, Enqiang; Qin, Tiehe; He, Zhenyang; Zhou, Lihua; Du, Bin

2014-01-01

Introduction Information about sepsis in mainland China remains scarce and incomplete. The purpose of this study was to describe the epidemiology and outcome of severe sepsis and septic shock in mixed ICU in mainland China, as well as the independent predictors of mortality. Methods We performed a 2-month prospective, observational cohort study in 22 closed multi-disciplinary intensive care units (ICUs). All admissions into those ICUs during the study period were screened and patients with severe sepsis or septic shock were included. Results A total of 484 patients, 37.3 per 100 ICU admissions were diagnosed with severe sepsis (n = 365) or septic shock (n = 119) according to clinical criteria and included into this study. The most frequent sites of infection were the lung and abdomen. The overall ICU and hospital mortality rates were 28.7% (n = 139) and 33.5% (n = 162), respectively. In multivariate analyses, APACHE II score (odds ratio[OR], 1.068; 95% confidential interval[CI], 1.027–1.109), presence of ARDS (OR, 2.676; 95%CI, 1.691–4.235), bloodstream infection (OR, 2.520; 95%CI, 1.142–5.564) and comorbidity of cancer (OR, 2.246; 95%CI, 1.141–4.420) were significantly associated with mortality. Conclusions Our results indicated that severe sepsis and septic shock were common complications in ICU patients and with high mortality in China, and can be of help to know more about severe sepsis and septic shock in China and to improve characterization and risk stratification in these patients. PMID:25226033

Recognition and treatment of severe sepsis in the emergency department: retrospective study in two French teaching hospitals.

PubMed

Le Conte, Philippe; Thibergien, Séverin; Obellianne, Jean Batiste; Montassier, Emmanuel; Potel, Gilles; Roy, Pierre Marie; Batard, Eric

2017-08-30

Sepsis management in the Emergency Department remains a daily challenge. The Surviving Sepsis Campaign (SSC) has released three-hour bundle. The implementation of these bundles in European Emergency Departments remains poorly described. The main objective was to assess the compliance with the Severe Sepsis Campaign 3-h bundle (blood culture, lactate dosage, first dose of antibiotics and 30 ml/kg fluid challenge). Secondary objectives were the analysis of the delay of severe sepsis recognition and description of the population. In accordance with STROBE statement, we performed a retrospective study in two French University Hospital Emergency Departments from February to August 2015. Patients admitted during the study period were screened using the electronic files of the hospital databases. Patient's files were reviewed and included in the study if they met severe sepsis criteria. Demographics, comorbities, treatments were recorded. Delays from admission to severe sepsis diagnosis, fluid loading onset and antibiotics administration were calculated. One hundred thirty patients were included (76 men, mean age 71 ± 14 years). Blood culture, lactate dosage, antibiotics and 30 ml/kg fluid loading were performed within 3 hours in % [95% confidence interval] 100% [96-100%], 62% [54-70%], 49% [41-58%] and 19% [13-27%], respectively. 25 patients out of 130 (19% [13-27%]) fulfilled each criteria of the 3-h bundle. The mean fluid loading volume was 18 ± 11 ml/kg. Mean delay between presentation and severe sepsis diagnosis was 200 ± 263 min, from diagnosis to fluid challenge and first antibiotic dose, 10 ± 27 min and 20 ± 55 min, respectively. Compliance with SSC 3-h bundle and delay between admission and sepsis recognition have to be improved. If confirmed by other studies, an improvement program might be deployed.

DcR3, a new biomarker for sepsis, correlates with infection severity and procalcitonin.

PubMed

Gao, Liqin; Yang, Bin; Zhang, Hairong; Ou, Qishui; Lin, Yulan; Zhang, Mei; Zhang, Zhenhuan; Kim, Sunghee; Wu, Bing; Wang, Zeng; Fu, Lengxi; Lin, Jingan; Chen, Ruiqing; Lan, Ruilong; Chen, Junying; Chen, Wei; Chen, Long; Zhang, Hengshan; Han, Deping; Chen, Jingrong; Okunieff, Paul; Lin, Jianhua; Zhang, Lurong

2018-02-16

Early diagnosis of sepsis is critical for successful treatment. The clinical value of DcR3 in early diagnosis of sepsis was determined in a dynamic follow-up study. Alterations in plasma levels of DcR3, PCT, CRP, and IL-6 were measured by ELISA and compared among patients with sepsis ( n = 134), SIRS ( n = 60) and normal adults ( n = 50). Correlations and dynamic patterns among the biomarkers, APACHE II scores, clinical outcomes, and pathogens were also examined. Plasma DcR3 was significantly increased in sepsis compared to SIRS and normal adults (median 3.87 vs. 1.28 and 0.17 ng/ml). The elevated DcR3 could be detected in 97.60% sepsis patients 1-2 days prior to the result of blood culture reported. For diagnosis of sepsis, the sensitivity was 97.69% and specificity 98.04%; and for differential diagnosis of sepsis from SIRS, the sensitivity was 90.77% and specificity 98.40%. DcR3 level was positively correlated with severity of sepsis ( r s = 0.82). In 41 patients who died of sepsis, DcR3 elevated as early as 1-2 days before blood culture and peaked on day 3 after blood culture performed. In 90% of sepsis patients, the dynamic alteration pattern of DcR3 was identical to that of PCT, while pattern of 10% patients differed in which clinical data was consistent with DcR3. In 13% sepsis patients, while PCT remained normal, DcR3 levels were at a high level. DcR3 levels had no difference among various pathogens infected. DcR3, a new biomarker, will aid in early diagnosis of sepsis and monitoring its outcome, especially when sepsis patients were PCT negative.

Cardiac hyporesponsiveness in severe sepsis is associated with nitric oxide-dependent activation of G protein receptor kinase.

PubMed

Dal-Secco, Daniela; DalBó, Silvia; Lautherbach, Natalia E S; Gava, Fábio N; Celes, Mara R N; Benedet, Patricia O; Souza, Adriana H; Akinaga, Juliana; Lima, Vanessa; Silva, Katiussia P; Kiguti, Luiz Ricardo A; Rossi, Marcos A; Kettelhut, Isis C; Pupo, André S; Cunha, Fernando Q; Assreuy, Jamil

2017-07-01

G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP). Heart function was assessed by isolated and perfused heart, echocardiography, and β-adrenergic receptor binding. GRK2 was determined by immunofluorescence and Western blot analysis in the heart and isolated cardiac myocytes. Sepsis increased NOS2 expression in the heart, increased plasma nitrite + nitrate levels, and reduced isoproterenol-induced isolated ventricle contraction, whole heart tension development, and β-adrenergic receptor density. Treatment with 1400W or with GRK2 inhibitor prevented CLP-induced cardiac hyporesponsiveness 12 and 24 h after CLP. Increased labeling of total and phosphorylated GRK2 was detected in hearts after CLP. With treatment of 1400W or in hearts taken from septic NOS2 knockout mice, the activation of GRK2 was reduced. 1400W or GRK2 inhibitor reduced mortality, improved echocardiographic cardiac parameters, and prevented organ damage. Therefore, during sepsis, NOS2-derived NO increases GRK2, which leads to a reduction in β-adrenergic receptor density, contributing to the heart dysfunction. Isolated cardiac myocyte data indicate that NO acts through the soluble guanylyl cyclase/cGMP/PKG pathway. GRK2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction. NEW & NOTEWORTHY The main novelty presented here is to show that septic shock induces cardiac hyporesponsiveness to isoproterenol by a mechanism dependent on nitric oxide and mediated by G protein-coupled receptor kinase isoform 2. Therefore

Clinical course of sepsis, severe sepsis, and septic shock in a cohort of infected patients from ten Colombian hospitals

PubMed Central

2013-01-01

Background Sepsis has several clinical stages, and mortality rates are different for each stage. Our goal was to establish the evolution and the determinants of the progression of clinical stages, from infection to septic shock, over the first week, as well as their relationship to 7-day and 28-day mortality. Methods This is a secondary analysis of a multicenter cohort of inpatients hospitalized in general wards or intensive care units (ICUs). The general estimating equations (GEE) model was used to estimate the risk of progression and the determinants of stages of infection over the first week. Cox regression with time-dependent covariates and fixed covariates was used to determine the factors related with 7-day and 28-day mortality, respectively. Results In 2681 patients we show that progression to severe sepsis and septic shock increases with intraabdominal and respiratory sources of infection [OR = 1,32; 95%IC = 1,20-1,46 and OR = 1.21, 95%CI = 1,11-1,33 respectively], as well as according to Acute Physiology and Chronic Health Evaluation II (APACHE II) [OR = 1,03; 95%CI = 1,02-1,03] and Sequential Organ Failure Assessment (SOFA) [OR = 1,16; 95%CI = 1,14-1,17] scores. The variables related with first-week mortality were progression to severe sepsis [HR = 2,13; 95%CI = 1,13-4,03] and septic shock [HR = 3,00; 95%CI = 1,50-5.98], respiratory source of infection [HR = 1,76; 95%IC = 1,12-2,77], APACHE II [HR = 1,07; 95% CI = 1,04-1,10] and SOFA [HR = 1,09; 95%IC = 1,04-1,15] scores. Conclusions Intraabdominal and respiratory sources of infection, independently of SOFA and APACHE II scores, increase the risk of clinical progression to more severe stages of sepsis; and these factors, together with progression of the infection itself, are the main determinants of 7-day and 28-day mortality. PMID:23883312

Increased serum thrombomodulin level is associated with disease severity and mortality in pediatric sepsis.

PubMed

Lin, Jainn-Jim; Hsiao, Hsiang-Ju; Chan, Oi-Wa; Wang, Yu; Hsia, Shao-Hsuan; Chiu, Cheng-Hsun

2017-01-01

Endothelial dysfunction plays an important role in the pathophysiology of sepsis. As previously reported, the serum thrombomodulin is elevated in diseases associated with endothelial injury. The aim of this study was to investigate the association of serum thrombomodulin level in different pediatric sepsis syndromes and evaluate the relationship with disease severity and mortality. We prospectively collected cases of sepsis treated in a pediatric intensive care unit from June 2012 to July 2015 at Chang Gung Children's Hospital in Taoyuan, Taiwan. Clinical characteristics and serum thrombomodulin levels were analyzed. Increased serum thrombomodulin levels on days 1 and 3 of the diagnosis of sepsis were found in different pediatric sepsis syndromes. Patients with septic shock had significantly increased serum thrombomodulin levels on days 1 and 3 [day 1: median, 6.9 mU/ml (interquartile range (IQR): 5.8-12.8) and day 3: median, 5.8 mU/ml (IQR: 4.6-10.8)] compared to healthy controls [median, 3.4 mU/ml (IQR: 2.3-4.2)] (p = <0.001 and 0.001, respectively) and those with sepsis [day 1: median, 2.9 mU/ml (IQR: 1.8-4.7) and day 3: median, 3 mU/ml (IQR: 1.5-3.5)] and severe sepsis [day 1: median, 3.3 mU/ml (IQR: 1.3-8.6) and day 3: median, 4.4 mU/ml (IQR: 0.5-6)] (p = <0.001 and 0.001, respectively). There was also a significant positive correlation between serum thrombomodulin level on day 1 and day 1 PRISM-II, PELOD, P-MOD and DIC scores. The patients who died had significantly higher serum thrombomodulin levels on days 1 and 3 [day 1: median, 9.9 mU/ml (IQR: 6.2-15.6) and day 3: median, 10.4 mU/ml (IQR: 9.2-11.7)] than the survivors [day 1; median, 4.4 mU/ml (IQR: 2.2-7.5) and day 3: [median, 3.5 mU/ml (IQR: 1.6-5.7)] (p = 0.046 and 0.012, respectively). Increased serum thrombomodulin levels were found in different pediatric sepsis syndromes and correlated with disease severity and mortality.

Endoplasmic Reticulum Stress in Sepsis

PubMed Central

Khan, Mohammad Moshahid; Yang, Weng-Lang; Wang, Ping

2015-01-01

Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units (ICU). Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with the sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. Under the stress and inflammation condition, ER loses the homeostasis in its function, which is termed as ER stress. During ER stress, unfolded protein response (UPR) is activated to restore ER function to its normal balance. However, once the stress is beyond the compensatory capacity of UPR or protracted, the apoptosis would be initiated by triggering cell injuries, even to cell death. As such, ER stress and UPR are reported to be implicated in several pathological and inflammatory conditions. Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidences that ER stress participate in the pathogenesis of sepsis. In this review, we summarize the current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma- hemorrhage, and ischemia/reperfusion (I/R) injury. We also discuss the potential implication of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis. PMID:26125088

Predictors of sepsis in moderately severely injured patients: an analysis of the National Trauma Data Bank.

PubMed

Kisat, Mehreen; Villegas, Cassandra V; Onguti, Sharon; Zafar, Syed Nabeel; Latif, Asad; Efron, David T; Haut, Elliott R; Schneider, Eric B; Lipsett, Pamela A; Zafar, Hasnain; Haider, Adil H

2013-02-01

Post-traumatic sepsis is a significant cause of in-hospital death. However, socio-demographic and clinical characteristics that may predict sepsis in injured patients are not well known. The objective of this study was to identify risk factors that may be associated with post-traumatic sepsis. Retrospective analysis of patients in the National Trauma Data Bank for 2007-2008. Patients older than 16 years of age with an Injury Severity Score (ISS) ≥ 9 points were included. Multivariable logistic regression was used to determine association of sepsis with patient (age, gender, ethnicity, and insurance status), injury (mechanism, ISS, injury type, hypotension), and clinical (major surgical procedure, intensive care unit admission) characteristics. Of a total of 1.3 million patients, 373,370 met the study criteria, and 1.4% developed sepsis, with an associated mortality rate of approximately 20%. Age, male gender, African-American race, hypotension on emergency department presentation, and motor vehicle crash as the injury mechanism were independently associated with post-traumatic sepsis. Socio-demographic and injury factors, such as age, race, hypotension on admission, and severity and mechanism of injury predict post-traumatic sepsis significantly. Further exploration to explain why these patient groups are at increased risk is warranted in order to understand better and potentially prevent this life-threatening complication.

Cellular and extracellular miRNAs are blood-compartment-specific diagnostic targets in sepsis.

PubMed

Reithmair, Marlene; Buschmann, Dominik; Märte, Melanie; Kirchner, Benedikt; Hagl, Daniel; Kaufmann, Ines; Pfob, Martina; Chouker, Alexander; Steinlein, Ortrud K; Pfaffl, Michael W; Schelling, Gustav

2017-10-01

Septic shock is a common medical condition with a mortality approaching 50% where early diagnosis and treatment are of particular importance for patient survival. Novel biomarkers that serve as prompt indicators of sepsis are urgently needed. High-throughput technologies assessing circulating microRNAs represent an important tool for biomarker identification, but the blood-compartment specificity of these miRNAs has not yet been investigated. We characterized miRNA profiles from serum exosomes, total serum and blood cells (leukocytes, erythrocytes, platelets) of sepsis patients by next-generation sequencing and RT-qPCR (n = 3 × 22) and established differences in miRNA expression between blood compartments. In silico analysis was used to identify compartment-specific signalling functions of differentially regulated miRNAs in sepsis-relevant pathways. In septic shock, a total of 77 and 103 miRNAs were down- and up-regulated, respectively. A majority of these regulated miRNAs (14 in serum, 32 in exosomes and 73 in blood cells) had not been previously associated with sepsis. We found a distinctly compartment-specific regulation of miRNAs between sepsis patients and healthy volunteers. Blood cellular miR-199b-5p was identified as a potential early indicator for sepsis and septic shock. miR-125b-5p and miR-26b-5p were uniquely regulated in exosomes and serum, respectively, while one miRNA (miR-27b-3p) was present in all three compartments. The expression of sepsis-associated miRNAs is compartment-specific. Exosome-derived miRNAs contribute significant information regarding sepsis diagnosis and survival prediction and could serve as newly identified targets for the development of novel sepsis biomarkers. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Bacteremic Urinary Tract Infection Caused by Multidrug-Resistant Enterobacteriaceae Are Associated With Severe Sepsis at Admission

PubMed Central

Lee, Yi-Chien; Hsiao, Chih-Yen; Hung, Miao-Chiu; Hung, Sheng-Che; Wang, Hung-Ping; Huang, Yun-Jhong; Wang, Jann-Tay

2016-01-01

Abstract The purpose of this study is to compare the clinical features and treatment outcomes among patients with bacteremic urinary tract infection (UTI) caused by multidrug-resistant (MDR) and non-MDR Enterobacteriaceae and to identify whether MDR pathogens were independently associated with severe sepsis or septic shock at presentation. The clinical data of adult patients visiting and being treated at Chia-Yi Christian Hospital due to bacteremic UTI caused by Enterobacteriaceae from January 2006 to August 2015 were retrospectively analyzed. A total of 585 patients were enrolled. Among them, 220 (37.6%) were caused by the MDR Enterobacteriaceae. A total of 206 patients (35.2%) developed severe sepsis or septic shock at presentation. Patients in the MDR group tend to be male and have a past history of gout, recurrent UTI, prior hospitalization, hydronephrosis, renal stone, ureteral stone, indwelling urinary catheter, newly development of renal dysfunction, severe sepsis or septic shock, intensive care unit (ICU) admission, receipt of ineffective empirical therapy, longer hospital stay, and higher in-hospital mortality (2.7% vs 1.9%, P = 0.569). Using multivariate logistic regression analysis, it is revealed that independent predictors associated with severe sepsis or septic shock at presentation were liver cirrhosis (OR 2.868; 95% CI 1.439–5.716; P = 0.003), indwelling urinary catheter (OR 1.936; 95% CI 1.238–3.027; P = 0.004), and MDR Enterobacteriaceae (OR 1.447; 95% CI 1.002–2.090; P = 0.049). Multidrug resistance was associated with the development of severe sepsis or septic shock upon presentation among patients with bacteremic UTI caused by Enterobacteriaceae. Therefore, empirical antibiotics therapy for patients with UTI presented with severe sepsis and/or septic shock should be more broad-spectrum to effectively cover MDR Enterobacteriaceae. PMID:27196480

The -260 C-->T promoter polymorphism of the lipopolysaccharide receptor CD14 and severe sepsis in trauma patients.

PubMed

Heesen, Michael; Bloemeke, Brunhilde; Schade, Ulrich; Obertacke, Udo; Majetschak, Matthias

2002-08-01

CD14, expressed on the cell surface of monocytes and hepatic Kupffer cells, interacts with Gram-positive and Gram-negative bacteria. Upon CD14 stimulation, these cells respond with the enhanced release of cytokines involved in the pathophysiology of sepsis. The purpose of this study was to evaluate whether the genotype distribution of the -260 C-->T promoter polymorphism of the CD14 gene is associated with the development of severe sepsis in trauma patients. Fifty-eight severely injured blunt trauma patients with an injury severity score of 16 or more and without pre-existing chronic diseases. Genotyping for the single nucleotide exchange polymorphism of the CD14 gene was performed by means of a real-time polymerase chain reaction with fluorescence-labeled hybridization probes. Diagnosis of severe sepsis was based on the criteria of the ACCP/SCCM criteria. Fourteen out of the 58 patients (24.6%) developed a trauma-related severe sepsis. The overall allele frequency was 0.58 for the C allele and 0.42 for the T allele. The genotype distribution (TT 0.19, CT 0.47 and CC 0.35) did not differ significantly from a previously reported control group of healthy blood donors. There was no significant difference of the genotype distribution or allele frequency between trauma patients with severe sepsis and patients with an uncomplicated clinical course. This pilot study suggests that the CD14 -260 polymorphism is not associated with an increased risk of severe sepsis in trauma patients.

Adoption and de-adoption of drotrecogin alfa for severe sepsis in the United States.

PubMed

Kahn, Jeremy M; Le, Tri Q

2016-04-01

Drotrecogin alfa was a landmark drug for treatment of severe sepsis, yet little is known about how it was adopted and de-adopted during its 10-year period of availability. We used hospitalization data on fee-for-service Medicare beneficiaries from 2002 to 2011 to characterize trends in the use of drotrecogin alfa in the United States. Drotrecogin alfa use peaked at 5.87 per 1000 severe sepsis hospitalizations in 2003 and then steadily declined to 0.94 administrations per 1000 severe sepsis hospitalizations in 2010. Large teaching hospitals were more likely to use drotrecogin alfa than small, nonteaching hospitals. The addition of "add-on payments" to hospitals for using drotrecogin alfa in 2002 was associated with significantly increased use (P < .0001), and the withdrawal of those payments in 2004 was associated significantly decreased use (P < .0001). Neither the publication of international sepsis guidelines with favorable drotrecogin alfa recommendations (in 2004 and 2008) nor the publication of a clinical trial focused on drotrecogin alfa (in 2005) were associated with consistent changes use (P > .05). Drotrecogin alfa use declined over time, with marked changes in use associated with drug-specific financial incentives but not the publication of clinical practice guidelines or clinical trials. Copyright © 2015 Elsevier Inc. All rights reserved.

Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis.

PubMed

Brueckmann, Martina; Huhle, Guenter; Lang, Siegfried; Haase, Karl K; Bertsch, Thomas; Weiss, Christel; Kaden, Jens J; Putensen, Christian; Borggrefe, Martin; Hoffmann, Ursula

2005-07-26

Increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been identified as predictors of cardiac dysfunction and prognosis in congestive heart failure and ischemic heart disease. In severe sepsis patients, however, no information is available yet about the prognostic value of natriuretic peptides. Therefore, the aim of the present study was to determine the role of the N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) in the context of outcome of septic patients. Furthermore, the effect of treatment with recombinant human activated protein C [drotrecogin alfa (activated)] on plasma levels of natriuretic peptides in severe sepsis was evaluated. Fifty-seven patients with severe sepsis were included. Levels of NT-proANP and NT-proBNP were measured on the second day of sepsis by ELISA. Septic patients with NT-proBNP levels >1400 pmol/L were 3.9 times more likely (relative risk [RR], 3.9; 95% CI, 1.6 to 9.7) to die from sepsis than patients with lower NT-proBNP values (P<0.01). NT-proANP levels, however, were not predictive of survival in our patient population. A highly significant correlation was found between troponin I levels and plasma concentrations of NT-proBNP in septic patients (r=0.68, P<0.0001). In addition, troponin I significantly accounted for the variation in NT-proBNP levels (P<0.0001), suggesting an important role for NT-proBNP in the context of cardiac injury and dysfunction in septic patients. Twenty-three septic patients who received treatment with drotrecogin alfa (activated) presented with significantly lower concentrations of NT-proANP, NT-proBNP, and troponin I compared with patients not receiving drotrecogin alfa (activated). NT-proBNP may serve as useful laboratory marker to predict survival in patients presenting with severe sepsis.

Systemic bioinformatics analysis of skeletal muscle gene expression profiles of sepsis

PubMed Central

Yang, Fang; Wang, Yumei

2018-01-01

Sepsis is a type of systemic inflammatory response syndrome with high morbidity and mortality. Skeletal muscle dysfunction is one of the major complications of sepsis that may also influence the outcome of sepsis. The aim of the present study was to explore and identify potential mechanisms and therapeutic targets of sepsis. Systemic bioinformatics analysis of skeletal muscle gene expression profiles from the Gene Expression Omnibus was performed. Differentially expressed genes (DEGs) in samples from patients with sepsis and control samples were screened out using the limma package. Differential co-expression and coregulation (DCE and DCR, respectively) analysis was performed based on the Differential Co-expression Analysis package to identify differences in gene co-expression and coregulation patterns between the control and sepsis groups. Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways of DEGs were identified using the Database for Annotation, Visualization and Integrated Discovery, and inflammatory, cancer and skeletal muscle development-associated biological processes and pathways were identified. DCE and DCR analysis revealed several potential therapeutic targets for sepsis, including genes and transcription factors. The results of the present study may provide a basis for the development of novel therapeutic targets and treatment methods for sepsis. PMID:29805480

Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain.

PubMed

Ferrer, Ricard; Artigas, Antonio; Levy, Mitchell M; Blanco, Jesús; González-Díaz, Gumersindo; Garnacho-Montero, José; Ibáñez, Jordi; Palencia, Eduardo; Quintana, Manuel; de la Torre-Prados, María Victoria

2008-05-21

Concern exists that current guidelines for care of patients with severe sepsis and septic shock are followed variably, possibly due to a lack of adequate education. To determine whether a national educational program based on the Surviving Sepsis Campaign guidelines affected processes of care and hospital mortality for severe sepsis. Before and after design in 59 medical-surgical intensive care units (ICUs) located throughout Spain. All ICU patients were screened daily and enrolled if they fulfilled severe sepsis or septic shock criteria. A total of 854 patients were enrolled in the preintervention period (November-December 2005), 1465 patients during the postintervention period (March-June 2006), and 247 patients during the long-term follow-up period 1 year later (November-December 2006) in a subset of 23 ICUs. The educational program consisted of training physicians and nursing staff from the emergency department, wards, and ICU in the definition, recognition, and treatment of severe sepsis and septic shock as outlined in the guidelines. Treatment was organized in 2 bundles: a resuscitation bundle (6 tasks to begin immediately and be accomplished within 6 hours) and a management bundle (4 tasks to be completed within 24 hours). Hospital mortality, differences in adherence to the bundles' process-of-care variables, ICU mortality, 28-day mortality, hospital length of stay, and ICU length of stay. Patients included before and after the intervention were similar in terms of age, sex, and Acute Physiology and Chronic Health Evaluation II score. At baseline, only 3 process-of-care measurements (blood cultures before antibiotics, early administration of broad-spectrum antibiotics, and mechanical ventilation with adequate inspiratory plateau pressure) we had compliance rates higher than 50%. Patients in the postintervention cohort had a lower risk of hospital mortality (44.0% vs 39.7%; P = .04). The compliance with process-of-care variables also improved after the

Heparin Reduced Mortality and Sepsis in Severely Burned Children

PubMed Central

Zayas, G.J.; Bonilla, A.M.; Saliba, M.J

2007-01-01

Summary Objectives. In El Salvador, before 1999, morbidity and mortality in severely burned children were high. In 1998, all children with burns of 40% or larger size died and sepsis was found. With heparin use in 1999, some similarly burned children survived, and sepsis, pain, procedures, and scars were noted to be less. This retrospective study presents the details. Methods. A study was conducted at the National Children's Hospital in El Salvador of all children with burns over 20% size treated in 1998, when no heparin was used, and in 1999, when heparin was added to burns treatment, using an ethics committee approved protocol in use in twelve other countries. Sodium aqueous heparin solution USP from an intestinal source was infused intravenously and applied topically onto burn surfaces and within blisters for the first 1-3 days post-burn. Then heparin, in diminishing doses, was continued only topically until healing. The treatments in 1998 and 1999 were otherwise the same, except that fewer procedures were needed in 1999. Results. There were no significant differences in gender, age, weight, burn aetiology, or burn size between the burned children in 1998 and those in 1999. Burn pain was relieved and pain medicine was not needed in children treated with heparin in 1999. In 1998, one child survived who had a 35% size burn, and the eight children died who had burns of 40% and over. The survival rate was one out of nine (11%). The average burn size was 51.7%. With heparin use in 1999, six of the ten children survived burns of 50.7% average size. The increase in survival with heparin from 11% to 60% and, therefore, the decrease in mortality from 89% to 40% were significant (p < 0.04). Clinical symptoms and positive blood cultures documented bacterial sepsis in the nine children in 1998. In 1999, the blood cultures for sepsis were positive in the four children who died and negative in the six who survived. The nine versus four differences in the incidence of sepsis

Impact of Source Control in Patients With Severe Sepsis and Septic Shock.

PubMed

Martínez, María Luisa; Ferrer, Ricard; Torrents, Eva; Guillamat-Prats, Raquel; Gomà, Gemma; Suárez, David; Álvarez-Rocha, Luis; Pozo Laderas, Juan Carlos; Martín-Loeches, Ignacio; Levy, Mitchell M; Artigas, Antonio

2017-01-01

Time to clearance of pathogens is probably critical to outcome in septic shock. Current guidelines recommend intervention for source control within 12 hours after diagnosis. We aimed to determine the epidemiology of source control in the management of sepsis and to analyze the impact of timing to source control on mortality. Prospective observational analysis of the Antibiotic Intervention in Severe Sepsis study, a Spanish national multicenter educational intervention to improve antibiotherapy in sepsis. Ninety-nine medical-surgical ICUs in Spain. We enrolled 3,663 patients with severe sepsis or septic shock during three 4-month periods between 2011 and 2013. Source control and hospital mortality. A total of 1,173 patients (32%) underwent source control, predominantly for abdominal, urinary, and soft-tissue infections. Compared with patients who did not require source control, patients who underwent source control were older, with a greater prevalence of shock, major organ dysfunction, bacteremia, inflammatory markers, and lactic acidemia. In addition, compliance with the resuscitation bundle was worse in those undergoing source control. In patients who underwent source control, crude ICU mortality was lower (21.2% vs 25.1%; p = 0.010); after adjustment for confounding factors, hospital mortality was also lower (odds ratio, 0.809 [95% CI, 0.658-0.994]; p = 0.044). In this observational database analysis, source control after 12 hours was not associated with higher mortality (27.6% vs 26.8%; p = 0.789). Despite greater severity and worse compliance with resuscitation bundles, mortality was lower in septic patients who underwent source control than in those who did not. The time to source control could not be linked to survival in this observational database.

Increased DNA damage and increased apoptosis and necrosis in patients with severe sepsis and septic shock.

PubMed

Bahar, Ilhan; Elay, Gülseren; Başkol, Gulden; Sungur, Murat; Donmez-Altuntas, Hamiyet

2018-02-01

Reactive oxygen species (ROS) has a key role in the pathogenesis of sepsis. We wanted to evaluate ROS-associated lymphocyte necrosis and apoptosis. A total of 51 patients were included in the study, 29 in the patient group and 22 in the control group. Blood samples were taken from patients in the patient group during severe sepsis or septic shock, then again once they had recovered. Oxidative DNA damage was evaluated by 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Peripheral blood lymphocytes from patients were evaluated with a microscope immediately. The rate of apoptosis and necrosis of lymphocytes were evaluated according to the number of cells in the peripheral. The level of 8-OHdG increased with severe sepsis or septic shock. There were significant differences between the pre- and post-treatment values for apoptotic cell frequency (4.21±3.15 vs. 3.82±3.07, P<0.05) and necrotic cell frequency (4.75±3.61 vs. 4.09±3.37, P<0.05). Apoptosis and necrosis was increased during severe sepsis and septic shock, and apoptosis increase also continued after recovery, but necrosis decreased following disease recovery. CONCLUSıONS: In patients with severe sepsis or septic shock, apoptosis and necrosis were increased along with increased 8-OHdG level. Copyright © 2017 Elsevier Inc. All rights reserved.

Acute Kidney Injury in Pediatric Severe Sepsis: An Independent Risk Factor for Death and New Disability.

PubMed

Fitzgerald, Julie C; Basu, Rajit K; Akcan-Arikan, Ayse; Izquierdo, Ledys M; Piñeres Olave, Byron E; Hassinger, Amanda B; Szczepanska, Maria; Deep, Akash; Williams, Duane; Sapru, Anil; Roy, Jason A; Nadkarni, Vinay M; Thomas, Neal J; Weiss, Scott L; Furth, Susan

2016-12-01

The prevalence of septic acute kidney injury and impact on functional status of PICU survivors are unknown. We used data from an international prospective severe sepsis study to elucidate functional outcomes of children suffering septic acute kidney injury. Secondary analysis of patients in the Sepsis PRevalence, OUtcomes, and Therapies point prevalence study: acute kidney injury was defined on the study day using Kidney Disease Improving Global Outcomes definitions. Patients with no acute kidney injury or stage 1 acute kidney injury ("no/mild acute kidney injury") were compared with those with stage 2 or 3 acute kidney injury ("severe acute kidney injury"). The primary outcome was a composite of death or new moderate disability at discharge defined as a Pediatric Overall Performance Category score of 3 or higher and increased by 1 from baseline. One hundred twenty-eight PICUs in 26 countries. Children with severe sepsis in the Sepsis PRevalence, OUtcomes, and Therapies study. None. One hundred two (21%) of 493 patients had severe acute kidney injury. More than twice as many patients with severe acute kidney injury died or developed new moderate disability compared with those with no/mild acute kidney injury (64% vs 30%; p < 0.001). Severe acute kidney injury was independently associated with death or new moderate disability (adjusted odds ratio, 2.5; 95% CI, 1.5-4.2; p = 0.001) after adjustment for age, region, baseline disability, malignancy, invasive mechanical ventilation, albumin administration, and the pediatric logistic organ dysfunction score. In a multinational cohort of critically ill children with severe sepsis and high mortality rates, septic acute kidney injury is independently associated with further increased death or new disability.

Increased serum thrombomodulin level is associated with disease severity and mortality in pediatric sepsis

PubMed Central

Lin, Jainn-Jim; Hsiao, Hsiang-Ju; Chan, Oi-Wa; Wang, Yu

2017-01-01

Background Endothelial dysfunction plays an important role in the pathophysiology of sepsis. As previously reported, the serum thrombomodulin is elevated in diseases associated with endothelial injury. Objective The aim of this study was to investigate the association of serum thrombomodulin level in different pediatric sepsis syndromes and evaluate the relationship with disease severity and mortality. Methods We prospectively collected cases of sepsis treated in a pediatric intensive care unit from June 2012 to July 2015 at Chang Gung Children’s Hospital in Taoyuan, Taiwan. Clinical characteristics and serum thrombomodulin levels were analyzed. Results Increased serum thrombomodulin levels on days 1 and 3 of the diagnosis of sepsis were found in different pediatric sepsis syndromes. Patients with septic shock had significantly increased serum thrombomodulin levels on days 1 and 3 [day 1: median, 6.9 mU/ml (interquartile range (IQR): 5.8–12.8) and day 3: median, 5.8 mU/ml (IQR: 4.6–10.8)] compared to healthy controls [median, 3.4 mU/ml (IQR: 2.3–4.2)] (p = <0.001 and 0.001, respectively) and those with sepsis [day 1: median, 2.9 mU/ml (IQR: 1.8–4.7) and day 3: median, 3 mU/ml (IQR: 1.5–3.5)] and severe sepsis [day 1: median, 3.3 mU/ml (IQR: 1.3–8.6) and day 3: median, 4.4 mU/ml (IQR: 0.5–6)] (p = <0.001 and 0.001, respectively). There was also a significant positive correlation between serum thrombomodulin level on day 1 and day 1 PRISM-II, PELOD, P-MOD and DIC scores. The patients who died had significantly higher serum thrombomodulin levels on days 1 and 3 [day 1: median, 9.9 mU/ml (IQR: 6.2–15.6) and day 3: median, 10.4 mU/ml (IQR: 9.2–11.7)] than the survivors [day 1; median, 4.4 mU/ml (IQR: 2.2–7.5) and day 3: [median, 3.5 mU/ml (IQR: 1.6–5.7)] (p = 0.046 and 0.012, respectively). Conclusion Increased serum thrombomodulin levels were found in different pediatric sepsis syndromes and correlated with disease severity and mortality. PMID

Patient and hospital correlates of clinical outcomes and resource utilization in severe pediatric sepsis.

PubMed

Odetola, Folafoluwa O; Gebremariam, Achamyeleh; Freed, Gary L

2007-03-01

Our goal was to describe patient and hospital characteristics associated with in-hospital mortality, length of stay, and charges for critically ill children with severe sepsis. Our study consisted of a retrospective study of children 0 to 19 years of age hospitalized with severe sepsis using the 2003 Kids' Inpatient Database. We generated national estimates of rates of hospitalization and then compared in-hospital mortality, length of stay, and total charges according to patient and hospital characteristics using multivariable regression methods. Severity of illness was measured by using all-patient refined diagnosis-related group severity of illness classification into minor, moderate, major, and extreme severity. There were an estimated 21,448 hospitalizations for severe pediatric sepsis nationally in 2003. The in-hospital mortality rate was 4.2%. Comorbid illness was present in 34% of hospitalized children. Most (70%) of the extremely ill children were admitted to children's hospitals. Length of stay was longer among patients with higher illness severity and nonsurvivors compared with survivors (13.5 vs 8.5 days). Hospitalizations at urban or children's hospitals were also associated with longer length of stay than nonchildren's or rural hospitals, respectively. Higher charges were associated with higher illness severity, and nonsurvivors had 2.5-fold higher total charges than survivors. Also, higher charges were observed among hospitalizations in urban or children's hospitals. In multivariable regression analysis, multiple comorbid illnesses, multiple organ dysfunction, and greater severity of illness were associated with higher odds of mortality and longer length of stay. Higher hospital charges and longer length of stay were observed among transfer hospitalizations and among hospitalizations to children's hospitals and nonchildren's teaching hospitals compared with hospitals, which had neither children's nor teaching status. Mortality from severe pediatric

Stress disorders following prolonged critical illness in survivors of severe sepsis.

PubMed

Wintermann, Gloria-Beatrice; Brunkhorst, Frank Martin; Petrowski, Katja; Strauss, Bernhard; Oehmichen, Frank; Pohl, Marcus; Rosendahl, Jenny

2015-06-01

To examine the frequency of acute stress disorder and posttraumatic stress disorder in chronically critically ill patients with a specific focus on severe sepsis, to classify different courses of stress disorders from 4 weeks to 6 months after transfer from acute care hospital to postacute rehabilitation, and to identify patients at risk by examining the relationship between clinical, demographic, and psychological variables and stress disorder symptoms. Prospective longitudinal cohort study, three assessment times within 4 weeks, 3 months, and 6 months after transfer to postacute rehabilitation. Patients were consecutively enrolled in a large rehabilitation hospital (Clinic Bavaria, Kreischa, Germany) admitted for ventilator weaning from acute care hospitals. We included 90 patients with admission diagnosis critical illness polyneuropathy or critical illness myopathy with or without severe sepsis, age between 18 and 70 years with a length of ICU stay greater than 5 days. None. Acute stress disorder and posttraumatic stress disorder were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria by a trained and experienced clinical psychologist using a semistructured clinical interview for Diagnostic and Statistical Manual of Mental Disorders. We further administered the Acute Stress Disorder Scale and the Posttraumatic Symptom Scale-10 to assess symptoms of acute stress disorder and posttraumatic stress disorder. Three percent of the patients had an acute stress disorder diagnosis 4 weeks after transfer to postacute rehabilitation. Posttraumatic stress disorder was found in 7% of the patients at 3-month follow-up and in 12% after 6 months, respectively. Eighteen percent of the patients showed a delayed onset of posttraumatic stress disorder. Sepsis turned out to be a significant predictor of posttraumatic stress disorder symptoms at 3-month follow-up. A regular screening of post-ICU patients after discharge from

Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity

PubMed Central

Rivers, Emanuel P.; McIntyre, Lauralyn; Morro, David C.; Rivers, Kandis K.

2005-01-01

The pathogenic, diagnostic and therapeutic landscape of sepsis is no longer confined to the intensive care unit: many patients from other portals of entry to care, both outside and within the hospital, progress to severe disease. Approaches that have led to improved outcomes with other diseases (e.g., acute myocardial infarction, stroke and trauma) can now be similarly applied to sepsis. Improved understanding of the pathogenesis of severe sepsis and septic shock has led to the development of new therapies that place importance on early identification and aggressive management. This review emphasizes approaches to the early recognition, diagnosis and therapeutic management of sepsis, giving the clinician the most contemporary and practical approaches with which to treat these patients. PMID:16247103

Gene Variations in the Protein C and Fibrinolytic Pathway: Relevance for Severity and Outcome in Pediatric Sepsis.

PubMed

Boeddha, Navin P; Emonts, Marieke; Cnossen, Marjon H; de Maat, Moniek P; Leebeek, Frank W; Driessen, Gertjan J; Hazelzet, Jan A

2017-02-01

The host response to infection involves complex interplays between inflammation, coagulation, and fibrinolysis. Deregulation of hemostasis and fibrinolysis are major causes of critical illness and important determinants of outcome in severe sepsis. The hemostatic responses to infection vary widely between individuals, and are in part explained by polymorphisms in genes responsible for the protein C and fibrinolytic pathway. This review gives an overview of genetic polymorphisms in the protein C and fibrinolytic pathway associated with susceptibility and severity of pediatric sepsis. In addition, genetic polymorphisms associated with adult sepsis and other pediatric thromboembolic disorders are discussed, as these polymorphisms might be candidates for future molecular genetic research in pediatric sepsis. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Improving Recognition of Pediatric Severe Sepsis in the Emergency Department: Contributions of a Vital Sign-Based Electronic Alert and Bedside Clinician Identification.

PubMed

Balamuth, Fran; Alpern, Elizabeth R; Abbadessa, Mary Kate; Hayes, Katie; Schast, Aileen; Lavelle, Jane; Fitzgerald, Julie C; Weiss, Scott L; Zorc, Joseph J

2017-12-01

Recognition of pediatric sepsis is a key clinical challenge. We evaluate the performance of a sepsis recognition process including an electronic sepsis alert and bedside assessment in a pediatric emergency department (ED). This was a cohort study with quality improvement intervention in a pediatric ED. Exposure was a positive electronic sepsis alert, defined as elevated pulse rate or hypotension, concern for infection, and at least one of the following: abnormal capillary refill, abnormal mental status, or high-risk condition. A positive electronic sepsis alert prompted team assessment or huddle to determine need for sepsis protocol. Clinicians could initiate team assessment or huddle according to clinical concern without positive electronic sepsis alert. Severe sepsis outcome defined as activation of the sepsis protocol in the ED or development of severe sepsis requiring ICU admission within 24 hours. There were 182,509 ED visits during the study period, with 86,037 before electronic sepsis alert implementation and 96,472 afterward, and 1,112 (1.2%) positive electronic sepsis alerts. Overall, 326 patients (0.3%) were treated for severe sepsis within 24 hours. Test characteristics of the electronic sepsis alert alone to detect severe sepsis were sensitivity 86.2% (95% confidence interval [CI] 82.0% to 89.5%), specificity 99.1% (95% CI 99.0% to 99.2%), positive predictive value 25.4% (95% CI 22.8% to 28.0%), and negative predictive value 100% (95% CI 99.9% to 100%). Inclusion of the clinician screen identified 43 additional electronic sepsis alert-negative children, with severe sepsis sensitivity 99.4% (95% CI 97.8% to 99.8%) and specificity 99.1% (95% CI 99.1% to 99.2%). Electronic sepsis alert implementation increased ED sepsis detection from 83% to 96%. Electronic sepsis alert for severe sepsis demonstrated good sensitivity and high specificity. Addition of clinician identification of electronic sepsis alert-negative patients further improved sensitivity

The epidemiology of adults with severe sepsis and septic shock in Scottish emergency departments.

PubMed

Gray, Alasdair; Ward, Kirsty; Lees, Fiona; Dewar, Colin; Dickie, Sarah; McGuffie, Crawford

2013-05-01

The Surviving Sepsis Campaign (SSC) promotes a bundle approach to the care of septic patients to improve outcome. Some have questioned the capability of delivering the bundle in emergency departments (EDs). The authors report the epidemiology and 6 h bundle compliance of patients with severe sepsis/septic shock presenting to Scottish EDs. Analysis of the previously reported Scottish Trauma Audit Group sepsis database was performed including 20 mainland Scottish EDs. A total of 308,910 attendances were screened (between 2 March and 31 May 2009), and 5285 of 27,046 patients were identified after case note review and included on the database. This analysis includes patients who had severe sepsis/septic shock before leaving the ED. Epidemiological, severity of illness criteria, and ED management data were analysed. 626 patients (median age 73; M/F ratio 1:1; 637 presentations) met entrance criteria. The median number of cases per site was 16 (range 3-103). 561 (88.1%) patients arrived by ambulance. The most common source of infection was the respiratory tract (n=411, 64.5%) The most common physiological derangements were heart rate (n=523, 82.1%), respiratory rate (n=452, 71%) and white cell count (n=432, 67.8%). The median hospital stay was 9 days (IQR 4-17 days). 201 (31.6%) patients were admitted to critical care within 2 days, 130 (20.4%) directly from the ED. 180 patients (28.3%) died. There was poor compliance with all aspect of the SSC resuscitation bundle. Sepsis presentations are of variable frequency but have typical epidemiology and clinical outcomes. SSC bundle resuscitation uptake is poor in Scottish EDs.

Early versus late pre-intensive care unit admission broad spectrum antibiotics for severe sepsis in adults.

PubMed

Siddiqui, Shahla; Razzak, Junaid

2010-10-06

Severe sepsis and septic shock have recently emerged as particularly acute and lethal challenges amongst critically ill patients presenting to the emergency department (ED). There are no existing data on the current practices of management of patients with severe sepsis comparing early versus late administration of appropriate broad spectrum antibiotics as part of the early goal-directed therapy that is commenced in the first few hours of presentation. To assess the difference in outcomes with early compared to late administration of antibiotics in patients with severe sepsis in the pre-intensive care unit (ICU) admission period. We defined early as within one hour of presentation to the ED. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2009); MEDLINE (1990 to February 2010); EMBASE (1990 to February 2010); and ISI web of Science (February 2010). We also searched for relevant ongoing trials in specific websites such as www.controlled-trials.com; www.clinicalstudyresults.org; and www.update-software.com. We searched the reference lists of articles. There were no constraints based on language or publication status. We planned to include randomized controlled trials of early versus late broad spectrum antibiotics in adult patients with severe sepsis in the ED, prior to admission to the intensive care unit. Two authors independently assessed articles for inclusion. We found no studies that satisfied the inclusion criteria. Based on this review we are unable to make a recommendation on the early or late use of broad spectrum antibiotics in adult patients with severe sepsis in the ED pre-ICU admission. There is a need to do large prospective double blinded randomized controlled trials on the efficacy of early (within one hour) versus late broad spectrum antibiotics in adult severe sepsis patients. Since it makes sense to start antibiotics as soon as possible in this group of seriously ill patients, administering

Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival

PubMed Central

Ratanarat, Ranistha; Brendolan, Alessandra; Piccinni, Pasquale; Dan, Maurizio; Salvatori, Gabriella; Ricci, Zaccaria; Ronco, Claudio

2005-01-01

Introduction Severe sepsis is the leading cause of mortality in critically ill patients. Abnormal concentrations of inflammatory mediators appear to be involved in the pathogenesis of sepsis. Based on the humoral theory of sepsis, a potential therapeutic approach involves high-volume haemofiltration (HVHF), which has exhibited beneficial effects in severe sepsis, improving haemodynamics and unselectively removing proinflammatory and anti-inflammatory mediators. However, concerns have been expressed about the feasibility and costs of continuous HVHF. Here we evaluate a new modality, namely pulse HVHF (PHVHF; 24-hour schedule: HVHF 85 ml/kg per hour for 6–8 hours followed by continuous venovenous haemofiltration 35 ml/kg per hour for 16–18 hours). Method Fifteen critically ill patients (seven male; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score 31.2, mean Simplified Acute Physiology Score [SAPS] II 62, and mean Sequential Organ Failure Assessment 14.2) with severe sepsis underwent daily PHVHF. We measured changes in haemodynamic variables and evaluated the dose of noradrenaline required to maintain mean arterial pressure above 70 mmHg during and after pulse therapy at 6 and 12 hours. PHVHF was performed with 250 ml/min blood flow rate. The bicarbonate-based replacement fluid was used at a 1:1 ratio in simultaneous pre-dilution and post-dilution. Results No treatment was prematurely discontinued. Haemodynamics were improved by PHVHF, allowing a significant reduction in noradrenaline dose during and at the end of the PHVHF session; this reduction was maintained at 6 and 12 hours after pulse treatment (P = 0.001). There was also an improvement in systolic blood pressure (P = 0.04). There were no changes in temperature, cardiac index, oxygenation, arterial pH or urine output during the period of observation. The mean daily Kt/V was 1.92. Predicted mortality rates were 72% (based on APACHE II score) and 68% (based on SAPS II score), and the

Cytokine profile in severe gram-positive and gram-negative abdominal sepsis

PubMed Central

Surbatovic, Maja; Popovic, Nada; Vojvodic, Danilo; Milosevic, Ivan; Acimovic, Gordana; Stojicic, Milan; Veljovic, Milic; Jevdjic, Jasna; Djordjevic, Dragan; Radakovic, Sonja

2015-01-01

Sepsis is a principal cause of death in critical care units worldwide and consumes considerable healthcare resources. The aim of our study was to determine whether the early cytokine profile can discriminate between Gram-positive and Gram-negative bacteraemia (GPB and GNB, respectively) and to assess the prognostic value regarding outcome in critically ill patients with severe abdominal sepsis. The outcome measure was hospital mortality. Blood samples were obtained from 165 adult patients with confirmed severe abdominal sepsis. Levels of the proinflammatory mediators TNF-α, IL-8, IL-12 and IFN-γ and the anti-inflammatory mediators IL-1ra, IL-4, IL-10 and TGF-β1 were determined and correlated with the nature of the bacteria isolated from the blood culture and outcome. The cytokine profile in our study indicated that the TNF-α levels were 2-fold, IL-8 were 3.3-fold, IFN-γ were 13-fold, IL-1ra were 1.05-fold, IL-4 were 1.4-fold and IL-10 were 1.83-fold higher in the GNB group compared with the GPB group. The TNF-α levels were 4.7-fold, IL-8 were 4.6-fold, IL-1ra were 1.5-fold and IL-10 were 3.3-fold higher in the non-survivors compared with the survivors. PMID:26079127

Structured lipid emulsion as nutritional therapy for the elderly patients with severe sepsis.

PubMed

Chen, Jin; Yan, Jing; Cai, Guo-Long; Xu, Qiang-Hong; Gong, Shi-Jin; Dai, Hai-Wen; Yu, Yi-Hua; Li, Li

2013-06-01

The nutritional support is one of the important therapeutic strategies for the elderly patients with severe sepsis, but there is controversial in choosing a parenteral nutrition formulation. This study was designed to compare the therapeutic effects of structured lipid emulsion, physically mixed medium, and long-chain fat emulsion in the treatment of severe sepsis in elderly patients. A total number of 64 elder patients with severe sepsis were enrolled in the study. After a week of enteral nutritional support, the patients were randomly divided into research (structured lipid emulsion as parenteral alimentation) and control groups (physically mixed medium and long-chain fat emulsion as parenteral alimentation). The alterations of plasma albumin, lipid metabolism, and blood glucose level were recorded after parenteral alimentation and were compared between the two groups. The plasma levels of albumin, prealbumin, cholesterol, and triglyceride were decreased in all the patients after one week of enteral nutritional support treatment (t = 7.78, P = 0.000; t = 10.21, P = 0.000; t = 7.99, P = 0.000; and t = 10.99, P = 0.000). Further parenteral alimentation with different lipid emulsions had significant effects on the serum prealbumin and albumin (t = 3.316, P = 0.002; t = 3.200, P = 0.002), whilst had no effects on the blood glucose and triglyceride level (t = 7.78, P = 0.000; t = 4.228, P = 0.000). In addition, the two groups had a significantly different Apache II score, ventilator time, and hospital stay time (t = -2.213, P = 0.031; t = 2.317, P = 0.024; t = 2.514, P = 0.015). The structured lipid emulsion was safe as parenteral nutrition for elderly patients with severe sepsis. It was demonstrated to be superior to the physically mixed medium and long-chain fat emulsion with respect to the protein synthesis and prognosis.

T helper type 2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis

PubMed Central

Anantha, R V; Mazzuca, D M; Xu, S X; Porcelli, S A; Fraser, D D; Martin, C M; Welch, I; Mele, T; Haeryfar, S M M; McCormick, J K

2014-01-01

Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNK T) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non-septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra-abdominal sepsis (IAS). Our data show that iNK T cells are pathogenic in IAS, and that T helper type 2 (Th2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13 and reduction of several proinflammatory cytokines within the spleen, notably interleukin (IL)-17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th2 phenotype may be an effective therapeutic strategy in early sepsis. PMID:24965554

Mitochondrial Function in Sepsis

PubMed Central

Arulkumaran, Nishkantha; Deutschman, Clifford S.; Pinsky, Michael R.; Zuckerbraun, Brian; Schumacker, Paul T.; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A.

2015-01-01

Mitochondria are an essential part of the cellular infrastructure, being the primary site for high energy adenosine triphosphate (ATP) production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered and end organ dysfunction not only common but predictive of long term morbidity and mortality. Clearly, interest is mitochondrial function both as a target for intracellular injury and response to extrinsic stress have been a major focus of basic science and clinical research into the pathophysiology of acute illness. However, mitochondria have multiple metabolic and signaling functions that may be central in both the expression of sepsis and its ultimate outcome. In this review, the authors address five primary questions centered on the role of mitochondria in sepsis. This review should be used as both a summary source in placing mitochondrial physiology within the context of acute illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide. PMID:26871665

MITOCHONDRIAL FUNCTION IN SEPSIS.

PubMed

Arulkumaran, Nishkantha; Deutschman, Clifford S; Pinsky, Michael R; Zuckerbraun, Brian; Schumacker, Paul T; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A

2016-03-01

Mitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long-term morbidity and mortality. Clearly, interest is mitochondrial function both as a target for intracellular injury and response to extrinsic stress have been a major focus of basic science and clinical research into the pathophysiology of acute illness. However, mitochondria have multiple metabolic and signaling functions that may be central in both the expression of sepsis and its ultimate outcome. In this review, the authors address five primary questions centered on the role of mitochondria in sepsis. This review should be used both as a summary source in placing mitochondrial physiology within the context of acute illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide.

A Multicenter Survey of House Staff Knowledge About Sepsis and the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock".

PubMed

Watkins, Richard R; Haller, Nairmeen; Wayde, Melinda; Armitage, Keith B

2017-01-01

We aimed to assess the knowledge, attitudes, and perceptions of resident physicians regarding sepsis in general and the Surviving Sepsis Campaign Guidelines in particular. After institutional review board approval, we surveyed internal medicine (IM) and emergency medicine (EM) house staff from 3 separate institutions. House staff were notified of the survey via e-mail from their residency director or chief resident. The survey was Internet-based (using http://www.surveymonkey.com ), voluntary, and anonymous. The Surviving Sepsis Campaign Guidelines were used to develop the survey. The survey was open between December 2015 and April 2016. No incentives for participation were given. Reminder e-mails were sent approximately every 3 to 4 weeks to all eligible participants. Comparisons of responses were evaluated using the N-1 2-proportion test. A total of 133 responses were received. These included 84 from IM house staff, 27 from EM house staff, and 22 who selected "other." Eighty (101/126) percent reported managing at least 1 patient with sepsis in the preceding 30 days, 85% (97/114) rated their knowledge of the Surviving Sepsis Guidelines as "very familiar" or at least "somewhat familiar," and 84% (91/108) believed their training in the diagnosis and management of sepsis was "excellent" or at least "good." However, 43% (47/108) reported not receiving any feedback on their treatment of patients with sepsis in the last 30 days, while 24% (26/108) received feedback once. Both IM and EM house staff received comparable rates of feedback (62% vs 48%, respectively; P = .21). For the 3 questions that directly tested knowledge of the guidelines, the scores of the IM and EM house staff were similar. Notably, <20% of both groups correctly identified diagnostic criteria for sepsis. Additional education of IM and EM house staff on the Surviving Sepsis Campaign Guidelines is warranted, along with more consistent feedback regarding their diagnosis and management of sepsis.

High prevalence of Mycobacterium tuberculosis bacteraemia among a cohort of HIV-infected patients with severe sepsis in Lusaka, Zambia.

PubMed

Muchemwa, Levy; Shabir, Lakhi; Andrews, Ben; Bwalya, Mwango

2017-05-01

Tuberculosis is recognised as one of the leading causes of severe sepsis among HIV-infected patients. Most patients with Mycobacterium tuberculosis bacteraemia have advanced HIV disease with CD4 counts less than 100 cells/μl and its presentation is non-specific in most instances. This was a cross-sectional study which was done by analyzing data from 201 adult HIV-infected patients who met the inclusion criteria for severe sepsis. The prevalence of Mycobacterium tuberculosis bactraemia in the study population was 34.8%. Severe sepsis caused by other etiologies was observed in 33 (16.4%) of the participants. Concomitant infection of Mycobacterium tuberculosis bactraemia with other organisms is not uncommon in patients with severe sepsis. This cohort of HIV-infected patients had severe immunosuppression with a median CD4 count of 51 (20-136) cells/μl with moderate anaemia, mean haemoglobin 8.0 (3.0) g/dl, and were generally underweight with a mean mid upper arm circumference (MUAC) of 21.0 (3.4) cm. Mycobacterium tuberculosis bacteraemia is very common in HIV-infected patients with advanced HIV disease who present with severe sepsis. Mycobacterium tuberculosis bacteraemia co-infection with aerobic organisms is not uncommon. Factors that were independently associated with Mycobacterium tuberculosis bacteraemia in our study population were MUAC and sodium level.

Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock.

PubMed

Mathias, Brittany; Delmas, Amber L; Ozrazgat-Baslanti, Tezcan; Vanzant, Erin L; Szpila, Benjamin E; Mohr, Alicia M; Moore, Frederick A; Brakenridge, Scott C; Brumback, Babette A; Moldawer, Lyle L; Efron, Philip A

2017-04-01

We hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, and also in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. After SS/SS, CD33CD11bHLA-DR MDSCs were dramatically increased out to 28 days (P < 0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (P < 0.05). Additionally, septic MDSCs had suppressed HLA gene expression and up-regulated ARG1 expression (P < 0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged intensive care unit stays, and poor functional status at discharge (P < 0.05). After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis.

PubMed

Lowes, Damon A; Thottakam, Bensita M V; Webster, Nigel R; Murphy, Michael P; Galley, Helen F

2008-12-01

Sepsis is characterised by a systemic dysregulated inflammatory response and oxidative stress, often leading to organ failure and death. Development of organ dysfunction associated with sepsis is now accepted to be due at least in part to oxidative damage to mitochondria. MitoQ is an antioxidant selectively targeted to mitochondria that protects mitochondria from oxidative damage and which has been shown to decrease mitochondrial damage in animal models of oxidative stress. We hypothesised that if oxidative damage to mitochondria does play a significant role in sepsis-induced organ failure, then MitoQ should modulate inflammatory responses, reduce mitochondrial oxidative damage, and thereby ameliorate organ damage. To assess this, we investigated the effects of MitoQ in vitro in an endothelial cell model of sepsis and in vivo in a rat model of sepsis. In vitro MitoQ decreased oxidative stress and protected mitochondria from damage as indicated by a lower rate of reactive oxygen species formation (P=0.01) and by maintenance of the mitochondrial membrane potential (P<0.005). MitoQ also suppressed proinflammatory cytokine release from the cells (P<0.05) while the production of the anti-inflammatory cytokine interleukin-10 was increased by MitoQ (P<0.001). In a lipopolysaccharide-peptidoglycan rat model of the organ dysfunction that occurs during sepsis, MitoQ treatment resulted in lower levels of biochemical markers of acute liver and renal dysfunction (P<0.05), and mitochondrial membrane potential was augmented (P<0.01) in most organs. These findings suggest that the use of mitochondria-targeted antioxidants such as MitoQ may be beneficial in sepsis.

Acute Kidney Injury in Pediatric Severe Sepsis, An Independent Risk Factor for Death and New Disability

PubMed Central

Fitzgerald, Julie C.; Basu, Rajit; Akcan-Arikan, Ayse; Izquierdo, Ledys M.; Piñeres Olave, Byron E.; Hassinger, Amanda B.; Szczepanska, Maria; Deep, Akash; Williams, Duane; Sapru, Anil; Roy, Jason A.; Nadkarni, Vinay M.; Thomas, Neal J.; Weiss, Scott L.; Furth, Susan

2017-01-01

Objective The prevalence of septic acute kidney injury (AKI) and impact on functional status of pediatric intensive care unit (PICU) survivors are unknown. We utilized data from an international prospective severe sepsis study to elucidate functional outcomes of children suffering septic AKI. Design Secondary analysis of patients in the Sepsis PRevalence, OUtcomes, and Therapies (SPROUT) point prevalence study. AKI was defined on the study day using Kidney Disease Improving Global Outcomes definitions. Patients with no AKI or stage 1 AKI (“No/mild AKI”) were compared to those with stage 2 or 3 AKI (“Severe AKI”). The primary outcome was a composite of death or new moderate disability at discharge defined as a Pediatric Overall Performance Category score of 3 or higher, and increased by 1 from baseline. Setting 128 PICUs in 26 countries. Patients Children with severe sepsis in the SPROUT study. Interventions None Measurements and Main Results One hundred two (21%) of 493 patients had Severe AKI. More than twice as many patients with Severe AKI died or developed new moderate disability compared to those with No/mild AKI (64% vs. 30%, p<0.001). Severe AKI was independently associated with death or new moderate disability (adjusted OR 2.5, 95% CI 1.5, 4.2; p=0.001) after adjustment for age, region, baseline disability, malignancy, invasive mechanical ventilation, albumin administration, and the pediatric logistic organ dysfunction score. Conclusions In a multi-national cohort of critically ill children with severe sepsis and high mortality rates, septic AKI is independently associated with further increased death or new disability. PMID:27513354

The Severity of Cecal Ligature and Puncture-Induced Sepsis Correlates with the Degree of Encephalopathy, but the Sepsis Does Not Lead to Acute Activation of Spleen Lymphocytes in Mice.

PubMed

Jeremias, I C; Victorino, V J; Machado, J L; Barroso, W A; Ariga, S K; Lima, T M; Soriano, F G

2016-07-01

Septic encephalopathy represents the most frequently observed form of encephalopathy in intensive care units. Interactions between the immune and nervous systems have been observed in experimental sepsis. Therefore, the aim of the current study was to characterize the effect of different severities of sepsis on encephalopathy and the inflammatory profile of the spleen. We hypothesized that different grades of sepsis severity would lead to variations in encephalopathy and activation of spleen cells. We induced sepsis of different severities in Balb/c mice by cecal ligature and puncture (CLP). Six and 12 h after CLP induction, behavioral impairment was assessed by the SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) test. The animals were then killed, and the plasma, spleen, and hippocampus were removed. Levels of the encephalopathy marker S100β were measured in plasma. Spleens were weighed and then a characterization of splenic lymphocytes was performed by flow cytometry (cytotoxic T lymphocyte, T helper lymphocytes, B lymphocytes, T regulatory cells, and Th17 cells). Cytokine levels in the spleen and hippocampus were determined by enzyme-linked immunosorbent assay (ELISA), and cytokine levels in plasma were performed with MilliPlex® technology. Our results showed that behavioral impairment as measured by the SHIRPA test and elevation in plasma S100β levels were significant in moderate and severe CLP groups compared to those in the sham control group. Regarding immunological alterations, we were unable to observe changes in the weights of the spleen and the profile of lymphocytes 6 h after CLP. However, several cytokines, including IL-6, IL-10, and IL-1β, were increased in spleen and plasma. In conclusion, we observed variations in encephalopathy as measured by plasma S100β, which were mediated by the severity of sepsis; however, we did not observe a different activation of spleen cells 6 h post-CLP, despite evidence of

Management and outcomes of severe dengue patients presenting with sepsis in a tropical country.

PubMed

Teparrukkul, Prapit; Hantrakun, Viriya; Day, Nicholas P J; West, T Eoin; Limmathurotsakul, Direk

2017-01-01

Dengue is a common cause of infection in adults in tropical countries. Sepsis is a syndrome of systemic manifestations induced by infection of any organisms; including bacterial, fungal and viral agents. Here, we investigated the diagnosis, management and outcomes of dengue patients presenting with sepsis in a prospective study of community-acquired sepsis in Thailand. From June to December 2015, 874 adult patients (age≥18 years) with suspected or documented community-acquired infection, with ≥3 diagnostic criteria for sepsis according to the Surviving Sepsis Campaign 2012, and within 24 hours of admission were evaluated. Serum was stored and later tested for dengue PCR assays. A total of 126 patients had dengue PCR assays positive (2 DENV-1, 12 DENV-2, 24 DENV-3 and 88 DENV-4), and 5 of them (4%) died. We found that attending physicians suspected dengue infection on admission in 84 patients (67%), and recorded dengue infection as the final diagnosis in 96 patients (76%). Four of five fatal cases were diagnosed and treated as septic shock not due to dengue. In multivariable analysis, there was a trend showing that age≥60 years, hypoxemia and misdiagnosis of dengue by attending physicians were associated with 28-day mortality. A number of adult patients who died of dengue are misdiagnosed as severe sepsis and septic shock. Diagnosis of dengue based on clinical features alone is difficult. Rapid diagnostic tests for dengue may need to be routinely used in adult patients presenting with sepsis and septic shock in tropical countries. This approach could improve diagnosis and management of those patients.

A retrospective cohort study examining the association between body mass index and mortality in severe sepsis.

PubMed

Gaulton, Timothy Glen; Marshall MacNabb, C; Mikkelsen, Mark Evin; Agarwal, Anish Kumar; Cham Sante, S; Shah, Chirag Vinay; Gaieski, David Foster

2015-06-01

Body mass index (BMI) is an easily calculated indicator of a patient's body mass including muscle mass and body fat percentage and is used to classify patients as underweight or obese. This study is to determine if BMI extremes are associated with increased 28-day mortality and hospital length of stay (LOS) in emergency department (ED) patients presenting with severe sepsis. We performed a retrospective chart review at an urban, level I trauma center of adults admitted with severe sepsis between 1/2005 and 10/2007, and collected socio-demographic variables, comorbidities, initial and most severe vital signs, laboratory values, and infection sources. The primary outcome variables were mortality and LOS. We performed bivariable analysis, logistic regression and restricted cubic spline regression to determine the association between BMI, mortality, and LOS. Amongst 1,191 severe sepsis patients (median age, 57 years; male, 54.7%; median BMI, 25.1 kg/m(2)), 28-day mortality was 19.9% (95% CI 17.8-22.4) and 60-day mortality was 24.4% (95% CI 21.5-26.5). Obese and morbidly obese patients were younger, less severely ill, and more likely to have soft tissue infections. There was no difference in adjusted mortality for underweight patients compared to the normal weight comparator (OR 0.74; CI 0.42-1.39; p = 0.38). The obese and morbidly obese experienced decreased mortality risk, vs. normal BMI; however, after adjustment for baseline characteristics, this was no longer significant (OR 0.66; CI 0.42-1.03; p = 0.06). There was no significant difference in LOS across BMI groups. Neither LOS nor adjusted 28-day mortality was significantly increased or decreased in underweight or obese patients with severe sepsis. Morbidly obese patients may have decreased 28-day mortality, partially due to differences in initial presentation and source of infection. Larger, prospective studies are needed to validate these findings related to BMI extremes in patients with severe sepsis.

Physical exercise induces specific adaptations resulting in reduced organ injury and mortality during severe polymicrobial sepsis.

PubMed

Sossdorf, Maik; Fischer, Jacqueline; Meyer, Stefan; Dahlke, Katja; Wissuwa, Bianka; Seidel, Carolin; Schrepper, Andrea; Bockmeyer, Clemens L; Lupp, Amelie; Neugebauer, Sophie; Schmerler, Diana; Rödel, Jürgen; Claus, Ralf A; Otto, Gordon P

2013-10-01

High physical activity levels are associated with wide-ranging health benefits, disease prevention, and longevity. In the present study, we examined the impact of regular physical exercise on the severity of organ injury and survival probability, as well as characteristics of the systemic immune and metabolic response during severe polymicrobial sepsis. Animal study. University laboratory. Male C57BL/6N mice. Mice were trained for 6 weeks by treadmill and voluntary wheel running or housed normally. Polymicrobial sepsis in mice was induced by injection of fecal slurry. Subsequently, mice were randomized into the following groups: healthy controls, 6 hours postsepsis, and 24 hours postsepsis. Blood and organ samples were collected and investigated by measuring clinical chemistry variables, cytokines, plasma metabolites, and bacterial clearance. Organ morphology and damage were characterized by histological staining. Physical exercise improved survival and the ability of bacterial clearance in blood and organs. The release of pro- and anti-inflammatory cytokines, including interleukin-6 and interleukin-10, was diminished in trained compared to untrained mice during sepsis. The sepsis-associated acute kidney tubular damage was less pronounced in pretrained animals. By metabolic profiling and regression analysis, we detected lysophosphatidylcholine 14:0, tryptophan, as well as pimelylcarnitine linked with levels of neutrophil gelatinase-associated lipocalin representing acute tubular injury (corrected R=0.910; p<0.001). We identified plasma lysophosphatidylcholine 16:0, lysophosphatidylcholine 17:0, and lysophosphatidylcholine 18:0 as significant metabolites discriminating between trained and untrained mice during sepsis. Regular physical exercise reduces sepsis-associated acute kidney injury and death. As a specific mechanism of exercise-induced adaptation, we identified various lysophosphatidylcholines that might function as surrogate for improved outcome in sepsis.

Fluid overload and kidney failure in children with severe sepsis and septic shock: A cohort study.

PubMed

Naveda Romero, Omar E; Naveda Meléndez, Andrea F

2017-04-01

In children with sepsis, fluid overload as a result of an aggressive fluid replacement or excessive fluid administration may result in kidney impairment and increased mortality. Objective. To determine the association between fluid overload and the rate of kidney failure in a group of children with severe sepsis and septic shock. This was a prospective cohort study conducted in the intensive care unit of Hospital Universitario de Pediatría “Dr. Agustín Zubillaga” (Barquisimeto, Lara State, Venezuela), between March 2013 and May 2016, in children with severe sepsis or septic shock. One hundred and forty-nine patients were included in the analysis. Sepsis predominated in 59.7% of cases; patients' average age was 6.4 ± 3.3 years old, their average weight was 17.8 ± 3.6 kg, 30.2% had fluid overload, and overall mortality was 25.5%. Kidney failure occurred in 16.1% of cases. A binary logistic regression model was used to identify fluid overload (odds ratio [OR]: 1.5; 95% confidence interval [CI]: 1.2-4.9, p = 0.028) and shock for more than 2 days (OR: 1.7; 95% CI: 1.3-6.3, p = 0.039) as independent predictors of kidney failure. In addition, a significant increase in the risk of mortality among children with kidney failure and fluid overload was observed as per the Kaplan-Meier method (p= 0.019). Fluid overload and shock for more than 2 days increase the risk for kidney failure in critically ill children with severe sepsis and septic shock.

International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics.

PubMed

Goldstein, Brahm; Giroir, Brett; Randolph, Adrienne

2005-01-01

Although general definitions of the sepsis continuum have been published for adults, no such work has been done for the pediatric population. Physiologic and laboratory variables used to define the systemic inflammatory response syndrome (SIRS) and organ dysfunction require modification for the developmental stages of children. An international panel of 20 experts in sepsis and clinical research from five countries (Canada, France, Netherlands, United Kingdom, and United States) was convened to modify the published adult consensus definitions of infection, sepsis, severe sepsis, septic shock, and organ dysfunction for children. Consensus conference. This document describes the issues surrounding consensus on four major questions addressed at the meeting: a) How should the pediatric age groups affected by sepsis be delineated? b) What are the specific definitions of pediatric SIRS, infection, sepsis, severe sepsis, and septic shock? c) What are the specific definitions of pediatric organ failure and the validity of pediatric organ failure scores? d) What are the appropriate study populations and study end points required to successfully conduct clinical trials in pediatric sepsis? Five subgroups first met separately and then together to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiological data, and coagulation variables. All conference participants approved the final draft of the proceedings of the meeting. Conference attendees modified the current criteria used to define SIRS and sepsis in adults to incorporate pediatric physiologic variables appropriate for the following subcategories of children: newborn, neonate, infant, child, and adolescent. In addition, the SIRS definition was modified so that either criteria for fever or white blood count had to be met. We also defined various organ dysfunction categories, severe sepsis, and septic shock specifically for children. Although no firm conclusion was made regarding

Predictive value of N-terminal pro-brain natriuretic peptide in severe sepsis and septic shock.

PubMed

Varpula, Marjut; Pulkki, Kari; Karlsson, Sari; Ruokonen, Esko; Pettilä, Ville

2007-05-01

The aim of this study was to evaluate the predictive value of N-terminal pro-brain natriuretic peptide (NT-proBNP) on mortality in a large, unselected patient population with severe sepsis and septic shock. Prospective observational cohort study about incidence and prognosis of sepsis in 24 intensive care units in Finland (the FINNSEPSIS study). A total of 254 patients with severe sepsis or septic shock. After informed consent, the blood tests for NT-proBNP analyses were drawn on the day of admission and 72 hrs thereafter. Patients' demographic data were collected, and intensive care unit and hospital mortality and basic hemodynamic and laboratory data were recorded daily. NT-proBNP levels at admission were significantly higher in hospital nonsurvivors (median, 7908 pg/mL) compared with survivors (median, 3479 pg/mL; p = .002), and the difference remained after 72 hrs (p = .002). The receiver operating characteristic curves of admission and 72-hr NT-proBNP levels for hospital mortality resulted in area under the curve values of 0.631 (95% confidence interval, 0.549-0.712; p = .002) and 0.648 (95% confidence interval, 0.554-0.741; p = .002), respectively. In logistic regression analyses, NT-proBNP values at 72 hrs after inclusion and Simplified Acute Physiology Score for the first 24 hrs were independent predictors of hospital mortality. Pulmonary artery occlusion pressure (p < .001), plasma creatinine clearance (p = .001), platelet count (p = .03), and positive blood culture (p = .04) had an independent effect on first-day NT-proBNP values, whereas after 72 hrs, only plasma creatinine clearance (p < .001) was significant in linear regression analysis. NT-proBNP values are frequently increased in severe sepsis and septic shock. Values are significantly higher in nonsurvivors than survivors. NT-proBNP on day 3 in the intensive care unit is an independent prognostic marker of mortality in severe sepsis.

Mortality predictors in renal transplant recipients with severe sepsis and septic shock.

PubMed

de Carvalho, Mônica Andrade; Freitas, Flávio Geraldo Rezende; Silva Junior, Hélio Tedesco; Bafi, Antônio Toneti; Machado, Flávia Ribeiro; Pestana, José Osmar Medina

2014-01-01

The growing number of renal transplant recipients in a sustained immunosuppressive state is a factor that can contribute to increased incidence of sepsis. However, relatively little is known about sepsis in this population. The aim of this single-center study was to evaluate the factors associated with hospital mortality in renal transplant patients admitted to the intensive care unit (ICU) with severe sepsis and septic shock. Patient demographics and transplant-related and ICU stay data were retrospectively collected. Multiple logistic regression was conducted to identify the independent risk factors associated with hospital mortality. A total of 190 patients were enrolled, 64.2% of whom received kidneys from deceased donors. The mean patient age was 51 ± 13 years (males, 115 [60.5%]), and the median APACHE II was 20 (16-23). The majority of patients developed sepsis late after the renal transplantation (2.1 [0.6-2.3] years). The lung was the most common infection site (59.5%). Upon ICU admission, 16.4% of the patients had ≤ 1 systemic inflammatory response syndrome criteria. Among the patients, 61.5% presented with ≥ 2 organ failures at admission, and 27.9% experienced septic shock within the first 24 hours of ICU admission. The overall hospital mortality rate was 38.4%. In the multivariate analysis, the independent determinants of hospital mortality were male gender (OR = 5.9; 95% CI, 1.7-19.6; p = 0.004), delta SOFA 24 h (OR = 1.7; 95% CI, 1.2-2.3; p = 0.001), mechanical ventilation (OR = 30; 95% CI, 8.8-102.2; p<0.0001), hematologic dysfunction (OR = 6.8; 95% CI, 2.0-22.6; p = 0.002), admission from the ward (OR = 3.4; 95% CI, 1.2-9.7; p = 0.02) and acute kidney injury stage 3 (OR = 5.7; 95% CI,1.9-16.6; p = 0.002). Hospital mortality in renal transplant patients with severe sepsis and septic shock was associated with male gender, admission from the wards, worse SOFA scores on the first day and the presence of hematologic dysfunction, mechanical

Severe maternal morbidity due to sepsis: The burden and preventability of disease in New Zealand.

PubMed

Lepine, Sam; Lawton, Beverley; Geller, Stacie; Abels, Peter; MacDonald, Evelyn J

2018-02-20

Sepsis is a life-threatening systemic condition that appears to be increasing in the obstetric population. Clinical detection can be difficult and may result in increased morbidity via delays in the continuum of patient care. To describe the burden of severe maternal morbidity (SMM) caused by sepsis in New Zealand and investigate the potential preventability. A multidisciplinary expert review panel was established to review cases of obstetric sepsis admitted to intensive care or high-dependency units over an 18 month span in New Zealand. Cases were then analysed for the characteristics of infection and their preventability. Fifty cases met the inclusion criteria, most commonly due to uterine, respiratory or kidney infection. Fifty per cent (25) of these cases were deemed potentially preventable, predominantly due to delays in diagnosis and treatment. A high index of suspicion, development of early recognition systems and multi-disciplinary training are recommended to decrease preventable cases of maternal sepsis. © 2018 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis.

PubMed

Lorente, Leonardo; Martín, María M; Labarta, Lorenzo; Díaz, César; Solé-Violán, Jordi; Blanquer, José; Orbe, Josune; Rodríguez, José A; Jiménez, Alejandro; Borreguero-León, Juan M; Belmonte, Felipe; Medina, Juan C; Llimiñana, Maria C; Ferrer-Agüero, José M; Ferreres, José; Mora, María L; Lubillo, Santiago; Sánchez, Manuel; Barrios, Ysamar; Sierra, Antonio; Páramo, José A

2009-01-01

Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). The novel findings of our study on

Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis

PubMed Central

2009-01-01

Introduction Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. Methods This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. Results Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-α/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-α and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). Conclusions

The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-analysis

PubMed Central

Sterling, Sarah A.; Miller, W. Ryan; Pryor, Jason; Puskarich, Michael A.; Jones, Alan E.

2015-01-01

Objectives We sought to systematically review and meta-analyze the available data on the association between timing of antibiotic administration and mortality in severe sepsis and septic shock. Data Sources and Study Selection A comprehensive search was performed using a pre-defined protocol. Inclusion criteria: adult patients with severe sepsis or septic shock, reported time to antibiotic administration in relation to ED triage and/or shock recognition, and mortality. Exclusion criteria: immunosuppressed populations, review article, editorial, or non-human studies. Data Extraction Two reviewers screened abstracts with a third reviewer arbitrating. The effect of time to antibiotic administration on mortality was based on current guideline recommendations: 1) administration within 3 hours of ED triage; 2) administration within 1 hour of severe sepsis/septic shock recognition. Odds Ratios (OR) were calculated using a random effect model. The primary outcome was mortality. Data Synthesis 1123 publications were identified and 11 were included in the analysis. Among the 11 included studies, 16,178 patients were evaluable for antibiotic administration from ED triage. Patients who received antibiotics more than 3 hours after ED triage (< 3 hours reference), had a pooled OR for mortality of 1.16 (0.92 to 1.46, p = 0.21). A total of 11,017 patients were evaluable for antibiotic administration from severe sepsis/septic shock recognition. Patients who received antibiotics more than 1 hour after severe sepsis/shock recognition (< 1 hour reference) had a pooled OR for mortality of 1.46 (0.89 to 2.40, p = 0.13). There was no increased mortality in the pooled ORs for each hourly delay from <1 to >5 hours in antibiotic administration from severe sepsis/shock recognition. Conclusion Using the available pooled data we found no significant mortality benefit of administering antibiotics within 3 hours of ED triage or within 1 hour of shock recognition in severe sepsis and septic shock

Modulation of myocardial mitochondrial mechanisms during severe polymicrobial sepsis in the rat.

PubMed

Chopra, Mani; Golden, Honey B; Mullapudi, Srinivas; Dowhan, William; Dostal, David E; Sharma, Avadhesh C

2011-01-01

We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoK(ATP) channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. Male Sprague-Dawley rats (350-400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (-40%) and at 6 hr post-sepsis (-20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C. The data suggest that Bax activation is an upstream event that may precede the opening of the mitoK(ATP) channels in sepsis. We concluded that mitoK(ATP) channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial contractile dysfunction.

Out-of-Hospital Fluid in Severe Sepsis: Effect on Early Resuscitation in the Emergency Department

PubMed Central

Seymour, Christopher W.; Cooke, Colin R.; Mikkelsen, Mark E.; Hylton, Julie; Rea, Tom D.; Goss, Christopher H.; Gaieski, David F.; Band, Roger A.

2014-01-01

Background Early identification and treatment of patients with severe sepsis improves outcome, yet the role of out-of-hospital intravenous (IV) fluid is unknown. Objective To determine if the delivery of out-of-hospital fluid in patients with severe sepsis is associated with reduced time to achievement of goal-oriented resuscitation in the emergency department (ED). Methods We performed a secondary data analysis of a retrospective cohort study in a metropolitan, tertiary care, university-based medical center supported by a two-tiered system of out-of-hospital emergency medical services (EMS) providers. We studied the association between delivery of out-of-hospital fluid by advanced life support (ALS) providers and the achievement of resuscitation endpoints (central venous pressure [CVP] ≥8 mmHg, mean arterial pressure [MAP] ≥65 mmHg, and central venous oxygen saturation [ScvO2] ≥70%) within six hours after triage during early goal-directed therapy (EGDT) in the ED. Results Twenty five (48%) of 52 patients transported by ALS with severe sepsis received out-of-hospital fluid. Data for age, gender, source of sepsis, and presence of comorbidities were similar between patients who did and did not receive out-of-hospital fluid. Patients receiving out-of-hospital fluid had lower out-of-hospital mean (± standard deviation) systolic blood pressure (95 ± 40 mmHg vs. 117 ± 29 mmHg; p = 0.03) and higher median (interquartile range) Sequential Organ Failure Assessment (SOFA) scores in the ED (7 [5–8] vs. 4 [4–6]; p = 0.01) than patients not receiving out-of-hospital fluid. Despite greater severity of illness, patients receiving out-of-hospital fluid approached but did not attain a statistically significant increase in the likelihood of achieving MAP ≥65 mmHg within six hours after ED triage (70% vs. 44%, p = 0.09). On average, patients receiving out-of-hospital fluid received twice the fluid volume within one hour after ED triage (1.1 L [1.0–2.0 L] vs. 0.6 L [0

Pediatric sepsis

PubMed Central

Randolph, Adrienne G; McCulloh, Russell J

2014-01-01

Sepsis is the leading cause of death in children worldwide. Although the diagnosis and management of sepsis in infants and children is largely influenced by studies done in adults, there are important considerations relevant for pediatrics. This article highlights pediatric-specific issues related to the definition of sepsis and its epidemiology and management. We review how the capacity of the immune system to respond to infection develops over early life. We also bring attention to primary immune deficiencies that should be considered in children recurrently infected with specific types of organisms. The management of pediatric sepsis must be tailored to the child’s age and immune capacity, and to the site, severity, and source of the infection. It is important for clinicians to be aware of infection-related syndromes that primarily affect children. Although children in developed countries are more likely to survive severe infections than adults, many survivors have chronic health impairments. PMID:24225404

Modified obstetric early warning scoring systems (MOEWS): validating the diagnostic performance for severe sepsis in women with chorioamnionitis.

PubMed

Edwards, Sian E; Grobman, William A; Lappen, Justin R; Winter, Cathy; Fox, Robert; Lenguerrand, Erik; Draycott, Timothy

2015-04-01

We sought to compare the predictive power of published modified obstetric early warning scoring systems (MOEWS) for the development of severe sepsis in women with chorioamnionitis. This was a retrospective cohort study using prospectively collected clinical observations at a single tertiary unit (Chicago, IL). Hospital databases and patient records were searched to identify and verify cases with clinically diagnosed chorioamnionitis during the study period (June 2006 through November 2007). Vital sign data (heart rate, respiratory rate, blood pressure, temperature, mental state) for these cases were extracted from an electronic database and the single worst composite recording was identified for analysis. Global literature databases were searched (2014) to identify examples of MOEWS. Scores for each identified MOEWS were derived from each set of vital sign recordings during the presentation with chorioamnionitis. The performance of these MOEWS (the primary outcome) was then analyzed and compared using their sensitivity, specificity, positive and negative predictive values, and receiver-operating characteristic curve for severe sepsis. Six MOEWS were identified. There was wide variation in design and pathophysiological thresholds used for clinical alerts. In all, 913 women with chorioamnionitis were identified from the clinical database. In all, 364 cases with complete data for all physiological indicators were included in analysis. Five women developed severe sepsis, including 1 woman who died. The sensitivities of the MOEWS in predicting the severe deterioration ranged from 40-100% and the specificities varied even more ranging from 4-97%. The positive predictive values were low for all MOEWS ranging from <2-15%. The MOEWS with simpler designs tended to be more sensitive, whereas the more complex MOEWS were more specific, but failed to identify some of the women who developed severe sepsis. Currently used MOEWS vary widely in terms of alert thresholds, format

New perspectives on immunomodulatory therapy for bacteraemia and sepsis.

PubMed

Opal, Steven M

2010-12-01

Systemic immune dysregulation is generally acknowledged to be the fundamental molecular mechanism that underlies the pathophysiology of severe sepsis and septic shock. In the presence of a systemic infection, microbial pathogens and their soluble mediators induce generalised immune activation and coagulation activation, leading to severe sepsis and septic shock. For decades, immune-based therapies have been devised with the specific intent of inhibiting the pro-inflammatory events that are thought to precipitate the septic process. Despite a clear therapeutic rationale based upon the available experimental evidence, anti-inflammatory therapies targeting the innate or acquired immune response have largely been unsuccessful in clinical trials of sepsis. Compelling evidence now exists that a prolonged state of sepsis-induced immune suppression follows the initial period of stabilisation and resuscitation in many critically ill patients. Sepsis-related immune suppression is evidenced by histological findings of markedly enhanced lymphocytic and monocytic apoptosis, poor response to neoantigens and recall antigens, and increased incidence of infections by opportunistic pathogens. Candidiasis, cytomegalovirus activation and secondary infections by relatively avirulent bacterial pathogens such as Stenotrophomonas and Acinetobacter spp. are commonplace in septic patients during prolonged Intensive Care Unit stays. Immunological tools to detect sepsis-induced immunosuppression are now available, and novel immunoadjuvants are in development to re-establish immune competence in sepsis patients. The intelligent use of immunomodulatory agents in sepsis will necessitate a personalised medicine approach to treat each patient at the appropriate time and with the optimal therapy. Copyright © 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

A case of severe sepsis presenting marked decrease of neutrophils and interesting findings on dynamic CT.

PubMed

Makino, Isamu; Tajima, Hidehiro; Kitagawa, Hirohisa; Nakagawara, Hisatoshi; Miyashita, Tomoharu; Nakanuma, Shinichi; Hayashi, Hironori; Takamura, Hiroyuki; Fushida, Sachio; Ohta, Tetsuo

2015-05-28

In a patient with severe sepsis, we sometimes observe immediate decrease of the counts of white blood cells (WBCs) and neutrophils, which is known as an indicator for poor prognosis. We observed marked decrease of white blood cells and neutrophils on blood examination and interesting findings on dynamic CT. Here, we present the case of a patient with severe postoperative sepsis occurring after major abdominal surgery and we discuss the mechanism of such clinical presentations. A 60-year-old man received pancreatoduodenectomy with colectomy for pancreatic cancer. He developed a high fever on postoperative day 3. We observed marked decrease of WBCs and neutrophils on blood examination. We also observed slight swelling of the liver, inhomogeneous enhancement of liver parenchyma in arterial phase, and periportal low density in the Glisson capsule in portal phase, without any findings indicating infectious complications on dynamic CT. WBCs and neutrophils increased above normal range in just 6 hours. Blood culture examination performed while the patient had a high fever was positive for Aeromonas hydrophila. After receiving intensive care, he promptly recovered from severe sepsis. The CT findings disappeared on second dynamic CT examination performed 3 days after the first examination. We treated a patient with severe sepsis after major abdominal surgery who presented very rapid change of the counts of WBCs and neutrophils and interesting CT findings in the liver. We rescued him from a critical situation by prompt and intensive treatment. Research is needed to accumulate and analyze data from more patients who present a similar clinical course to better understand their pathophysiological conditions.

Persisting high levels of plasma pentraxin 3 over the first days after severe sepsis and septic shock onset are associated with mortality.

PubMed

Mauri, Tommaso; Bellani, Giacomo; Patroniti, Nicolo'; Coppadoro, Andrea; Peri, Giuseppe; Cuccovillo, Ivan; Cugno, Massimo; Iapichino, Gaetano; Gattinoni, Luciano; Pesenti, Antonio; Mantovani, Alberto

2010-04-01

Pentraxin 3 (PTX3) is an inflammatory mediator produced by neutrophils, macrophages, myeloid dendritic and endothelial cells. During sepsis a massive inflammatory activation and coagulation/fibrinolysis dysfunction occur. PTX3, as a mediator of inflammation, may represent an early marker of severity and outcome in sepsis. This study is based on a prospective trial regarding the impact of glycemic control on coagulation in sepsis. Ninety patients admitted to three general intensive care units were enrolled when severe sepsis or septic shock was diagnosed. At enrollment, we recorded sepsis signs, disease severity, coagulation activation [prothrombin fragments 1 + 2 (F(1+2))] and fibrinolysis inhibition [plasminogen activator inhibitor-1 (PAI-1)]. We measured plasma PTX3 levels at enrollment, everyday until day 7, then at days 9, 11, 13, 18, 23 and 28. Mortality was recorded at day 90. Although not different on day 1, PTX3 remained significantly higher in non-survivors than in survivors over the first 5 days (p = 0.002 by general linear model). On day 1, PTX3 levels were higher in septic shock than in severely septic patients (p = 0.029). Day 1 PTX3 was significantly correlated with platelet count (p < 0.001), SAPS II score (p = 0.006) and SOFA score (p < 0.001). Day 1 PTX3 was correlated with F(1+2) concentration and with PAI-1 activity and concentration (p < 0.05 for all). Persisting high levels of circulating PTX3 over the first days from sepsis onset may be associated with mortality. PTX3 correlates with severity of sepsis and with sepsis-associated coagulation/fibrinolysis dysfunction.

LONG-TERM QUALITY OF LIFE AMONG SURVIVORS OF SEVERE SEPSIS: ANALYSES OF TWO INTERNATIONAL TRIALS

PubMed Central

Yende, Sachin; Austin, Shamly; Rhodes, Andrew; Finfer, Simon; Opal, Steven; Thompson, Taylor; Bozza, Fernando A.; LaRosa, Steven P.; Ranieri, V. Marco; Angus, Derek C.

2016-01-01

Objective To describe quality of life (QoL) among sepsis survivors. Design Secondary analyses of 2 international, randomized clinical trials (ACCESS [derivation cohort] and PROWESS-SHOCK [validation cohort]). Patients Adults with severe sepsis admitted to the intensive care unit. We analyzed only patients who were functional and living at home without help before sepsis hospitalization (n=1,143 and 987 from ACCESS and PROWESS-SHOCK). Measurements and Main Results In ACCESS and PROWESS-SHOCK, the average age of patients living at home independently was 63 and 61 years; 400 (34.9%) and 298 (30.2%) died by 6 months. In ACCESS, 580 patients had a QoL measured using EQ-5D at 6 months. Of these, 41.6% could not live independently (22.7% were home but required help, 5.1% were in nursing home or rehabilitation facilities, and 5.3% were in acute care hospitals). Poor QoL at 6 months, as evidenced by problems in mobility, usual activities, and self-care domains were reported in 37.4%, 43.7%, and 20.5%, respectively, and the high incidence of poor QoL was also seen in patients in PROWESS-SHOCK. Over 45%of patients with mobility and self-care problems at 6 months in ACCESS died or reported persistent problems at 1 year. Conclusions Among individuals enrolled in a clinical trial who lived independently prior to severe sepsis, one third had died and of those who survived, a further one third had not returned to independent living by 6 months. Both mortality and QoL should be considered when designing new interventions and considering endpoints for sepsis trials. PMID:26992066

Modulation of Myocardial Mitochondrial Mechanisms during Severe Polymicrobial Sepsis in the Rat

PubMed Central

Chopra, Mani; Golden, Honey B.; Mullapudi, Srinivas; Dowhan, William; Dostal, David E.; Sharma, Avadhesh C.

2011-01-01

Background We tested the hypothesis that 5-Hydroxydecanoic acid (5HD), a putative mitoKATP channel blocker, will reverse sepsis-induced cardiodynamic and adult rat ventricular myocyte (ARVM) contractile dysfunction, restore mitochondrial membrane permeability alterations and improve survival. Methodology/Principal Findings Male Sprague-Dawley rats (350–400 g) were made septic using 400 mg/kg cecal inoculum, ip. Sham animals received 5% dextrose water, ip. The Voltage Dependent Anion Channels (VDAC1), Bax and cytochrome C levels were determined in isolated single ARVMs obtained from sham and septic rat heart. Mitochondria and cytosolic fractions were isolated from ARVMs treated with norepinephrine (NE, 10 µmoles) in the presence/absence of 5HD (100 µmoles). A continuous infusion of 5HD using an Alzet pump reversed sepsis-induced mortality when administered at the time of induction of sepsis (−40%) and at 6 hr post-sepsis (−20%). Electrocardiography revealed that 5HD reversed sepsis-induced decrease in the average ejection fraction, Simpsons+m Mode (53.5±2.5 in sepsis and 69.2±1.2 at 24 hr in sepsis+5HD vs. 79.9±1.5 basal group) and cardiac output (63.3±1.2 mL/min sepsis and 79.3±3.9 mL/min at 24 hr in sepsis+5HD vs. 85.8±1.5 mL/min basal group). The treatment of ARVMs with 5HD also reversed sepsis-induced depressed contractility in both the vehicle and NE-treated groups. Sepsis produced a significant downregulation of VDAC1, and upregulation of Bax levels, along with mitochondrial membrane potential collapse in ARVMs. Pretreatment of septic ARVMs with 5HD blocked a NE-induced decrease in the VDAC1 and release of cytochrome C. Conclusion The data suggest that Bax activation is an upstream event that may precede the opening of the mitoKATP channels in sepsis. We concluded that mitoKATP channel inhibition via decreased mitochondrial membrane potential and reduced release of cytochrome C provided protection against sepsis-induced ARVM and myocardial

Mortality Predictors in Renal Transplant Recipients with Severe Sepsis and Septic Shock

PubMed Central

de Carvalho, Mônica Andrade; Freitas, Flávio Geraldo Rezende; Silva Junior, Hélio Tedesco; Bafi, Antônio Toneti; Machado, Flávia Ribeiro; Pestana, José Osmar Medina

2014-01-01

Introduction The growing number of renal transplant recipients in a sustained immunosuppressive state is a factor that can contribute to increased incidence of sepsis. However, relatively little is known about sepsis in this population. The aim of this single-center study was to evaluate the factors associated with hospital mortality in renal transplant patients admitted to the intensive care unit (ICU) with severe sepsis and septic shock. Methods Patient demographics and transplant-related and ICU stay data were retrospectively collected. Multiple logistic regression was conducted to identify the independent risk factors associated with hospital mortality. Results A total of 190 patients were enrolled, 64.2% of whom received kidneys from deceased donors. The mean patient age was 51±13 years (males, 115 [60.5%]), and the median APACHE II was 20 (16–23). The majority of patients developed sepsis late after the renal transplantation (2.1 [0.6–2.3] years). The lung was the most common infection site (59.5%). Upon ICU admission, 16.4% of the patients had ≤1 systemic inflammatory response syndrome criteria. Among the patients, 61.5% presented with ≥2 organ failures at admission, and 27.9% experienced septic shock within the first 24 hours of ICU admission. The overall hospital mortality rate was 38.4%. In the multivariate analysis, the independent determinants of hospital mortality were male gender (OR = 5.9; 95% CI, 1.7–19.6; p = 0.004), delta SOFA 24 h (OR = 1.7; 95% CI, 1.2–2.3; p = 0.001), mechanical ventilation (OR = 30; 95% CI, 8.8–102.2; p<0.0001), hematologic dysfunction (OR = 6.8; 95% CI, 2.0–22.6; p = 0.002), admission from the ward (OR = 3.4; 95% CI, 1.2–9.7; p = 0.02) and acute kidney injury stage 3 (OR = 5.7; 95% CI,1.9–16.6; p = 0.002). Conclusions Hospital mortality in renal transplant patients with severe sepsis and septic shock was associated with male gender, admission from the wards

Bacteremic Urinary Tract Infection Caused by Multidrug-Resistant Enterobacteriaceae Are Associated With Severe Sepsis at Admission: Implication for Empirical Therapy.

PubMed

Lee, Yi-Chien; Hsiao, Chih-Yen; Hung, Miao-Chiu; Hung, Sheng-Che; Wang, Hung-Ping; Huang, Yun-Jhong; Wang, Jann-Tay

2016-05-01

The purpose of this study is to compare the clinical features and treatment outcomes among patients with bacteremic urinary tract infection (UTI) caused by multidrug-resistant (MDR) and non-MDR Enterobacteriaceae and to identify whether MDR pathogens were independently associated with severe sepsis or septic shock at presentation.The clinical data of adult patients visiting and being treated at Chia-Yi Christian Hospital due to bacteremic UTI caused by Enterobacteriaceae from January 2006 to August 2015 were retrospectively analyzed.A total of 585 patients were enrolled. Among them, 220 (37.6%) were caused by the MDR Enterobacteriaceae. A total of 206 patients (35.2%) developed severe sepsis or septic shock at presentation. Patients in the MDR group tend to be male and have a past history of gout, recurrent UTI, prior hospitalization, hydronephrosis, renal stone, ureteral stone, indwelling urinary catheter, newly development of renal dysfunction, severe sepsis or septic shock, intensive care unit (ICU) admission, receipt of ineffective empirical therapy, longer hospital stay, and higher in-hospital mortality (2.7% vs 1.9%, P = 0.569). Using multivariate logistic regression analysis, it is revealed that independent predictors associated with severe sepsis or septic shock at presentation were liver cirrhosis (OR 2.868; 95% CI 1.439-5.716; P = 0.003), indwelling urinary catheter (OR 1.936; 95% CI 1.238-3.027; P = 0.004), and MDR Enterobacteriaceae (OR 1.447; 95% CI 1.002-2.090; P = 0.049).Multidrug resistance was associated with the development of severe sepsis or septic shock upon presentation among patients with bacteremic UTI caused by Enterobacteriaceae. Therefore, empirical antibiotics therapy for patients with UTI presented with severe sepsis and/or septic shock should be more broad-spectrum to effectively cover MDR Enterobacteriaceae.

Mortality Associated with Severe Sepsis Among Age-Similar Women with and without Pregnancy-Associated Hospitalization in Texas: A Population-Based Study.

PubMed

Oud, Lavi

2016-06-10

BACKGROUND The reported mortality among women with pregnancy-associated severe sepsis (PASS) has been considerably lower than among severely septic patients in the general population, with the difference being attributed to the younger age and lack of chronic illness among the women with PASS. However, no comparative studies were reported to date between patients with PASS and age-similar women with severe sepsis not associated with pregnancy (NPSS). MATERIAL AND METHODS We used the Texas Inpatient Public Use Data File to compare the crude and adjusted hospital mortality between women with severe sepsis, aged 20-34 years, with and without pregnancy-associated hospitalizations during 2001-2010, following exclusion of those with reported chronic comorbidities, as well as alcohol and drug abuse. RESULTS Crude hospital mortality among PASS vs. NPSS hospitalizations was lower for the whole cohort (6.7% vs. 14.1% [p<0.0001]) and those with ≥3 organ failures (17.6% vs. 33.2% [p=0.0100]). Adjusted PASS mortality (odds ratio [95% CI]) was 0.57 (0.38-0.86) [p=0.0070]. CONCLUSIONS Hospital mortality was unexpectedly markedly and consistently lower among women with severe sepsis associated with pregnancy, as compared with contemporaneous, age-similar women with severe sepsis not associated with pregnancy, without reported chronic comorbidities. Further studies are warranted to examine the sources of the observed differences and to corroborate our findings.

Clinical Characteristics and Outcomes of Sepsis-Related vs Non-Sepsis-Related ARDS

PubMed Central

Sheu, Chau-Chyun; Gong, Michelle N.; Zhai, Rihong; Chen, Feng; Bajwa, Ednan K.; Clardy, Peter F.; Gallagher, Diana C.; Thompson, B. Taylor

2010-01-01

-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities. PMID:20507948

Venous-to-arterial carbon dioxide difference in the resuscitation of patients with severe sepsis and septic shock: A systematic review.

PubMed

Diaztagle Fernández, J J; Rodríguez Murcia, J C; Sprockel Díaz, J J

2017-10-01

The way to assess tissue perfusion during the resuscitation of patients with severe sepsis and septic shock is a current subject of research and debate. Venous oxygen saturation and lactate concentration have been the most frequently used criteria, though they involve known limitations. The venous-to-arterial difference of carbon dioxide (pCO 2 delta) is a parameter than can be used to indicate tissue perfusion, and its determination therefore may be useful in these patients. A qualitative systematic review of the literature was made, comprising studies that assessed pCO 2 delta in adult patients with severe sepsis or septic shock, and published between January 1966 and November 2016 in the Medline-PubMed, Embase-Elsevier, Cochrane Library, and LILACS databases. There was no language restriction. The PRISMA statement was followed, and methodological quality was evaluated. Twelve articles were included, all of an observational nature, and including 10 prospective studies (9 published since 2010). Five documented greater mortality among patients with high pCO 2 delta values, in 3 cases even when achieving venous oxygen saturation targets. In 4 studies, a high pCO 2 delta was related to lower venous oxygen saturation and higher lactate levels, and another 3 documented lesser percentage lactate reductions. The parameter pCO 2 delta has been more frequently assessed in the management of patients with severe sepsis during the last few years. The studies demonstrate its correlation to mortality and other clinical outcomes, defining pCO 2 delta as a useful tool in the management of these patients. Copyright © 2017 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Role of kidney injury in sepsis.

PubMed

Doi, Kent

2016-01-01

Kidney injury, including acute kidney injury (AKI) and chronic kidney disease (CKD), has become very common in critically ill patients treated in ICUs. Many epidemiological studies have revealed significant associations of AKI and CKD with poor outcomes of high mortality and medical costs. Although many basic studies have clarified the possible mechanisms of sepsis and septic AKI, translation of the obtained findings to clinical settings has not been successful to date. No specific drug against human sepsis or AKI is currently available. Remarkable progress of dialysis techniques such as continuous renal replacement therapy (CRRT) has enabled control of "uremia" in hemodynamically unstable patients; however, dialysis-requiring septic AKI patients are still showing unacceptably high mortality of 60-80 %. Therefore, further investigations must be conducted to improve the outcome of sepsis and septic AKI. A possible target will be remote organ injury caused by AKI. Recent basic studies have identified interleukin-6 and high mobility group box 1 (HMGB1) as important mediators for acute lung injury induced by AKI. Another target is the disease pathway that is amplified by pre-existing CKD. Vascular endothelial growth factor and HMGB1 elevations in sepsis were demonstrated to be amplified by CKD in CKD-sepsis animal models. Understanding the role of kidney injury as an amplifier in sepsis and multiple organ failure might support the identification of new drug targets for sepsis and septic AKI.

Accuracy of microscopic urine analysis and chest radiography in patients with severe sepsis and septic shock.

PubMed

Capp, Roberta; Chang, Yuchiao; Brown, David F M

2012-01-01

Diagnosis of source of infection in patients with septic shock and severe sepsis needs to be done rapidly and accurately to guide appropriate antibiotic therapy. The purpose of this study is to evaluate the accuracy of two diagnostic studies used in the emergency department (ED) to guide diagnosis of source of infection in this patient population. This was a retrospective review of ED patients admitted to an intensive care unit with the diagnosis of severe sepsis or septic shock over a 12-month period. We evaluated accuracy of initial microscopic urine analysis testing and chest radiography in the diagnosis of urinary tract infections and pneumonia, respectively. Of the 1400 patients admitted to intensive care units, 170 patients met criteria for severe sepsis and septic shock. There were a total of 47 patients diagnosed with urinary tract infection, and their initial microscopic urine analysis with counts>10 white blood cells were 80% sensitive (95% confidence interval [CI] .66-.90) and 66% specific (95% CI .52-.77) for the positive final urine culture result. There were 85 patients with final diagnosis of pneumonia. The sensitivity and specificity of initial chest radiography were, respectively, 58% (95% CI .46-.68) and 91% (95% CI .81-.95) for the diagnosis of pneumonia. In patients with severe sepsis and septic shock, the chest radiograph has low sensitivity of 58%, whereas urine analysis has a low specificity of 66%. Given the importance of appropriate antibiotic selection and optimal but not perfect test characteristics, this population may benefit from broad-spectrum antibiotics, rather than antibiotics tailored toward a particular source of infection. Published by Elsevier Inc.

Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis.

PubMed

Finfer, Simon; McEvoy, Suzanne; Bellomo, Rinaldo; McArthur, Colin; Myburgh, John; Norton, Robyn

2011-01-01

To determine the effect of random assignment to fluid resuscitation with albumin or saline on organ function and mortality in patients with severe sepsis. Pre-defined subgroup analysis of a randomized controlled trial conducted in the intensive care units of 16 hospitals in Australia and New Zealand. Of 1,218 patients with severe sepsis at baseline, 603 and 615 were assigned to receive albumin and saline, respectively. The two groups had similar baseline characteristics. During the first 7 days mean arterial pressure was similar in the two groups, but patients assigned albumin had a lower heart rate on days 1 and 3 (p = 0.002 and p = 0.03, respectively) and a higher central venous pressure on days 1-3 (p < 0.005 each day). There was no difference in the renal or total Sequential Organ Failure Assessment score of the two groups; 113/603 (18.7%) of patients assigned albumin were treated with renal replacement therapy compared to 112/615 (18.2%) assigned saline (p = 0.98). The unadjusted relative risk of death for albumin versus saline was 0.87 [95% confidence interval (CI) 0.74-1.02] for patients with severe sepsis and 1.05 (0.94-1.17) for patients without severe sepsis (p = 0.06 for heterogeneity). From multivariate logistic regression analysis adjusting for baseline factors in patients with complete baseline data (919/1,218, 75.5%), the adjusted odds ratio for death for albumin versus saline was 0.71 (95% CI: 0.52-0.97; p = 0.03). Administration of albumin compared to saline did not impair renal or other organ function and may have decreased the risk of death.

Global validation of the WSES Sepsis Severity Score for patients with complicated intra-abdominal infections: a prospective multicentre study (WISS Study).

PubMed

Sartelli, Massimo; Abu-Zidan, Fikri M; Catena, Fausto; Griffiths, Ewen A; Di Saverio, Salomone; Coimbra, Raul; Ordoñez, Carlos A; Leppaniemi, Ari; Fraga, Gustavo P; Coccolini, Federico; Agresta, Ferdinando; Abbas, Asrhaf; Abdel Kader, Saleh; Agboola, John; Amhed, Adamu; Ajibade, Adesina; Akkucuk, Seckin; Alharthi, Bandar; Anyfantakis, Dimitrios; Augustin, Goran; Baiocchi, Gianluca; Bala, Miklosh; Baraket, Oussama; Bayrak, Savas; Bellanova, Giovanni; Beltràn, Marcelo A; Bini, Roberto; Boal, Matthew; Borodach, Andrey V; Bouliaris, Konstantinos; Branger, Frederic; Brunelli, Daniele; Catani, Marco; Che Jusoh, Asri; Chichom-Mefire, Alain; Cocorullo, Gianfranco; Colak, Elif; Costa, David; Costa, Silvia; Cui, Yunfeng; Curca, Geanina Loredana; Curry, Terry; Das, Koray; Delibegovic, Samir; Demetrashvili, Zaza; Di Carlo, Isidoro; Drozdova, Nadezda; El Zalabany, Tamer; Enani, Mushira Abdulaziz; Faro, Mario; Gachabayov, Mahir; Giménez Maurel, Teresa; Gkiokas, Georgios; Gomes, Carlos Augusto; Gonsaga, Ricardo Alessandro Teixeira; Guercioni, Gianluca; Guner, Ali; Gupta, Sanjay; Gutierrez, Sandra; Hutan, Martin; Ioannidis, Orestis; Isik, Arda; Izawa, Yoshimitsu; Jain, Sumita A; Jokubauskas, Mantas; Karamarkovic, Aleksandar; Kauhanen, Saila; Kaushik, Robin; Kenig, Jakub; Khokha, Vladimir; Kim, Jae Il; Kong, Victor; Koshy, Renol; Krasniqi, Avidyl; Kshirsagar, Ashok; Kuliesius, Zygimantas; Lasithiotakis, Konstantinos; Leão, Pedro; Lee, Jae Gil; Leon, Miguel; Lizarazu Pérez, Aintzane; Lohsiriwat, Varut; López-Tomassetti Fernandez, Eudaldo; Lostoridis, Eftychios; Mn, Raghuveer; Major, Piotr; Marinis, Athanasios; Marrelli, Daniele; Martinez-Perez, Aleix; Marwah, Sanjay; McFarlane, Michael; Melo, Renato Bessa; Mesina, Cristian; Michalopoulos, Nick; Moldovanu, Radu; Mouaqit, Ouadii; Munyika, Akutu; Negoi, Ionut; Nikolopoulos, Ioannis; Nita, Gabriela Elisa; Olaoye, Iyiade; Omari, Abdelkarim; Ossa, Paola Rodríguez; Ozkan, Zeynep; Padmakumar, Ramakrishnapillai; Pata, Francesco; Pereira Junior, Gerson Alves; Pereira, Jorge; Pintar, Tadeja; Pouggouras, Konstantinos; Prabhu, Vinod; Rausei, Stefano; Rems, Miran; Rios-Cruz, Daniel; Sakakushev, Boris; Sánchez de Molina, Maria Luisa; Seretis, Charampolos; Shelat, Vishal; Simões, Romeo Lages; Sinibaldi, Giovanni; Skrovina, Matej; Smirnov, Dmitry; Spyropoulos, Charalampos; Tepp, Jaan; Tezcaner, Tugan; Tolonen, Matti; Torba, Myftar; Ulrych, Jan; Uzunoglu, Mustafa Yener; van Dellen, David; van Ramshorst, Gabrielle H; Vasquez, Giorgio; Venara, Aurélien; Vereczkei, Andras; Vettoretto, Nereo; Vlad, Nutu; Yadav, Sanjay Kumar; Yilmaz, Tonguç Utku; Yuan, Kuo-Ching; Zachariah, Sanoop Koshy; Zida, Maurice; Zilinskas, Justas; Ansaloni, Luca

2015-01-01

To validate a new practical Sepsis Severity Score for patients with complicated intra-abdominal infections (cIAIs) including the clinical conditions at the admission (severe sepsis/septic shock), the origin of the cIAIs, the delay in source control, the setting of acquisition and any risk factors such as age and immunosuppression. The WISS study (WSES cIAIs Score Study) is a multicenter observational study underwent in 132 medical institutions worldwide during a four-month study period (October 2014-February 2015). Four thousand five hundred thirty-three patients with a mean age of 51.2 years (range 18-99) were enrolled in the WISS study. Univariate analysis has shown that all factors that were previously included in the WSES Sepsis Severity Score were highly statistically significant between those who died and those who survived (p < 0.0001). The multivariate logistic regression model was highly significant (p < 0.0001, R2 = 0.54) and showed that all these factors were independent in predicting mortality of sepsis. Receiver Operator Curve has shown that the WSES Severity Sepsis Score had an excellent prediction for mortality. A score above 5.5 was the best predictor of mortality having a sensitivity of 89.2 %, a specificity of 83.5 % and a positive likelihood ratio of 5.4. WSES Sepsis Severity Score for patients with complicated Intra-abdominal infections can be used on global level. It has shown high sensitivity, specificity, and likelihood ratio that may help us in making clinical decisions.

Monitoring sepsis using electrical cell profiling.

PubMed

Prieto, Javier L; Su, Hao-Wei; Hou, Han Wei; Vera, Miguel Pinilla; Levy, Bruce D; Baron, Rebecca M; Han, Jongyoon; Voldman, Joel

2016-11-01

Sepsis is a potentially lethal condition that may be ameliorated through early monitoring of circulating activated leukocytes for faster stratification of severity of illness and improved administration of targeted treatment. Characterization of the intrinsic electrical properties of leukocytes is label-free and can provide a quick way to quantify the number of activated cells as sepsis progresses. Iso-dielectric separation (IDS) uses dielectrophoresis (DEP) to characterize the electrical signatures of cells. Here, we use IDS to show that activated and non-activated leukocytes have different electrical properties. We then present a double-sided version of the IDS platform to increase throughput to characterize thousands of cells. This new platform is less prone to cell fouling and allows faster characterization. Using peripheral blood samples from a cecal ligation and puncture (CLP) model of polymicrobial sepsis in mice, we estimate the number of activated leukocytes by looking into differences in the electrical properties of cells. We show for the first time using animal models that electrical cell profiling correlates with flow cytometry (FC) results and that IDS is therefore a good candidate for providing rapid monitoring of sepsis by quantifying the number of circulating activated leukocytes.

The new sepsis definition: limitations and contribution to research and diagnosis of sepsis.

PubMed

Verdonk, Franck; Blet, Alice; Mebazaa, Alexandre

2017-04-01

Based on recent clinical, epidemiological, and pathophysiological data, a third international consensus conference was carried out to define new criteria of sepsis in February 2016. This review presents the different items of this new definition, their limitations and their contribution to research and diagnosis of sepsis, in comparison with the previous definitions. Incidence, management, and pathophysiological knowledge of sepsis have improved over the past 20 years. However, sepsis still evolves to a mortal outcome, in one case out of five, with no new recent or specific therapy showing its efficacy on the patient's prognosis. These findings have led to the development of new definition. The new definition of sepsis incorporates relevant clinical and biological criteria such as SOFA score or serum lactate levels. It no longer takes into account the items of the systemic inflammatory response syndrome, which present a lack of specificity. It also simplifies the different stages of severity by deleting the term of 'severe sepsis' and by defining septic shock as a subset of sepsis. This definition, endorsed by only two international societies of intensive care, has some limitations and so merits prospective validation at different levels.

Application of a simplified definition of diastolic function in severe sepsis and septic shock.

PubMed

Lanspa, Michael J; Gutsche, Andrea R; Wilson, Emily L; Olsen, Troy D; Hirshberg, Eliotte L; Knox, Daniel B; Brown, Samuel M; Grissom, Colin K

2016-08-04

Left ventricular diastolic dysfunction is common in patients with severe sepsis or septic shock, but the best approach to categorization is unknown. We assessed the association of common measures of diastolic function with clinical outcomes and tested the utility of a simplified definition of diastolic dysfunction against the American Society of Echocardiography (ASE) 2009 definition. In this prospective observational study, patients with severe sepsis or septic shock underwent transthoracic echocardiography within 24 h of onset of sepsis (median 4.3 h). We measured echocardiographic parameters of diastolic function and used random forest analysis to assess their association with clinical outcomes (28-day mortality and ICU-free days to day 28) and thereby suggest a simplified definition. We then compared patients categorized by the ASE 2009 definition and our simplified definition. We studied 167 patients. The ASE 2009 definition categorized only 35 % of patients. Random forest analysis demonstrated that the left atrial volume index and deceleration time, central to the ASE 2009 definition, were not associated with clinical outcomes. Our simplified definition used only e' and E/e', omitting the other measurements. The simplified definition categorized 87 % of patients. Patients categorized by either ASE 2009 or our novel definition had similar clinical outcomes. In both definitions, worsened diastolic function was associated with increased prevalence of ischemic heart disease, diabetes, and hypertension. A novel, simplified definition of diastolic dysfunction categorized more patients with sepsis than ASE 2009 definition. Patients categorized according to the simplified definition did not differ from patients categorized according to the ASE 2009 definition in respect to clinical outcome or comorbidities.

Mortality Associated with Severe Sepsis Among Age-Similar Women with and without Pregnancy-Associated Hospitalization in Texas: A Population-Based Study

PubMed Central

Oud, Lavi

2016-01-01

Background The reported mortality among women with pregnancy-associated severe sepsis (PASS) has been considerably lower than among severely septic patients in the general population, with the difference being attributed to the younger age and lack of chronic illness among the women with PASS. However, no comparative studies were reported to date between patients with PASS and age-similar women with severe sepsis not associated with pregnancy (NPSS). Material/Methods We used the Texas Inpatient Public Use Data File to compare the crude and adjusted hospital mortality between women with severe sepsis, aged 20–34 years, with and without pregnancy-associated hospitalizations during 2001–2010, following exclusion of those with reported chronic comorbidities, as well as alcohol and drug abuse. Results Crude hospital mortality among PASS vs. NPSS hospitalizations was lower for the whole cohort (6.7% vs. 14.1% [p<0.0001]) and those with ≥3 organ failures (17.6% vs. 33.2% [p=0.0100]). Adjusted PASS mortality (odds ratio [95% CI]) was 0.57 (0.38–0.86) [p=0.0070]. Conclusions Hospital mortality was unexpectedly markedly and consistently lower among women with severe sepsis associated with pregnancy, as compared with contemporaneous, age-similar women with severe sepsis not associated with pregnancy, without reported chronic comorbidities. Further studies are warranted to examine the sources of the observed differences and to corroborate our findings. PMID:27286326

Cardiovascular response to dobutamine stress predicts outcome in severe sepsis and septic shock.

PubMed

Kumar, Anand; Schupp, Elizabeth; Bunnell, Eugene; Ali, Amjad; Milcarek, Barry; Parrillo, Joseph E

2008-01-01

During septic shock, resistance to the haemodynamic effects of catecholamine vasopressors and inotropes is a well-recognised marker of mortality risk. However, the specific cardiovascular or metabolic response elements that are most closely associated with outcome have not been well defined. The objective of this study was to assess cardiovascular and metabolic responses to dobutamine as correlates of outcome in patients with severe sepsis or septic shock. A prospective, non-randomised, non-blinded interventional study of graded dobutamine challenge (0, 5, 10, and 15 mug/kg/min) in adult patients who had undergone pulmonary artery catheterisation within 48 hours of onset of severe sepsis or septic shock (8 survivors/15 non-survivors) was performed. Radionuclide cineangiography during graded infusion was used to determine biventricular ejection fractions at each increment of dobutamine. In univariate analysis, a variety of cardiovascular or haemodynamic and oxygen transport or metabolic variables (at the point of maximum cardiac index response for a given subject) were associated with survival including: increased stroke volume index (p = 0.0003); right ventricular end-diastolic volume index (p = 0.0047); left ventricular stroke work index (p = 0.0054); oxygen delivery index (p = 0.0084); cardiac index (p = 0.0093); systolic blood pressure/left ventricular end-systolic volume index ratio (p = 0.0188); left ventricular ejection fraction (p = 0.0160); venous oxygen content (p = 0.0208); mixed venous oxygen saturation (p = 0.0234); pulse pressure (p = 0.0403); decreased pulmonary artery diastolic pressure (p = 0.0133); systemic vascular resistance index (p = 0.0154); extraction ratio (p = 0.0160); and pulmonary vascular resistance index (p = 0.0390). Increases of stroke volume index of greater than or less than 8.5 mL/m2 were concordant with survival or death in 21 of 23 cases. Multivariate profile construction showed stroke volume index as the dominant discriminating

Comparison of PIRO, SOFA, and MEDS scores for predicting mortality in emergency department patients with severe sepsis and septic shock.

PubMed

Macdonald, Stephen P J; Arendts, Glenn; Fatovich, Daniel M; Brown, Simon G A

2014-11-01

The Predisposition Insult Response and Organ failure (PIRO) scoring system has been developed for use in the emergency department (ED) to risk stratify sepsis cases, but has not been well studied among high-risk patients with severe sepsis and septic shock. The PIRO score was compared with the Sequential Organ Failure Assessment (SOFA) and Mortality in ED Sepsis (MEDS) scores to predict mortality in ED patients with features suggesting severe sepsis or septic shock in the ED. This was an analysis of sepsis patients enrolled in a prospective observational ED study of patients presenting with evidence of shock, hypoxemia, or other organ failure. PIRO, MEDS, and SOFA scores were calculated from ED data. Analysis compared areas under the receiver operator characteristic (ROC) curves for 30-day mortality. Of 240 enrolled patients, final diagnoses were septic shock in 128 (53%), severe sepsis without shock in 70 (29%), and infection with no organ dysfunction in 42 (18%). Forty-eight (20%) patients died within 30 days of presentation. Area under the ROC curve (AUC) for mortality was 0.86 (95% confidence interval [CI] = 0.80 to 0.92) for PIRO, 0.81 (95% CI = 0.74 to 0.88) for MEDS, and 0.78 (95% CI = 0.71 to 0.87) for SOFA scores. Pairwise comparisons of the AUC were as follows: PIRO versus SOFA, p = 0.01; PIRO versus MEDS, p = 0.064; and MEDS versus SOFA; p = 0.37. Mortality increased with increasing PIRO scores: PIRO < 5, 0%; PIRO 5 to 9, 5%; PIRO 10 to 14, 5%; PIRO 15 to 19, 37%; and PIRO ≥ 20, 80% (p < 0.001). The MEDS score also showed increasing mortality with higher scores: MEDS < 5, 0%; MEDS 5 to 7, 12%; MEDS 8 to 11, 15%; MEDS 12 to 14, 48%; and MEDS > 15, 65% (p < 0.001). The PIRO model, taking into account comorbidities and septic source as well as physiologic status, performed better than the SOFA score and similarly to the MEDS score for predicting mortality in ED patients with severe sepsis and septic shock. These findings have implications for identifying

The Rate of Sepsis in a National Pediatric Population, 2006 to 2012.

PubMed

Schuller, Kristin A; Hsu, Benson S; Thompson, Allyson B

2017-10-01

The rate of pediatric severe sepsis is reported to be on the rise in the United States, increasing by approximately 6000 cases annually. The goal of this study was to determine the rate of pediatric sepsis per 100 000 inpatient discharges over time. The 2006, 2009, and 2012 Agency for Healthcare Research and Quality Healthcare Cost Utilization Project Kid's Inpatient Databases were used to analyze the rate of sepsis in children over time. The rate of pediatric sepsis has increased over time from 92.8 per 100 000 in 2006 to 158.7 per 100 000 in 2012. Children less than a year old with Medicaid coverage and 3 or more procedures during hospitalization have significantly higher rates than their counterparts. This study helps clarify the population demographics that are at greater risk for sepsis infections. Understanding the at-risk population aids policymakers and care providers in targeting these populations and make drastic changes to sepsis policies.

Association of Fluid Accumulation with Clinical Outcomes in Critically Ill Children with Severe Sepsis

PubMed Central

Chen, Jiao; Li, Xiaozhong; Bai, Zhenjiang; Fang, Fang; Hua, Jun; Li, Ying; Pan, Jian; Wang, Jian; Feng, Xing; Li, Yanhong

2016-01-01

Objective To evaluate whether early and acquired daily fluid overload (FO), as well as fluctuations in fluid accumulation, were associated with adverse outcomes in critically ill children with severe sepsis. Methods This study enrolled 202 children in a pediatric intensive care unit (PICU) with severe sepsis. Early fluid overload was defined as ≥5% fluid accumulation occurring in the first 24 hours of PICU admission. The maximum daily fluid accumulation ≥5% occurring during the next 6 days in patients with at least 48 hours of PICU stay was defined as PICU-acquired daily fluid overload. The fluctuation in fluid accumulation was calculated as the difference between the maximum and the minimum daily fluid accumulation obtained during the first 7 days after admission. Results Of the 202 patients, 61 (30.2%) died during PICU stay. Among all patients, 41 (20.3%) experienced early fluid overload, including 9 with a FO ≥10%. Among patients with at least 48 hours of PICU stay (n = 154), 36 (23.4%) developed PICU-acquired daily fluid overload, including 2 with a FO ≥10%. Both early fluid overload (AOR = 1.20; 95% CI 1.08–1.33; P = 0.001; n = 202) and PICU-acquired daily fluid overload (AOR = 5.47 per log increase; 95% CI 1.15–25.96; P = 0.032; n = 154) were independent risk factors associated with mortality after adjusting for age, illness severity, etc. However, fluctuations in fluid accumulation were not associated with mortality after adjustment. Length of PICU stay increased with greater fluctuations in fluid accumulation in all patients with at least 48 hours of PICU stay (FO <5%, 5%-10% vs. ≥10%: 4 [3–8], 7 [4–11] vs. 10 [6–16] days; P <0.001; n = 154) and in survivors (4 [3–8], 7 [5–11] vs. 10 [5–15] days; P <0.001; n = 121). Early fluid overload achieved an area under-the-receiver-operating-characteristic curve of 0.74 (95% CI 0.65–0.82; P <0.001; n = 202) for predicting mortality in patients with severe sepsis, with a sensitivity of 67

Effect of dextran-70 on outcome in severe sepsis; a propensity-score matching study.

PubMed

Bentzer, Peter; Broman, Marcus; Kander, Thomas

2017-07-06

Albumin may be beneficial in patients with septic shock but availability is limited and cost is high. The objective of the present study was to investigate if the use of dextran-70 in addition to albumin and crystalloids influences organ failure or mortality in patients with severe sepsis or septic shock. Patients with severe sepsis or septic shock (n = 778) admitted to a university hospital intensive care unit (ICU) between 2007 and 2015 that received dextran-70 during resuscitation were propensity score matched to controls at a 1 to 1 ratio. Outcomes were highest acute kidney injury network (AKIN) score the first 10 days in the ICU, use of renal replacement therapy, days alive and free of organ support the first 28 days after admission to ICU, mortality and events of severe bleeding. Outcomes were assessed using paired hypothesis testing. Propensity score matching resulted in two groups of patients with 245 patients in each group. The dextran group received a median volume of 1483 ml (interquartile range, 1000-2000 ml) of dextran-70 during the ICU stay. Highest AKIN score did not differ between the control- and dextran groups (1 (0-3) versus 2 (0-3), p = 0.06). Incidence of renal replacement therapy in the control- and dextran groups was similar (19% versus 22%, p = 0.42, absolute risk reduction -2.9% [95% CI: -9.9 to 4.2]). Days alive and free of renal replacement, vasopressors and mechanical ventilation did not differ between the control- and dextran groups. The 180-day mortality was 50.2% in the control group and 41.6% in the dextran group (p = 0.046, absolute risk reduction 8.6% [-0.2 to 17.4]). Fraction of patients experiencing a severe bleeding in the first 10 days in the ICU did not differ between the control and dextran groups (14% versus 18%, p = 0.21). There is a paucity of high quality data regarding effects of dextran solutions on outcome in sepsis. In the present study, propensity score matching was used in attempt to reduce bias. No

Human severe sepsis cytokine mixture increases β2-integrin-dependent polymorphonuclear leukocyte adhesion to cerebral microvascular endothelial cells in vitro.

PubMed

Blom, Chris; Deller, Brittany L; Fraser, Douglas D; Patterson, Eric K; Martin, Claudio M; Young, Bryan; Liaw, Patricia C; Yazdan-Ashoori, Payam; Ortiz, Angelica; Webb, Brian; Kilmer, Greg; Carter, David E; Cepinskas, Gediminas

2015-04-07

Sepsis-associated encephalopathy (SAE) is a state of acute brain dysfunction in response to a systemic infection. We propose that systemic inflammation during sepsis causes increased adhesion of leukocytes to the brain microvasculature, resulting in blood-brain barrier dysfunction. Thus, our objectives were to measure inflammatory analytes in plasma of severe sepsis patients to create an experimental cytokine mixture (CM), and to use this CM to investigate the activation and interactions of polymorphonuclear leukocytes (PMN) and human cerebrovascular endothelial cells (hCMEC/D3) in vitro. The concentrations of 41 inflammatory analytes were quantified in plasma obtained from 20 severe sepsis patients and 20 age- and sex-matched healthy controls employing an antibody microarray. Two CMs were prepared to mimic severe sepsis (SSCM) and control (CCM), and these CMs were then used for PMN and hCMEC/D3 stimulation in vitro. PMN adhesion to hCMEC/D3 was assessed under conditions of flow (shear stress 0.7 dyn/cm(2)). Eight inflammatory analytes elevated in plasma obtained from severe sepsis patients were used to prepare SSCM and CCM. Stimulation of PMN with SSCM led to a marked increase in PMN adhesion to hCMEC/D3, as compared to CCM. PMN adhesion was abolished with neutralizing antibodies to either β2 (CD18), αL/β2 (CD11α/CD18; LFA-1) or αM/β2 (CD11β/CD18; Mac-1) integrins. In addition, immune-neutralization of the endothelial (hCMEC/D3) cell adhesion molecule, ICAM-1 (CD54) also suppressed PMN adhesion. Human SSCM up-regulates PMN pro-adhesive phenotype and promotes PMN adhesion to cerebrovascular endothelial cells through a β2-integrin-ICAM-1-dependent mechanism. PMN adhesion to the brain microvasculature may contribute to SAE.

Platelets and Multi-Organ Failure in Sepsis.

PubMed

Greco, Elisabetta; Lupia, Enrico; Bosco, Ornella; Vizio, Barbara; Montrucchio, Giuseppe

2017-10-20

Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models.

Platelets and Multi-Organ Failure in Sepsis

PubMed Central

Greco, Elisabetta; Lupia, Enrico; Bosco, Ornella; Vizio, Barbara; Montrucchio, Giuseppe

2017-01-01

Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models. PMID:29053592

Choice of Fluid Therapy in the Initial Management of Sepsis, Severe Sepsis, and Septic Shock.

PubMed

Chang, Ronald; Holcomb, John B

2016-07-01

Sepsis results in disruption of the endothelial glycocalyx layer and damage to the microvasculature, resulting in interstitial accumulation of fluid and subsequently edema. Fluid resuscitation is a mainstay in the initial treatment of sepsis, but the choice of fluid is unclear. The ideal resuscitative fluid is one that restores intravascular volume while minimizing edema; unfortunately, edema and edema-related complications are common consequences of current resuscitation strategies. Crystalloids are recommended as first-line therapy, but the type of crystalloid is not specified. There is increasing evidence that normal saline is associated with increased mortality and kidney injury; balanced crystalloids may be a safer alternative. Albumin is similar to crystalloids in terms of outcomes in the septic population but is costlier. Hydroxyethyl starches appear to increase mortality and kidney injury in the critically ill and are no longer indicated in these patients. In the trauma population, the shift to plasma-based resuscitation with decreased use of crystalloid and colloid in the treatment of hemorrhagic shock has led to decreased inflammatory and edema-mediated complications. Studies are needed to determine if these benefits also occur with a similar resuscitation strategy in the setting of sepsis.

Effect of SeptimebTM as a new natural extract on severe sepsis: A randomized clinical trial.

PubMed

Pourdast, Alieh; Sanaei, Maryam; Jafari, Sirous; Mohammadi, Mostafa; Khalili, Hossein; Shafiee, Gita; Ahadi, Zeinab; Rostami, Mahsa; Alizad, Saba; Heshmat, Ramin; Mohraz, Minoo

2017-01-01

Septimeb as a herbal medicine has regulatory effects on inflammation. This study set to evaluate the effects of Septimeb among patients with sepsis on inflammatory biomarkers and survival rate. In this randomized clinical trial, 51 patients with sepsis from the ICU and medical ward of Imam Khomeini Hospital were divided into two groups: Septimeb (n=25) and control group (n=26). In the control group, the patients received a standard treatment only for 7 days, while Septimeb group received Septimeb (6cc vial with 500cc serum glucose infusion 5% daily for one to two hours) plus standard treatment of sepsis for 7 days. Then, blood samples were analyzed. APACHE (Acute Physiologic and Chronic Health Evaluation), SOFA (Sequential Organ Failure Assessment), and GCS (Glasgow Coma Score) values were calculated daily. Treatment with Septimeb showed a significant decrease in SOFA value (1.54±0.83) compared to the control group (2.39±0.88) (P<0.001) and a significant increase in GCS value (14.46±0.88) compared to the control group (12.86±1.78) (P<0.001). Improvements of these values can confirm the potential of Septimeb in the reduction of severity of sepsis (P<0.05). There were significant decreases in lactate and blood sugar and WBC levels. In addition, inflammatory factors such as ESR (Septimeb group: 52.07±34.80, control group: 51.75±42.10, P=0.98) and CRP (Septimeb group: 48.86±23.21, control group: 49.93±36.22, P=0.92) decreased, but did not show a significant reduction. Septimeb has positive effects on reduction of the severity of sepsis which leads to reduction of patients' mortality rates.

Effect of SeptimebTM as a new natural extract on severe sepsis: A randomized clinical trial

PubMed Central

Pourdast, Alieh; Sanaei, Maryam; Jafari, Sirous; Mohammadi, Mostafa; Khalili, Hossein; Shafiee, Gita; Ahadi, Zeinab; Rostami, Mahsa; Alizad, Saba; Heshmat, Ramin; Mohraz, Minoo

2017-01-01

Background: Septimeb as a herbal medicine has regulatory effects on inflammation. This study set to evaluate the effects of Septimeb among patients with sepsis on inflammatory biomarkers and survival rate. Methods: In this randomized clinical trial, 51 patients with sepsis from the ICU and medical ward of Imam Khomeini Hospital were divided into two groups: Septimeb (n=25) and control group (n=26). In the control group, the patients received a standard treatment only for 7 days, while Septimeb group received Septimeb (6cc vial with 500cc serum glucose infusion 5% daily for one to two hours) plus standard treatment of sepsis for 7 days. Then, blood samples were analyzed. APACHE (Acute Physiologic and Chronic Health Evaluation), SOFA (Sequential Organ Failure Assessment), and GCS (Glasgow Coma Score) values were calculated daily. Results: Treatment with Septimeb showed a significant decrease in SOFA value (1.54±0.83) compared to the control group (2.39±0.88) (P<0.001) and a significant increase in GCS value (14.46±0.88) compared to the control group (12.86±1.78) (P<0.001). Improvements of these values can confirm the potential of Septimeb in the reduction of severity of sepsis (P<0.05). There were significant decreases in lactate and blood sugar and WBC levels. In addition, inflammatory factors such as ESR (Septimeb group: 52.07±34.80, control group: 51.75±42.10, P=0.98) and CRP (Septimeb group: 48.86±23.21, control group: 49.93±36.22, P=0.92) decreased, but did not show a significant reduction. Conclusion: Septimeb has positive effects on reduction of the severity of sepsis which leads to reduction of patients’ mortality rates. PMID:28503281

A comprehensive review of Vibrio vulnificus: an important cause of severe sepsis and skin and soft-tissue infection.

PubMed

Horseman, Michael A; Surani, Salim

2011-03-01

Vibrio vulnificus is a halophilic Gram-negative bacillus found worldwide in warm coastal waters. The pathogen has the ability to cause primary sepsis in certain high-risk populations, including patients with chronic liver disease, immunodeficiency, iron storage disorders, end-stage renal disease, and diabetes mellitus. Most reported cases of primary sepsis in the USA are associated with the ingestion of raw or undercooked oysters harvested from the Gulf Coast. The mortality rate for patients with severe sepsis is high, exceeding 50% in most reported series. Other clinical presentations include wound infection and gastroenteritis. Mild to moderate wound infection and gastroenteritis may occur in patients without obvious risk factors. Severe wound infection is often characterized by necrotizing skin and soft-tissue infection, including fasciitis and gangrene. V. vulnificus possesses several virulence factors, including the ability to evade destruction by stomach acid, capsular polysaccharide, lipopolysaccharide, cytotoxins, pili, and flagellum. The preferred antimicrobial therapy is doxycycline in combination with ceftazidime and surgery for necrotizing soft-tissue infection. Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Role of Cytokines as a Double-edged Sword in Sepsis

PubMed Central

CHAUDHRY, HINA; ZHOU, JUHUA; ZHONG, YIN; ALI, MIR MUSTAFA; MCGUIRE, FRANKLIN; NAGARKATTI, PRAKASH S.; NAGARKATTI, MITZI

2014-01-01

Background Sepsis is a deadly immunological disorder and its pathophysiology is still poorly understood. We aimed to determine if specific pro-inflammatory and anti-inflammatory cytokines can be used as diagnostic and therapeutic targets for sepsis. Materials and Methods Recent publications in the MEDLINE database were searched for articles regarding the clinical significance of inflammatory cytokines in sepsis. Results In response to pathogen infection, pro-inflammatory cytokines [interleukin-6 (IL-6), IL-8, IL-18 and tumor necrosis factor-α (TNF-α)] and anti-inflammatory cytokine (IL-10) increased in patients with sepsis. Importantly, a decrease in IL-6 was associated with a better prognosis and overproduction of IL-10 was found to be the main predictor of severity and fatal outcome. Conclusion Both pro-inflammatory and anti-inflammatory cytokines constitute a double-edged sword in sepsis; on one hand they are critical to eliminate the infection while on the other, excessive production can cause tissue and organ damage. Increase in cytokines such as IL-6, Il-8, IL-10, IL-18 and TNF-α may have implications in diagnosis and treatment of sepsis. PMID:24292568

The accuracy of pulse oximetry in emergency department patients with severe sepsis and septic shock: a retrospective cohort study.

PubMed

Wilson, Ben J; Cowan, Hamish J; Lord, Jason A; Zuege, Dan J; Zygun, David A

2010-05-05

Pulse oximetry is routinely used to continuously and noninvasively monitor arterial oxygen saturation (SaO2) in critically ill patients. Although pulse oximeter oxygen saturation (SpO2) has been studied in several patient populations, including the critically ill, its accuracy has never been studied in emergency department (ED) patients with severe sepsis and septic shock. Sepsis results in characteristic microcirculatory derangements that could theoretically affect pulse oximeter accuracy. The purposes of the present study were twofold: 1) to determine the accuracy of pulse oximetry relative to SaO2 obtained from ABG in ED patients with severe sepsis and septic shock, and 2) to assess the impact of specific physiologic factors on this accuracy. This analysis consisted of a retrospective cohort of 88 consecutive ED patients with severe sepsis who had a simultaneous arterial blood gas and an SpO2 value recorded. Adult ICU patients that were admitted from any Calgary Health Region adult ED with a pre-specified, sepsis-related admission diagnosis between October 1, 2005 and September 30, 2006, were identified. Accuracy (SpO2 - SaO2) was analyzed by the method of Bland and Altman. The effects of hypoxemia, acidosis, hyperlactatemia, anemia, and the use of vasoactive drugs on bias were determined. The cohort consisted of 88 subjects, with a mean age of 57 years (19 - 89). The mean difference (SpO2 - SaO2) was 2.75% and the standard deviation of the differences was 3.1%. Subgroup analysis demonstrated that hypoxemia (SaO2 < 90) significantly affected pulse oximeter accuracy. The mean difference was 4.9% in hypoxemic patients and 1.89% in non-hypoxemic patients (p < 0.004). In 50% (11/22) of cases in which SpO2 was in the 90-93% range the SaO2 was <90%. Though pulse oximeter accuracy was not affected by acidoisis, hyperlactatementa, anemia or vasoactive drugs, these factors worsened precision. Pulse oximetry overestimates ABG-determined SaO2 by a mean of 2.75% in

Systolic blood pressure variability in patients with early severe sepsis or septic shock: a prospective cohort study.

PubMed

Tang, Yi; Sorenson, Jeff; Lanspa, Michael; Grissom, Colin K; Mathews, V J; Brown, Samuel M

2017-06-17

Severe sepsis and septic shock are often lethal syndromes, in which the autonomic nervous system may fail to maintain adequate blood pressure. Heart rate variability has been associated with outcomes in sepsis. Whether systolic blood pressure (SBP) variability is associated with clinical outcomes in septic patients is unknown. The propose of this study is to determine whether variability in SBP correlates with vasopressor independence and mortality among septic patients. We prospectively studied patients with severe sepsis or septic shock, admitted to an intensive care unit (ICU) with an arterial catheter. We analyzed SBP variability on the first 5-min window immediately following ICU admission. We performed principal component analysis of multidimensional complexity, and used the first principal component (PC 1 ) as input for Firth logistic regression, controlling for mean systolic pressure (SBP) in the primary analyses, and Acute Physiology and Chronic Health Evaluation (APACHE) II score or NEE dose in the ancillary analyses. Prespecified outcomes were vasopressor independence at 24 h (primary), and 28-day mortality (secondary). We studied 51 patients, 51% of whom achieved vasopressor independence at 24 h. Ten percent died at 28 days. PC 1 represented 26% of the variance in complexity measures. PC 1 was not associated with vasopressor independence on Firth logistic regression (OR 1.04; 95% CI: 0.93-1.16; p = 0.54), but was associated with 28-day mortality (OR 1.16, 95% CI: 1.01-1.35, p = 0.040). Early SBP variability appears to be associated with 28-day mortality in patients with severe sepsis and septic shock.

Sepsis in Children: Global Implications of the World Health Assembly Resolution on Sepsis.

PubMed

Kissoon, Niranjan; Reinhart, Konrad; Daniels, Ron; Machado, Machado Flavia R; Schachter, Raymond D; Finfer, Simon

2017-12-01

Sepsis, worldwide the leading cause of death in children, has now been recognized as the global health emergency it is. On May 26, 2017, the World Health Assembly, the decision-making body of the World Health Organization, adopted a resolution proposed by the Global Sepsis Alliance to improve the prevention, diagnosis, and management of sepsis. To discuss the implications of this resolution for children worldwide. The resolution highlights sepsis as a global threat and urges the 194 United Nations member states to take specific actions and implement appropriate measures to reduce its human and health economic burden. The resolution is a major step toward achieving the targets outlined by the Sustainable Developmental Goals for decreasing mortality in infants and children, but implementing it will require a concerted global effort.

[Monoclonal antibodies against inflammatory mediators for the treatment of patients with sepsis].

PubMed

Matsubara, Tomoyo

2002-03-01

Sepsis is a common cause of morbidity and mortality, particularly in immunocompromised and critically ill patients. Recently, a new designation, systemic inflammatory response syndrome(SIRS), has been studied. When an abnormal generalized inflammatory reaction is due to an infection, the terms sepsis and SIRS are synonymous. The systemic response to infection is mediated via the macrophage-derived cytokines that target end organ receptors in response to injury or infection. One strategy used to perturb the septic cascade is to block a particular inflammatory molecule. Results have been published on clinical trials in sepsis patients treated with several monoclonal antibodies, such as antiendotoxin antibodies, anti-tumor necrosis factor antibodies, and anti CD14 antibodies. In this chapter, the results of clinical trials in patients and in vivo data from animal models of sepsis are summarized.

Sepsis in Pediatric Cardiac Intensive Care.

PubMed

Wheeler, Derek S; Wong, Hector R

2016-08-01

In this review, we will discuss risk factors for developing sepsis; the role of biomarkers in establishing an early diagnosis, in monitoring therapeutic efficacy, in stratification, and for the identification of sepsis endotypes; and the pathophysiology and management of severe sepsis and septic shock, with an emphasis on the impact of sepsis on cardiovascular function. MEDLINE and PubMed. There is a lot of excitement in the field of sepsis research today. Scientific advances in the diagnosis and clinical staging of sepsis, as well as a personalized approach to the treatment of sepsis, offer tremendous promise for the future. However, at the same time, it is also evident that sepsis mortality has not improved enough, even with progress in our understanding of the molecular pathophysiology of sepsis.

Comparative analysis of survival between elderly and non-elderly severe sepsis and septic shock resuscitated patients

PubMed Central

Palomba, Henrique; Corrêa, Thiago Domingos; Silva, Eliézer; Pardini, Andreia; de Assuncao, Murillo Santucci Cesar

2015-01-01

Objective To compare outcomes between elderly (≥65 years old) and non-elderly (<65 years old) resuscitated severe sepsis and septic shock patients and determine predictors of death among elderly patients. Methods Retrospective cohort study including 848 severe sepsis and septic shock patients admitted to the intensive care unit between January 2006 and March 2012. Results Elderly patients accounted for 62.6% (531/848) and non-elderly patients for 37.4% (317/848). Elderly patients had a higher APACHE II score [22 (18-28) versus 19 (15-24); p<0.001], compared to non-elderly patients, although the number of organ dysfunctions did not differ between the groups. No significant differences were found in 28-day and in-hospital mortality rates between elderly and non-elderly patients. The length of hospital stay was higher in elderly compared to non-elderly patients admitted with severe sepsis and septic shock [18 (10-41) versus 14 (8-29) days, respectively; p=0.0001]. Predictors of death among elderly patients included age, site of diagnosis, APACHE II score, need for mechanical ventilation and vasopressors. Conclusion In this study population early resuscitation of elderly patients was not associated with increased in-hospital mortality. Prospective studies addressing the long-term impact on functional status and quality of life are necessary. PMID:26313436

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

PubMed Central

Iskander, Kendra N.; Osuchowski, Marcin F.; Stearns-Kurosawa, Deborah J.; Kurosawa, Shinichiro; Stepien, David; Valentine, Catherine

2013-01-01

Sepsis represents the host's systemic inflammatory response to a severe infection. It causes substantial human morbidity resulting in hundreds of thousands of deaths each year. Despite decades of intense research, the basic mechanisms still remain elusive. In either experimental animal models of sepsis or human patients, there are substantial physiological changes, many of which may result in subsequent organ injury. Variations in age, gender, and medical comorbidities including diabetes and renal failure create additional complexity that influence the outcomes in septic patients. Specific system-based alterations, such as the coagulopathy observed in sepsis, offer both potential insight and possible therapeutic targets. Intracellular stress induces changes in the endoplasmic reticulum yielding misfolded proteins that contribute to the underlying pathophysiological changes. With these multiple changes it is difficult to precisely classify an individual's response in sepsis as proinflammatory or immunosuppressed. This heterogeneity also may explain why most therapeutic interventions have not improved survival. Given the complexity of sepsis, biomarkers and mathematical models offer potential guidance once they have been carefully validated. This review discusses each of these important factors to provide a framework for understanding the complex and current challenges of managing the septic patient. Clinical trial failures and the therapeutic interventions that have proven successful are also discussed. PMID:23899564

Post–Acute Care Use and Hospital Readmission after Sepsis

PubMed Central

Jones, Tiffanie K.; Fuchs, Barry D.; Small, Dylan S.; Halpern, Scott D.; Hanish, Asaf; Umscheid, Craig A.; Baillie, Charles A.; Kerlin, Meeta Prasad; Gaieski, David F.

2015-01-01

Rationale: The epidemiology of post–acute care use and hospital readmission after sepsis remains largely unknown. Objectives: To examine the rate of post–acute care use and hospital readmission after sepsis and to examine risk factors and outcomes for hospital readmissions after sepsis. Methods: In an observational cohort study conducted in an academic health care system (2010–2012), we compared post–acute care use at discharge and hospital readmission after 3,620 sepsis hospitalizations with 108,958 nonsepsis hospitalizations. We used three validated, claims-based approaches to identify sepsis and severe sepsis. Measurements and Main Results: Post–acute care use at discharge was more likely after sepsis, driven by skilled care facility placement (35.4% after sepsis vs. 15.8%; P < 0.001), with the highest rate observed after severe sepsis. Readmission rates at 7, 30, and 90 days were higher postsepsis (P < 0.001). Compared with nonsepsis hospitalizations (15.6% readmitted within 30 d), the increased readmission risk was present regardless of sepsis severity (27.3% after sepsis and 26.0–26.2% after severe sepsis). After controlling for presepsis characteristics, the readmission risk was found to be 1.51 times greater (95% CI, 1.38–1.66) than nonsepsis hospitalizations. Readmissions after sepsis were more likely to result in death or transition to hospice care (6.1% vs. 13.3% after sepsis; P < 0.001). Independent risk factors associated with 30-day readmissions after sepsis hospitalizations included age, malignancy diagnosis, hospitalizations in the year prior to the index hospitalization, nonelective index admission type, one or more procedures during the index hospitalization, and low hemoglobin and high red cell distribution width at discharge. Conclusions: Post–acute care use and hospital readmissions were common after sepsis. The increased readmission risk after sepsis was observed regardless of sepsis severity and was associated with

Troponin elevation in severe sepsis and septic shock: the role of left ventricular diastolic dysfunction and right ventricular dilatation*.

PubMed

Landesberg, Giora; Jaffe, Allan S; Gilon, Dan; Levin, Phillip D; Goodman, Sergey; Abu-Baih, Abed; Beeri, Ronen; Weissman, Charles; Sprung, Charles L; Landesberg, Amir

2014-04-01

Serum troponin concentrations predict mortality in almost every clinical setting they have been examined, including sepsis. However, the causes for troponin elevations in sepsis are poorly understood. We hypothesized that detailed investigation of myocardial dysfunction by echocardiography can provide insight into the possible causes of troponin elevation and its association with mortality in sepsis. Prospective, analytic cohort study. Tertiary academic institute. A cohort of ICU patients with severe sepsis or septic shock. Advanced echocardiography using global strain, strain-rate imaging and 3D left and right ventricular volume analyses in addition to the standard echocardiography, and concomitant high-sensitivity troponin-T measurement in patients with severe sepsis or septic shock. Two hundred twenty-five echocardiograms and concomitant high-sensitivity troponin-T measurements were performed in a cohort of 106 patients within the first days of severe sepsis or septic shock (2.1 ± 1.4 measurements/patient). Combining echocardiographic and clinical variables, left ventricular diastolic dysfunction defined as increased mitral E-to-strain-rate e'-wave ratio, right ventricular dilatation (increased right ventricular end-systolic volume index), high Acute Physiology and Chronic Health Evaluation-II score, and low glomerular filtration rate best correlated with elevated log-transformed concomitant high-sensitivity troponin-T concentrations (mixed linear model: t = 3.8, 3.3, 2.8, and -2.1 and p = 0.001, 0.0002, 0.006, and 0.007, respectively). Left ventricular systolic dysfunction determined by reduced strain-rate s'-wave or low ejection fraction did not significantly correlate with log(concomitant high-sensitivity troponin-T). Forty-one patients (39%) died in-hospital. Right ventricular end-systolic volume index and left ventricular strain-rate e'-wave predicted in-hospital mortality, independent of Acute Physiology and Chronic Health Evaluation-II score (logistic

Differences in reported sepsis incidence according to study design: a literature review.

PubMed

Mariansdatter, Saga Elise; Eiset, Andreas Halgreen; Søgaard, Kirstine Kobberøe; Christiansen, Christian Fynbo

2016-10-12

Sepsis and severe sepsis are common conditions in hospital settings, and are associated with high rates of morbidity and mortality, but reported incidences vary considerably. In this literature review, we describe the variation in reported population-based incidences of sepsis and severe sepsis. We also examine methodological and demographic differences between studies that may explain this variation. We carried out a literature review searching three major databases and reference lists of relevant articles, to identify all original studies reporting the incidence of sepsis or severe sepsis in the general population. Two authors independently assessed all articles, and the final decision to exclude an article was reached by consensus. We extracted data according to predetermined variables, including study country, sepsis definition, and data source. We then calculated descriptive statistics for the reported incidences of sepsis and severe sepsis. The studies were classified according to the method used to identify cases of sepsis or severe sepsis: chart-based (i.e. review of patient charts) or code-based (i.e. predetermined International Classification of Diseases [ICD] codes). Among 482 articles initially screened, we identified 23 primary publications reporting incidence of sepsis and/or severe sepsis in the general population. The reported incidences ranged from 74 to 1180 per 100,000 person-years and 3 to 1074 per 100,000 person-years for sepsis and severe sepsis, respectively. Most chart-based studies used the Bone criteria (or a modification hereof) and Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study criteria to identify cases of sepsis and severe sepsis. Most code-based studies used ICD-9 codes, but the number of codes used ranged from 1 to more than 1200. We found that the incidence varied according to how sepsis was identified (chart-based vs. code-based), calendar year, data source, and world region. The reported incidences of sepsis and

Sepsis in Pediatric Cardiac Intensive Care

PubMed Central

Wheeler, Derek S.; Wong, Hector R.

2016-01-01

Objectives In this review we will discuss risk factors for developing sepsis; the role of biomarkers in establishing an early diagnosis, monitoring therapeutic efficacy, stratification, and for the identification of sepsis endotypes; and the pathophysiology and management of severe sepsis and septic shock, with an emphasis on the impact of sepsis on cardiovascular function. Data Source MEDLINE, PubMed Conclusion There is a lot of excitement in the field of sepsis research today. Scientific advances in the diagnosis and clinical staging of sepsis, as well as a personalized approach to the treatment of sepsis, offer tremendous promise for the future. However, at the same time, it is also evident that sepsis mortality has not improved enough, even with progress in our understanding of the molecular pathophysiology of sepsis. PMID:27490609

Circulating Plasma microRNAs can differentiate Human Sepsis and Systemic Inflammatory Response Syndrome (SIRS).

PubMed

Caserta, Stefano; Kern, Florian; Cohen, Jonathan; Drage, Stephen; Newbury, Sarah F; Llewelyn, Martin J

2016-06-20

Systemic inflammation in humans may be triggered by infection, termed sepsis, or non-infective processes, termed non-infective systemic inflammatory response syndrome (SIRS). MicroRNAs regulate cellular processes including inflammation and may be detected in blood. We aimed to establish definitive proof-of-principle that circulating microRNAs are differentially affected during sepsis and non-infective SIRS. Critically ill patients with severe (n = 21) or non-severe (n = 8) intra-abdominal sepsis; severe (n = 23) or non-severe (n = 21) non-infective SIRS; or no SIRS (n = 16) were studied. Next-generation sequencing and qRT-PCR were used to measure plasma microRNAs. Detectable blood miRNAs (n = 116) were generally up-regulated in SIRS compared to no-SIRS patients. Levels of these 'circulating inflammation-related microRNAs' (CIR-miRNAs) were 2.64 (IQR: 2.10-3.29) and 1.52 (IQR: 1.15-1.92) fold higher for non-infective SIRS and sepsis respectively (p < 0.0001), hence CIR-miRNAs appeared less abundant in sepsis than in SIRS. Six CIR-miRNAs (miR-30d-5p, miR-30a-5p, miR-192-5p, miR-26a-5p, miR-23a-5p, miR-191-5p) provided good-to-excellent discrimination of severe sepsis from severe SIRS (0.742-0.917 AUC of ROC curves). CIR-miRNA levels inversely correlated with pro-inflammatory cytokines (IL-1, IL-6 and others). Thus, among critically ill patients, sepsis and non-infective SIRS are associated with substantial, differential changes in CIR-miRNAs. CIR-miRNAs may be regulators of inflammation and warrant thorough evaluation as diagnostic and therapeutic targets.

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

PubMed Central

Singer, Mervyn; Deutschman, Clifford S.; Seymour, Christopher Warren; Shankar-Hari, Manu; Annane, Djillali; Bauer, Michael; Bellomo, Rinaldo; Bernard, Gordon R.; Chiche, Jean-Daniel; Coopersmith, Craig M.; Hotchkiss, Richard S.; Levy, Mitchell M.; Marshall, John C.; Martin, Greg S.; Opal, Steven M.; Rubenfeld, Gordon D.; van der Poll, Tom; Vincent, Jean-Louis; Angus, Derek C.

2016-01-01

IMPORTANCE Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. OBJECTIVE To evaluate and, as needed, update definitions for sepsis and septic shock. PROCESS A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). KEY FINDINGS FROMEVIDENCE SYNTHESIS Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. RECOMMENDATIONS Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

PubMed

Singer, Mervyn; Deutschman, Clifford S; Seymour, Christopher Warren; Shankar-Hari, Manu; Annane, Djillali; Bauer, Michael; Bellomo, Rinaldo; Bernard, Gordon R; Chiche, Jean-Daniel; Coopersmith, Craig M; Hotchkiss, Richard S; Levy, Mitchell M; Marshall, John C; Martin, Greg S; Opal, Steven M; Rubenfeld, Gordon D; van der Poll, Tom; Vincent, Jean-Louis; Angus, Derek C

2016-02-23

Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination. To evaluate and, as needed, update definitions for sepsis and septic shock. A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment). Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant. Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock

Selected Biomarkers Correlate with the Origin and Severity of Sepsis

PubMed Central

Růžková, Michaela; Stráníková, Alžběta; Bartáková, Eva; Máca, Jan; Beneš, Jiří

2018-01-01

The microbial etiology and source of sepsis influence the inflammatory response. Therefore, the plasma levels of cytokines (IL-6, IL-8, and IL-10), chemokines (CCL2/MCP-1, MIP-1β), heparin-binding protein (HBP), soluble CD14 (sCD14), and cortisol were analyzed in blood from septic patients obtained during the first 96 hours of intensive care unit hospitalization. The etiology was established in 56 out of a total of 62 patients enrolled in the study. Plasma concentrations of MCP-1, sCD14, IL-6, and IL-10 were significantly higher in patients with community-acquired pneumonia (CAP; n = 10) and infective endocarditis (IE; n = 11) compared to those with bacterial meningitis (BM; n = 18). Next, cortisol levels were higher in IE patients than in those with BM and CAP, and at one time point, cortisol was also higher in patients with gram-negative sepsis when compared to those with gram-positive infections. Furthermore, cortisol and MCP-1 levels correlated positively with the daily measured SOFA score. In addition, HBP levels were significantly higher in patients with IE than in those with BM. Our findings suggest that MCP-1, sCD14, IL-6, IL-10, cortisol, and HBP are modulated by the source of sepsis and that elevated MCP-1 and cortisol plasma levels are associated with sepsis-induced organ dysfunction. PMID:29769838

Implementation of an Inpatient Pediatric Sepsis Identification Pathway.

PubMed

Bradshaw, Chanda; Goodman, Ilyssa; Rosenberg, Rebecca; Bandera, Christopher; Fierman, Arthur; Rudy, Bret

2016-03-01

Early identification and treatment of severe sepsis and septic shock improves outcomes. We sought to identify and evaluate children with possible sepsis on a pediatric medical/surgical unit through successful implementation of a sepsis identification pathway. The sepsis identification pathway, a vital sign screen and subsequent physician evaluation, was implemented in October 2013. Quality improvement interventions were used to improve physician and nursing adherence with the pathway. We reviewed charts of patients with positive screens on a monthly basis to assess for nursing recognition/physician notification, physician evaluation for sepsis, and subsequent physician diagnosis of sepsis and severe sepsis/septic shock. Adherence data were analyzed on a run chart and statistical process control p-chart. Nursing and physician pathway adherence of >80% was achieved over a 6-month period and sustained for the following 6 months. The direction of improvements met standard criteria for special causes. Over a 1-year period, there were 963 admissions to the unit. Positive screens occurred in 161 (16.7%) of these admissions and 38 (23.5%) of these had a physician diagnosis of sepsis, severe sepsis, or septic shock. One patient with neutropenia and septic shock had a negative sepsis screen due to lack of initial fever. Using quality improvement methodology, we successfully implemented a sepsis identification pathway on our pediatric unit. The pathway provided a standardized process to identify and evaluate children with possible sepsis requiring timely evaluation and treatment. Copyright © 2016 by the American Academy of Pediatrics.

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

PubMed Central

Wynn, James Lawrence; Wilson, Chris S.; Hawiger, Jacek; Scumpia, Philip O.; Marshall, Andrew F.; Liu, Jin-Hua; Zharkikh, Irina; Wong, Hector R.; Lahni, Patrick; Benjamin, John T.; Plosa, Erin J.; Weitkamp, Jörn-Hendrik; Sherwood, Edward R.; Moldawer, Lyle L.; Ungaro, Ricardo; Baker, Henry V.; Lopez, M. Cecilia; McElroy, Steven J.; Colliou, Natacha; Mohamadzadeh, Mansour; Moore, Daniel Jensen

2016-01-01

Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18–null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G+ myeloid cells, and blocking IL-17A reduced IL-18–potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18–mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis. PMID:27114524

Prospective evaluation of an automated method to identify patients with severe sepsis or septic shock in the emergency department.

PubMed

Brown, Samuel M; Jones, Jason; Kuttler, Kathryn Gibb; Keddington, Roger K; Allen, Todd L; Haug, Peter

2016-08-22

Sepsis is an often-fatal syndrome resulting from severe infection. Rapid identification and treatment are critical for septic patients. We therefore developed a probabilistic model to identify septic patients in the emergency department (ED). We aimed to produce a model that identifies 80 % of sepsis patients, with no more than 15 false positive alerts per day, within one hour of ED admission, using routine clinical data. We developed the model using retrospective data for 132,748 ED encounters (549 septic), with manual chart review to confirm cases of severe sepsis or septic shock from January 2006 through December 2008. A naïve Bayes model was used to select model features, starting with clinician-proposed candidate variables, which were then used to calculate the probability of sepsis. We evaluated the accuracy of the resulting model in 93,733 ED encounters from April 2009 through June 2010. The final model included mean blood pressure, temperature, age, heart rate, and white blood cell count. The area under the receiver operating characteristic curve (AUC) for the continuous predictor model was 0.953. The binary alert achieved 76.4 % sensitivity with a false positive rate of 4.7 %. We developed and validated a probabilistic model to identify sepsis early in an ED encounter. Despite changes in process, organizational focus, and the H1N1 influenza pandemic, our model performed adequately in our validation cohort, suggesting that it will be generalizable.

Severe sepsis and septic shock in pre-hospital emergency medicine: survey results of medical directors of emergency medical services concerning antibiotics, blood cultures and algorithms.

PubMed

Casu, Sebastian; Häske, David

2016-06-01

Delayed antibiotic treatment for patients in severe sepsis and septic shock decreases the probability of survival. In this survey, medical directors of different emergency medical services (EMS) in Germany were asked if they are prepared for pre-hospital sepsis therapy with antibiotics or special algorithms to evaluate the individual preparations of the different rescue areas for the treatment of patients with this infectious disease. The objective of the survey was to obtain a general picture of the current status of the EMS with respect to rapid antibiotic treatment for sepsis. A total of 166 medical directors were invited to complete a short survey on behalf of the different rescue service districts in Germany via an electronic cover letter. Of the rescue districts, 25.6 % (n = 20) stated that they keep antibiotics on EMS vehicles. In addition, 2.6 % carry blood cultures on the vehicles. The most common antibiotic is ceftriaxone (third generation cephalosporin). In total, 8 (10.3 %) rescue districts use an algorithm for patients with sepsis, severe sepsis or septic shock. Although the German EMS is an emergency physician-based rescue system, special opportunities in the form of antibiotics on emergency physician vehicles are missing. Simultaneously, only 10.3 % of the rescue districts use a special algorithm for sepsis therapy. Sepsis, severe sepsis and septic shock do not appear to be prioritized as highly as these deadly diseases should be in the pre-hospital setting.

Glycaemic variability in patients with severe sepsis or septic shock admitted to an Intensive Care Unit.

PubMed

Silveira, L M; Basile-Filho, A; Nicolini, E A; Dessotte, C A M; Aguiar, G C S; Stabile, A M

2017-08-01

Sepsis is associated with morbidity and mortality, which implies high costs to the global health system. Metabolic alterations that increase glycaemia and glycaemic variability occur during sepsis. To verify mean body glucose levels and glycaemic variability in Intensive Care Unit (ICU) patients with severe sepsis or septic shock. Retrospective and exploratory study that involved collection of patients' sociodemographic and clinical data and calculation of severity scores. Glycaemia measurements helped to determine glycaemic variability through standard deviation and mean amplitude of glycaemic excursions. Analysis of 116 medical charts and 6730 glycaemia measurements revealed that the majority of patients were male and aged over 60 years. Surgical treatment was the main reason for ICU admission. High blood pressure and diabetes mellitus were the most usual comorbidities. Patients that died during the ICU stay presented the highest SOFA scores and mean glycaemia; they also experienced more hypoglycaemia events. Patients with diabetes had higher mean glycaemia, evaluated through standard deviation and mean amplitude of glycaemia excursions. Organic impairment at ICU admission may underlie glycaemic variability and lead to a less favourable outcome. High glycaemic variability in patients with diabetes indicates that monitoring of these individuals is crucial to ensure better outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Importance of vital signs to the early diagnosis and severity of sepsis: association between vital signs and sequential organ failure assessment score in patients with sepsis.

PubMed

Kenzaka, Tsuneaki; Okayama, Masanobu; Kuroki, Shigehiro; Fukui, Miho; Yahata, Shinsuke; Hayashi, Hiroki; Kitao, Akihito; Sugiyama, Daisuke; Kajii, Eiji; Hashimoto, Masayoshi

2012-01-01

While much attention is given to the fifth vital sign, the utility of the 4 classic vital signs (blood pressure, respiratory rate, body temperature, and heart rate) has been neglected. The aim of this study was to assess a possible association between vital signs and the Sequential Organ Failure Assessment (SOFA) score in patients with sepsis. We performed a prospective, observational study of 206 patients with sepsis. Blood pressure, respiratory rate, body temperature, and heart rate were measured on arrival at the hospital. The SOFA score was also determined on the day of admission. Bivariate correlation analysis showed that all of the vital signs were correlated with the SOFA score. Multiple regression analysis indicated that decreased values of systolic blood pressure (multivariate regression coefficient [Coef] = -0.030, 95% confidence interval [CI] = -0.046 to -0.013) and diastolic blood pressure (Coef = -0.045, 95% CI = -0.070 to -0.019), increased respiratory rate (Coef = 0.176, 95% CI = 0.112 to 0.240), and increased shock index (Coef = 4.232, 95% CI = 2.401 to 6.062) significantly influenced the SOFA score. Increased respiratory rate and shock index were significantly correlated with disease severity in patients with sepsis. Evaluation of these signs may therefore improve early identification of severely ill patients at triage, allowing more aggressive and timely interventions to improve the prognosis of these patients.

Comprehensive Analysis of Gene Expression Profiles of Sepsis-Induced Multiorgan Failure Identified Its Valuable Biomarkers.

PubMed

Wang, Yumei; Yin, Xiaoling; Yang, Fang

2018-02-01

Sepsis is an inflammatory-related disease, and severe sepsis would induce multiorgan dysfunction, which is the most common cause of death of patients in noncoronary intensive care units. Progression of novel therapeutic strategies has proven to be of little impact on the mortality of severe sepsis, and unfortunately, its mechanisms still remain poorly understood. In this study, we analyzed gene expression profiles of severe sepsis with failure of lung, kidney, and liver for the identification of potential biomarkers. We first downloaded the gene expression profiles from the Gene Expression Omnibus and performed preprocessing of raw microarray data sets and identification of differential expression genes (DEGs) through the R programming software; then, significantly enriched functions of DEGs in lung, kidney, and liver failure sepsis samples were obtained from the Database for Annotation, Visualization, and Integrated Discovery; finally, protein-protein interaction network was constructed for DEGs based on the STRING database, and network modules were also obtained through the MCODE cluster method. As a result, lung failure sepsis has the highest number of DEGs of 859, whereas the number of DEGs in kidney and liver failure sepsis samples is 178 and 175, respectively. In addition, 17 overlaps were obtained among the three lists of DEGs. Biological processes related to immune and inflammatory response were found to be significantly enriched in DEGs. Network and module analysis identified four gene clusters in which all or most of genes were upregulated. The expression changes of Icam1 and Socs3 were further validated through quantitative PCR analysis. This study should shed light on the development of sepsis and provide potential therapeutic targets for sepsis-induced multiorgan failure.

Alkalosis in Critically Ill Patients with Severe Sepsis and Septic Shock

PubMed Central

Jazrawi, Allan; Miller, Jan; Baigi, Amir; Chew, Michelle

2017-01-01

Introduction Although metabolic alkalosis is a common occurrence in intensive care units (ICUs), no study has evaluated its prevalence or outcomes in patients with severe sepsis or septic shock. Methods This is a retrospective cohort study of critically ill patients suffering from severe sepsis and septic shock admitted to the ICUs of Halmstad and Varberg County hospitals. From 910 patient records, 627 patients met the inclusion criteria. We investigated the relationship between metabolic alkalosis and mortality. Further, we studied the relationship between metabolic alkalosis and ICU length of stay (LOS). Results Metabolic alkalosis was associated with decreased 30-day and 12-month mortalities. This effect was however lost when a multivariate analysis was conducted, correcting for age, gender, pH on admission, base excess (BE) on admission, Simplified Acute Physiology Score III (SAPS III) and acute kidney injury (AKI). We then analyzed for any dose-response effect between the severity of metabolic alkalosis and mortality and found no relationship. Bivariate analysis showed that metabolic alkalosis had a significant effect on the length of ICU stay. When adjusting for age, sex, pH at admission, BE at admission, SAPS III and AKI in a multivariate analysis, metabolic alkalosis significantly contributed to prolonged ICU length of stay. In two separate sensitivity analyses pure metabolic alkalosis and late metabolic alkalosis (time of onset >48 hours) were the only significant predictor of increased ICU length of stay. Conclusion Metabolic alkalosis did not have any effect on 30-day and 12-month mortalities after adjusting for age, sex, SAPS III-score, pH and BE on admission and AKI in a multivariate analysis. The presence of metabolic alkalosis was independently associated with an increased ICU length of stay. PMID:28045915

Pediatric Sepsis Endotypes Among Adults With Sepsis.

PubMed

Wong, Hector R; Sweeney, Timothy E; Hart, Kimberly W; Khatri, Purvesh; Lindsell, Christopher J

2017-12-01

Recent transcriptomic studies describe two subgroups of adults with sepsis differentiated by a sepsis response signature. The implied biology and related clinical associations are comparable with recently reported pediatric sepsis endotypes, labeled "A" and "B." We classified adults with sepsis using the pediatric endotyping strategy and the sepsis response signature and determined how endotype assignment, sepsis response signature membership, and age interact with respect to mortality. Retrospective analysis of publically available transcriptomic data representing critically ill adults with sepsis from which the sepsis response signature groups were derived and validated. Multiple ICUs. Adults with sepsis. None. Transcriptomic data were conormalized into a single dataset yielding 549 unique cases with sepsis response signature assignments. Each subject was assigned to endotype A or B using the expression data for the 100 endotyping genes. There were 163 subjects (30%) assigned to endotype A and 386 to endotype B. There was a weak, positive correlation between endotype assignment and sepsis response signature membership. Mortality rates were similar between patients assigned endotype A and those assigned endotype B. A multivariable logistic regression model fit to endotype assignment, sepsis response signature membership, age, and the respective two-way interactions revealed that endotype A, sepsis response signature 1 membership, older age, and the interactions between them were associated with mortality. Subjects coassigned to endotype A, and sepsis response signature 1 had the highest mortality. Combining the pediatric endotyping strategy with sepsis response signature membership might provide complementary, age-dependent, biological, and prognostic information.

DYSFUNCTION OF VARIOUS ORGAN SYSTEMS INDUCED BY SEPSIS WITH UNDERLYING SEVERE MYELOMIC DISEASES AND PROSTATE CANCER (CASE REPORT).

PubMed

Ratiani, L; Intskirveli, N; Goliadze, L; Chkhikvadze, T; Koptonashvili, L; Khuchua, E

2018-02-01

A 65-year-old male patient, unconscious, was admitted into the clinic by the Ambulance. From the patient's medical history it was revealed that several hours before the admission in the clinic the following symptoms were present: shortness of breath, fever, hypotonia, consciousness inhibition, because of which emergency brigade was called and was brought by the Emergency Brigade. The history is loaded by chronic pathologies: myeloma disease, prostate cancer, ciliary arrhythmia, heart failure; received several courses of polichemotherapy, last ten days has been treated for pneumonia with antibiotics of ceftriaxone group in outpatient setting. It is also noteworthy that for the last three months dysfunction of musculoskeletal system with muscle weakness, restricted motion has been present. Clinically there was present dysfunction syndrome of several organs: disorder of function of several organs that required emergency intervention, recovery chance was very low, correlation with morbidity in PIRO was high. By investigation it is known, that as SIRS aggravates, and turns into septic shock, lethal index increases, especially when the underlying severe diseases are present. On basis of certain data we can conclude that the severity of the disease may have some compatibility with results, although it is alteration of further clinical status of initial stage that has the closest compatibility with results. Sepsis toward MODS experiences progress with lethal results. Mortality rate in the patients with acute respiratory deficiency increases from 50% to 80%. In most patients with sepsis syndrome, who have 3 or more organs damaged, lethality is more than 90%. In this certain case organ systems that are mostly involved in the process during the sepsis, are respiratory, blood, renal and cardiovascular systems, were all involved , in the mentioned case a reasonable symptomatic and pathognomic treatment and the appropriate measures led to the recovery of the above mentioned

Triage sepsis alert and sepsis protocol lower times to fluids and antibiotics in the ED.

PubMed

Hayden, Geoffrey E; Tuuri, Rachel E; Scott, Rachel; Losek, Joseph D; Blackshaw, Aaron M; Schoenling, Andrew J; Nietert, Paul J; Hall, Greg A

2016-01-01

Early identification of sepsis in the emergency department (ED), followed by adequate fluid hydration and appropriate antibiotics, improves patient outcomes. We sought to measure the impact of a sepsis workup and treatment protocol (SWAT) that included an electronic health record (EHR)-based triage sepsis alert, direct communication, mobilization of resources, and standardized order sets. We conducted a retrospective, quasiexperimental study of adult ED patients admitted with suspected sepsis, severe sepsis, or septic shock. We defined a preimplementation (pre-SWAT) group and a postimplementation (post-SWAT) group and further broke these down into SWAT A (septic shock) and SWAT B (sepsis with normal systolic blood pressure). We performed extensive data comparisons in the pre-SWAT and post-SWAT groups, including demographics, systemic inflammatory response syndrome criteria, time to intravenous fluids bolus, time to antibiotics, length-of-stay times, and mortality rates. There were 108 patients in the pre-SWAT group and 130 patients in the post-SWAT group. The mean time to bolus was 31 minutes less in the postimplementation group, 51 vs 82 minutes (95% confidence interval, 15-46; P value < .01). The mean time to antibiotics was 59 minutes less in the postimplementation group, 81 vs 139 minutes (95% confidence interval, 44-74; P value < .01). Segmented regression modeling did not identify secular trends in these outcomes. There was no significant difference in mortality rates. An EHR-based triage sepsis alert and SWAT protocol led to a significant reduction in the time to intravenous fluids and time to antibiotics in ED patients admitted with suspected sepsis, severe sepsis, and septic shock. Copyright © 2015 Elsevier Inc. All rights reserved.

Prognosis Biomarkers of Severe Sepsis and Septic Shock by 1H NMR Urine Metabolomics in the Intensive Care Unit

PubMed Central

Modesto-Alapont, Vicente; Gonzalez-Marrachelli, Vannina; Vento-Rehues, Rosa; Jorda-Miñana, Angela; Blanquer-Olivas, Jose; Monleon, Daniel

2015-01-01

Early diagnosis and patient stratification may improve sepsis outcome by a timely start of the proper specific treatment. We aimed to identify metabolomic biomarkers of sepsis in urine by 1H-NMR spectroscopy to assess the severity and to predict outcomes. Urine samples were collected from 64 patients with severe sepsis or septic shock in the ICU for a 1H NMR spectra acquisition. A supervised analysis was performed on the processed spectra, and a predictive model for prognosis (30-days mortality/survival) of sepsis was constructed using partial least-squares discriminant analysis (PLS-DA). In addition, we compared the prediction power of metabolomics data respect the Sequential Organ Failure Assessment (SOFA) score. Supervised multivariate analysis afforded a good predictive model to distinguish the patient groups and detect specific metabolic patterns. Negative prognosis patients presented higher values of ethanol, glucose and hippurate, and on the contrary, lower levels of methionine, glutamine, arginine and phenylalanine. These metabolites could be part of a composite biopattern of the human metabolic response to sepsis shock and its mortality in ICU patients. The internal cross-validation showed robustness of the metabolic predictive model obtained and a better predictive ability in comparison with SOFA values. Our results indicate that NMR metabolic profiling might be helpful for determining the metabolomic phenotype of worst-prognosis septic patients in an early stage. A predictive model for the evolution of septic patients using these metabolites was able to classify cases with more sensitivity and specificity than the well-established organ dysfunction score SOFA. PMID:26565633

Antibiotic prescription patterns in the empiric therapy of severe sepsis: combination of antimicrobials with different mechanisms of action reduces mortality.

PubMed

Díaz-Martín, Ana; Martínez-González, María Luisa; Ferrer, Ricard; Ortiz-Leyba, Carlos; Piacentini, Enrique; Lopez-Pueyo, Maria Jesus; Martín-Loeches, Ignacio; Levy, Mitchell M; Artigas, Antoni; Garnacho-Montero, José

2012-11-18

Although early institution of adequate antimicrobial therapy is lifesaving in sepsis patients, optimal antimicrobial strategy has not been established. Moreover, the benefit of combination therapy over monotherapy remains to be determined. Our aims are to describe patterns of empiric antimicrobial therapy in severe sepsis, assessing the impact of combination therapy, including antimicrobials with different mechanisms of action, on mortality. This is a Spanish national multicenter study, analyzing all patients admitted to ICUs who received antibiotics within the first 6 hours of diagnosis of severe sepsis or septic shock. Antibiotic-prescription patterns in community-acquired infections and nosocomial infections were analyzed separately and compared. We compared the impact on mortality of empiric antibiotic treatment, including antibiotics with different mechanisms of action, termed different-class combination therapy (DCCT), with that of monotherapy and any other combination therapy possibilities (non-DCCT). We included 1,372 patients, 1,022 (74.5%) of whom had community-acquired sepsis and 350 (25.5%) of whom had nosocomial sepsis. The most frequently prescribed antibiotic agents were β-lactams (902, 65.7%) and carbapenems (345, 25.1%). DCCT was administered to 388 patients (28.3%), whereas non-DCCT was administered to 984 (71.7%). The mortality rate was significantly lower in patients administered DCCTs than in those who were administered non-DCCTs (34% versus 40%; P = 0.042). The variables independently associated with mortality were age, male sex, APACHE II score, and community origin of the infection. DCCT was a protective factor against in-hospital mortality (odds ratio (OR), 0.699; 95% confidence interval (CI), 0.522 to 0.936; P = 0.016), as was urologic focus of infection (OR, 0.241; 95% CI, 0.102 to 0.569; P = 0.001). β-Lactams, including carbapenems, are the most frequently prescribed antibiotics in empiric therapy in patients with severe sepsis and

Genome Wide Association Study of Sepsis in Extremely Premature Infants

PubMed Central

Srinivasan, Lakshmi; Page, Grier; Kirpalani, Haresh; Murray, Jeffrey C.; Das, Abhik; Higgins, Rosemary D.; Carlo, Waldemar A.; Bell, Edward F.; Goldberg, Ronald N.; Schibler, Kurt; Sood, Beena G.; Stevenson, David K.; Stoll, Barbara J.; Van Meurs, Krisa P.; Johnson, Karen J.; Levy, Joshua; McDonald, Scott A.; Zaterka-Baxter, Kristin M.; Kennedy, Kathleen A.; Sánchez, Pablo J.; Duara, Shahnaz; Walsh, Michele C.; Shankaran, Seetha; Wynn, James L.; Cotten, C. Michael

2017-01-01

Objective To identify genetic variants associated with sepsis (early and late-onset) using a genome wide association (GWA) analysis in a cohort of extremely premature infants. Study Design Previously generated GWA data from the Neonatal Research Network’s anonymized genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole genome amplified DNA was genotyped for 1.2 million single nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. P values and false discovery rates were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10−5. Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. Results Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10−8); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram positive sepsis), RALA, IMMP2L (Gram negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and Interleukin-1 associated receptor kinase 2 (p values<0.001 and FDR<20%). Conclusions No SNPs met genome-wide significance in this cohort of ELBW infants; however, areas of potential association and pathways meriting further study were identified. PMID:28283553

An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis.

PubMed

Soares, M O; Welton, N J; Harrison, D A; Peura, P; Shankar- Hari, M; Harvey, S E; Madan, J J; Ades, A E; Palmer, S J; Rowan, K M

2012-01-01

Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or

Prognostic value of the reactive oxygen species in severe sepsis and septic shock patients: a pilot study.

PubMed

Montini, Luca; DE Sole, Pasquale; Pennisi, Mariano A; Rossi, Cristina; Scatena, Roberto; DE Pascale, Gennaro; Bello, Giuseppe; Cutuli, Salvatore L; Antonelli, Massimo

2016-12-01

Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of sepsis. The aim of this study was to investigate ROS production over time in critically ill with sepsis patients and its correlation with outcome. This was a pilot single-centre prospective, observational study of patients consecutively admitted to our 18-general ICU. Over a period of 6 months all the consecutive patients with recent-onset of severe sepsis or septic shock were enrolled. Clinical and demographic characteristics of all patients were recorded. ROMs (ROS metabolites), reduced sulfhydryl groups (SH) and plasmatic lactate levels were collected at enrollment in the study and then every 5-7 days over 28 days or until sepsis resolution or death during sepsis. ROMs were analysed spectrophotometrically by the d-ROMs test (Diacron-Italia). SH were assayed in plasma by Ellman's reaction by spectrophotometric method. Septic shock-related mortality was defined as death that occurred during the follow up period, when the signs of shock remained, and death could not be attributed to causes other than septic shock by the attending physician. Twenty-five patients were studied. The SOFA score and the plasmatic lactate levels significantly correlated with the ROMs plasmatic levels. The mortality rate was higher in patients whose ROMs plasmatic levels decreased during septic shock evolution. Serial measurements of the ROMs plasmatic levels together with the SOFA score and lactate levels could help to identify septic shock patients with a very high probability of death.

High Mortality in Severe Sepsis and Septic Shock Patients with Do-Not-Resuscitate Orders in East Asia.

PubMed

Huang, Chun-Ta; Chuang, Yu-Chung; Tsai, Yi-Ju; Ko, Wen-Je; Yu, Chong-Jen

2016-01-01

Severe sepsis is a potentially deadly illness and always requires intensive care. Do-not-resuscitate (DNR) orders remain a debated issue in critical care and limited data exist about its impact on care of septic patients, particularly in East Asia. We sought to assess outcome of severe sepsis patients with regard to DNR status in Taiwan. A retrospective cohort study was conducted in intensive care units (ICUs) between 2008 and 2010. All severe sepsis patients were included for analysis. Primary outcome was association between DNR orders and ICU mortality. Volume of interventions was used as proxy indicator to indicate aggressiveness of care. Sixty-seven (9.4%) of 712 patients had DNR orders on ICU admission, and these patients were older and had higher disease severity compared with patients without DNR orders. Notably, DNR patients experienced high ICU mortality (90%). Multivariate analysis revealed that the presence of DNR orders was independently associated with ICU mortality (odds ratio: 6.13; 95% confidence interval: 2.66-14.10). In propensity score-matched cohort, ICU mortality rate (91%) in the DNR group was statistically higher than that (62%) in the non-DNR group (p <0.001). Regarding ICU interventions, arterial and central venous catheterization were more commonly used in DNR patients than in non-DNR patients. From the Asian perspective, septic patients placed on DNR orders on ICU admission had exceptionally high mortality. In contrast to Western reports, DNR patients received more ICU interventions, reflecting more aggressive approach to dealing with this patient population. The findings in some ways reflect differences between East and West cultures and suggest that DNR status is an important confounder in ICU studies involving severely septic patients.

Management of sepsis: a 47-year-old woman with an indwelling intravenous catheter and sepsis.

PubMed

Angus, Derek C

2011-04-13

Severe sepsis is the term used to describe the host response to infection when complicated by acute organ dysfunction. Severe sepsis occurs in more than 750,000 individuals in the United States each year, with a hospital mortality of about 30%. Although the classic presentation is of florid shock with frank hypotension, fever, and elevated white blood cell count, many patients can present with cryptogenic shock (shock without hypotension) with more subtle signs of vital organ compromise. Using the case of Ms C, a 47-year-old woman with short gut syndrome and an indwelling intravenous catheter who developed an episode of severe sepsis secondary to a central line infection, treatment of sepsis is discussed. Management consists of prompt intervention with broad-spectrum antibiotics and fluid resuscitation, even in the absence of hypotension, and institution of a variety of strategies in the emergency setting to prevent development or worsening of vital organ dysfunction. Although advances in understanding the host immune response have fueled considerable interest in immunomodulatory therapy, the role of such agents in clinical practice remains limited and controversial.

Severe Acinetobacter baumannii Sepsis Is Associated With Elevation of Pentraxin 3

DTIC Science & Technology

2014-09-01

and disseminated intravascular coagulation have been reported fol- lowing fulminant A. baumannii sepsis, little is known about the protective host...ATCC 19606 and clinical isolates (CI) 77, 78, 79, 80, and 86. Interestingly, only CI strains 79, 80, and 86 induced PTX3 synthesis in murine J774a.1...that elevation of PTX3 is associated with fulminant disease during A. baumannii sepsis. Since the initial widespread use of antibiotics in hospitals

The Temporal Kinetics of Circulating Angiopoietin Levels in Children with Sepsis

PubMed Central

Giuliano, John S.; Tran, Kevin; Li, Fang-yong; Northrup, Veronika; Tala, Joana A.; Bhandari, Vineet

2013-01-01

Objective Capillary integrity continues to challenge critical care physicians worldwide when treating children with sepsis. Vascular growth factors, specifically angiopoietin (angpt)-1 and angpt-2, play opposing roles in capillary stabilization in septic patients, respectively. We aim to determine whether pediatric patients with severe sepsis/shock have persistently high angpt-2/1 ratios when compared to non-septic pediatric intensive care unit (PICU) patients over a 7-day period. Design Prospective, observational study. Patients were classified within 24h of admission into: non-systemic inflammatory response syndrome (non-SIRS), SIRS/sepsis, or severe sepsis/shock. Plasma levels of angpt-1 and angpt-2 were measured via ELISA. The angpt-2/1 ratio was graphically plotted and determined whether patients fell into ‘constant’ or ‘variable’ patterns. Setting Tertiary care center PICU. Patients Critically ill pediatric patients with varying sepsis severity. Interventions None Measurements and Main Results Forty five patients were enrolled (n=9 non-SIRS, n=19 SIRS/sepsis, and n=17 severe sepsis/shock). Gender, age, weight, comorbidities and PICU length of stay were not significantly different between the groups. Admission pediatric risk stratification scores and net fluid ins/outs were significantly elevated in the severe sepsis/shock group when compared (all p<0.05). Admission angpt-2 levels and angpt-2/1 ratios were significantly different in the severe sepsis/shock group when all groups were compared (both p<0.05). Additionally, the latter were significantly elevated in the severe sepsis/shock group at multiple time points (all p≤0.05) with the peak occurring on day 2 of illness. In a separate analysis, 32% of SIRS/sepsis and 82% of severe sepsis/shock had ‘variable’ angpt-2/1 ratio patterns compared to none in the control group (p<0.001). Conclusions Pediatric patients with severe sepsis and septic shock possess significantly elevated angpt-2/1 ratios

Development of a novel score for the prediction of hospital mortality in patients with severe sepsis: the use of electronic healthcare records with LASSO regression.

PubMed

Zhang, Zhongheng; Hong, Yucai

2017-07-25

There are several disease severity scores being used for the prediction of mortality in critically ill patients. However, none of them was developed and validated specifically for patients with severe sepsis. The present study aimed to develop a novel prediction score for severe sepsis. A total of 3206 patients with severe sepsis were enrolled, including 1054 non-survivors and 2152 survivors. The LASSO score showed the best discrimination (area under curve: 0.772; 95% confidence interval: 0.735-0.810) in the validation cohort as compared with other scores such as simplified acute physiology score II, acute physiological score III, Logistic organ dysfunction system, sequential organ failure assessment score, and Oxford Acute Severity of Illness Score. The calibration slope was 0.889 and Brier value was 0.173. The study employed a single center database called Medical Information Mart for Intensive Care-III) MIMIC-III for analysis. Severe sepsis was defined as infection and acute organ dysfunction. Clinical and laboratory variables used in clinical routines were included for screening. Subjects without missing values were included, and the whole dataset was split into training and validation cohorts. The score was coined LASSO score because variable selection was performed using the least absolute shrinkage and selection operator (LASSO) technique. Finally, the LASSO score was evaluated for its discrimination and calibration in the validation cohort. The study developed the LASSO score for mortality prediction in patients with severe sepsis. Although the score had good discrimination and calibration in a randomly selected subsample, external validations are still required.

Pediatric sepsis: actions to decrease sepsis in children.

PubMed

Marraro, Giuseppe A

2009-10-01

The European Society of Pediatric and Neonatal Intensive Care is the physicians' and nurses' annual meeting that was held in Verona, Italy from 14 to 17 June 2009, and approximately 1000 participants from around the world (84 countries) attended. The Congress gave an opportunity to experts to discuss ongoing research and exchange opinions on the future development of studies to identify optimal supportive, preventive and therapeutic strategies for sepsis. A wide range of topics were discussed and several lectures, oral presentations and posters were dedicated to sepsis and its treatment. High scientific-level topics were presented, and stimulated much interest and discussion.

Update on pediatric sepsis: a review.

PubMed

Kawasaki, Tatsuya

2017-01-01

Sepsis is one of the leading causes of mortality among children worldwide. Unfortunately, however, reliable evidence was insufficient in pediatric sepsis and many aspects in clinical practice actually depend on expert consensus and some evidence in adult sepsis. More recent findings have given us deep insights into pediatric sepsis since the publication of the Surviving Sepsis Campaign guidelines 2012. New knowledge was added regarding the hemodynamic management and the timely use of antimicrobials. Quality improvement initiatives of pediatric "sepsis bundles" were reported to be successful in clinical outcomes by several centers. Moreover, a recently published global epidemiologic study (the SPROUT study) did not only reveal the demographics, therapeutic interventions, and prognostic outcomes but also elucidated the inappropriateness of the current definition of pediatric sepsis. With these updated knowledge, the management of pediatric sepsis would be expected to make further progress. In addition, it is meaningful that the fundamental data on which future research should be based were established through the SPROUT study.

In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine.

PubMed

Okeke, Emeka B; Uzonna, Jude E

2016-01-01

In spite of over half a century of research, sepsis still constitutes a major problem in health care delivery. Although advances in research have significantly increased our knowledge of the pathogenesis of sepsis and resulted in better prognosis and improved survival outcome, sepsis still remains a major challenge in modern medicine with an increase in occurrence predicted and a huge socioeconomic burden. It is generally accepted that sepsis is due to an initial hyperinflammatory response. However, numerous efforts aimed at targeting the proinflammatory cytokine network have been largely unsuccessful and the search for novel potential therapeutic targets continues. Recent studies provide compelling evidence that dysregulated anti-inflammatory responses may also contribute to sepsis mortality. Our previous studies on the role of regulatory T cells and phosphoinositide 3-kinases in sepsis highlight immunological approaches that could be explored for sepsis therapy. In this article, we review the current and emerging concepts in sepsis, highlight novel potential therapeutic targets and immunological approaches for sepsis treatment and propose a biphasic treatment approach for management of the condition. © 2016 S. Karger AG, Basel.

Surviving the first hours in sepsis: getting the basics right (an intensivist's perspective).

PubMed

Daniels, Ron

2011-04-01

Severe sepsis is a major cause of morbidity and mortality, claiming between 36 000 and 64 000 lives annually in the UK, with a mortality rate of 35%. International guidelines for the management of severe sepsis were published in 2004 by the Surviving Sepsis Campaign and condensed into two Care Bundles. In 2010, the Campaign published results from its improvement programme showing that, although an absolute mortality reduction of 5.4% was seen over a 2 year period in line with increasing compliance with the Bundles, reliability was not achieved and Bundle compliance reached only 31%. This article explores current challenges in sepsis care and opportunities for further improvements. Basic care tasks [microbiological sampling and antibiotic delivery within 1 h, fluid resuscitation, and risk stratification using serum lactate (or alternative)] are likely to benefit patients most, yet are unreliably performed. Barriers include lack of awareness and robust process, the lack of supporting controlled trials, and complex diagnostic criteria leading to recognition delays. Reliable, timely delivery of more complex life-saving tasks (such as early goal-directed therapy) demands greater awareness, faster recognition and initiation of basic care, and more effective collaboration between clinicians and nurses on the front line, in critical care and in specialist support services, such as microbiology and infectious diseases. Organizations such as Survive Sepsis, the Surviving Sepsis Campaign and the Global Sepsis Alliance are working to raise awareness and promote further improvement initiatives. Future developments will focus on sepsis biomarkers and microarray techniques to rapidly screen for pathogens, risk stratification using genetic profiling, and the development of novel therapeutic agents targeting immunomodulation.

Sepsis and Shock Response Team: Impact of a Multidisciplinary Approach to Implementing Surviving Sepsis Campaign Guidelines and Surviving the Process.

PubMed

Grek, Ami; Booth, Sandra; Festic, Emir; Maniaci, Michael; Shirazi, Ehsan; Thompson, Kristine; Starbuck, Angela; Mcree, Chad; Naessens, James M; Moreno Franco, Pablo

The Surviving Sepsis Campaign guidelines are designed to decrease mortality through consistent application of a 7-element bundle. This study evaluated the impact of improvement in bundle adherence using a time-series analysis of compliance with the bundle elements before and after interventions intended to improve the process, while also looking at hospital mortality. This article describes interventions used to improve bundle compliance and hospital mortality in patients admitted through the emergency department with sepsis, severe sepsis, or septic shock. Quality improvement methodology was used to develop high-impact interventions that led to dramatically improved adherence to the Surviving Sepsis Campaign guidelines bundle. Improved performance was associated with a significant decrease in the in-hospital mortality of severe sepsis patients presenting to the emergency department.

Understanding the Inflammatory Cytokine Response in Pneumonia and Sepsis

PubMed Central

Kellum, John A.; Kong, Lan; Fink, Mitchell P.; Weissfeld, Lisa A.; Yealy, Donald M.; Pinsky, Michael R.; Fine, Jonathan; Krichevsky, Alexander; Delude, Russell L.; Angus, Derek C.

2015-01-01

Background Severe sepsis is common and frequently fatal, and community-acquired pneumonia (CAP) is the leading cause. Although severe sepsis is often attributed to uncontrolled and unbalanced inflammation, evidence from humans with infection syndromes across the breadth of disease is lacking. In this study we describe the systemic cytokine response to pneumonia and determine if specific patterns, including the balance of pro-inflammatory and anti-inflammatory markers, are associated with severe sepsis and death. Methods This is a cohort study of 1886 subjects hospitalized with CAP through the emergency departments in 28 US academic and community hospitals. We defined severe sepsis as CAP complicated by new-onset organ dysfunction, following international consensus conference criteria. We measured plasma tumor necrosis factor, IL-6 (interleukin 6), and IL-10 levels daily for the first week and weekly thereafter. Our main outcome measures were severe sepsis and 90-day mortality. Results A total of 583 patients developed severe sepsis (31%), of whom 149 died (26%). Systemic cytokine level elevation occurred in 82% of all subjects with CAP. Mean cytokine concentrations were highest at presentation, declined rapidly over the first few days, but remained elevated throughout the first week, beyond resolution of clinical signs of infection. Cytokine levels were highest in fatal severe sepsis and lowest in CAP with no severe sepsis. Unbalanced (high/low) cytokine patterns were unusual (4.6%) and not associated with decreased survival. Highest risk of death was with combined high levels of the proinflammatory IL-6 and anti-inflammatory IL-10 cytokine activity (hazard ratio, 20.5; 95% confidence interval, 10.8–39.0) (P<.001). Conclusions The circulating cytokine response to pneumonia is heterogeneous and continues for more than a week after presentation, with considerable overlap between those who do and do not develop severe sepsis. Unbalanced activation is uncommon, and

The DISPARITY-II study: delays to antibiotic administration in women with severe sepsis or septic shock.

PubMed

Madsen, Tracy E; Napoli, Anthony M

2014-12-01

Early antibiotics reduce mortality in patients with severe sepsis and septic shock. Recent work demonstrated that women experience greater delays to antibiotic administration, but it is unknown if this relationship remains after adjusting for factors such as source of infection. The objective was to investigate whether gender and/or source of infection are associated with delays to antibiotics in patients with severe sepsis or septic shock. This was a retrospective, observational study in an urban academic emergency department and national Surviving Sepsis Campaign (SSC) database study site. Consecutive patients age 18 years and older admitted to intensive care with severe sepsis or septic shock and entered into the SSC database from October 2005 to March 2012 were included. Two trained research assistants, blinded to the primary outcome, used a standardized abstraction form to obtain patient demographic and clinical data, including the Sequential Organ Failure Assessment (SOFA) scores and comorbidities. Time to first antibiotic and presumed source of infection were extracted from the SSC database. Univariate analyses were performed with Pearson chi-square tests and t-tests. Linear regression was performed with time to first antibiotic as the primary outcome. Covariates, chosen a priori by study authors, included age, race, ethnicity, source of infection, SOFA score, and lactate. A total of 771 patients were included. Women were 45.3% of the sample, the mean age was 66 years (95% confidence interval [CI] = 65.1 to 67.5 years), 19.4% were nonwhite, and 8% were Hispanic. Mean time to first antibiotic was 153 minutes (95% CI = 143 to 163 minutes) for men and 184 minutes (95% CI = 171 to 197 minutes) for women (p < 0.001). The urinary tract was source of infection for 35.2% of women (95% CI = 30.2% to 40.3%) versus 23.7% (95% CI = 19.6% to 27.8%) of men. Pneumonia was present in 46.9% of men (95% CI = 42.1% to 51.7%) versus 35.8% (95% CI = 30.8% to 40.8%) of women. The

Assessment of incidence of severe sepsis in Sweden using different ways of abstracting International Classification of Diseases codes: difficulties with methods and interpretation of results.

PubMed

Wilhelms, Susanne B; Huss, Fredrik R; Granath, Göran; Sjöberg, Folke

2010-06-01

To compare three International Classification of Diseases code abstraction strategies that have previously been reported to mirror severe sepsis by examining retrospective Swedish national data from 1987 to 2005 inclusive. Retrospective cohort study. Swedish hospital discharge database. All hospital admissions during the period 1987 to 2005 were extracted and these patients were screened for severe sepsis using the three International Classification of Diseases code abstraction strategies, which were adapted for the Swedish version of the International Classification of Diseases. Two code abstraction strategies included both International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes, whereas one included International Classification of Diseases, Tenth Revision codes alone. None. The three International Classification of Diseases code abstraction strategies identified 37,990, 27,655, and 12,512 patients, respectively, with severe sepsis. The incidence increased over the years, reaching 0.35 per 1000, 0.43 per 1000, and 0.13 per 1000 inhabitants, respectively. During the International Classification of Diseases, Ninth Revision period, we found 17,096 unique patients and of these, only 2789 patients (16%) met two of the code abstraction strategy lists and 14,307 (84%) met one list. The International Classification of Diseases, Tenth Revision period included 46,979 unique patients, of whom 8% met the criteria of all three International Classification of Diseases code abstraction strategies, 7% met two, and 84% met one only. The three different International Classification of Diseases code abstraction strategies generated three almost separate cohorts of patients with severe sepsis. Thus, the International Classification of Diseases code abstraction strategies for recording severe sepsis in use today provides an unsatisfactory way of estimating the true incidence of severe sepsis. Further studies relating

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS.

PubMed

Kangelaris, Kirsten Neudoerffer; Prakash, Arun; Liu, Kathleen D; Aouizerat, Bradley; Woodruff, Prescott G; Erle, David J; Rogers, Angela; Seeley, Eric J; Chu, Jeffrey; Liu, Tom; Osterberg-Deiss, Thomas; Zhuo, Hanjing; Matthay, Michael A; Calfee, Carolyn S

2015-06-01

The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS. Copyright © 2015 the American Physiological Society.

Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS

PubMed Central

Prakash, Arun; Liu, Kathleen D.; Aouizerat, Bradley; Woodruff, Prescott G.; Erle, David J.; Rogers, Angela; Seeley, Eric J.; Chu, Jeffrey; Liu, Tom; Osterberg-Deiss, Thomas; Zhuo, Hanjing; Matthay, Michael A.; Calfee, Carolyn S.

2015-01-01

The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS. PMID:25795726

Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials.

PubMed

Xu, Jing-Yuan; Chen, Qi-Hong; Xie, Jian-Feng; Pan, Chun; Liu, Song-Qiao; Huang, Li-Wei; Yang, Cong-Shan; Liu, Ling; Huang, Ying-Zi; Guo, Feng-Mei; Yang, Yi; Qiu, Hai-Bo

2014-12-15

The aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis. We searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software. A total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I(2) = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09). In this meta-analysis, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly.

In-Hospital Quality-of-Care Measures for Pediatric Sepsis Syndrome.

PubMed

Odetola, Folafoluwa O; Freed, Gary; Shevrin, Caroline; Madden, Brian; McCormick, Julie; Dombkowski, Kevin

2017-07-24

Sepsis syndrome, comprising sepsis, severe sepsis, and septic shock, is a leading cause of child mortality and morbidity, for which the delivery of time-sensitive care leads to improved survival. We aimed to describe the development and testing of quality measures for in-hospital care of pediatric sepsis syndrome. Seven measures of quality of care for children hospitalized with sepsis syndrome were developed by using an iterative process including literature review, development of concepts and candidate measures, and selection of measures for feasibility and importance by 2 panels of experts. The measures were tested for reliability and validity among children 0 to 18 years of age hospitalized with sepsis syndrome from January 1, 2012, to June 30, 2013. Of 27 hospitals, 59% had no protocol for the identification and treatment of pediatric sepsis syndrome. Blood culture was performed in only 70% of patients with pediatric sepsis syndrome. Antibiotics were administered within 1 hour of diagnosis in 70% of patients with pediatric severe sepsis or septic shock, and timely fluid resuscitation was performed in 50% of patients with severe sepsis or septic shock. Documentation of heart rate during fluid resuscitation of children with severe sepsis or septic shock was observed in 18% of cases. Two measures could not be rigorously tested for validity and reliability given the rarity of septic shock and were deemed infeasible. This multisite study to develop and validate measures of the quality of hospital care of children with sepsis syndrome highlights the existence of important gaps in delivery of care. Copyright © 2017 by the American Academy of Pediatrics.

A blueprint for a sepsis protocol.

PubMed

Shapiro, Nathan I; Howell, Michael; Talmor, Daniel

2005-04-01

Despite numerous advances in medicine, sepsis remains an unconquered challenge. Although outcomes have improved slightly over decades, the unacceptably high mortality rate of 30%-50% for severe sepsis and septic shock continues. However, after years of unsuccessful clinical trials, several investigations over the last few years have reported survival benefit in the treatment of sepsis. Physicians now have several proven therapies to treat sepsis, but have yet to implement them on a widespread, systematic basis. This led 11 international professional societies spanning multiple specialties and continents to come together to create the Surviving Sepsis Campaign. The product of their work is an international effort organized to improve care of patients with sepsis and includes consensus, evidence-based guidelines for care that improves survival in septic patients, and an action plan for change. Given the clear role of early identification and treatment in stopping the sepsis cascade, therapy must start early in the emergency department (ED) and continue throughout the hospital course. The first of the recommendations by the Surviving Sepsis Campaign is the aggressive resuscitation strategy of early goal-directed therapy (EGDT). EGDT is reported to reduce absolute mortality by a staggering 16%. The use of recombinant activated protein C was demonstrated to confer a 6% absolute survival benefit. Steroid supplementation in adrenal insufficiency produced a 10% benefit. Additionally, early and appropriate use of antibiotics remains a cornerstone of therapy. Although no randomized trial will be performed, the effects are undisputed. Finally, although predominantly intensive care unit therapies, tight glucose control and low-tidal-volume ventilation strategies have also led to improved survival. Armed with these new therapies, the medical community must rise to this call to action. Clinicians must change the approach to this disease, as well as the way the septic patient is

Protective Effect of Nicotine on Sepsis-Induced Oxidative Multiorgan Damage: Role of Neutrophils.

PubMed

Özdemir-Kumral, Zarife N; Özbeyli, Dilek; Özdemir, Ahmet F; Karaaslan, Bugra M; Kaytaz, Kübra; Kara, Mustafa F; Tok, Olgu E; Ercan, Feriha; Yegen, Berrak Ç

2017-07-01

Despite its adverse health consequences, tobacco smoking is associated with lower incidence of several neurodegenerative and inflammatory diseases. The present study is aimed to show the effects of nicotine, major tobacco constituent, on five organs targeted by sepsis. Male Wistar albino rats received tap water with (5mg/kg) or without nicotine for 14 days. Under ketamine anesthesia, sepsis (n = 50) was induced by ligation and puncture of the cecum, while sham group (n = 8) had only laparotomy. In other rats, nicotine drink was withdrawn for 5 days before sepsis induction, while in acute nicotine group, rats were injected with nicotine (30mg/kg, i.p.) before sepsis, but had no oral intake. Rats were decapitated 24 hours after surgery to obtain lung, liver, ileum, heart, and kidney tissues to determine malondialdehyde (MDA) and glutathione (GSH) levels and myeloperoxidase (MPO) activities. Data were analyzed by one-way analysis of variance and Tukey multiple comparison tests or Student's t test. Chronic nicotine administration or its withdrawal reduced lipid peroxidation and MPO activity and prevented GSH depletion with some varying results in different target tissues. Nicotine injection prior to sepsis depressed MPO activity in all tissues and reduced MDA levels except for the lung, while GSH levels were elevated only in the hepatic and ileal tissues. Histologically observed injury was ameliorated by all nicotine treatments at varying degrees. The findings of the present study indicate that long-term nicotine administration reduces sepsis-induced oxidative damage in several tissues, which appears to involve inhibition of neutrophil activity in the inflamed tissues. Nicotine administration or its withdrawal reduced lipid peroxidation and neutrophil content and prevented GSH depletion with some varying results in different target tissues. A single injection prior to sepsis induction depressed MPO activity in all the tissues and reduced all tissue MDA levels except

Cyclooxygenase Inhibition in Sepsis: Is There Life after Death?

PubMed Central

Aronoff, David M.

2012-01-01

Prostaglandins are important mediators and modulators of the inflammatory response to infection. The prostaglandins participate in the pathogenesis of hemodynamic collapse, organ failure, and overwhelming inflammation that characterize severe sepsis and shock. In light of this, cyclooxygenase (COX) inhibiting pharmacological agents have been extensively studied for their capacity to ameliorate the aberrant physiological and immune responses during severe sepsis. Animal models of sepsis, using the systemic administration of pathogen-associated molecular patterns (PAMPs) or live pathogens, have been used to examine the effectiveness of COX inhibition as a treatment for severe sepsis. These studies have largely shown beneficial effects on mortality. However, human studies have failed to show clinical utility of COX inhibitor treatment in severely septic patients. Why this approach “worked” in animals but not in humans might reflect differences in the controlled nature of animal investigations compared to human studies. This paper contrasts the impact of COX inhibitors on mortality in animal models of sepsis and human studies of sepsis and examines potential reasons for differences between these two settings. PMID:22665954

ABO Blood Type A Is Associated With Increased Risk of ARDS in Whites Following Both Major Trauma and Severe Sepsis

PubMed Central

Meyer, Nuala J.; Shashaty, Michael G. S.; Feng, Rui; Lanken, Paul N.; Gallop, Robert; Kaplan, Sandra; Herlim, Maximilian; Oz, Nathaniel L.; Hiciano, Isabel; Campbell, Ana; Holena, Daniel N.; Reilly, Muredach P.; Christie, Jason D.

2014-01-01

Background: ABO glycosyltransferases catalyze antigen modifications on various glycans and glycoproteins and determine the ABO blood types. Blood type A has been associated with increased risk of vascular diseases and differential circulating levels of proteins related to inflammation and endothelial function. The objective of this study was to determine the association of ABO blood types with ARDS risk in patients with major trauma and severe sepsis. Methods: We conducted prospective cohort studies in two populations at an urban tertiary referral, level I trauma center. Critically ill patients (n = 732) presenting after major trauma were followed for 5 days for ARDS development. Additionally, 976 medical patients with severe sepsis were followed for 5 days for ARDS. Multivariable logistic regression was used to adjust for confounders. Results: ARDS developed in 197 of the 732 trauma patients (27%). Blood type A was associated with increased ARDS risk among whites (37% vs 24%; adjusted OR, 1.88; 95% CI, 1.14-3.12; P = .014), but not blacks (adjusted OR, 0.61; 95% CI, 0.33-1.13; P = .114). ARDS developed in 222 of the 976 patients with severe sepsis (23%). Blood type A was also associated with an increased ARDS risk among whites (31% vs 21%; adjusted OR, 1.67; 95% CI, 1.08-2.59; P = .021) but, again, not among blacks (adjusted OR, 1.17; 95% CI, 0.59-2.33; P = .652). Conclusions: Blood type A is associated with an increased risk of ARDS in white patients with major trauma and severe sepsis. These results suggest a role for ABO glycans and glycosyltransferases in ARDS susceptibility. PMID:24385226

Antibody to endotoxin core glycolipid reverses reticuloendothelial system depression in an animal model of severe sepsis and surgical injury

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

Aldridge, M.C.; Chadwick, S.J.; Cheslyn-Curtis, S.

To study the effect of severe sepsis on the function of the reticuloendothelial system (RES) we have measured the clearance kinetics and organ distribution of both low-dose technetium tin colloid (TTC) and /sup 75/selenomethionine-labelled E. coli in rabbits 24 hours after either sham laparotomy or appendix devascularization. Sepsis resulted in similar delayed blood clearance and reduced liver (Kupffer cell) uptake of both TTC and E. coli. To investigate the ability of polyclonal antibody to E. coli-J-5 (core glycolipid) to improve RES function in the same model of sepsis, further animals were pretreated with either core glycolipid antibody or control serummore » (10 ml IV) 2 hours before induction of sepsis. TTC clearance kinetics were determined 24 hours later. Antibody pretreated animals showed: a reduced incidence of bacteremia; normalization of the rate of blood clearance and liver uptake of TTC; and a 'rebound' increase in splenic uptake of TTC. We conclude that antibody to E. coli-J-5 enhances bacterial clearance by the RES.« less

Population Pharmacokinetics and Pharmacodynamics Modeling To Optimize Dosage Regimens of Sulbactam in Critically Ill Patients with Severe Sepsis Caused by Acinetobacter baumannii

PubMed Central

Wongpoowarak, Wibul; Wattanavijitkul, Thitima; Sukarnjanaset, Waroonrat; Samaeng, Maseetoh; Nawakitrangsan, Monchana; Ingviya, Natnicha

2016-01-01

Sulbactam is being considered as an alternative concomitant medication with other effective antibiotics for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii infections. Pathophysiological changes in critically ill patients with severe sepsis, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors in determining therapeutic success. The aims of this study were (i) to examine the population PK parameters and (ii) to assess the probability of target attainment (PTA) for sulbactam in patients with severe sepsis caused by A. baumannii. PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 4th day of drug administration in 27 patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentration remained above the MIC (T>MIC) and 60% T>MIC. The central and peripheral volumes of distribution were 14.56 and 9.55 liters, respectively, and total clearances of sulbactam were 2.26 liters/h and 7.64 liters/h in patients aged >65 years and ≤65 years, respectively. The high PTAs (≥90%) for targets of 40% T>MIC and 60% T>MIC with a MIC of 4 μg/ml were observed when sulbactam was administered by a 4-h infusion of 1 g every 12 h and 1 g every 8 h, respectively. Sulbactam would be an alternative antibiotic option to coadminister with colistin for the treatment of infections caused by MDR A. baumannii. However, for pathogens with MICs of >4 μg/ml, higher dosage regimens of sulbactam are required. PMID:27671056

Molecular Regulatory Pathways Link Sepsis With Metabolic Syndrome: Non-coding RNA Elements Underlying the Sepsis/Metabolic Cross-Talk.

PubMed

Meydan, Chanan; Bekenstein, Uriya; Soreq, Hermona

2018-01-01

Sepsis and metabolic syndrome (MetS) are both inflammation-related entities with high impact for human health and the consequences of concussions. Both represent imbalanced parasympathetic/cholinergic response to insulting triggers and variably uncontrolled inflammation that indicates shared upstream regulators, including short microRNAs (miRs) and long non-coding RNAs (lncRNAs). These may cross talk across multiple systems, leading to complex molecular and clinical outcomes. Notably, biomedical and RNA-sequencing based analyses both highlight new links between the acquired and inherited pathogenic, cardiac and inflammatory traits of sepsis/MetS. Those include the HOTAIR and MIAT lncRNAs and their targets, such as miR-122, -150, -155, -182, -197, -375, -608 and HLA-DRA. Implicating non-coding RNA regulators in sepsis and MetS may delineate novel high-value biomarkers and targets for intervention.

THE IMPACT OF AGE ON THE INNATE IMMUNE RESPONSE AND OUTCOMES AFTER SEVERE SEPSIS/SEPTIC SHOCK IN TRAUMA AND SURGICAL INTENSIVE CARE UNIT PATIENTS.

PubMed

Brakenridge, Scott C; Efron, Philip A; Stortz, Julie A; Ozrazgat-Baslanti, Teczan; Ghita, Gabriela; Wang, Zhongkai; Bihorac, Azra; Mohr, Alicia M; Brumback, Babette A; Moldawer, Lyle L; Moore, Frederick A

2018-04-02

Advancing age is a strong risk factor for adverse outcomes across multiple disease processes. However, septic surgical and trauma patients are unique in they incur two or more inflammatory insults. The effects of advanced age on sepsis pathophysiology and outcomes remain unclear. We performed a single center, prospective observational cohort study of Surgical ICU patients with severe sepsis/septic shock. Peripheral blood was collected for genomic, cytokine and biomarker analysis at 0.5, 1, 4, 7, 14, 21 and 28 days after sepsis onset. Based on sensitivity analysis, cohorts were defined as "young" (<55 years) and "aged" (≥55 years). We compared age-defined cohorts to determine differences in patient characteristics, biomarker profiles and clinical outcomes. The cohort included 173 patients with severe sepsis (n=93; 53.8%) or septic shock (n=80; 46.2%), with a mean age of 60.9 (±14.5) years. Intra-abdominal sepsis was the leading source (n=81; 46.8%), followed by NSTI (n=33, 19.1%) and pneumonia (n=30; 17.3%). Aged patients had a higher comorbidity burden, but were otherwise similar to the young cohort. The aged cohort had a higher severity of early physiologic derangement (median APACHE II, 23 vs 18, p=0.002), greater incidence of multiple organ failure (MOF; 64.3% vs 40.4%, p=0.006), and hospital mortality (15.9% vs 2.1%, p=0.016). Six-month mortality was significantly higher in the aged as compared to young cohort (31% vs 9%, p=0.003). Aged septic patients biomarker trajectories suggestive of persistent immunosuppression (Absolute lymphocyte count, sPDL-1) and catabolism (Urine 3MH-Cr ratio, IGF, IGF1BP3, albumin) out to 28 days after sepsis. Aged, critically ill surgical patients have greater organ dysfunction, and incidence of adverse clinical outcomes after sepsis. Biomarker profiles suggest an immunophenotype of persistent immunosuppression and catabolism. Advanced age may necessitate novel therapeutic strategies to promote multi-system organ recovery and

Complement Factor B is the Downstream Effector of Toll-Like Receptors and Plays an Important Role in a Mouse Model of Severe Sepsis¶

PubMed Central

Zou, Lin; Feng, Yan; Li, Yan; Zhang, Ming; Chen, Chan; Cai, Jiayan; Gong, Yu; Wang, Larry; Thurman, Joshua M.; Wu, Xiaobo; Atkinson, John P.; Chao, Wei

2013-01-01

Severe sepsis involves massive activation of the innate immune system and leads to high mortality. Previous studies have demonstrated that various types of Toll-like receptors (TLRs) mediate a systemic inflammatory response and contribute to organ injury and mortality in animal models of severe sepsis. However, the downstream mechanisms responsible for TLR-mediated septic injury are poorly understood. Here, we show that activation of TLR2, TLR3 and TLR4 markedly enhanced complement factor B (cfB) synthesis and release by macrophages and cardiac cells. Polymicrobial sepsis, created by cecal ligation and puncture (CLP) in a mouse model, augmented cfB levels in the serum, peritoneal cavity and major organs including the kidney and heart. CLP also led to the alternative pathway (AP) activation, C3 fragment deposition in the kidney and heart, and cfB-dependent C3dg elevation. Bacteria isolated from septic mice activated the serum AP via a factor D-dependent manner. MyD88 deletion attenuated cfB/C3 up-regulation as well as cleavage induced by polymicrobial infection. Importantly, during sepsis, absence of cfB conferred a protective effect with improved survival and cardiac function, and markedly attenuated acute kidney injury. cfB deletion also led to increased neutrophil migratory function during the early phase of sepsis, decreased local and systemic bacterial load, attenuated cytokine production and reduced neutrophil reactive oxygen species production. Together, our data indicate that cfB acts as a downstream effector of TLR signaling and plays a critical role in the pathogenesis of severe bacterial sepsis. PMID:24154627

The Association Between Lymphotoxin Alpha (Tumor Necrosis Factor β) Intron Polymorphism and Predisposition to Severe Sepsis is Modified by Gender and Age

PubMed Central

Watanabe, Eizo; Buchman, Timothy G.; Hirasawa, Hiroyuki; Zehnbauer, Barbara A.

2009-01-01

Objective To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice. Design Collaborative case-control study conducted from July 2001 to December 2005. Setting A heterogeneous population of patients from 12 USA intensive care units (ICUs) represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive. Patients Eight hundred and fifty-four patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the ICU without evidence of any infection (matched nonseptic controls). Measurements and Main Results We developed assays for six functional single nucleotide polymorphisms (SNPs) present before the first codon of TNF at −308, IL1B at −511, IL6 at −174, IL10 at −819, and CD14 at −159, and in the first intron of LTA (also known as TNF-β) at +252 (LTA(+252)). The Project IMPACT™ critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics, Inc. and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high-throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3 % and 6.4 % of Caucasian and African American racial types, respectively. Overall mortality was 35.1 % in both severe sepsis (SS) and matched nonseptic control (MC) patients group. Average ages (SD) of the SS and MC patients were 63.0 (16.05) and 65.0 (15.58) years old, respectively. Among the 6 SNPs, LTA(+252) was most over-represented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, P = .005). Moreover, the genetic risk

High plasma levels of high mobility group box 1 is associated with the risk of sepsis in severe blunt chest trauma patients: a prospective cohort study.

PubMed

Wang, Xiao-Wen; Karki, Avash; Zhao, Xing-Ji; Xiang, Xiao-Yong; Lu, Zhi-Qian

2014-08-02

High mobility group box 1 (HMGB1) is a late mediator of systemic inflammation. Extracellular HMGB1 play a central pathogenic role in critical illness. The purpose of the study was to investigate the association between plasma HMGB1 concentrations and the risk of poor outcomes in patients with severe blunt chest trauma. The plasma concentrations of HMGB1 in patients with severe blunt chest trauma (AIS ≥ 3) were measured by a quantitative enzyme-linked immunosorbent assay at four time points during seven days after admission, and the dynamic release patterns were monitored. The biomarker levels were compared between patients with sepsis and non-sepsis, and between patients with multiple organ dysfunction syndrome (MODS) and non-MODS. The related factors of prognosis were analyzed by using multivariate logistic regression analysis. The short-form 36 was used to evaluate the quality of life of patients at 12 months after injury. Plasma HMGB1 levels were significantly higher both in sepsis and MODS group on post-trauma day 3, 5, and 7 compared with the non-sepsis and non-MODS groups, respectively. Multivariate analysis showed that HMGB1 levels and ISS were independent risk factors for sepsis and MODS in patients with severe blunt chest trauma. Plasma HMGB1 levels were significantly elevated in patients with severe blunt chest trauma. HMGB1 levels were associated with the risk of poor outcome in patients with severe blunt chest trauma. Daily HMGB1 levels measurements is a potential useful tool in the early identification of post-trauma complications. Further studies are needed to determine whether HMGB1 intervention could prevent the development of sepsis and MODS in patients with severe blunt chest trauma.

HMGB1 redox during sepsis.

PubMed

Abdulmahdi, Wasan; Patel, Devika; Rabadi, May M; Azar, Tala; Jules, Edson; Lipphardt, Mark; Hashemiyoon, Rameen; Ratliff, Brian B

2017-10-01

During sepsis, the alarmin HMGB1 is released from tissues and promotes systemic inflammation that results in multi-organ damage, with the kidney particularly susceptible to injury. The severity of inflammation and pro-damage signaling mediated by HMGB1 appears to be dependent on the alarmin's redox state. Therefore, we examined HMGB1 redox in kidney cells during sepsis. Using intravital microscopy, CellROX labeling of kidneys in live mice indicated increased ROS generation in the kidney perivascular endothelium and tubules during lipopolysaccharide (LPS)-induced sepsis. Subsequent CellROX and MitoSOX labeling of LPS-stressed endothelial and kidney proximal tubule cells demonstrated increased ROS generation in these cells as sepsis worsens. Consequently, HMGB1 oxidation increased in the cytoplasm of kidney cells during its translocation from the nucleus to the circulation, with the degree of oxidation dependent on the severity of sepsis, as measured in in vivo mouse samples using a thiol assay and mass spectrometry (LC-MS/MS). The greater the oxidation of HMGB1, the greater the ability of the alarmin to stimulate pro-inflammatory cyto-/chemokine release (measured by Luminex Multiplex) and alter mitochondrial ATP generation (Luminescent ATP Detection Assay). Administration of glutathione and thioredoxin inhibitors to cell cultures enhanced HMGB1 oxidation during sepsis in endothelial and proximal tubule cells, respectively. In conclusion, as sepsis worsens, ROS generation and HMGB1 oxidation increases in kidney cells, which enhances HMGB1's pro-inflammatory signaling. Conversely, the glutathione and thioredoxin systems work to maintain the protein in its reduced state. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Sepsis

PubMed Central

Karnatovskaia, Lioudmila V.; Festic, Emir

2012-01-01

Sepsis represents a major challenge in medicine. It begins as a systemic response to infection that can affect virtually any organ system, including the central and peripheral nervous systems. Akin to management of stroke, early recognition and treatment of sepsis are just as crucial to a successful outcome. Sepsis can precipitate myasthenic crisis and lead to encephalopathy and critical illness neuropathy. Stroke and traumatic brain injury can predispose a patient to develop sepsis, whereas Guillain-Barré syndrome is similarly not uncommon following infection. This review article will first describe the essential principles of sepsis recognition, pathophysiology, and management and will then briefly cover the neurologic aspects associated with sepsis. Vigilant awareness of the clinical features of sepsis and timeliness of intervention can help clinicians prevent progression of this disease to a multisystem organ failure, which can be difficult to reverse even after the original source of infection is under control. PMID:23983879

Maternal sepsis: a Scottish population-based case-control study.

PubMed

Acosta, C D; Bhattacharya, S; Tuffnell, D; Kurinczuk, J J; Knight, M

2012-03-01

To describe the risk of maternal sepsis associated with obesity and other understudied risk factors such as operative vaginal delivery. Population-based, case-control study. North NHS region of Scotland. All cases of pregnant, intrapartum and postpartum women with International Classification of Disease-9 codes for sepsis or severe sepsis recorded in the Aberdeen Maternal and Neonatal Databank (AMND) from 1986 to 2009. Four controls per case selected from the AMND were frequency matched on year-of-delivery. Cases and controls were compared; significant variables from univariable regression were adjusted in a multivariable logistic regression model. Dependent variables were uncomplicated sepsis or severe ('near-miss') sepsis. Independent variables were demographic, medical and clinical delivery characteristics. Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals (95% CI) are reported. Controlling for mode of delivery and demographic and clinical factors, obese women had twice the odds of uncomplicated sepsis (OR 2.12; 95% CI 1.14-3.89) compared with women of normal weight. Age <25 years (OR 5.15; 95% CI 2.43-10.90) and operative vaginal delivery (OR 2.20; 95% CI 1.02-4.87) were also significant predictors of sepsis. Known risk factors for maternal sepsis were also significant in this study (OR for uncomplicated and severe sepsis respectively): multiparity (OR 6.29, 12.04), anaemia (OR 3.43, 18.49), labour induction (OR 3.92 severe only), caesarean section (OR 3.23, 13.35), and preterm birth (OR 2.46 uncomplicated only). Obesity, operative vaginal delivery and age <25 years are significant risk factors for sepsis and should be considered in clinical obstetric care. © 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.

Predictive Value of Soluble Programmed Death-1 for Severe Sepsis and Septic Shock During the First Week in an Intensive Care Unit.

PubMed

Zhao, Yongzhen; Jia, Yumei; Li, Chunsheng; Shao, Rui; Fang, Yingying

2018-04-26

Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) exists in both membrane-bound and soluble forms. In this study, we evaluated the predictive value of soluble PD-1 (sPD-1) for severity and 28-day mortality in patients with severe sepsis and septic shock during the first week in an intensive care unit (ICU). In this prospective cohort study, patients were classified into the severe sepsis group or the septic shock group according to the severity of their condition on ICU admission. All patients were also separated into the survivor or nonsurvivor groups according to their 28-day outcomes. Peripheral blood sPD-1 and soluble PD-L1 (sPD-L1) levels, PD-1 expression on CD4 and CD8 T cells, and PD-L1 expression on monocytes were measured and compared between the groups on days 1 and 7 after ICU admission. In all, 45 healthy volunteers and 112 patients were recruited. Serum sPD-1 levels were positively correlated with the severity of sepsis, sPD-L1 levels, PD-1 expression on CD4 or CD8 T cells, and PD-L1 expression on monocytes. The sPD-1 was an independent predictive factor for 28-day mortality both on day 1 and day 7. The area under the curve (AUC) of the sPD-1 on day 7 (0.871) was higher than that on day 1 (0.785) (P < 0.05), and better than the AUC of the percentages of PD-L1 on monocytes (0.770) on day 7 (P < 0.05). Serum sPD-1 shows valuable predictive ability for the severity and 28-day mortality of severe sepsis and septic shock during the first week of ICU treatment.

Oxidative stress biomarkers in pediatric sepsis: a prospective observational pilot study.

PubMed

Molina, Víctor; von Dessauer, Bettina; Rodrigo, Ramón; Carvajal, Cristian

2017-11-01

Oxidative stress is known to participate in the progression of sepsis. Definite data regarding the behavior of oxidative stress biomarkers in pediatric sepsis is still lacking. This study hypothesized that oxidative stress occurs in pediatric sepsis and that the magnitude of the redox derangement is associated with worse clinical progression. Forty-two previously healthy pediatric patients with sepsis and a group of control subjects were included. Oxidative stress and inflammatory activity biomarkers were determined in blood samples. Patients were prospectively followed until their discharge or death. Patients with non-severe and severe sepsis showed higher levels of plasmatic antioxidant capacity, lower erythrocyte thiol index, lower superoxide dismutase and catalase activities, higher glutathione peroxidase activity, and higher plasmatic F 2 -isoprostanes concentration than controls. Patients with severe sepsis had higher NF-kappaB activation than those with non-severe sepsis. Although we observed changes in some biomarkers in patients with worse clinical evolution, the explored biomarkers did not correlate with clinical estimators of outcome. Oxidative stress occurs in pediatric sepsis, resulting in oxidative damage. The explored biomarkers are not useful as outcome predictors in the studied population. The behavior of these biomarkers still needs to be addressed in broader groups of pediatric patients with sepsis.

Therapeutic mild hypothermia improves early outcomes in rats subjected to severe sepsis.

PubMed

Ding, Wu; Shen, Yuehong; Li, Qiang; Jiang, Shouyin; Shen, Huahao

2018-04-15

Therapeutic hypothermia has shown beneficial effects in sepsis. This study focused on its mechanism. Sixteen male Sprague-Dawley rats underwent cecal ligation and perforation and subsequently were treated with either hypothermia (HT; body temperature cooled and maintained at 34 °C by ice pad for 10 h; n = 8) or normothermia (NT; n = 8). Three additional rats underwent sham surgery. The body temperatures of the sham-operated and NT groups were maintained at 38 °C with a thermal pad. After the hypothermia treatment, the HT rats were rewarmed for 2 h. The groups were compared for circulating cytokines (IL-6, IL-10), lactate, high mobility group box-1 protein (HMGB1), and lung and intestinal lesions. Animals were observed for 24 h. Compared with the sham-operated group, the 2 sepsis group rats had significantly higher circulating IL-6, HMGB1, and lactate levels, and tissue injury. In the HT rats, the levels of IL-6, HMGB1, and lactate, the lung wet-to-dry ratio, and lung and intestinal damage were significantly lower than that of the NT group. Circulating IL-10 levels increased significantly after 12 h in the sepsis groups compared with sham animals, while that of the NT and HT groups were comparable. The survival rates of the NT and HT rats were also comparable. Therapeutic hypothermia in a rat model of sepsis was associated with lower levels of circulating IL-6 and HMGB1, and less capillary leakage and tissue edema. These results suggest that mild hypothermia has potential as a therapy in sepsis. Copyright © 2018 Elsevier Inc. All rights reserved.

Multicentre observational study of adherence to Sepsis Six guidelines in emergency general surgery.

PubMed

2017-01-01

Evidence-based interventions may reduce mortality in surgical patients. This study documented the prevalence of sepsis, adherence to guidelines in its management, and timing of source control in general surgical patients presenting as an emergency. Patients aged 16 years or more presenting with emergency general surgery problems were identified over a 7-day period and then screened for sepsis compliance (using the Sepsis Six standards, devised for severe sepsis) and the timing of source control (whether radiological or surgical). Exploratory analyses examined associations between the mode (emergency department or general practitioner) and time of admission, adherence to the sepsis guidelines, and outcomes (complications or death within 30 days). Of a total of 5067 patients from 97 hospitals across the UK, 911 (18·0 per cent) fulfilled the criteria for sepsis, 165 (3·3 per cent) for severe sepsis and 24 (0·5 per cent) for septic shock. Timely delivery of all Sepsis Six guidelines for patients with severe sepsis was achieved in four patients. For patients with severe sepsis, 17·6-94·5 per cent of individual guidelines within the Sepsis Six were delivered. Oxygen was the criterion most likely to be missed, followed by blood cultures in all sepsis severity categories. Surgery for source control occurred a median of 19·8 (i.q.r. 10·0-35·4) h after diagnosis. Omission of Sepsis Six parameters did not appear to be associated with an increase in morbidity or mortality. Although sepsis was common in general surgical patients presenting as an emergency, adherence to severe sepsis guidelines was incomplete in the majority. Despite this, no evidence of harm was apparent. © 2017 BJS Society Ltd Published by John Wiley & Sons Ltd.

Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial.

PubMed

Keh, Didier; Trips, Evelyn; Marx, Gernot; Wirtz, Stefan P; Abduljawwad, Emad; Bercker, Sven; Bogatsch, Holger; Briegel, Josef; Engel, Christoph; Gerlach, Herwig; Goldmann, Anton; Kuhn, Sven-Olaf; Hüter, Lars; Meier-Hellmann, Andreas; Nierhaus, Axel; Kluge, Stefan; Lehmke, Josefa; Loeffler, Markus; Oppert, Michael; Resener, Kerstin; Schädler, Dirk; Schuerholz, Tobias; Simon, Philipp; Weiler, Norbert; Weyland, Andreas; Reinhart, Konrad; Brunkhorst, Frank M

2016-11-01

Adjunctive hydrocortisone therapy is suggested by the Surviving Sepsis Campaign in refractory septic shock only. The efficacy of hydrocortisone in patients with severe sepsis without shock remains controversial. To determine whether hydrocortisone therapy in patients with severe sepsis prevents the development of septic shock. Double-blind, randomized clinical trial conducted from January 13, 2009, to August 27, 2013, with a follow-up of 180 days until February 23, 2014. The trial was performed in 34 intermediate or intensive care units of university and community hospitals in Germany, and it included 380 adult patients with severe sepsis who were not in septic shock. Patients were randomly allocated 1:1 either to receive a continuous infusion of 200 mg of hydrocortisone for 5 days followed by dose tapering until day 11 (n = 190) or to receive placebo (n = 190). The primary outcome was development of septic shock within 14 days. Secondary outcomes were time until septic shock, mortality in the intensive care unit or hospital, survival up to 180 days, and assessment of secondary infections, weaning failure, muscle weakness, and hyperglycemia (blood glucose level >150 mg/dL [to convert to millimoles per liter, multiply by 0.0555]). The intention-to-treat population consisted of 353 patients (64.9% male; mean [SD] age, 65.0 [14.4] years). Septic shock occurred in 36 of 170 patients (21.2%) in the hydrocortisone group and 39 of 170 patients (22.9%) in the placebo group (difference, -1.8%; 95% CI, -10.7% to 7.2%; P = .70). No significant differences were observed between the hydrocortisone and placebo groups for time until septic shock; mortality in the intensive care unit or in the hospital; or mortality at 28 days (15 of 171 patients [8.8%] vs 14 of 170 patients [8.2%], respectively; difference, 0.5%; 95% CI, -5.6% to 6.7%; P = .86), 90 days (34 of 171 patients [19.9%] vs 28 of 168 patients [16.7%]; difference, 3.2%; 95% CI, -5.1% to 11.4%; P = .44

The impact of intrarenal nitric oxide synthase inhibition on renal blood flow and function in mild and severe hyperdynamic sepsis.

PubMed

Ishikawa, Ken; Bellomo, Rinaldo; May, Clive N

2011-04-01

In experimental hyperdynamic sepsis, renal function deteriorates despite renal vasodilatation and increased renal blood flow. Because nitric oxide is increased in sepsis and participates in renal blood flow control, we investigated the effects of intrarenal Nω-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor, in mild and severe sepsis. Prospective crossover and randomized control interventional studies. University-affiliated research institute. Thirty-two merino ewes. Examination of responses to intrarenal infusion of Nω-nitro-L-arginine methyl ester for 8 hrs in unilaterally nephrectomized normal sheep and in sheep administered Escherichia coli. : In normal sheep, Nω-nitro-L-arginine methyl ester decreased renal blood flow (301 ± 30 to 228 ± 26 mL/min) and creatinine clearance (40.0 ± 5.8 to 31.1 ± 2.8 mL/min), whereas plasma creatinine increased, but fractional excretion of sodium was unchanged. In sheep with nonhypotensive hyperdynamic sepsis, plasma creatinine increased and there were decreases in creatinine clearance (34.5 ± 4.6 to 20.1 ± 3.7 mL/min) and fractional excretion of sodium despite increased renal blood flow. Infusion of Nω-nitro-L-arginine methyl ester normalized renal blood flow and increased urine output, but creatinine clearance did not improve and plasma creatinine and fractional excretion of sodium increased. In sheep with severe hypotensive sepsis, creatinine clearance decreased further (31.1 ± 5.4 to 16.0 ± 1.7 mL/min) despite increased renal blood flow. Infusion of Nω-nitro-L-arginine methyl ester restored mean arterial pressure and reduced renal blood flow but did not improve plasma creatinine or creatinine clearance. In hyperdynamic sepsis, with or without hypotension, creatinine clearance decreased despite increasing renal blood flow. Intrarenal Nω-nitro-L-arginine methyl ester infusion reduced renal blood flow but did not improve creatinine clearance. These data indicate that septic acute kidney

Multicenter clinical trials in sepsis: understanding the big picture and building a successful operation at your hospital.

PubMed

Dellinger, R Phillip; Schorr, Christa; Trzeciak, Stephen

2011-03-01

Only through adequately designed and adequately conducted clinical trials can new treatments be found for the benefit of the septic patient. Over the past 20 years, tens of thousands of patients have been enrolled in sepsis clinical trials with little success. These efforts, however, have not been without worth. Much has been learned and the knowledge gained has changed our approach to trial design in this very difficult field. Animal studies are better designed to match the clinical picture of severe sepsis. Phase II studies are more carefully engineered to answer questions about the most suitable target population and end points. Trial conduct likely benefits from use of CROs and a CCC. The future of clinical trials may include more standardization of sepsis management across investigative sites. Before the decision is made to become an investigative site in a multicenter industry-sponsored clinical trial in sepsis or severe sepsis, it is important to recognize what is required to succeed. Once these key-to-success elements are in place, members of the investigative team are more likely to realize the satisfaction and career growth from becoming a successful site. The most professional satisfaction comes from the knowledge of contributing to original science in the field of the sepsis. Copyright © 2011 Elsevier Inc. All rights reserved.

A two-hit mechanism for sepsis-induced impairment of renal tubule function

PubMed Central

Watts, Bruns A.; George, Thampi; Sherwood, Edward R.

2013-01-01

Renal insufficiency is a common and severe complication of sepsis, and the development of kidney dysfunction increases morbidity and mortality in septic patients. Sepsis is associated with a variety of defects in renal tubule function, but the underlying mechanisms are incompletely understood. We used a cecal ligation and puncture (CLP) model to examine mechanisms by which sepsis influences the transport function of the medullary thick ascending limb (MTAL). MTALs from sham and CLP mice were studied in vitro 18 h after surgery. The results show that sepsis impairs the ability of the MTAL to absorb HCO3− through two distinct mechanisms. First, sepsis induces an adaptive decrease in the intrinsic capacity of the tubules to absorb HCO3−. This effect is associated with an increase in ERK phosphorylation in MTAL cells and is prevented by pretreatment of CLP mice with a MEK/ERK inhibitor. The CLP-induced reduction in intrinsic HCO3− absorption rate appears to involve loss of function of basolateral Na+/H+ exchange. Second, sepsis enhances the ability of LPS to inhibit HCO3− absorption, mediated through upregulation of Toll-like receptor 4 (TLR4)-ERK signaling in the basolateral membrane. The two inhibitory mechanisms are additive and thus can function in a two-hit capacity to impair renal tubule function in sepsis. Both effects depend on ERK and are eliminated by interventions that prevent ERK activation. Thus the TLR4 and ERK signaling pathways represent potential therapeutic targets to treat or prevent sepsis-induced renal tubule dysfunction. PMID:23324175

Long non-coding RNA NEAT1 plays an important role in sepsis-induced acute kidney injury by targeting miR-204 and modulating the NF-κB pathway.

PubMed

Chen, Yi; Qiu, Jialing; Chen, Bin; Lin, Youping; Chen, Yulan; Xie, Guojin; Qiu, Junming; Tong, Huasheng; Jiang, Dongxin

2018-06-01

This study aimed to explore the role of long non-coding RNA NEAT1 in sepsis-induced acute kidney injury (AKI). The expression levels of NEAT1 in sepsis-induced AKI patients were detected. The rat mesangial cells (RMCs) were treated with lipopolysaccharide (LPS) to induce cell injury. Then, the effects of NEAT1 suppression on the cell viability, apoptosis, cytokines expression, and oxidative stress in the LPS-stimulated RMCs were tested. The regulatory miRNA of NEAT1, as well as the target genes of this miRNA, were investigated. Moreover, the regulatory relationship between NEAT1 and the NF-κB pathway was explored. The results demonstrated that NEAT1 was significantly upregulated in the sepsis-induced AKI patients. Moreover, the upregulation of NEAT1 was associated with the serious degrees of AKI in sepsis patients. In addition, the suppression of NEAT1 alleviated LPS-induced injury in RMCs. MiR-204 was negatively regulated by NEAT1. Suppression of NEAT1 alleviated LPS-induced injury by overexpression of miR-204. Moreover, IL-6R was a target of miR-204, and the effects of the suppression of NEAT1 on LPS-induced cell injury were caused by inactivating the NF-κB pathway. In conclusion, upregulation of NEAT1 may aggravate the LPS-induced injury by targeting miR-204 and activating the NF-κB pathway. NEAT1 may serve as an important diagnostic marker and therapeutic target in sepsis-induced AKI. Copyright © 2018 Elsevier B.V. All rights reserved.

Biomarker and Drug Target Discovery Using Proteomics in a New Rat Model of Sepsis-Induced Acute Renal Failure

PubMed Central

Holly, Mikaela K.; Dear, James W.; Hu, Xuzhen; Schechter, Alan N.; Gladwin, Mark T.; Hewitt, Stephen M.; Yuen, Peter S.T.; Star, Robert A.

2008-01-01

Background Sepsis is one of the common causes of acute renal failure (ARF). The objective of this study was to identify new biomarkers and therapeutic targets. We present a new rat model of sepsis-induced ARF based on cecal ligation and puncture (CLP). We used this model to find urinary proteins which may be potential biomarkers and/or drug targets. Methods Aged rats were treated with fluids and antibiotics after CLP. Urinary proteins from septic rats without ARF and urinary proteins from septic rats with ARF were compared by difference in-gel electrophoresis (DIGE). Results CLP surgery elevated IL-6 and IL-10 serum cytokines and blood nitrite compared with sham-operated rats. However there was a range of serum creatinine values at 24 hrs (0.4–2.3 mg/dL) and only 24% developed ARF. Histology confirmed renal injury in these rats. 49% of rats did not develop ARF. Rats without ARF also had less liver injury. The mortality rate at 24 hrs was 27% but was increased by housing the post-surgery rats in metabolic cages. Creatinine clearance and urine output 2–8 hours after CLP was significantly reduced in rats which died within 24 hours. Using DIGE we identified changes in a number of urinary proteins including albumin, brush-border enzymes (eg., meprin-1-alpha) and serine protease inhibitors. The meprin-1-alpha inhibitor actinonin prevented ARF in aged mice. Conclusion In summary we describe a new rat model of sepsis-induced ARF which has a heterogeneous response similar to humans. This model allowed us to use DIGE to find changes in urinary proteins and this approach identified a potential biomarker and drug target – meprin-1-alpha. PMID:16760904

Noninvasive sensors in critical care medicine: near-infrared spectroscopy for the detection of altered microvascular blood flow in severe sepsis and septic shock

NASA Astrophysics Data System (ADS)

Walz, J. Matthias; Soller, Babs; Soyemi, Olusola; Yang, Ye; Landry, Michelle; Heard, Stephen O.

2006-10-01

It is estimated that 750,000 cases of severe sepsis occur in the United States annually, at least 225,000 of which are fatal, resulting in significant utilization of healthcare resources and expenses. Significant progress in the understanding of pathophysiology and treatment of this condition has been made lately. Among the newer treatment strategies for critically ill patients are the administration of early goal directed therapy, and Recombinant Human Activated Protein C (Drotrecogrin alfa (activated) [DTAA]) for severe sepsis. However, mortality remains unacceptably high.

Rural Patients with Severe Sepsis or Septic Shock who Bypass Rural Hospitals have Increased Mortality: An Instrumental Variables Approach

PubMed Central

Mohr, Nicholas M.; Harland, Karisa K.; Shane, Dan M.; Ahmed, Azeemuddin; Fuller, Brian M.; Ward, Marcia M.; Torner, James C.

2016-01-01

Objective To identify factors associated with rural sepsis patients’ bypassing rural emergency departments (EDs) to seek emergency care in larger hospitals, and to measure the association between rural hospital bypass and sepsis survival. Design, Setting, and Patients Cohort study of adults treated in EDs of a rural Midwestern state with severe sepsis or septic shock between 2005 and 2014, using administrative claims data. Patients residing ≥ 20 miles from a top-decile sepsis volume hospital and < 20 miles from a local hospital were included. Interventions Patients bypassing local rural hospitals to seek care in larger hospitals. Measurements and Main Results A total of 13,461 patients were included, and only 5.4% (n = 731) bypassed a rural hospital for their ED care. Patients who initially chose a top-decile sepsis volume hospital were younger (64.7 vs. 72.7 y, p<0.001) and were more likely to have commercial insurance (19.6% vs. 10.6%, p<0.001) than those who were seen initially at a local rural hospital. They were also more likely to have significant medical comorbidities, such as liver failure (9.9% vs 4.2%, p<0.001), metastatic cancer (5.9% vs 3.2%, p<0.001), and diabetes with complications (25.2% vs. 21.6%, p=0.024). Using an instrumental variables approach, rural hospital bypass was associated with a 5.6% increase (95%CI 2.2 – 8.9%) in mortality. Conclusions Most rural patients with sepsis seek care in local EDs, but demographic and disease-oriented factors are associated with rural hospital bypass. Rural hospital bypass is independently associated with increased mortality. PMID:27611977

Neutrophil dysregulation during sepsis: an overview and update.

PubMed

Shen, Xiao-Fei; Cao, Ke; Jiang, Jin-Peng; Guan, Wen-Xian; Du, Jun-Feng

2017-09-01

Sepsis remains a leading cause of death worldwide, despite advances in critical care, and understanding of the pathophysiology and treatment strategies. No specific therapy or drugs are available for sepsis. Neutrophils play a critical role in controlling infection under normal conditions, and it is suggested that their migration and antimicrobial activity are impaired during sepsis which contribute to the dysregulation of immune responses. Recent studies further demonstrated that interruption or reversal of the impaired migration and antimicrobial function of neutrophils improves the outcome of sepsis in animal models. In this review, we provide an overview of the associated mediators and signal pathways involved which govern the survival, migration and antimicrobial function of neutrophils in sepsis, and discuss the potential of neutrophils as a target to specifically diagnose and/or predict the outcome of sepsis. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Pharmacological management of sepsis

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

Fletcher, J.R.

Systemic sepsis continues to be the most-difficult management problem in caring for the combat casualty. The complications of sepsis pervade all areas of injury to soldiers in the field, whether it is mechanical (missiles), thermal (burns), chemical, biological, or radiation injury. With the advent of tactical nuclear weapons, the problem of sepsis will be much higher in future wars than has previously been experienced through the world. The purpose of this chapter is a) to review the data suggesting pharmacological agents that may benefit the septic patient, and b) to emphasize the adjunctive therapies that should be explored in clinicalmore » trials. The pharmacological management of sepsis remains controversial. Most of the drugs utilized clinically treat the symptoms of the disease and are not necessarily directed at fundamental mechanisms that are known to be present in sepsis. A broad data base is emerging, indicating that NSAID should be used in human clinical trials. Prostaglandins are sensitive indicators of cellular injury and may be mediators for a number of vasoactive chemicals. Opiate antagonists and calcium channel blockers require more in-depth data; however, recent studies generate excitement for their potential use in the critically ill patient. Pharmacological effects of antibiotics, in concert with other drugs, suggest an entirely new approach to pharmacological treatment in sepsis. There is no doubt that new treatment modalities or adjunctive therapies must be utilized to alter the poor prognosis of severe sepsis that we have observed in the past 4 decades.« less

Therapeutic interventions in sepsis: current and anticipated pharmacological agents

PubMed Central

Shukla, Prashant; Rao, G Madhava; Pandey, Gitu; Sharma, Shweta; Mittapelly, Naresh; Shegokar, Ranjita; Mishra, Prabhat Ranjan

2014-01-01

Sepsis is a clinical syndrome characterized by a multisystem response to a pathogenic assault due to underlying infection that involves a combination of interconnected biochemical, cellular and organ–organ interactive networks. After the withdrawal of recombinant human-activated protein C (rAPC), researchers and physicians have continued to search for new therapeutic approaches and targets against sepsis, effective in both hypo- and hyperinflammatory states. Currently, statins are being evaluated as a viable option in clinical trials. Many agents that have shown favourable results in experimental sepsis are not clinically effective or have not been clinically evaluated. Apart from developing new therapeutic molecules, there is great scope for for developing a variety of drug delivery strategies, such as nanoparticulate carriers and phospholipid-based systems. These nanoparticulate carriers neutralize intracorporeal LPS as well as deliver therapeutic agents to targeted tissues and subcellular locations. Here, we review and critically discuss the present status and new experimental and clinical approaches for therapeutic intervention in sepsis. PMID:24977655

Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure.

PubMed

Rudiger, Alain; Gasser, Stefan; Fischler, Manuel; Hornemann, Thorsten; von Eckardstein, Arnold; Maggiorini, Marco

2006-08-01

B-type natriuretic peptide (BNP) and N-terminal pro-BNP measurements are used for the diagnosis of congestive heart failure (HF). However, the diagnostic value of these tests is unknown under septic conditions. We compared patients with severe sepsis or septic shock and patients with acute HF to unravel the influence of the underlying diagnosis on BNP and N-terminal pro-BNP levels. Prospective, clinical study. Academic medical intensive care unit (ICU). A total of 249 consecutive patients were screened for the diagnosis of sepsis or HF. Sepsis was defined according to published guidelines. HF was diagnosed in the presence of an underlying heart disease and congestive HF, pulmonary edema, or cardiogenic shock. BNP and N-terminal pro-BNP were measured from blood samples that were drawn daily for routine analysis. We identified 24 patients with severe sepsis or septic shock and 51 patients with acute HF. At admission, the median (range) BNP and N-terminal pro-BNP levels were 572 (13-1,300) and 6,526 (198-70,000) ng/L in patients with sepsis and 581 (6-1,300) and 4,300 (126-70,000) ng/L in patients with HF. The natriuretic peptide levels increased during the ICU stay, but the differences between the groups were not significant. Nine patients with sepsis and eight patients with HF were monitored with a pulmonary artery catheter. Mean (sd) pulmonary artery occlusion pressure were 16 (4.2) and 22 (5.3) mm Hg (p = .02), and cardiac indexes were 4.6 (2.8) and 2.2 (0.6) L/min/m (p = .03) in patients with sepsis and HF, respectively. Despite these clear hemodynamic differences BNP and N-terminal pro-BNP levels were not statistically different between the two groups. In patients with severe sepsis or septic shock, BNP and N-terminal pro-BNP values are highly elevated and, despite significant hemodynamic differences, comparable with those found in acute HF patients. It remains to be determined how elevations of natriuretic peptide levels are linked to inflammation and sepsis

The pediatric sepsis biomarker risk model: potential implications for sepsis therapy and biology.

PubMed

Alder, Matthew N; Lindsell, Christopher J; Wong, Hector R

2014-07-01

Sepsis remains a major cause of morbidity and mortality in adult and pediatric intensive care units. Heterogeneity of demographics, comorbidities, biological mechanisms, and severity of illness leads to difficulty in determining which patients are at highest risk of mortality. Determining mortality risk is important for weighing the potential benefits of more aggressive interventions and for deciding whom to enroll in clinical trials. Biomarkers can be used to parse patients into different risk categories and can outperform current methods of patient risk stratification based on physiologic parameters. Here we review the Pediatric Sepsis Biomarker Risk Model that has also been modified and applied to estimate mortality risk in adult patients. We compare the two models and speculate on the biological implications of the biomarkers in patients with sepsis.

The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis

PubMed Central

Minneci, P. C.; Deans, K. J.; Eichacker, P. Q.; Natanson, C.

2012-01-01

A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p <0.001, I2 = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I2 = 14%, OR of death 1.39 (95% CI 1.04–1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I2 = 0%, OR of shock reversal 1.66 [95% CI 1.25–2.20), p <0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I2 = 25%, OR of death 0.64 (95% CI 0.45–0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis. PMID:19416302

The Effect of Drotrecogin Alfa (activated) on Long-Term Survival after Severe Sepsis

PubMed Central

Angus, Derek C.; Laterre, Pierre-Francois; Helterbrand, Jeff; Ely, E. Wesley; Ball, Daniel E.; Garg, Rekha; Weissfeld, Lisa A.; Bernard, Gordon

2016-01-01

Objective To determine long-term survival for subjects with severe sepsis enrolled in the previous multicenter trial (PROWESS) of drotrecogin alfa (activated) [DrotAA] versus placebo. Design Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled trial. Setting 164 tertiary care institutions in 11 countries. Interventions DrotAA (n=850), 24 μg/kg/h for 96 hours, or placebo (n=840). Participants The 1690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1220 were alive at 28 days (the end of the original PROWESS follow-up). Measurements and Main Results Long-term survival data were collected. We had follow-up information on 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at 1 year. The longest follow-up was 3.6 years. Hospital survival was higher with DrotAA versus placebo (70.3% vs. 65.1%, p=0.03). There was no statistically significant difference in duration of survival time or in landmark survival rates in subjects who received DrotAA compared with those who received placebo, [median duration of survival = 1113d vs. 846d for DrotAA vs. placebo, p=0.10; landmark survival rates for DrotAA vs. placebo, 66.1% vs. 62.4% at 3 months (p=0.11), 62.2% vs. 60.3% at 6 months (p=0.44), 58.9% vs. 57.2% at 1 year (p=0.49), and 52.6% vs. 49.3% at 2½ years (p=0.21)]. There was a significant interaction (p=0.0008) between treatment assignment and baseline APACHE II scores, suggesting qualitative differences in treatment effect with severity of illness. Subjects with APACHE II ≥25 had better survival time with DrotAA (median duration of survival: 450d vs. 71d, p=0.0005). Survival rates were also higher at landmark timepoints [DrotAA vs. placebo, 58.9% vs. 48.4% at 3 months (p=0.003), 55.2% vs. 45.3% at 6 months (p=0.005), 52.1% vs. 41.3% at 1 year (p=0.002), and 41.7% vs. 32.9% at 2½ years (p=0.001)]. In the APACHE II <25 group there was no significant

[Pharmaconutrition with parenteral selenium in sepsis].

PubMed

Langlois, P L; de Oliveira Figliolino, L F; Hardy, G; Manzanares, W

2014-04-01

Critical illness is characterized by oxidative stress which leads to multiple organ failure, and sepsis-related organ dysfunction remains the most common cause of death in the intensive care unit. Over the last 2 decades, different antioxidant therapies have been developed to improve outcomes in septic patients. According to recent evidence, selenium therapy should be considered the cornerstone of the antioxidant strategies. Selenium given as selenious acid or sodium selenite should be considered as a drug or pharmaconutrient with prooxidant and cytotoxic effects when a loading dose in intravenous bolus form is administered, particularly in the early stage of severe sepsis/septic shock. To date, several phase ii trials have demonstrated that selenium therapy may be able to decrease mortality, improve organ dysfunction and reduce infections in critically ill septic patients. The effect of selenium therapy in sepsis syndrome must be confirmed by large, well designed phase iii clinical trials. The purpose of this review is to discuss current evidence on selenium pharmaconutrition in sepsis syndrome. Copyright © 2013 Elsevier España, S.L. and SEMICYUC. All rights reserved.

Multiplex identification of sepsis-causing Gram-negative pathogens from the plasma of infected blood.

PubMed

Chung, Boram; Park, Chulmin; Cho, Sung-Yeon; Shin, Juyoun; Shin, Sun; Yim, Seon-Hee; Lee, Dong-Gun; Chung, Yeun-Jung

2018-02-01

Early and accurate detection of bacterial pathogens in the blood is the most crucial step for sepsis management. Gram-negative bacteria are the most common organisms causing severe sepsis and responsible for high morbidity and mortality. We aimed to develop a method for rapid multiplex identification of clinically important Gram-negative pathogens and also validated whether our system can identify Gram-negative pathogens with the cell-free plasm DNA from infected blood. We designed five MLPA probe sets targeting the genes specific to major Gram-negative pathogens (uidA and lacY for E. coli, ompA for A. baumannii, phoE for K. pneumoniae, and ecfX for P. aeruginosa) and one set targeting the CTX-M group 1 to identify the ESBL producing Gram-negative pathogens. All six target-specific peaks were clearly separated without any non-specific peaks in a multiplex reaction condition. The minimum detection limit was 100 fg of pathogen DNA. When we tested 28 Gram-negative clinical isolates, all of them were successfully identified without any non-specific peaks. To evaluate the clinical applicability, we tested seven blood samples from febrile patients. Three blood culture positive cases showed E. coli specific peaks, while no peak was detected in the other four culture negative samples. This technology can be useful for detection of major sepsis-causing, drug-resistant Gram-negative pathogens and also the major ESBL producing Gram-negatives from the blood of sepsis patients in a clinical setting. This system can help early initiation of effective antimicrobial treatment against Gram-negative pathogens for sepsis patients, which is very crucial for better treatment outcomes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Efficiency of high-volume hemofiltration in patients with severe sepsis and intracranial hypertension].

PubMed

Musaeva, T S; Berdnikov, A P; Goncharenko, S I; Denisova, E A

2014-01-01

We performed a retrospective study in 68 patients (144 procedures) with severe sepsis and intracranial hypertension measured by the pressure in the central retinal vein. The patients underwent high-volume hemofiltration (HV-HF) for extrarenal indications. Increased pressure in the central retinal vein was accompanied by critical points of cerebral perfusion pressure and the growth of neurological deficit with inhibition level of consciousness to coma 1. In this case, IHV-HF may be associated with the formation of the critical points of cerebral perfihsion and severe disorders of microcirculation and the lack of resolution of tissue hypoperfusion. In case of intracranial hypertension IHV-HF is not effective in the category of patients where there is a combination ΔpCO2 > 5.9 mm Hg level and GCS <10 points.

[Cost-effectiveness of drotrecogin alpha [activated] in the treatment of severe sepsis in Spain].

PubMed

Sacristán, José A; Prieto, Luis; Huete, Teresa; Artigas, Antonio; Badia, Xavier; Chinn, Christopher; Hudson, Peter

2004-01-01

The PROWESS clinical trial has shown that treatment with drotrecogin alpha (activated) in patients with severe sepsis is associated with a reduction in the absolute risk of death compared with standard treatment. The aim of the present study was to assess the cost-effectiveness of drotrecogin alpha (activated) versus that of standard care in the treatment of severe sepsis in Spain. A decision analysis model was drawn up to compare costs to hospital discharge and the long-term efficacy of drotrecogin alpha (activated) versus those of standard care in the treatment of severe sepsis in Spain from the perspective of the health care payer. Most of the information for creating the model was obtained from the PROWESS clinical trial. A two-fold baseline analysis was performed: a) for all patients included in the PROWESS clinical trial and b) for the patients with two or more organ failures. The major variables for clinical assessment were the reduction in mortality and years of life gained (YLG). Cost-effectiveness was expressed as cost per YLG. A sensitivity analysis was applied using 3% and 5% discount rates for YLG and by modifying the patterns of health care, intensive care unit costs, and life expectancy by initial co-morbidity and therapeutic efficacy of drotrecogin alpha (activated). Treatment with drotrecogin alfa (activated) was associated with a 6.0% drop in the absolute risk of death (p = 0.005) when all of the patients from the PROWESS trial were included and with a 7.3% reduction (p = 0.005) when the analysis was restricted to patients with two or more organ failures. The cost-effectiveness of drotrecogin alfa (activated) was 13,550 euros per YLG with respect to standard care after analysing all of the patients and 9,800 euros per YLG in the group of patients with two or more organ failures. In the sensitivity analysis, the results ranged from 7,322 to 16,493 euros per YLG. The factors with the greatest impact on the results were the change in the efficacy of

Multicentric Standardized Flow Cytometry Routine Assessment of Patients With Sepsis to Predict Clinical Worsening.

PubMed

Daix, Thomas; Guerin, Estelle; Tavernier, Elsa; Mercier, Emmanuelle; Gissot, Valérie; Hérault, Olivier; Mira, Jean-Paul; Dumas, Florence; Chapuis, Nicolas; Guitton, Christophe; Béné, Marie C; Quenot, Jean-Pierre; Tissier, Cindy; Guy, Julien; Piton, Gaël; Roggy, Anne; Muller, Grégoire; Legac, Éric; de Prost, Nicolas; Khellaf, Mehdi; Wagner-Ballon, Orianne; Coudroy, Rémi; Dindinaud, Elodie; Uhel, Fabrice; Roussel, Mikaël; Lafon, Thomas; Jeannet, Robin; Vargas, Frédéric; Fleureau, Catherine; Roux, Mickaël; Allou, Kaoutar; Vignon, Philippe; Feuillard, Jean; François, Bruno

2018-04-26

In this study, we primarily sought to assess the ability of flow cytometry to predict early clinical deterioration and overall survival in patients with sepsis admitted in the ED and ICU. Patients admitted for community-acquired acute sepsis from 11 hospital centers were eligible. Early (day 7) and late (day 28) deaths were notified. Levels of CD64 pos granulocytes, CD16 pos monocytes, CD16 dim immature granulocytes (IGs), and T and B lymphocytes were assessed by flow cytometry using an identical, cross-validated, robust, and simple consensus standardized protocol in each center. Among 1,062 patients screened, 781 patients with confirmed sepsis were studied (age, 67 ± 48 years; Simplified Acute Physiology Score II, 36 ± 17; Sequential Organ Failure Assessment, 5 ± 4). Patients were divided into three groups (sepsis, severe sepsis, and septic shock) on day 0 and on day 2. On day 0, patients with sepsis exhibited increased levels of CD64 pos granulocytes, CD16 pos monocytes, and IGs with T-cell lymphopenia. Clinical severity was associated with higher percentages of IGs and deeper T-cell lymphopenia. IG percentages tended to be higher in patients whose clinical status worsened on day 2 (35.1 ± 35.6 vs 43.5 ± 35.2, P = .07). Increased IG percentages were also related to occurrence of new organ failures on day 2. Increased IG percentages, especially when associated with T-cell lymphopenia, were independently associated with early (P < .01) and late (P < .01) death. Increased circulating IGs at the acute phase of sepsis are linked to clinical worsening, especially when associated with T-cell lymphopenia. Early flow cytometry could help clinicians to target patients at high risk of clinical deterioration. ClinicalTrials.gov; No.: NCT01995448; URL: www.clinicaltrials.gov. Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Temporal trends in the systemic inflammatory response syndrome, sepsis, and medical coding of sepsis.

PubMed

Thomas, Benjamin S; Jafarzadeh, S Reza; Warren, David K; McCormick, Sandra; Fraser, Victoria J; Marschall, Jonas

2015-11-24

Recent reports using administrative claims data suggest the incidence of community- and hospital-onset sepsis is increasing. Whether this reflects changing epidemiology, more effective diagnostic methods, or changes in physician documentation and medical coding practices is unclear. We performed a temporal-trend study from 2008 to 2012 using administrative claims data and patient-level clinical data of adult patients admitted to Barnes-Jewish Hospital in St. Louis, Missouri. Temporal-trend and annual percent change were estimated using regression models with autoregressive integrated moving average errors. We analyzed 62,261 inpatient admissions during the 5-year study period. 'Any SIRS' (i.e., SIRS on a single calendar day during the hospitalization) and 'multi-day SIRS' (i.e., SIRS on 3 or more calendar days), which both use patient-level data, and medical coding for sepsis (i.e., ICD-9-CM discharge diagnosis codes 995.91, 995.92, or 785.52) were present in 35.3 %, 17.3 %, and 3.3 % of admissions, respectively. The incidence of admissions coded for sepsis increased 9.7 % (95 % CI: 6.1, 13.4) per year, while the patient data-defined events of 'any SIRS' decreased by 1.8 % (95 % CI: -3.2, -0.5) and 'multi-day SIRS' did not change significantly over the study period. Clinically-defined sepsis (defined as SIRS plus bacteremia) and severe sepsis (defined as SIRS plus hypotension and bacteremia) decreased at statistically significant rates of 5.7 % (95 % CI: -9.0, -2.4) and 8.6 % (95 % CI: -4.4, -12.6) annually. All-cause mortality, SIRS mortality, and SIRS and clinically-defined sepsis case fatality did not change significantly during the study period. Sepsis mortality, based on ICD-9-CM codes, however, increased by 8.8 % (95 % CI: 1.9, 16.2) annually. The incidence of sepsis, defined by ICD-9-CM codes, and sepsis mortality increased steadily without a concomitant increase in SIRS or clinically-defined sepsis. Our results highlight the need to develop

Effect of early goal-directed therapy on mortality in patients with severe sepsis or septic shock: a meta-analysis of randomised controlled trials

PubMed Central

Yu, Hong; Chi, Dongmei; Wang, Siyang; Liu, Bin

2016-01-01

Objective To determine whether patients with severe sepsis or septic shock could benefit from a strict and early goal-directed therapy (EGDT) protocol recommended by Surviving Sepsis Campaign (SSC) Guidelines. Methods MEDLINE/PubMed, EMBASE/OVID and Cochrane Central Register of Controlled Trials (CENTRAL) were searched between March 1983 and March 2015. Eligible studies evaluated the outcomes of EGDT versus usual care or standard therapy in patients with severe sepsis or septic shock. The primary outcomes were mortality within 28 days, 60 days and 90 days. Included studies must report at least one metric of mortality. Results 5 studies that enrolled 4303 patients with 2144 in the EGDT group and 2159 in the control group were included in this meta-analysis. Overall, there were slight decreases of mortality within 28 days, 60 days and 90 days in the random-effect model in patients with severe sepsis or septic shock receiving EGDT resuscitation. However, none of the differences reached statistical significance (RR=0.86; 95% CI 0.69 to 1.06; p=0.16; p for heterogeneity=0.008, I2=71%; RR=0.94; 95% CI 0.81 to 1.10; p=0.46; p for heterogeneity=0.16, I2=43%; RR=0.98; 95% CI 0.88 to 1.10; p=0.75; p for heterogeneity=0.87, I2=0%, respectively). Conclusions The current meta-analysis pooled data from five RCTs and found no survival benefit of EGDT in patients with sepsis. However, the included trials are not sufficiently homogeneous and potential confounding factors in the negative trials (ProCESS, ARISE and ProMISe) might bias the results and diminish the treatment effect of EGDT. Further well-designed studies should eliminate all potential source of bias to determine if EGDT has a mortality benefit. PMID:26932135

Effects of pentastarch and albumin infusion on cardiorespiratory function and coagulation in patients with severe sepsis and systemic hypoperfusion.

PubMed

Rackow, E C; Mecher, C; Astiz, M E; Griffel, M; Falk, J L; Weil, M H

1989-05-01

Twenty consecutive patients with severe sepsis were randomized to fluid challenge with 5% albumin or 10% low MW hydroxyethyl starch (pentastarch) solutions. Fluid challenge was administered iv as 250 ml of test colloid every 15 min until the pulmonary artery wedge pressure (WP) was greater than or equal to 15 mm Hg or a maximum dose of 2000 ml was infused. Hemodynamic, respiratory, and coagulation profiles were measured before and after fluid infusion. The amount of colloid required to achieve a WP of 15 mm Hg was comparable between groups. Both colloid infusions resulted in similar increases in cardiac output, stroke output, and stroke work. The effect of fluid infusion with pentastarch on coagulation was not significantly different from albumin, although pentastarch was associated with a 45% decrease in factor VIII:c. We conclude that pentastarch is equivalent to albumin for fluid resuscitation of patients with severe sepsis.

Changes in fibrinolysis and severity of organ failure in sepsis: a prospective observational study using point-of-care test--ROTEM.

PubMed

Prakash, Shivesh; Verghese, Santosh; Roxby, David; Dixon, Dani; Bihari, Shailesh; Bersten, Andrew

2015-04-01

We hypothesized that the thromboelastometry (ROTEM; Pentapharm GmbH, Munich, Germany) fibrinolysis parameter "maximum lysis" (ML) would have an independent inverse association with the severity of organ failure in sepsis. Selected adult patients with sepsis (n = 77) were recruited within 24 hours of antibiotic commencement. Patients with Sequential Organ Failure Assessment score higher than 1 (n = 57) were followed for 72 hours. Prothrombin fragments 1 + 2, plasminogen activator inhibitor-1 (aPAI-1), ROTEM, and routine coagulation tests were measured daily along with Sequential Organ Failure Assessment scores. The activity of functional aPAI-1 increased with increasing severity of organ failure (P = .01) and was higher as compared with healthy controls (95% confidence interval, -65.4 to -29.9; P < .001). There was a decreasing trend in ML with increased organ failure (P = .001); however, there was no trend in d-dimer. Among all tests, only the lower ML (ß = -0.38, P < .001) and higher international normalized ratio (INR; ß = 0.32, P = .002) values significantly contributed to greater severity of organ failure (R(2) = 0.35, F2,73 = 19.29, P < .001). Despite an increase in INR, the prothrombin fragment remained unchanged (P = .89). Strong correlations were observed between early (24 hours) increase in fibrinolysis and recovery of organ failures for 48 hours (ML: r = 0.679, P = .001; aPAI-1: r = 0.694, P < .001). Lower ML and higher INR values predicted greater severity of organ failure at presentation. Further studies are required, as ROTEM could aid selection of patients and guide interventions aimed at fibrinolysis in severe sepsis. Copyright © 2014 Elsevier Inc. All rights reserved.

Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice

PubMed Central

Wang, Xianfeng; Buechler, Nancy L.; Martin, Ayana; Wells, Jonathan; Yoza, Barbara; McCall, Charles E.; Vachharajani, Vidula

2016-01-01

provide a novel treatment target for obesity with sepsis. PMID:27500833

Immunosuppression in patients who die of sepsis and multiple organ failure.

PubMed

Boomer, Jonathan S; To, Kathleen; Chang, Kathy C; Takasu, Osamu; Osborne, Dale F; Walton, Andrew H; Bricker, Traci L; Jarman, Stephen D; Kreisel, Daniel; Krupnick, Alexander S; Srivastava, Anil; Swanson, Paul E; Green, Jonathan M; Hotchkiss, Richard S

2011-12-21

Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections. Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28-stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, -5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, -269 to 1534) vs 58 (95% CI, -39 to 156) pg/mL; (P < .001 for all). There were similar

Monocyte Profiles in Critically Ill Patients With Pseudomonas Aeruginosa Sepsis

ClinicalTrials.gov

2017-02-02

Pseudomonas Infections; Pseudomonas Septicemia; Pseudomonas; Pneumonia; Pseudomonal Bacteraemia; Pseudomonas Urinary Tract Infection; Pseudomonas Gastrointestinal Tract Infection; Sepsis; Sepsis, Severe; Critically Ill

Pediatric Sepsis

PubMed Central

Mathias, Brittany; Mira, Juan; Larson, Shawn D.

2016-01-01

Purpose of Review Sepsis is the leading cause of pediatric death worldwide. In the United States alone, there are 72,000 children hospitalized for sepsis annually with a reported mortality rate of 25% and an economic cost estimated to be $4.8 billion. However, it is only recently that the definition and management of pediatric sepsis has been recognized as being distinct from adult sepsis. Recent Findings The definition of pediatric sepsis is currently in a state of evolution and there is a large disconnect between the clinical and research definitions of sepsis which impacts the application of research findings into clinical practice. Despite this, it is the speed of diagnosis and the timely implementation of current treatment guidelines that has been shown to improve outcomes. However, adherence to treatment guidelines is currently low and it is only through the implementation of protocols that improved care and outcomes have been demonstrated. Summary Current management of pediatric sepsis is largely based on adaptations from adult sepsis treatment; however, distinct physiology demands more prospective pediatric trials to tailor management to the pediatric population. Adherence to current and emerging practice guidelines will require that protocolized care pathways become commonplace. PMID:26983000

Pediatric sepsis.

PubMed

Mathias, Brittany; Mira, Juan C; Larson, Shawn D

2016-06-01

Sepsis is the leading cause of pediatric death worldwide. In the United States alone, there are 72 000 children hospitalized for sepsis annually with a reported mortality rate of 25% and an economic cost estimated to be $4.8 billion. However, it is only recently that the definition and management of pediatric sepsis has been recognized as being distinct from adult sepsis. The definition of pediatric sepsis is currently in a state of evolution, and there is a large disconnect between the clinical and research definitions of sepsis which impacts the application of research findings into clinical practice. Despite this, it is the speed of diagnosis and the timely implementation of current treatment guidelines that has been shown to improve outcomes. However, adherence to treatment guidelines is currently low and it is only through the implementation of protocols that improved care and outcomes have been demonstrated. The current management of pediatric sepsis is largely based on adaptations from adult sepsis treatment; however, distinct physiology demands more prospective pediatric trials to tailor management to the pediatric population. Adherence to current and emerging practice guidelines will require that protocolized care pathways become a commonplace.

Severe Acinetobacter baumannii Sepsis Is Associated with Elevation of Pentraxin 3

PubMed Central

Ketter, Patrick M.; Guentzel, M. Neal; Schaffer, Beverly; Herzig, Maryanne; Wu, Xiaowu; Montgomery, Robbie K.; Parida, Bijaya K.; Fedyk, Chriselda G.; Yu, Jieh-Juen; Jorgensen, James; Chambers, James P.; Cap, Andrew P.

2014-01-01

Multidrug-resistant Acinetobacter baumannii is among the most prevalent bacterial pathogens associated with trauma-related wound and bloodstream infections. Although septic shock and disseminated intravascular coagulation have been reported following fulminant A. baumannii sepsis, little is known about the protective host immune response to this pathogen. In this study, we examined the role of PTX3, a soluble pattern recognition receptor with reported antimicrobial properties and stored within neutrophil granules. PTX3 production by murine J774a.1 macrophages was assessed following challenge with A. baumannii strains ATCC 19606 and clinical isolates (CI) 77, 78, 79, 80, and 86. Interestingly, only CI strains 79, 80, and 86 induced PTX3 synthesis in murine J774a.1 macrophages, with greatest production observed following CI 79 and 86 challenge. Subsequently, C57BL/6 mice were challenged intraperitoneally with CI 77 and 79 to assess the role of PTX3 in vivo. A. baumannii strain CI 79 exhibited significantly (P < 0.0005) increased mortality, with an approximate 50% lethal dose (LD50) of 105 CFU, while an equivalent dose of CI 77 exhibited no mortality. Plasma leukocyte chemokines (KC, MCP-1, and RANTES) and myeloperoxidase activity were also significantly elevated following challenge with CI 79, indicating neutrophil recruitment/activation associated with significant elevation in serum PTX3 levels. Furthermore, 10-fold-greater PTX3 levels were observed in mouse serum 12 h postchallenge, comparing CI 79 to CI 77 (1,561 ng/ml versus 145 ng/ml), with concomitant severe pathology (liver and spleen) and coagulopathy. Together, these results suggest that elevation of PTX3 is associated with fulminant disease during A. baumannii sepsis. PMID:25001601

A rational approach to fluid therapy in sepsis.

PubMed

Marik, P; Bellomo, R

2016-03-01

Aggressive fluid resuscitation to achieve a central venous pressure (CVP) greater than 8 mm Hg has been promoted as the standard of care, in the management of patients with severe sepsis and septic shock. However recent clinical trials have demonstrated that this approach does not improve the outcome of patients with severe sepsis and septic shock. Pathophysiologically, sepsis is characterized by vasoplegia with loss of arterial tone, venodilation with sequestration of blood in the unstressed blood compartment and changes in ventricular function with reduced compliance and reduced preload responsiveness. These data suggest that sepsis is primarily not a volume-depleted state and recent evidence demonstrates that most septic patients are poorly responsive to fluids. Furthermore, almost all of the administered fluid is sequestered in the tissues, resulting in severe oedema in vital organs and, thereby, increasing the risk of organ dysfunction. These data suggest that a physiologic, haemodynamically guided conservative approach to fluid therapy in patients with sepsis would be prudent and would likely reduce the morbidity and improve the outcome of this disease. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Regulators of Intestinal Epithelial Migration in Sepsis.

PubMed

Meng, Mei; Klingensmith, Nathan J; Liang, Zhe; Lyons, John D; Fay, Katherine T; Chen, Ching-Wen; Ford, Mandy L; Coopersmith, Craig M

2018-02-08

The gut is a continuously renewing organ, with cell proliferation, migration and death occurring rapidly under basal conditions. Since the impact of critical illness on cell movement from crypt base to villus tip is poorly understood, the purpose of this study was to determine how sepsis alters enterocyte migration. Wild type, transgenic and knockout mice were injected with 5-bromo-2'deoxyuridine (BrdU) to label cells in S phase before and after the onset of cecal ligation and puncture and were sacrificed at pre-determined endpoints to determine distance proliferating cells migrated up the crypt-villus unit. Enterocyte migration rate was decreased from 24-96 hours following sepsis. BrdU was not detectable on villi 6 days after sham laparotomy, meaning all cells had migrated the length of the gut and been exfoliated into its lumen. However, BrdU positive cells were detectable on villi 10 days after sepsis. Multiple components of gut integrity altered enterocyte migration. Sepsis decreased crypt proliferation, which further slowed enterocyte transit as mice injected with BrdU after the onset of sepsis (decreased proliferation) had slower migration than mice injected with BrdU prior to the onset of sepsis (normal proliferation). Decreasing intestinal apoptosis via gut-specific overexpression of Bcl-2 prevented sepsis-induced slowing of enterocyte migration. In contrast, worsened intestinal hyperpermeability by genetic deletion of JAM-A increased enterocyte migration. Sepsis therefore significantly slows enterocyte migration, and intestinal proliferation, apoptosis and permeability all affect migration time, which can potentially be targeted both genetically and pharmacologically.

Sequential N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin Measurements During Albumin Replacement in Patients With Severe Sepsis or Septic Shock.

PubMed

Masson, Serge; Caironi, Pietro; Fanizza, Caterina; Carrer, Sara; Caricato, Anselmo; Fassini, Paola; Vago, Tarcisio; Romero, Marilena; Tognoni, Gianni; Gattinoni, Luciano; Latini, Roberto

2016-04-01

Myocardial dysfunction is a frequent complication in patients with severe sepsis and can worsen the prognosis. We investigated whether circulating biomarkers related to myocardial function and injury predicted outcome and were associated with albumin replacement. A multicenter, randomized clinical trial about albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). Forty ICUs in Italy. Nine hundred and ninety-five patients with severe sepsis or septic shock. Randomization to albumin and crystalloid solutions or crystalloid solutions alone. Plasma concentrations of N- terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T were measured 1, 2, and 7 days after enrollment. We tested the relationship of single marker measurements or changes over time with clinical events, organ dysfunctions, albumin replacement, and ICU or 90-day mortality in the overall population and after stratification by shock. N-terminal pro-B-type natriuretic peptide levels were abnormal in 97.4% of the patients and high-sensitivity cardiac troponin T in 84.5%, with higher concentrations in those with shock. After extensive adjustments, N-terminal pro-B-type natriuretic peptide concentrations predicted ICU or 90-day mortality, better than high-sensitivity cardiac troponin T. Early changes in N-terminal pro-B-type natriuretic peptide or high-sensitivity cardiac troponin T concentrations were independently associated with subsequent mortality in patients with shock. Patients given albumin had significantly higher N-terminal pro-B-type natriuretic peptide levels; in addition, early rise in N-terminal pro-B-type natriuretic peptide was associated with a better outcome in this subgroup. Circulating N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T are frequently elevated in severe sepsis or septic shock and have relevant prognostic value, which may be important in monitoring the clinical efficacy of

The Prevalence and Clinical Significance of Low Procalcitonin Levels Among Patients With Severe Sepsis or Septic Shock in the Emergency Department.

PubMed

Choe, Eun A; Shin, Tae Gun; Jo, Ik Joon; Hwang, Sung Yeon; Lee, Tae Rim; Cha, Won Chul; Sim, Min Seob

2016-07-01

The aims of this study were to evaluate the prevalence of low procalcitonin (PCT) levels among patients with severe sepsis or septic shock, and to investigate clinical characteristics and outcomes associated with low PCT levels. We analyzed data from the sepsis registry for patients with severe sepsis or septic shock in the emergency department. Based on a specific PCT cutoff value, patients were classified into two groups: a low PCT group, PCT <0.25 ng/mL; and a high PCT group, PCT ≥0.25 ng/mL. The primary endpoint was 28-day mortality. A multivariable logistic regression model was used to evaluate independent factors associated with low PCT and 28-day mortality. A total of 1,212 patients were included. Of the eligible patients, 154 (12.7%) were assigned to the low PCT group, and 1,058 (87.3%) to the high PCT group. The 28-day mortality was 4.6% in the low PCT group and 13.5% in the high PCT group (P < 0.01). The adjusted odds ratio of the low PCT group for 28-day mortality was 0.43 (95% CI 0.19-0.98; P = 0.04). There was no trend of increasing mortality among higher PCT level patients. In a logistic regression model, factors associated with low PCT were pneumonia, lower C-reactive protein levels, lower lactate levels, the absence of bacteremia, and the absence of organ failure. Intra-abdominal infection and obesity were associated with high PCT. Initial low PCT levels were common among patients diagnosed with severe sepsis or septic shock in the emergency department, suggesting favorable outcomes. The prevalence of low PCT levels was significantly different according to obesity, the source of infection, C-reactive protein levels, lactate levels, bacteremia, and organ failure.

The impact of duration of organ dysfunction on the outcome of patients with severe sepsis and septic shock.

PubMed

Freitas, Flávio G R; Salomão, Reinaldo; Tereran, Nathalia; Mazza, Bruno Franco; Assunção, Murillo; Jackiu, Mirian; Fernandes, Haggeas; Machado, Flávia Ribeiro

2008-08-01

This study aimed to assess the impact of the duration of organ dysfunction on the outcome of patients with severe sepsis or septic shock. Clinical data were collected from hospital charts of patients with severe sepsis and septic shock admitted to a mixed intensive care unit from November 2003 to February 2004. The duration of organ dysfunction prior to diagnosis was correlated with mortality. Results were considered significant if p<0.05. Fifty-six patients were enrolled. Mean age was 55.6+/-20.7 years, mean APACHE II score was 20.6+/-6.9, and mean SOFA score was 7.9+/-3.7. Thirty-six patients (64.3%) had septic shock. The mean duration of organ dysfunction was 1.9+/-1.9 days. Within the univariate analysis, the variables correlated with hospital mortality were: age (p=0.015), APACHE II (p=0.008), onset outside the intensive care unit (p=0.05), blood glucose control (p=0.05) and duration of organ dysfunction (p=0.0004). In the multivariate analysis, only a duration of organ dysfunction persisting longer than 48 hours correlated with mortality (p=0.004, OR: 8.73 (2.37-32.14)), whereas the APACHE II score remained only a slightly significant factor (p=0.049, OR: 1.11 (1.00-1.23)). Patients who received therapeutic interventions within the first 48 hours after the onset of organ dysfunction exhibited lower mortality (32.1% vs. 82.1%, p=0.0001). These findings suggest that the diagnosis of organ dysfunction is not being made in a timely manner. The time elapsed between the onset of organ dysfunction and initiation of therapeutic intervention can be quite long, and this represents an important determinant of survival in cases of severe sepsis and septic shock.

Randomized, Placebo-controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis: The ACROSS Trial

PubMed Central

Janz, David R; Bastarache, Julie A; Rice, Todd W; Bernard, Gordon R; Warren, Melissa A; Wickersham, Nancy; Sills, Gillian; Oates, John A; Roberts, L Jackson; Ware, Lorraine B

2014-01-01

Objective This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-Isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin. Design Single center, randomized, double-blind, placebo controlled phase II trial. Setting Medical ICU in a tertiary, academic medical center. Patients Critically ill patients ≥18 years old with severe sepsis and detectable plasma cell-free hemoglobin. Interventions Patients were randomized 1:1 to enteral acetaminophen 1 gram every 6 hours for three days (n = 18) or placebo (n = 22) with the same dosing schedule and duration. Measurements and Main Results F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL, IQR 24–41) and placebo (36 pg/mL, IQR 25–80, p = 0.35). However, F2-Isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL, IQR 19 – 36) compared with placebo (36 pg/mL, IQR 23–55, p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL, IQR 0.6–1.4) compared with placebo (1.3 mg/dL, IQR 0.83 – 2.0, p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs. placebo 18.2%, p = 0.355) or adverse events (AST or ALT >400)(acetaminophen 9.5% vs. placebo 4.3%, p = 0.599). Conclusions In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Further study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes. PMID:25474535

Sepsis Fact Sheet

MedlinePlus

... News & Meetings Science Education About NIGMS NIGMS Home > Science Education > Sepsis Sepsis Tagline (Optional) Middle/Main Content Area PDF Version (392 KB) En español Other Fact Sheets What is sepsis? Sepsis is a serious ...

Sepsis (For Parents)

MedlinePlus

... Staying Safe Videos for Educators Search English Español Sepsis KidsHealth / For Parents / Sepsis What's in this article? ... When to Call the Doctor Print What Is Sepsis? Sepsis is when the immune system responds to ...

Sepsis Definitions: The Search for Gold and What CMS Got Wrong.

PubMed

Kalantari, Annahieta; Mallemat, Haney; Weingart, Scott D

2017-08-01

On October 1, 2015, the United States Centers for Medicare and Medicaid Services (CMS) issued a core measure addressing the care of septic patients. These core measures are controversial among healthcare providers. This article will address that there is no gold standard definition for sepsis, severe sepsis or septic shock and the CMS-assigned definitions for severe sepsis and septic shock are premature and inconsistent with evidence-based definitions.

Pediatric Sepsis.

PubMed

Prusakowski, Melanie K; Chen, Audrey P

2017-02-01

Pediatric sepsis is distinct from adult sepsis in its definitions, clinical presentations, and management. Recognition of pediatric sepsis is complicated by the various pediatric-specific comorbidities that contribute to its mortality and the age- and development-specific vital sign and clinical parameters that obscure its recognition. This article outlines the clinical presentation and management of sepsis in neonates, infants, and children, and highlights some key populations who require specialized care. Copyright © 2016 Elsevier Inc. All rights reserved.

Methionine Metabolites in Patients With Sepsis.

PubMed

Wexler, Orren; Gough, Michael S; Morgan, Mary Anne M; Mack, Cynthia M; Apostolakos, Michael J; Doolin, Kathleen P; Mooney, Robert A; Arning, Erland; Bottiglieri, Teodoro; Pietropaoli, Anthony P

2018-01-01

Sepsis is characterized by microvascular dysfunction and thrombophilia. Several methionine metabolites may be relevant to this sepsis pathophysiology. S-adenosylmethionine (SAM) serves as the methyl donor for trans-methylation reactions. S-adenosylhomocysteine (SAH) is the by-product of these reactions and serves as the precursor to homocysteine. Relationships between plasma total homocysteine concentrations (tHcy) and vascular disease and thrombosis are firmly established. We hypothesized that SAM, SAH, and tHcy levels are elevated in patients with sepsis and associated with mortality. This was a combined case-control and prospective cohort study consisting of 109 patients with sepsis and 50 control participants without acute illness. The study was conducted in the medical and surgical intensive care units of the University of Rochester Medical Center. Methionine, SAM, SAH, and tHcy concentrations were compared in patients with sepsis versus control participants and in sepsis survivors versus nonsurvivors. Patients with sepsis had significantly higher plasma SAM and SAH concentrations than control participants (SAM: 164 [107-227] vs73 [59-87 nM], P < .001; SAH: 99 [60-165] vs 35 [28-45] nM, P < .001). In contrast, plasma tHcy concentrations were lower in sepsis patients compared to healthy control participants (4 [2-6]) vs 7 [5-9] μM; P = .04). In multivariable analysis, quartiles of SAM, SAH, and tHcy were independently associated with sepsis ( P = .006, P = .05, and P < .001, respectively). Sepsis nonsurvivors had significantly higher plasma SAM and SAH concentrations than survivors (SAM: 223 [125-260] vs 136 [96-187] nM; P = .01; SAH: 139 [81-197] vs 86 [55-130] nM, P = .006). Plasma tHcy levels were similar in survivors vs nonsurvivors. The associations between SAM or SAH and hospital mortality were no longer significant after adjusting for renal dysfunction. Methionine metabolite concentrations are abnormal in sepsis and linked with clinical outcomes

A Review of GM-CSF Therapy in Sepsis

PubMed Central

Mathias, Brittany; Szpila, Benjamin E.; Moore, Frederick A.; Efron, Philip A.; Moldawer, Lyle L.

2015-01-01

Abstract Determine what clinical role, if any, GM-CSF may have in the clinical treatment of sepsis in the adult patient. Advancements in the management of sepsis have led to significant decreases in early mortality; however, sepsis remains a significant source of long-term mortality and disability which places strain on healthcare resources with a substantial growing economic impact. Historically, early multiple organ failure (MOF) and death in patients with severe sepsis was thought to result from an exaggerated proinflammatory response called the systemic inflammatory response syndrome (SIRS). Numerous prospective randomized controlled trials (PRCTs) tested therapies aimed at decreasing the organ injury associated with an exaggerated inflammatory response. With few exceptions, the results from these PRCTs have been disappointing, and currently no specific therapeutic agent is approved to counteract the early SIRS response in patients with severe sepsis. It has long been recognized that there is a delayed immunosuppressive state that contributes to long-term morbidity. However, recent findings now support a concurrent proinflammatory and anti-inflammatory response present throughout sepsis. Multiple immunomodulating agents have been studied to combat the immunosuppressive phase of sepsis with the goal of decreasing secondary infection, reducing organ dysfunction, decreasing ICU stays, and improving survival. Granulocyte-macrophage colony stimulating factor (GM-CSF), a myelopoietic growth factor currently used in patients with neutropenia secondary to chemotherapy-induced myelosuppression, has been studied as a potential immune-activating agent. The applicability of GM-CSF as a standard therapy for generalized sepsis is still largely understudied; however, small-scale studies available have demonstrated some improved recovery from infection, decreased hospital length of stay, decreased days requiring mechanical ventilation, and decreased medical costs. PMID

[New recommendations on the use of human albumin solutions in patients with severe sepsis and septic shock. A critical evaluation of the literature].

PubMed

Latour-Pérez, J

2013-01-01

The third edition of the Surviving Sepsis Campaign guidelines opens the door to the use of albumin for fluid resuscitation in patients with severe sepsis and septic shock. This recommendation is based on a recent meta-analysis that included studies with evidence of insufficient plasma expansion in the control group and studies performed in children with malaria with clear statistical heterogeneity (P for interaction=.02). After excluding pediatric studies, the confidence interval of the effect estimate was consistent with a mortality excess in the group treated with albumin (OR=.87 [95%CI: .71 to 1.07]). Two new randomized studies reported after publication of the meta-analysis found no benefit in patients treated with albumin. Given the uncertainty about the true effect of albumin (due to the existence of indirectness and imprecision) and its cost considerations, it is suggested not to use albumin in the initial resuscitation of patients with severe sepsis and septic shock (GRADE2C). Copyright © 2013 Elsevier España, S.L. and SEMICYUC. All rights reserved.

Trends and disparities in sepsis hospitalisations in Victoria, Australia.

PubMed

Ore, Timothy

2016-11-01

Objective The aim of the present study was to determine the clinical and epidemiological characteristics of patients with sepsis admitted to hospitals in Victoria, Australia, during the period 2004-14. The data include incidence, severity and mortality. Methods In all, 44222 sepsis hospitalisations were identified between 2004-05 and 2013-14 from the Victorian Admitted Episodes Dataset. The dataset contains clinical and demographic information on all admissions to acute public and private hospitals. Using the International Classification of Diseases (10th Revision) Australian Modification codes, incidence rates, severity of disease and mortality were calculated. Results Sepsis hospitalisation rates per 10000 population increased significantly (P<0.01) over the period, from 6.9 (95% confidence interval (CI) 5.6-7.8) to 10.0 (95% CI 9.1-11.1), an annual growth rate of 3.8%. The age-standardised in-hospital death rates per 100000 population grew significantly (P<0.01) from 9.2 (95% CI 7.8-10.4) in 2004-05 to 13.0 (95% CI 11.7-14.6) in 2013-14, an annual growth rate of 3.1%. Among people under 45 years of age, the 0-4 years age group had the highest hospitalisation rate (3.0 per 10000 population; 95% CI 2.7-3.4). Nearly half (46.2%) of all sepsis hospitalisations were among patients born overseas, with a rate of 14.5 per 10000 population (95% CI 12.4-16.2) in that group compared with a rate of 5.9 per 10000 population (95% CI 5.3-6.7) for patients born in Australia. The age-standardised sepsis hospitalisation rate was 2.6-fold greater in the lowest compared with highest socioeconomic areas (12.7 per 10000 population (95% CI 11.2-13.8) vs 4.8 per 10000 population (95% CI 4.1-5.7), respectively). Conclusion This paper shows a significant upward trend in both sepsis separation rates and in-hospital death rates over the period; unlike sepsis, in-hospital death rates from all diagnoses fell over the same period. The results can be used to stimulate review of clinical

Sepsis

MedlinePlus

Septicemia; Sepsis syndrome; Systemic inflammatory response syndrome; SIRS; Septic shock ... The symptoms of sepsis are not caused by the germs themselves. Instead, chemicals the body releases cause the response. A bacterial infection anywhere ...

Vasopressin, Sepsis, and Renal Perfusion - A VASST Deficit in Our Understanding

DTIC Science & Technology

2014-06-01

including the Pediatric Subgroup: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care...JUN 2014 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Vasopressin, Sepsis , and Renal PerfusionâA VASST Deficit in Our...AKI with vasopressin. The current Surviving Sepsis Campaign Guidelines (3), based largely on the results of the VASST trial (4), recommend vasopressin

Readmissions for Recurrent Sepsis: New or Relapsed Infection?

PubMed

DeMerle, Kimberley Marie; Royer, Stephanie C; Mikkelsen, Mark E; Prescott, Hallie C

2017-10-01

Sepsis hospitalizations are frequently followed by hospital readmissions, often for recurrent sepsis. However, it is unclear how often sepsis readmissions are for relapsed/recrudescent versus new infections. The aim of this study was to assess the extent to which 90-day readmissions for recurrent sepsis are due to infection of the same site and same pathogen as the initial episode. Retrospective cohort study. University of Michigan Health System. All hospitalizations (May 15, 2013 to May 14, 2015) with a principal International Classification of Diseases, Ninth revision, Clinical Modification diagnosis of septicemia (038.x), severe sepsis (995.92), or septic shock (785.52), as well as all subsequent hospitalizations and sepsis readmissions within 90 days. We determined organism and site of sepsis through manual chart abstraction. None. We identified 472 readmissions within 90 days of sepsis, of which 137 (29.1%) were for sepsis. In sepsis readmissions, the site and organisms were most commonly urinary (29.2%), gastrointestinal (20.4%), Gram negative (29.9%), Gram positive (16.8%), and culture negative (30.7%). Ninety-four readmissions (68.6%) were for infection at the same site as initial sepsis hospitalization. Nineteen percent of readmissions were confirmed to be same site and same organism. However, accounting for the uncertainty from culture-negative sepsis, as many as 53.2% of readmissions could plausibly due to infections with both the same organism and same site. Of the patients readmitted with sepsis within 90 days, two thirds had infection at the same site as their initial admission. Just 19% had infection confirmed to be from the same site and organism as the initial sepsis hospitalization. Half of readmissions were definitively for new infections, whereas an additional 34% were unclear since cultures were negative in one of the hospitalizations.

Poor performance of quick-SOFA (qSOFA) score in predicting severe sepsis and mortality - a prospective study of patients admitted with infection to the emergency department.

PubMed

Askim, Åsa; Moser, Florentin; Gustad, Lise T; Stene, Helga; Gundersen, Maren; Åsvold, Bjørn Olav; Dale, Jostein; Bjørnsen, Lars Petter; Damås, Jan Kristian; Solligård, Erik

2017-06-09

We aimed to evaluate the clinical usefulness of qSOFA as a risk stratification tool for patients admitted with infection compared to traditional SIRS criteria or our triage system; the Rapid Emergency Triage and Treatment System (RETTS). The study was an observational cohort study performed at one Emergency Department (ED) in an urban university teaching hospital in Norway, with approximately 20,000 visits per year. All patients >16 years presenting with symptoms or clinical signs suggesting an infection (n = 1535) were prospectively included in the study from January 1 to December 31, 2012. At arrival in the ED, vital signs were recorded and all patients were triaged according to RETTS vital signs, presenting infection, and sepsis symptoms. These admission data were also used to calculate qSOFA and SIRS. Treatment outcome was later retrieved from the patients' electronic records (EPR) and mortality data from the Norwegian population registry. Of the 1535 admitted patients, 108 (7.0%) fulfilled the Sepsis2 criteria for severe sepsis. The qSOFA score ≥2 identified only 33 (sensitivity 0.32, specificity 0.98) of the patients with severe sepsis, whilst the RETTS-alert ≥ orange identified 92 patients (sensitivity 0.85, specificity 0.55). Twenty-six patients died within 7 days of admission; four (15.4%) of them had a qSOFA ≥2, and 16 (61.5%) had RETTS ≥ orange alert. Of the 68 patients that died within 30 days, only eight (11.9%) scored ≥2 on the qSOFA, and 45 (66.1%) had a RETTS ≥ orange alert. In order to achieve timely treatment for sepsis, a sensitive screening tool is more important than a specific one. Our study is the fourth study were qSOFA finds few of the sepsis cases in prehospital or at arrival to the ED. We add information on the RETTS triage system, the two highest acuity levels together had a high sensitivity (85%) for identifying sepsis at arrival to the ED - and thus, RETTS should not be replaced by qSOFA as a screening and

Immune cell phenotype and function in sepsis

PubMed Central

Rimmelé, Thomas; Payen, Didier; Cantaluppi, Vincenzo; Marshall, John; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A.

2015-01-01

Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis. The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of non extracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed. A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8 and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes and the cell function. PMID:26529661

IMMUNE CELL PHENOTYPE AND FUNCTION IN SEPSIS.

PubMed

Rimmelé, Thomas; Payen, Didier; Cantaluppi, Vincenzo; Marshall, John; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A

2016-03-01

Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis.The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed.A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.

Prognostic markers of pediatric meningococcal sepsis.

PubMed

Briassoulis, George; Galani, Angeliki

2014-09-01

Having available tools to determine the prognosis of pediatric meningococcal sepsis at admission to the Intensive Care Unit or during the course of the disease constitutes a clinical necessity. Recently, new readily measurable circulating biomarkers have been described as an additional tool for severity classification and prediction of mortality in meningococcal disease. These biomarkers have been associated with increased risk of mortality scores and a number of organ failures in heterogeneous samples of critically ill children. In future, genetic markers may be used for identification of high-risk patients by creating prediction rules for clinical course and sequelae, and potentially provide more insight in the complex immune response in meningococcal sepsis. We briefly summarize the data pointing at the emerging genome-wide expression profiling studies and review the prognostic value of the main markers investigated in pediatric meningococcal sepsis putting them in the current frame of sepsis in general.

Science review: Mechanisms of impaired adrenal function in sepsis and molecular actions of glucocorticoids

PubMed Central

Prigent, Hélène; Maxime, Virginie; Annane, Djillali

2004-01-01

This review describes current knowledge on the mechanisms that underlie glucocorticoid insufficiency in sepsis and the molecular action of glucocorticoids. In patients with severe sepsis, numerous factors predispose to glucocorticoid insufficiency, including drugs, coagulation disorders and inflammatory mediators. These factors may compromise the hypothalamic–pituitary axis (i.e. secondary adrenal insufficiency) or the adrenal glands (i.e. primary adrenal failure), or may impair glucocorticoid access to target cells (i.e. peripheral tissue resistance). Irreversible anatomical damages to the hypothalamus, pituitary, or adrenal glands rarely occur. Conversely, transient functional impairment in hormone synthesis may be a common complication of severe sepsis. Glucocorticoids interact with a specific cytosolic glucocorticoid receptor, which undergoes conformational changes, sheds heat shock proteins and translocates to the nucleus. Glucocorticoids may also interact with membrane binding sites at the surface of the cells. The molecular action of glucocorticoids results in genomic and nongenomic effects. Direct and indirect transcriptional and post-transcriptional effects related to the cytosolic glucocorticoid receptor account for the genomic effects. Nongenomic effects are probably subsequent to cytosolic interaction between the glucocorticoid receptor and proteins, or to interaction between glucocorticoids and specific membrane binding sites. PMID:15312206

Age-related differences in biomarkers of acute inflammation during hospitalization for sepsis.

PubMed

Ginde, Adit A; Blatchford, Patrick J; Trzeciak, Stephen; Hollander, Judd E; Birkhahn, Robert; Otero, Ronny; Osborn, Tiffany M; Moretti, Eugene; Nguyen, H Bryant; Gunnerson, Kyle J; Milzman, David; Gaieski, David F; Goyal, Munish; Cairns, Charles B; Rivers, Emanuel P; Shapiro, Nathan I

2014-08-01

The authors aimed to evaluate age-related differences in inflammation biomarkers during the first 72 h of hospitalization for sepsis. This was a secondary analysis of a prospective observational cohort of adult patients (n = 855) from 10 urban academic emergency departments with confirmed infection and two or more systemic inflammatory response syndrome criteria. Six inflammation-related biomarkers were analyzed-chemokine (CC-motif) ligand-23, C-reactive protein, interleukin-1 receptor antagonist, neutrophil gelatinase-associated lipocalin (NGAL), peptidoglycan recognition protein, and tumor necrosis factor receptor-1a (TNFR-1a)-measured at presentation and 3, 6, 12, 24, 48, or 72 h later. The median age was 56 (interquartile range, 43 - 72) years, and sepsis severity was 38% sepsis, 16% severe sepsis without shock, and 46% septic shock; the overall 30-day mortality was 12%. Older age was associated with higher sepsis severity: 41% of subjects aged 18 to 34 years had severe sepsis or septic shock compared with 71% for those aged 65 years or older (P < 0.001). In longitudinal models adjusting for demographics, comorbidities, and infection source, older age was associated with higher baseline values for chemokine (CC-motif) ligand-23, interleukin-1 receptor antagonist, NGAL, and TNFR-1a (all P < 0.05). However, older adults had higher mean values during the entire 72-h period only for NGAL and TNFR-1a and higher final 72-h values only for TNFR-1a. Adjustment or stratification by sepsis severity did not change the age-inflammation associations. Although older adults had higher levels of inflammation at presentation and an increased incidence of severe sepsis and septic shock, these age-related differences in inflammation largely resolved during the first 72 h of hospitalization.

[Potential lowering of sepsis-related mortality via screening and implementation of guidelines].

PubMed

van Zanten, Arthur R H; Arbous, M Sesmu; Brinkman, Sylvia

2014-01-01

The incidence of sepsis continues to increase. However, over the past decade marked reductions in sepsis-related in-hospital mortality have been reported. Large variations in the presentation and severity of illness may be encountered in ICU patients with severe sepsis, which might preclude the success of screening and guideline programmes. However, the authors of this article were able to prove that a national programme involving screening and a package of interventions did lower relative in-hospital mortality by 16.7% over 3.5 years in 52 participating hospitals in the Netherlands. In-hospital mortality did not change in 30 non-participating hospitals. Therefore, the authors recommend implementing updated guidelines, sepsis quality indicators and programmes with a package of interventions to further reduce sepsis mortality. Furthermore, additional research on long term consequences in sepsis survivors is warranted.

Association Between Muscle Wasting and Muscle Strength in Patients WHO Developed Severe Sepsis and Septic Shock.

PubMed

Borges, Rodrigo Cerqueira; Soriano, Francisco Garcia

2018-05-11

To evaluate the association between the rectus femoris cross-sectional area (RFCSA) and the muscular strength obtained at the bedside in patients forwarded to the intensive care unit (ICU) for severe sepsis and septic shock. A prospective cohort study. RFCSA was assessed by ultrasound on the following day of the ICU admission and monitored during hospitalization. The patients performed clinical tests of muscle strength (Medical Research Council (MRC) scale and handgrip dynamometry), when they could understand the verbal commands of the examiners. In 37 patients hospitalized for sepsis there was a significant decline in RFCSA of 5.18 (4.49-5.96)cm on the 2nd day of ICU for 4.37 (3.71-5.02)cm at hospital discharge. Differently, the handgrip strength showed an increase from the awakening of 12.00 (7.00-20.00)Kgf to 19.00 (14.00-26.00)Kgf until hospital discharge. Patients in mechanical ventilation had a greater tendency to decline in the RFCSA compared to patients who did not receive mechanical ventilation, however without being significant (p = 0.08). There was a negative association between RFCSA delta (2nd day of ICU - ICU discharge) and handgrip strength (r = 0.51, p < 0.05), and a male and SOFA score positive association with the RFCSA delta. There was an association of RFCSA with clinical muscle strength tests. In addition, it has been shown that sepsis can lead to short-term muscle degradation, regardless of whether they are submitted to mechanical ventilation or not.

Initial fractal exponent of heart-rate variability is associated with success of early resuscitation in patients with severe sepsis or septic shock: a prospective cohort study

PubMed Central

Brown, Samuel M.; Tate, Quinn; Jones, Jason P.; Knox, Daniel; Kuttler, Kathryn G.; Lanspa, Michael; Rondina, Matthew T.; Grissom, Colin K.; Behera, Subhasis; Mathews, V.J.; Morris, Alan

2013-01-01

Introduction Heart-rate variability reflects autonomic nervous system tone as well as the overall health of the baroreflex system. We hypothesized that loss of complexity in heart-rate variability upon ICU admission would be associated with unsuccessful early resuscitation of sepsis. Methods We prospectively enrolled patients admitted to ICUs with severe sepsis or septic shock from 2009 to 2011. We studied 30 minutes of EKG, sampled at 500 Hz, at ICU admission and calculated heart-rate complexity via detrended fluctuation analysis. Primary outcome was vasopressor independence at 24 hours after ICU admission. Secondary outcome was 28-day mortality. Results We studied 48 patients, of whom 60% were vasopressor independent at 24 hours. Five (10%) died within 28 days. The ratio of fractal alpha parameters was associated with both vasopressor independence and 28-day mortality (p=0.04) after controlling for mean heart rate. In the optimal model, SOFA score and the long-term fractal alpha parameter were associated with vasopressor independence. Conclusions Loss of complexity in heart rate variability is associated with worse outcome early in severe sepsis and septic shock. Further work should evaluate whether complexity of heart rate variability (HRV) could guide treatment in sepsis. PMID:23958243

Surviving sepsis: a trust-wide approach. A multi-disciplinary team approach to implementing evidence-based guidelines.

PubMed

Gerber, Karin

2010-01-01

To share an experience of examining the true extent of the number of patients with severe sepsis being admitted, and the overall compliance with existing treatment guidelines in a district general hospital (DGH). Because of its aggressive, multi-factorial nature, sepsis is a rapid killer. Mortality associated with severe sepsis remains unacceptably high: 30-50%. When shock is present, mortality is reported to be even higher: 50-60%. The rapid diagnosis and management of sepsis is vital to successful treatment. The International Surviving Sepsis Campaign (SSC) was developed to help meet the challenges of sepsis and to improve its management, diagnosis and treatment. The overall aim is to reduce mortality from sepsis by 25% by 2009. Data on the number of patients admitted with severe sepsis to the DGH were previously unknown. The aim of the baseline audits was to determine the true extent of the problem and baseline mortality rates, resulting in an action plan to provide evidence-based care to patients with sepsis regardless of where in the hospital they were located. It was found that 11% of the patients audited presented with signs of severe sepsis and demonstrated elements of poor compliance with some elements of existing treatment guidelines as set out by the resuscitation component of the Surviving Sepsis Care Bundle. As an international campaign introduced predominantly within critical care, within this DGH the SSC teams' innovative approach has resulted in: * Better educated staff; * Objectives agreed within multi-disciplinary teams; * The appropriate assessment of resources; * Standardization of practice in terms of patients presenting with severe sepsis.

Circulating Angiopopietin-1 Correlates With the Clinical Course of Multiple Organ Dysfunction Syndrome and Mortality in Patients With Severe Sepsis

PubMed Central

Lin, Shu-Min; Chung, Fu-Tsai; Kuo, Chih-Hsi; Chou, Pai-Chien; Wang, Tsai-Yu; Chang, Po-Jui; Lo, Yu-Lun; Huang, Chien-Da; Lin, Horng-Chyuan; Wang, Chun-Hua; Kuo, Han-Pin

2015-01-01

Abstract To determine plasma concentrations of angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in patients with sepsis-induced multiple organ dysfunction syndrome (MODS) and determine their association with mortality. The study prospectively recruited 96 consecutive patients with severe sepsis in a l intensive care unit of a tertiary hospital. Plasma Ang-1, Ang-2, Tie-2, and VEGF levels and MODS were determined in patients on days 1, 3, and 7 of sepsis. Univariate and Cox proportional hazards analysis were performed to develop a prognostic model. Days 1, 3, and 7 plasma Ang-1 concentrations were persistently decreased in MODS patients than in non-MODS patients (day1: 4.0 ± 0.5 vs 8.0 ± 0.5 ng/mL, P < 0.0001; day 3, 3.2 ± 0.6 vs 7.3 ± 0.5 ng/mL, P < 0.0001, day 7, 2.8 ± 0.6 vs 10.4 ± 0.7 ng/mL, P < 0.0001). In patients with resolved MODS on day 7 of sepsis, Ang-1 levels were increased from day 1 (4.7 ± 0.6 ng/mL vs 9.1 ± 1.4 ng/mL, n = 43, P = 0.004). Plasma Ang-1 levels were lower in nonsurvivors than in survivors on days 1 (4.0 ± 0.5 vs 7.1 ± 0.5 ng/mL, P < 0.0001), 3 (3.8 ± 0.6 vs 7.1 ± 0.5 ng/mL, P < 0.0001), and 7 (4.7 ± 0.7 vs 11.0 ± 0.8 ng/mL, P < 0.0001) of severe sepsis. In contrast, plasma Ang-2 levels were higher in nonsurvivors than in survivors only on day 1 (15.8 ± 2.0 vs 9.5 ± 1.2 ng/mL, P = 0.035). VEGF and Tie-2 levels were not associated with MODS and mortality. Ang-1 level less than the median value was the only independent predictor of mortality (hazard ratio, 2.57; 95% CI 1.12–5.90, P = 0.025). Persistently decreased Ang-1 levels are associated with MODS and subsequently, mortality in patients with sepsis. PMID:25997069

Characteristics of a Pseudomonas aeruginosa induced porcine sepsis model for multi-organ metabolic flux measurements.

PubMed

Ten Have, Gabriella A M; Deutz, Renske C I; Engelen, Mariëlle P K J; Wolfe, Robert R; Deutz, Nicolaas E P

2018-04-01

Survival of sepsis is related to loss of muscle mass. Therefore, it is imperative to further define and understand the basic alterations in nutrient metabolism in order to improve targeted sepsis nutritional therapies. We developed and evaluated a controlled hyperdynamic severe sepsis pig model that can be used for in vivo multi-organ metabolic studies in a conscious state. In this catheterized pig model, bacteremia was induced intravenously with 10 9 CFU/h Pseudomonas aeruginosa (PA) in 13 pigs for 18 h. Both the PA and control (nine) animals received fluid resuscitation and were continuously monitored. We examined in detail their hemodynamics, blood gases, clinical chemistry, inflammation, histopathology and organ plasma flows. The systemic inflammatory response (SIRS) diagnostic scoring system was used to determine the clinical septic state. Within 6 h from the start of PA infusion, a septic state developed, as was reflected by hyperthermia and cardiovascular changes. After 12 h of PA infusion, severe sepsis was diagnosed. Disturbed cardiovascular function, decreased portal drained viscera plasma flow (control: 37.6 ± 4.6 mL/kg body weight (bw)/min; PA 20.3 ± 2.6 mL/kg bw/min, P < 0.001), as well as moderate villous injury in the small intestines were observed. No lung, kidney or liver failure was observed. Acute phase C-reactive protein (CRP) and interleukin-6 (IL-6) levels did not change in the PA group. However, significant metabolic changes such as enhanced protein breakdown, hypocalcemia and hypocholesterolemia were found. In conclusion, PA-induced bacteremia in a catheterized pig is a clinically relevant model for acute severe sepsis and enables the study of complex multi-organ metabolisms.

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

PubMed Central

Csóka, Balázs; Németh, Zoltán H.; Szabó, Ildikó; Davies, Daryl L.; Varga, Zoltán V.; Pálóczi, János; Falzoni, Simonetta; Di Virgilio, Francesco; Muramatsu, Rieko; Pacher, Pál

2018-01-01

The macrophage is a major phagocytic cell type, and its impaired function is a primary cause of immune paralysis, organ injury, and death in sepsis. An incomplete understanding of the endogenous molecules that regulate macrophage bactericidal activity is a major barrier for developing effective therapies for sepsis. Using an in vitro killing assay, we report here that the endogenous purine ATP augments the killing of sepsis-causing bacteria by macrophages through P2X4 receptors (P2X4Rs). Using newly developed transgenic mice expressing a bioluminescent ATP probe on the cell surface, we found that extracellular ATP levels increase during sepsis, indicating that ATP may contribute to bacterial killing in vivo. Studies with P2X4R-deficient mice subjected to sepsis confirm the role of extracellular ATP acting on P2X4Rs in killing bacteria and protecting against organ injury and death. Results with adoptive transfer of macrophages, myeloid-specific P2X4R-deficient mice, and P2rx4 tdTomato reporter mice indicate that macrophages are essential for the antibacterial, antiinflammatory, and organ protective effects of P2X4Rs in sepsis. Pharmacological targeting of P2X4Rs with the allosteric activator ivermectin protects against bacterial dissemination and mortality in sepsis. We propose that P2X4Rs represent a promising target for drug development to control bacterial growth in sepsis and other infections. PMID:29875325

Hypoalbuminemia, Low Base Excess Values, and Tachypnea Predict 28-Day Mortality in Severe Sepsis and Septic Shock Patients in the Emergency Department.

PubMed

Seo, Min Ho; Choa, Minhong; You, Je Sung; Lee, Hye Sun; Hong, Jung Hwa; Park, Yoo Seok; Chung, Sung Phil; Park, Incheol

2016-11-01

The objective of this study was to develop a new nomogram that can predict 28-day mortality in severe sepsis and/or septic shock patients using a combination of several biomarkers that are inexpensive and readily available in most emergency departments, with and without scoring systems. We enrolled 561 patients who were admitted to an emergency department (ED) and received early goal-directed therapy for severe sepsis or septic shock. We collected demographic data, initial vital signs, and laboratory data sampled at the time of ED admission. Patients were randomly assigned to a training set or validation set. For the training set, we generated models using independent variables associated with 28-day mortality by multivariate analysis, and developed a new nomogram for the prediction of 28-day mortality. Thereafter, the diagnostic accuracy of the nomogram was tested using the validation set. The prediction model that included albumin, base excess, and respiratory rate demonstrated the largest area under the receiver operating characteristic curve (AUC) value of 0.8173 [95% confidence interval (CI), 0.7605-0.8741]. The logistic analysis revealed that a conventional scoring system was not associated with 28-day mortality. In the validation set, the discrimination of a newly developed nomogram was also good, with an AUC value of 0.7537 (95% CI, 0.6563-0.8512). Our new nomogram is valuable in predicting the 28-day mortality of patients with severe sepsis and/or septic shock in the emergency department. Moreover, our readily available nomogram is superior to conventional scoring systems in predicting mortality.

Objective Sepsis Surveillance Using Electronic Clinical Data

PubMed Central

Rhee, Chanu; Kadri, Sameer; Huang, Susan S.; Murphy, Michael V.; Li, Lingling; Platt, Richard; Klompas, Michael

2016-01-01

OBJECTIVE To compare the accuracy of surveillance of severe sepsis using electronic health record clinical data vs claims and to compare incidence and mortality trends using both methods. DESIGN We created an electronic health record–based surveillance definition for severe sepsis using clinical indicators of infection (blood culture and antibiotic orders) and concurrent organ dysfunction (vasopressors, mechanical ventilation, and/or abnormal laboratory values). We reviewed 1,000 randomly selected medical charts to characterize the definition’s accuracy and stability over time compared with a claims-based definition requiring infection and organ dysfunction codes. We compared incidence and mortality trends from 2003–2012 using both methods. SETTING Two US academic hospitals. PATIENTS Adult inpatients. RESULTS The electronic health record–based clinical surveillance definition had stable and high sensitivity over time (77% in 2003–2009 vs 80% in 2012, P=.58) whereas the sensitivity of claims increased (52% in 2003–2009 vs 67% in 2012, P=.02). Positive predictive values for claims and clinical surveillance definitions were comparable (55% vs 53%, P=.65) and stable over time. From 2003 to 2012, severe sepsis incidence imputed from claims rose by 72% (95% CI, 57%–88%) and absolute mortality declined by 5.4% (95% CI, 4.6%–6.7%). In contrast, incidence using the clinical surveillance definition increased by 7.7% (95% CI, −1.1% to 17%) and mortality declined by 1.7% (95% CI, 1.1%–2.3%). CONCLUSIONS Sepsis surveillance using clinical data is more sensitive and more stable over time compared with claims and can be done electronically. This may enable more reliable estimates of sepsis burden and trends. PMID:26526737

Severe sepsis facilitates intestinal colonization by extended-spectrum-β-lactamase-producing Klebsiella pneumoniae and transfer of the SHV-18 resistance gene to Escherichia coli during antimicrobial treatment.

PubMed

Guan, Jun; Liu, Shaoze; Lin, Zhaofen; Li, Wenfang; Liu, Xuefeng; Chen, Dechang

2014-01-01

Infections caused by multidrug-resistant pathogens are frequent and life threatening in critically ill patients. To investigate whether severe sepsis affects gut colonization by resistant pathogens and genetic exchange between opportunistic pathogens, we tested the intestinal-colonization ability of an extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strain carrying the SHV-18 resistance gene and the transfer ability of the resistance gene to endogenous Escherichia coli under ceftriaxone treatment in rats with burn injury only or severe sepsis induced by burns plus endotoxin exposure. Without ceftriaxone treatment, the K. pneumoniae strain colonized the intestine in both septic and burned rats for a short time, with clearance occurring earlier in burn-only rats but never in sham burn rats. In both burned and septic rats, the colonization level of the challenge strain dropped at the beginning and then later increased during ceftriaxone treatment, after which it declined gradually. This pattern coincided with the change in resistance of K. pneumoniae to ceftriaxone during and after ceftriaxone treatment. Compared with burn-only injury, severe sepsis had a more significant effect on the change in antimicrobial resistance to ceftriaxone. Only in septic rats was the resistance gene successfully transferred from the challenge strain to endogenous E. coli during ceftriaxone treatment; the gene persisted for at least 4 weeks after ceftriaxone treatment. We concluded that severe sepsis can facilitate intestinal colonization by an exogenous resistant pathogen and the transfer of the resistance gene to a potential endogenous pathogen during antimicrobial treatment.

The impact of a multifaceted intervention including sepsis electronic alert system and sepsis response team on the outcomes of patients with sepsis and septic shock.

PubMed

Arabi, Yaseen M; Al-Dorzi, Hasan M; Alamry, Ahmed; Hijazi, Ra'ed; Alsolamy, Sami; Al Salamah, Majid; Tamim, Hani M; Al-Qahtani, Saad; Al-Dawood, Abdulaziz; Marini, Abdellatif M; Al Ehnidi, Fatimah H; Mundekkadan, Shihab; Matroud, Amal; Mohamed, Mohamed S; Taher, Saadi

2017-12-01

Compliance with the clinical practice guidelines of sepsis management has been low. The objective of our study was to describe the results of implementing a multifaceted intervention including an electronic alert (e-alert) with a sepsis response team (SRT) on the outcome of patients with sepsis and septic shock presenting to the emergency department. This was a pre-post two-phased implementation study that consisted of a pre-intervention phase (January 01, 2011-September 24, 2012), intervention phase I (multifaceted intervention including e-alert, from September 25, 2012-March 03, 2013) and intervention phase II when SRT was added (March 04, 2013-October 30, 2013) in a 900-bed tertiary-care academic hospital. We recorded baseline characteristics and processes of care in adult patients presenting with sepsis or septic shock. The primary outcome measures were hospital mortality. Secondary outcomes were the need for mechanical ventilation and length of stay in the intensive unit and in the hospital. After implementing the multifaceted intervention including e-alert and SRT, cases were identified with less severe clinical and laboratory abnormalities and the processes of care improved. When adjusted to propensity score, the interventions were associated with reduction in hospital mortality [for intervention phase II compared to pre-intervention: adjusted odds ratio (aOR) 0.71, 95% CI 0.58-0.85, p = 0.003], reduction in the need for mechanical ventilation (aOR 0.45, 95% CI 0.37-0.55, p < 0.0001) and reduction in ICU LOS and hospital LOS for all patients as well as ICU LOS for survivors. Implementing a multifaceted intervention including sepsis e-alert with SRT was associated with earlier identification of sepsis, increase in compliance with sepsis resuscitation bundle and reduction in the need for mechanical ventilation and reduction in hospital mortality and LOS.

Comparison of Two Sepsis Recognition Methods in a Pediatric Emergency Department

PubMed Central

Balamuth, Fran; Alpern, Elizabeth R.; Grundmeier, Robert W.; Chilutti, Marianne; Weiss, Scott L.; Fitzgerald, Julie C.; Hayes, Katie; Bilker, Warren; Lautenbach, Ebbing

2015-01-01

Objectives To compare the effectiveness of physician judgment and an electronic algorithmic alert to identify pediatric patients with severe sepsis/septic shock in a pediatric emergency department (ED). Methods This was an observational cohort study of patients older than 56 days with fever or hypothermia. All patients were evaluated for potential sepsis in real time by the ED clinical team. An electronic algorithmic alert was retrospectively applied to identify patients with potential sepsis independent of physician judgment. The primary outcome was the proportion of patients correctly identified with severe sepsis/septic shock defined by consensus criteria. Test characteristics were determined and receiver operating characteristic (ROC) curves were compared. Results Of 19,524 eligible patient visits, 88 patients developed consensus-confirmed severe sepsis or septic shock. Physician judgment identified 159, and the algorithmic alert identified 3,301 patients with potential sepsis. Physician judgment had sensitivity of 72.7% (95% CI = 72.1% to 73.4%) and specificity 99.5% (95% CI = 99.4% to 99.6%); the algorithmic alert had sensitivity 92.1% (95% CI = 91.7% to 92.4%), and specificity 83.4% (95% CI = 82.9% to 83.9%) for severe sepsis/septic shock. There was no significant difference in the area under the ROC curve for physician judgment (0.86, 95% CI = 0.81 to 0.91) or the algorithm (0.88, 95% CI = 0.85 to 0.91; p = 0.54). A combination method using either positive physician judgment or an algorithmic alert improved sensitivity to 96.6% and specificity to 83.3%. A sequential approach, in which positive identification by the algorithmic alert was then confirmed by physician judgment, achieved 68.2% sensitivity and 99.6% specificity. Positive and negative predictive values for physician judgment vs. algorithmic alert were 40.3% vs. 2.5% and 99.88 % vs. 99.96%, respectively. Conclusions The electronic algorithmic alert was more sensitive but less specific than

Comparison of Two Sepsis Recognition Methods in a Pediatric Emergency Department.

PubMed

Balamuth, Fran; Alpern, Elizabeth R; Grundmeier, Robert W; Chilutti, Marianne; Weiss, Scott L; Fitzgerald, Julie C; Hayes, Katie; Bilker, Warren; Lautenbach, Ebbing

2015-11-01

The objective was to compare the effectiveness of physician judgment and an electronic algorithmic alert to identify pediatric patients with severe sepsis/septic shock in a pediatric emergency department (ED). This was an observational cohort study of patients older than 56 days with fever or hypothermia. All patients were evaluated for potential sepsis in real time by the ED clinical team. An electronic algorithmic alert was retrospectively applied to identify patients with potential sepsis independent of physician judgment. The primary outcome was the proportion of patients correctly identified with severe sepsis/septic shock defined by consensus criteria. Test characteristics were determined and receiver operating characteristic (ROC) curves were compared. Of 19,524 eligible patient visits, 88 patients developed consensus-confirmed severe sepsis or septic shock. Physician judgment identified 159 and the algorithmic alert identified 3,301 patients with potential sepsis. Physician judgment had sensitivity of 72.7% (95% confidence interval [CI] = 72.1% to 73.4%) and specificity of 99.5% (95% CI = 99.4% to 99.6%); the algorithmic alert had sensitivity of 92.1% (95% CI = 91.7% to 92.4%) and specificity of 83.4% (95% CI = 82.9% to 83.9%) for severe sepsis/septic shock. There was no significant difference in the area under the ROC curve for physician judgment (0.86, 95% CI = 0.81 to 0.91) or the algorithm (0.88, 95% CI = 0.85 to 0.91; p = 0.54). A combination method using either positive physician judgment or an algorithmic alert improved sensitivity to 96.6% and specificity to 83.3%. A sequential approach, in which positive identification by the algorithmic alert was then confirmed by physician judgment, achieved 68.2% sensitivity and 99.6% specificity. Positive and negative predictive values for physician judgment versus algorithmic alert were 40.3% versus 2.5% and 99.88% versus 99.96%, respectively. The electronic algorithmic alert was more sensitive but less

Pulmonary vs Nonpulmonary Sepsis and Mortality in Acute Lung Injury

PubMed Central

Sevransky, Jonathan E.; Martin, Greg S.; Mendez-Tellez, Pedro; Shanholtz, Carl; Brower, Roy; Pronovost, Peter J.; Needham, Dale M.

2010-01-01

Background Acute lung injury (ALI) is a frequent complication of sepsis. It is unclear if a pulmonary vs nonpulmonary source of sepsis affects mortality in patients with sepsis-induced ALI. Methods Two hundred eighty-eight consecutive patients with sepsis-induced ALI from 14 ICUs at four hospitals in Baltimore,MDwere prospectively classified as having a pulmonary vs nonpulmonary source of sepsis. Multiple logistic regression was conducted to evaluate the independent association of a pulmonary vs nonpulmonary source of sepsis with inpatient mortality. Results In an unadjusted analysis, in-hospital mortality was lower for pulmonary vs nonpulmonary source of sepsis (42% vs 66%, p < 0.0001). Patients with pulmonary sepsis had lower acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores, shorter ICU stays prior to the development of ALI, and higher lung injury scores. In the adjusted analysis, several factors were predictive of mortality: age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01 to 1.06), Charlson comorbidity index (OR, 1.15; 95% CI, 1.02 to 1.30), ICU length of stay prior to ALI diagnosis (OR, 1.19; 95% CI, 1.01 to 1.39), APACHE II score (OR, 1.07; 95% CI, 1.03 to 1.12), lung injury score (OR, 1.64; 95% CI, 1.11 to 2.43), SOFA score (OR, 1.15; 95% CI, 1.06 to 1.26), and cumulative fluid balance in the first 7 days after ALI diagnosis (OR, 1.06; 95% CI, 1.03 to 1.10). A pulmonary vs nonpulmonary source of sepsis was not independently associated with mortality (OR, 0.72; 95% CI, 0.38 to 1.35). Conclusions Although lower mortality was observed for ALI patients with a pulmonary vs nonpulmonary source of sepsis, this finding is likely due to a lower severity of illness in those with pulmonary sepsis. Pulmonary vs nonpulmonary source of sepsis was not independently predictive of mortality for patients with ALI. PMID:18641112

Intranuclear interactomic inhibition of NF-κB suppresses LPS-induced severe sepsis

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

Park, Sung-Dong; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749; Cheon, So Yeong

Suppression of nuclear factor-κB (NF-κB) activation, which is best known as a major regulator of innate and adaptive immune responses, is a potent strategy for the treatment of endotoxic sepsis. To inhibit NF-κB functions, we designed the intra-nuclear transducible form of transcription modulation domain (TMD) of RelA (p65), called nt-p65-TMD, which can be delivered effectively into the nucleus without influencing the cell viability, and work as interactomic inhibitors via disruption of the endogenous p65-mediated transcription complex. nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines, including TNF-α, IL-1β, or IL-6 from BV2 microglia cells stimulated by lipopolysaccharide (LPS). nt-p65-TMD did notmore » inhibit tyrosine phosphorylation of signaling mediators such as ZAP-70, p38, JNK, or ERK involved in T cell activation, but was capable of suppressing the transcriptional activity of NF-κB without the functional effect on that of NFAT upon T-cell receptor (TCR) stimulation. The transduced nt-p65-TMD in T cell did not affect the expression of CD69, however significantly inhibited the secretion of T cell-specific cytokines such as IL-2, IFN-γ, IL-4, IL-17A, or IL-10. Systemic administration of nt-p65-TMD showed a significant therapeutic effect on LPS-induced sepsis model by inhibiting pro-inflammatory cytokines secretion. Therefore, nt-p65-TMD can be a novel therapeutics for the treatment of various inflammatory diseases, including sepsis, where a transcription factor has a key role in pathogenesis, and further allows us to discover new functions of p65 under normal physiological condition without genetic alteration. - Highlights: • The nt-p65-TMD is intra-nuclear interactomic inhibitor of endogenous p65. • The nt-p65-TMD effectively inhibited the secretion of pro-inflammatory cytokines. • The excellent therapeutic potential of nt-p65-TMD was confirmed in sepsis model.« less

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

PubMed Central

Hotchkiss, Richard S.; Monneret, Guillaume; Payen, Didier

2014-01-01

Sepsis — severe life-threatening infection with organ dysfunction — initiates a complex interplay of host pro- and anti-inflammatory processes. In a real sense, sepsis can be considered a race to the death between the pathogens and the host immune system. It is the proper balance between the often competing pro- and anti-inflammatory pathways that determines the fate of the individual. Although the field of sepsis research has witnessed the failure of many highly-touted clinical trials, a better understanding of the pathophysiological basis of the disorder and the mechanisms responsible for the associated pro- and anti-inflammatory responses is leading to a novel approach to treat this highly lethal condition. Biomarker-guided immunotherapy administered to patients at the proper immune phase of sepsis represents a potential major advance in the treatment of sepsis and more broadly in the field of infectious disease. PMID:24232462

Clinical Epidemiology of SIRS and Sepsis in Newly Admitted Children.

PubMed

Ganjoo, Sheetal; Ahmad, Kaisar; Qureshi, Umar Amin; Mir, Zahed Hussain

2015-08-01

To assess the clinical and demographic profile of Systemic Inflammatory Response Syndrome (SIRS) and sepsis, among newly admitted children in different age groups in a hospital in North India. This prospective study was conducted at a referral care centre in Northern India. All children, age group 0 to <18 y, admitted on days selected for study were screened and those with abnormal temperature and abnormal leukocyte count were included for further assessment. A total of twenty "24 h" periods were randomly chosen during the study period. Patients were assessed according to age specific vital signs and laboratory values to diagnose Systemic Inflammatory Response Syndrome (SIRS) and sepsis and to gain clinical and demographic data. The criteria laid at International consensus conference, 2002, were used to define patients as SIRS, Sepsis, Severe sepsis and Septic shock. During the study period, a total of 865 patients were screened for SIRS. Prevalence of SIRS amongst hospitalised children was 23 % (n = 201). Seventy nine percent (n = 159) of patients had infection associated SIRS and 21 % (42) had non-infective SIRS. Sixty four percent (n = 129) SIRS patients had uncomplicated sepsis, 15 % (n = 30) patients fulfilled criteria for severe sepsis. Out of the latter 30, 19 had septic shock. Organ dysfunction in SIRS was noted in 25 % (n = 51). 37.25 % (n = 19) had multiple organ dysfunction syndrome (MODS). The most common organism isolated was Staphylococcus aureus (n = 9). Focus of infection in majority was pulmonary (44 %). Mean duration of antibiotic therapy and hospital stay in the SIRS group were 6.4 and 6.5 d respectively. In the group without SIRS, mean duration were 2.44 d and 3.07 d respectively The differences were statistically significant. In conclusion, the proportion of sepsis contributing to SIRS is high in a tertiary care hospital. Therefore rapid recognition of SIRS is essential. Goal directed treatment of sepsis is

Protein C: a potential biomarker in severe sepsis and a possible tool for monitoring treatment with drotrecogin alfa (activated)

PubMed Central

Shorr, Andrew F; Nelson, David R; Wyncoll, Duncan LA; Reinhart, Konrad; Brunkhorst, Frank; Vail, George Matthew; Janes, Jonathan

2008-01-01

Introduction Drotrecogin alfa (activated; DrotAA) treatment, a 96-hour infusion, reduces 28-day mortality in severe sepsis to approximately 25%. The question remains whether a longer infusion or higher dose could increase rate of survival. The goal of this study was to identify a dependable, sensitive measure with which to monitor disease progression and response in patients during DrotAA treatment. Methods Data on severe sepsis patients included in PROWESS (placebo-controlled, double-blind, randomized study of 850 DrotAA and 840 placebo individuals) and ENHANCE (single-arm, open-label study of 2,375 DrotAA patients) studies were analyzed. In these studies, DrotAA (24 μg/kg per hour) or placebo was infused for 96 hours and patients were followed for 28 days. Data on six laboratory measures and five organ dysfunctions were systematically analyzed to identify a potential surrogate end-point for monitoring DrotAA therapy and predicting 28-day mortality at the end of therapy. To allow comparison across variables, sensitivity and specificity analyses identified cut-off values for preferred outcome, and relative risks for being above or below cut-offs were calculated, as was the 'proportion of treatment effect explained' (PTEE) to identify biomarkers that contribute to benefit from DrotAA. Results Protein C was the only variable that correlated with outcome across all analyses. Using placebo data, a baseline protein C under 40% was established as a useful predictor of outcome (odds ratio 2.12). Similar odds ratios were associated with cut-off values of other biomarkers, but the treatment benefit associated with DrotAA was significantly greater below the cut-off than above the cut-off only for protein C (relative risk for 28-day mortality 0.66 versus 0.88; P = 0.04). Protein C was the only end-of-infusion biomarker that potentially explained at least 50% of the benefit from DrotAA (PTEE 57.2%). The PTEE was 41% for cardiovascular Sequential Organ Failure Assessment score

Epidemiology and Changes in Mortality of Sepsis After the Implementation of Surviving Sepsis Campaign Guidelines.

PubMed

Herrán-Monge, Rubén; Muriel-Bombín, Arturo; García-García, Marta M; Merino-García, Pedro A; Martínez-Barrios, Miguel; Andaluz, David; Ballesteros, Juan Carlos; Domínguez-Berrot, Ana María; Moradillo-Gonzalez, Susana; Macías, Santiago; Álvarez-Martínez, Braulio; Fernández-Calavia, M José; Tarancón, Concepción; Villar, Jesús; Blanco, Jesús

2017-01-01

To determine the epidemiology and outcome of severe sepsis and septic shock after 9 years of the implementation of the Surviving Sepsis Campaign (SSC) and to build a mortality prediction model. This is a prospective, multicenter, observational study performed during a 5-month period in 2011 in a network of 11 intensive care units (ICUs). We compared our findings with those obtained in the same ICUs in a study conducted in 2002. The current cohort included 262 episodes of severe sepsis and/or septic shock, and the 2002 cohort included 324. The prevalence was 14% (95% confidence interval: 12.5-15.7) with no differences to 2002. The population-based incidence was 31 cases/100 000 inhabitants/year. Patients in 2011 had a significantly lower Acute Physiology and Chronic Health Evaluation II (APACHE II; 21.9 ± 6.6 vs 25.5 ± 7.07), Logistic Organ Dysfunction Score (5.6 ± 3.2 vs 6.3 ± 3.6), and Sequential Organ Failure Assessment (SOFA) scores on day 1 (8 ± 3.5 vs 9.6 ± 3.7; P < .01). The main source of infection was intraabdominal (32.5%) although microbiologic isolation was possible in 56.7% of cases. The 2011 cohort had a marked reduction in 48-hour (7% vs 14.8%), ICU (27.2% vs 48.2%), and in-hospital (36.7% vs 54.3%) mortalities. Most relevant factors associated with death were APACHE II score, age, previous immunosuppression and liver insufficiency, alcoholism, nosocomial infection, and Delta SOFA score. Although the incidence of sepsis/septic shock remained unchanged during a 10-year period, the implementation of the SSC guidelines resulted in a marked decrease in the overall mortality. The lower severity of patients on ICU admission and the reduced early mortality suggest an improvement in early diagnosis, better initial management, and earlier antibiotic treatment.

[Clinical study on sepsis in 2 pediatric intensive care units in Beijing].

PubMed

2012-03-01

To investigate the incidence, mortality, causes and risk factors of sepsis in children in pediatric intensive care units (PICU) in Beijing through large sample prospective clinical research. From 1st November 2008 to 31st December 2009, all patients aged from 29 days to 18 years admitted to PICU of the two children's hospitals in Beijing were surveyed. Patients who met the conditions of Chinese pediatric critical illness score (PCIS) < 90 or American guidelines for PICU admission were defined as critically ill cases. According to the definitions of sepsis of 2005 international pediatric sepsis consensus conference and 2006 Chinese Medical Association meeting, sepsis, sever sepsis, and septic shock cases were selected from these critically ill patients. The qualified subjects were surveyed by questionnaire until discharge or death the data were analyzed by SPSS. A total of 1531 of PICU admissions were enrolled within a 14-month period, of whom 1250 met the criteria of critically ill case; 486 developed sepsis, of whom 55 died. The morbidity of sepsis for all in critically ill patients in PICU was 38.9% (486/1250) and the mortality was 11.3% (55/486). The morbidity of sepsis, severe sepsis and septic shock in these PICU was 25.5% (319/1250), 10.3% (129/1250), 3.0% (38/1250) and the mortality was 2.2% (7/319), 23.3% (30/129), and 47.4% (18/38), respectively. The proportion of less than 3 years old was 75.5% (367/486). Respiratory system diseases (71.8%), such as pneumonia (63.6%), were the underlying primary infectious diseases of sepsis. Bacterial etiology accounted for 64.1% of the cases with sepsis with definite etiological test results. The proportion of gram-positive bacteria and gram-negative bacteria were 46.1% and 53.9%, respectively. PCIS and disease severity were negatively correlated (r = -0.583, P < 0.01). Multiple stepwise logistic regression analysis showed that depressed PCIS and use of mechanical ventilation were the risk factors for death. Average

The Timing of Early Antibiotics and Hospital Mortality in Sepsis.

PubMed

Liu, Vincent X; Fielding-Singh, Vikram; Greene, John D; Baker, Jennifer M; Iwashyna, Theodore J; Bhattacharya, Jay; Escobar, Gabriel J

2017-10-01

Prior sepsis studies evaluating antibiotic timing have shown mixed results. To evaluate the association between antibiotic timing and mortality among patients with sepsis receiving antibiotics within 6 hours of emergency department registration. Retrospective study of 35,000 randomly selected inpatients with sepsis treated at 21 emergency departments between 2010 and 2013 in Northern California. The primary exposure was antibiotics given within 6 hours of emergency department registration. The primary outcome was adjusted in-hospital mortality. We used detailed physiologic data to quantify severity of illness within 1 hour of registration and logistic regression to estimate the odds of hospital mortality based on antibiotic timing and patient factors. The median time to antibiotic administration was 2.1 hours (interquartile range, 1.4-3.1 h). The adjusted odds ratio for hospital mortality based on each hour of delay in antibiotics after registration was 1.09 (95% confidence interval [CI], 1.05-1.13) for each elapsed hour between registration and antibiotic administration. The increase in absolute mortality associated with an hour's delay in antibiotic administration was 0.3% (95% CI, 0.01-0.6%; P = 0.04) for sepsis, 0.4% (95% CI, 0.1-0.8%; P = 0.02) for severe sepsis, and 1.8% (95% CI, 0.8-3.0%; P = 0.001) for shock. In a large, contemporary, and multicenter sample of patients with sepsis in the emergency department, hourly delays in antibiotic administration were associated with increased odds of hospital mortality even among patients who received antibiotics within 6 hours. The odds increased within each sepsis severity strata, and the increased odds of mortality were greatest in septic shock.

A risk-model for hospital mortality among patients with severe sepsis or septic shock based on German national administrative claims data

PubMed Central

Fleischmann-Struzek, Carolin; Rüddel, Hendrik; Reinhart, Konrad; Thomas-Rüddel, Daniel O.

2018-01-01

Background Sepsis is a major cause of preventable deaths in hospitals. Feasible and valid methods for comparing quality of sepsis care between hospitals are needed. The aim of this study was to develop a risk-adjustment model suitable for comparing sepsis-related mortality between German hospitals. Methods We developed a risk-model using national German claims data. Since these data are available with a time-lag of 1.5 years only, the stability of the model across time was investigated. The model was derived from inpatient cases with severe sepsis or septic shock treated in 2013 using logistic regression with backward selection and generalized estimating equations to correct for clustering. It was validated among cases treated in 2015. Finally, the model development was repeated in 2015. To investigate secular changes, the risk-adjusted trajectory of mortality across the years 2010–2015 was analyzed. Results The 2013 deviation sample consisted of 113,750 cases; the 2015 validation sample consisted of 134,851 cases. The model developed in 2013 showed good validity regarding discrimination (AUC = 0.74), calibration (observed mortality in 1st and 10th risk-decile: 11%-78%), and fit (R2 = 0.16). Validity remained stable when the model was applied to 2015 (AUC = 0.74, 1st and 10th risk-decile: 10%-77%, R2 = 0.17). There was no indication of overfitting of the model. The final model developed in year 2015 contained 40 risk-factors. Between 2010 and 2015 hospital mortality in sepsis decreased from 48% to 42%. Adjusted for risk-factors the trajectory of decrease was still significant. Conclusions The risk-model shows good predictive validity and stability across time. The model is suitable to be used as an external algorithm for comparing risk-adjusted sepsis mortality among German hospitals or regions based on administrative claims data, but secular changes need to be taken into account when interpreting risk-adjusted mortality. PMID:29558486

A risk-model for hospital mortality among patients with severe sepsis or septic shock based on German national administrative claims data.

PubMed

Schwarzkopf, Daniel; Fleischmann-Struzek, Carolin; Rüddel, Hendrik; Reinhart, Konrad; Thomas-Rüddel, Daniel O

2018-01-01

Sepsis is a major cause of preventable deaths in hospitals. Feasible and valid methods for comparing quality of sepsis care between hospitals are needed. The aim of this study was to develop a risk-adjustment model suitable for comparing sepsis-related mortality between German hospitals. We developed a risk-model using national German claims data. Since these data are available with a time-lag of 1.5 years only, the stability of the model across time was investigated. The model was derived from inpatient cases with severe sepsis or septic shock treated in 2013 using logistic regression with backward selection and generalized estimating equations to correct for clustering. It was validated among cases treated in 2015. Finally, the model development was repeated in 2015. To investigate secular changes, the risk-adjusted trajectory of mortality across the years 2010-2015 was analyzed. The 2013 deviation sample consisted of 113,750 cases; the 2015 validation sample consisted of 134,851 cases. The model developed in 2013 showed good validity regarding discrimination (AUC = 0.74), calibration (observed mortality in 1st and 10th risk-decile: 11%-78%), and fit (R2 = 0.16). Validity remained stable when the model was applied to 2015 (AUC = 0.74, 1st and 10th risk-decile: 10%-77%, R2 = 0.17). There was no indication of overfitting of the model. The final model developed in year 2015 contained 40 risk-factors. Between 2010 and 2015 hospital mortality in sepsis decreased from 48% to 42%. Adjusted for risk-factors the trajectory of decrease was still significant. The risk-model shows good predictive validity and stability across time. The model is suitable to be used as an external algorithm for comparing risk-adjusted sepsis mortality among German hospitals or regions based on administrative claims data, but secular changes need to be taken into account when interpreting risk-adjusted mortality.

Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study.

PubMed

Mansur, Ashham; Steinau, Maximilian; Popov, Aron Frederik; Ghadimi, Michael; Beissbarth, Tim; Bauer, Martin; Hinz, José

2015-06-01

Previous investigations have presumed a potential therapeutic effect of statin therapy in patients with acute respiratory distress syndrome (ARDS). Statins are expected to attenuate inflammation in the lungs of patients with ARDS due to their anti-inflammatory effects. Clinical investigations of the role of statin therapy have revealed contradictory results. This study aimed to investigate whether pretreatment and continuous therapy with statins in patients with sepsis-associated ARDS are associated with 28-day survival according to disease severity (mild, moderate, or severe). Patients with sepsis-associated ARDS from the surgical intensive care were enrolled in this prospective observational investigation. ARDS was classified into three groups (mild, moderate, and severe); 28-day mortality was recorded as the primary outcome variable and organ failure was recorded as secondary outcome variable. Sequential Organ Failure Assessment scores and the requirements for organ support were evaluated throughout the observational period to assess organ failure. 404 patients with sepsis-associated ARDS were enrolled in this investigation. The distribution of the ARDS subgroups was 13 %, 59 %, and 28 % for mild, moderate, and severe disease, respectively. Statin therapy improved 28-day survival exclusively in the patients with severe ARDS compared with patients without statin therapy (88.5 % and 62.5 %, respectively; P = 0.0193). To exclude the effects of several confounders, we performed multivariate Cox regression analysis, which showed that statin therapy remained a significant covariate for mortality (hazard ratio, 5.46; 95 % CI, 1.38-21.70; P = 0.0156). Moreover, after carrying a propensity score-matching in the severe ARDS cohort, Kaplan-Meier survival analysis confirmed the improved 28-day survival among patients with statin therapy (P = 0.0205). Patients with severe ARDS who received statin therapy had significantly more vasopressor-free days compared with those

Community-onset sepsis and its public health burden: a systematic review.

PubMed

Tsertsvadze, Alexander; Royle, Pam; Seedat, Farah; Cooper, Jennifer; Crosby, Rebecca; McCarthy, Noel

2016-05-18

Sepsis is a life-threatening condition and major contributor to public health and economic burden in the industrialised world. The difficulties in accurate diagnosis lead to great variability in estimates of sepsis incidence. There has been even greater uncertainty regarding the incidence of and risk factors for community-onset sepsis (COS). We systematically reviewed the recent evidence on the incidence and risk factors of COS in high income countries (North America, Australasia, and North/Western Europe). Cohort and case-control studies were eligible for inclusion. Medline and Embase databases were searched from 2002 onwards. References of relevant publications were hand-searched. Two reviewers screened titles/abstracts and full-texts independently. One reviewer extracted data and appraised studies which were cross-checked by independent reviewers. Disagreements were resolved via consensus. Odds ratios (ORs) and 95 percent confidence intervals (95 % CIs) were ascertained by type of sepsis (non-severe, severe, and septic shock). Ten cohort and 4 case-control studies were included. There was a wide variation in the incidence (# cases per 100,000 per year) of non-severe sepsis (range: 64-514), severe sepsis (range: 40-455), and septic shock (range: 9-31). Heterogeneity precluded statistical pooling. Two cohort and 4 case-control studies reported risk factors for sepsis. In one case-control and one cohort study, older age and diabetes were associated with increased risk of sepsis. The same case-control study showed an excess risk for sepsis in participants with clinical conditions (e.g., immunosuppression, lung disease, and peripheral artery disease). In one cohort study, higher risk of sepsis was associated with being a nursing home resident (OR = 2.60, 95 % CI: 1.20, 5.60) and in the other cohort study with being physically inactive (OR = 1.33, 95 % CI: 1.13, 1.56) and smoking tobacco (OR = 1.85, 95 % CI: 1.54, 2.22). The evidence on sex, ethnicity, statin use, and

Preventing intensive care admissions for sepsis in tropical Africa (PICASTA): an extension of the international pediatric global sepsis initiative: an African perspective.

PubMed

Pollach, Gregor; Namboya, Felix

2013-07-01

The Global Sepsis Initiative recommends prevention of sepsis through immunizations, vitamins, breast feeding, and other important interventions. In our study, we consider a second set of proposals for preventing intensive care admissions for sepsis in tropical Africa, which have been specifically designed to further prevent ICU admissions for sepsis in the group A nation hospital setting. To reduce admissions with severe sepsis in an ICU of a group A nation through the identification of challenges leading to preventable, foreseeable, or nosocomial sepsis specific to our setting. Malawi is one of the poorest countries in the world. Lacking the ability to comply with standard sepsis treatment, we conducted over 4 years several studies, audits, and surveys to identify challenges leading to preventable pediatric sepsis in our setting. We developed a method to identify malnourished children through a "gatekeeper" in the theaters without any equipment, tried to implement the World Health Organization's Safe Surgery Campaign checklist, evaluated our educational courses for the districts to improve the quality of referrals, looked into the extreme fasting times discovered in our hospital, trained different cadres in the districts to deal with peripartal and posttraumatic sepsis, and identified the needs in human resources to deal with pediatric sepsis in our setting. Six foci were identified as promising to work on in future. Focus 1: Preventing elective operations and procedures in malnourished children in the hospital and in the district: 134 of 145 nurses (92.4%) and even 25 of 31 African laymen (80.6%) were able to identify malnourished children with their own fingers. Focus 2: Preventing sepsis-related problems in emergencies through the implementation of the Safe Surgery Campaign checklist: only 100 of 689 forms (14.5%) were filled in due to challenges in ownership, communication responsibility, and time constraints. Focus 3: Preventing sepsis through the reduction

A simple scoring system based on neutrophil count in sepsis patients.

PubMed

Ueda, Takahiro; Aoyama-Ishikawa, Michiko; Nakao, Atsunori; Yamada, Taihei; Usami, Makoto; Kotani, Joji

2014-03-01

The assessment of critically ill patients is often a challenge for clinicians. There are a number of scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and C-reactive protein test (CRP), which have been shown to correlate with outcome in a variety of Intensive Care Unit (ICU) patients. Therefore, use of repeated measures of these preexisting scores over time is a reasonable attempt to assess the severity of organ dysfunction and predict outcome in critically ill patients. Several reports suggest that the neutrophil is a useful marker of sepsis. However, since both a large number and a small number of neutrophils indicate a severe situation, neutrophil count is difficult to use to directly predict patients'. We proposed a novel scoring system identify predictive factors using a simple blood cell count that may be associated with mortality in ICU patients. Our novel scoring system (n-score) was calculated as follows: ranges of neutrophils of 0-4999 cells/mm(3) and 5000-9999 cells/mm(3) were defined as 3 and 1 points, respectively. When the neutrophil count was over 10,000 cells/mm(3), the score was calculated by dividing the number of cells by 10,000. Then, 1 or 2 points were added when patients were female or male, respectively. We hypothesize that n-score may be a simple and easy scoring system to estimate mortality of the patients with sepsis and severe sepsis/septic shock without requirement of special methods or special measuring equipment, and may be as reliable as the APACHE II score or SOFA score. The retrospective evaluation was conducted at the Department of Emergency, Disaster and Critical Care Medicine at the Hyogo College of Medicine. Seventy-seven patients who were admitted to the emergency center and diagnosed sepsis or severe sepsis/septic shock between June 2007 and December 2012 and gave informed consent were enrolled. The n-score was significantly higher in non

Autophagy and skeletal muscles in sepsis.

PubMed

Mofarrahi, Mahroo; Sigala, Ioanna; Guo, Yeting; Godin, Richard; Davis, Elaine C; Petrof, Basil; Sandri, Marco; Burelle, Yan; Hussain, Sabah N A

2012-01-01

Mitochondrial injury develops in skeletal muscles during the course of severe sepsis. Autophagy is a protein and organelle recycling pathway which functions to degrade or recycle unnecessary, redundant, or inefficient cellular components. No information is available regarding the degree of sepsis-induced mitochondrial injury and autophagy in the ventilatory and locomotor muscles. This study tests the hypotheses that the locomotor muscles are more prone to sepsis-induced mitochondrial injury, depressed biogenesis and autophagy induction compared with the ventilatory muscles. Adult male C57/Bl6 mice were injected with i.p. phosphate buffered saline (PBS) or E. coli lipopolysaccharide (LPS, 20 mg/kg) and sacrificed 24 h later. The tibialis anterior (TA), soleus (SOLD) and diaphragm (DIA) muscles were quickly excised and examined for mitochondrial morphological injury, Ca(++) retention capacity and biogenesis. Autophagy was detected with electron microscopy, lipidation of Lc3b proteins and by measuring gene expression of several autophagy-related genes. Electron microscopy revealed ultrastructural injuries in the mitochondria of each muscle, however, injuries were more severe in the TA and SOL muscles than they were in the DIA. Gene expressions of nuclear and mitochondrial DNA transcription factors and co-activators (indicators of biogenesis) were significantly depressed in all treated muscles, although to a greater extent in the TA and SOL muscles. Significant autophagosome formation, Lc3b protein lipidation and upregulation of autophagy-related proteins were detected to a greater extent in the TA and SOL muscles and less so in the DIA. Lipidation of Lc3b and the degree of induction of autophagy-related proteins were significantly blunted in mice expressing a muscle-specific IκBα superrepresor. We conclude that locomotor muscles are more prone to sepsis-induced mitochondrial injury, decreased biogenesis and increased autophagy compared with the ventilatory muscles

Autophagy and Skeletal Muscles in Sepsis

PubMed Central

Mofarrahi, Mahroo; Sigala, Ioanna; Guo, Yeting; Godin, Richard; Davis, Elaine C.; Petrof, Basil; Sandri, Marco

2012-01-01

Background Mitochondrial injury develops in skeletal muscles during the course of severe sepsis. Autophagy is a protein and organelle recycling pathway which functions to degrade or recycle unnecessary, redundant, or inefficient cellular components. No information is available regarding the degree of sepsis-induced mitochondrial injury and autophagy in the ventilatory and locomotor muscles. This study tests the hypotheses that the locomotor muscles are more prone to sepsis-induced mitochondrial injury, depressed biogenesis and autophagy induction compared with the ventilatory muscles. Methodology/Principal Findings Adult male C57/Bl6 mice were injected with i.p. phosphate buffered saline (PBS) or E. coli lipopolysaccharide (LPS, 20 mg/kg) and sacrificed 24 h later. The tibialis anterior (TA), soleus (SOLD) and diaphragm (DIA) muscles were quickly excised and examined for mitochondrial morphological injury, Ca++ retention capacity and biogenesis. Autophagy was detected with electron microscopy, lipidation of Lc3b proteins and by measuring gene expression of several autophagy-related genes. Electron microscopy revealed ultrastructural injuries in the mitochondria of each muscle, however, injuries were more severe in the TA and SOL muscles than they were in the DIA. Gene expressions of nuclear and mitochondrial DNA transcription factors and co-activators (indicators of biogenesis) were significantly depressed in all treated muscles, although to a greater extent in the TA and SOL muscles. Significant autophagosome formation, Lc3b protein lipidation and upregulation of autophagy-related proteins were detected to a greater extent in the TA and SOL muscles and less so in the DIA. Lipidation of Lc3b and the degree of induction of autophagy-related proteins were significantly blunted in mice expressing a muscle-specific IκBα superrepresor. Conclusion/Significance We conclude that locomotor muscles are more prone to sepsis-induced mitochondrial injury, decreased biogenesis

Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis.

PubMed

Yamakawa, K; Aihara, M; Ogura, H; Yuhara, H; Hamasaki, T; Shimazu, T

2015-04-01

Although recombinant human soluble thrombomodulin (rhTM) is a widely used novel anticoagulant agent for disseminated intravascular coagulation (DIC) in Japan, its clinical efficacy in sepsis-induced DIC has not been demonstrated convincingly. To assess the benefits and harms of rhTM in sepsis-induced DIC patients. We conducted a systematic review and meta-analysis of rhTM therapy for sepsis-induced DIC for both randomized controlled trials (RCTs) and observational studies (retrospective case-control studies and/or prospective cohort studies) separately. All-cause mortality (28-30 days) as efficacy and serious bleeding complications as adverse effect were measured as primary outcomes. We assessed body of evidence quality at the outcome level by using the Grading of Evidence, Assessment, Development and Evaluation (GRADE) approach. We analyzed 12 studies (838 patients/3 RCTs; 571 patients/9 observational studies). Pooled relative risk was 0.81 (95% CI, 0.62-1.06) in the RCTs, indicating non-significant reduction in mortality, and 0.59 (95% CI, 0.45-0.77) in the observational studies. Meta-regression analysis revealed a significant negative slope between effect size of rhTM therapy and baseline mortality rate in individual studies (P = 0.012), suggesting that probability of a beneficial effect with rhTM therapy increases with increasing baseline risk. Risk of serious bleeding complications was not significantly different between rhTM and control groups. We judged the quality of evidence as moderate for mortality and serious bleeding. The rhTM was associated with a trend in reduction of mortality at 28-30 days in sepsis-induced DIC patients. Further large rigorous trials are needed to confirm or refute these findings before implications for practice are clear. © 2015 International Society on Thrombosis and Haemostasis.

Predictive Value of IL-8 for Sepsis and Severe Infections after Burn Injury - A Clinical Study

PubMed Central

Kraft, Robert; Herndon, David N; Finnerty, Celeste C; Cox, Robert A; Song, Juquan; Jeschke, Marc G

2014-01-01

The inflammatory response induced by burn injury contributes to increased incidence of infections, sepsis, organ failure, and mortality. Thus, monitoring post-burn inflammation is of paramount importance but so far there are no reliable biomarkers available to monitor and/or predict infectious complications after burn. As IL-8 is a major mediator for inflammatory responses, the aim of our study was to determine whether IL-8 expression can be used to predict post-burn sepsis, infections, and mortality other outcomes post-burn. Plasma cytokines, acute phase proteins, constitutive proteins, and hormones were analyzed during the first 60 days post injury from 468 pediatric burn patients. Demographics and clinical outcome variables (length of stay, infection, sepsis, multiorgan failure (MOF), and mortality were recorded. A cut-off level for IL-8 was determined using receiver operating characteristic (ROC) analysis. Statistical significance is set at (p<0.05). ROC analysis identified a cut-off level of 234 pg/ml for IL-8 for survival. Patients were grouped according to their average IL-8 levels relative to this cut off and stratified into high (H) (n=133) and low (L) (n=335) groups. In the L group, regression analysis revealed a significant predictive value of IL-8 to percent of total body surface area (TBSA) burned and incidence of MOF (p<0.001). In the H group IL-8 levels were able to predict sepsis (p<0.002). In the H group, elevated IL-8 was associated with increased inflammatory and acute phase responses compared to the L group (p<0.05). High levels of IL-8 correlated with increased MOF, sepsis, and mortality. These data suggest that serum levels of IL-8 may be a valid biomarker for monitoring sepsis, infections, and mortality in burn patients. PMID:25514427

Association of Fluid Resuscitation Initiation Within 30 Minutes of Severe Sepsis and Septic Shock Recognition With Reduced Mortality and Length of Stay.

PubMed

Leisman, Daniel; Wie, Benjamin; Doerfler, Martin; Bianculli, Andrea; Ward, Mary Frances; Akerman, Meredith; D'Angelo, John K; Zemmel D'Amore, Jason A

2016-09-01

We evaluate the association of intravenous fluid resuscitation initiation within 30 minutes of severe sepsis or septic shock identification in the emergency department (ED) with inhospital mortality and hospital length of stay. We also compare intravenous fluid resuscitation initiated at various times from severe sepsis or septic shock identification's association with the same outcomes. This was a review of a prospective, observational cohort of all ED severe sepsis or septic shock patients during 13 months, captured in a performance improvement database at a single, urban, tertiary care facility (90,000 ED visits/year). The primary exposure was initiation of a crystalloid bolus at 30 mL/kg within 30 minutes of severe sepsis or septic shock identification. Secondary analysis compared intravenous fluid initiated within 30, 31 to 60, or 61 to 180 minutes, or when intravenous fluid resuscitation was initiated at greater than 180 minutes or not provided. Of 1,866 subjects, 53.6% were men, 72.5% were white, mean age was 72 years (SD 16.6 years), and mean initial lactate level was 2.8 mmol/L. Eighty-six percent of subjects were administered intravenous antibiotics within 180 minutes; 1,193 (64%) had intravenous fluid initiated within 30 minutes. Mortality was lower in the within 30 minutes group (159 [13.3%] versus 123 [18.3%]; 95% confidence interval [CI] 1.4% to 8.5%), as was median hospital length of stay (6 days [95% CI 6 to 7] versus 7 days [95% CI 7 to 8]). In multivariate regression that included adjustment for age, lactate, hypotension, acute organ dysfunction, and Emergency Severity Index score, intravenous fluid within 30 minutes was associated with lower mortality (odds ratio 0.63; 95% CI 0.46 to 0.86) and 12% shorter length of stay (hazard ratio=1.14; 95% CI 1.02 to 1.27). In secondary analysis, mortality increased with later intravenous fluid resuscitation initiation: 13.3% (≤30 minutes) versus 16.0% (31 to 60 minutes) versus 16.9% (61 to 180 minutes

Admission Cell Free DNA Levels Predict 28-Day Mortality in Patients with Severe Sepsis in Intensive Care

PubMed Central

Almog, Yaniv; Perl, Yael; Novack, Victor; Galante, Ori; Klein, Moti; Pencina, Michael J.; Douvdevani, Amos

2014-01-01

Aim The aim of the current study is to assess the mortality prediction accuracy of circulating cell-free DNA (CFD) level at admission measured by a new simplified method. Materials and Methods CFD levels were measured by a direct fluorescence assay in severe sepsis patients on intensive care unit (ICU) admission. In-hospital and/or twenty eight day all-cause mortality was the primary outcome. Results Out of 108 patients with median APACHE II of 20, 32.4% have died in hospital/or at 28-day. CFD levels were higher in decedents: median 3469.0 vs. 1659 ng/ml, p<0.001. In multivariable model APACHE II score and CFD (quartiles) were significantly associated with the mortality: odds ratio of 1.05, p = 0.049 and 2.57, p<0.001 per quartile respectively. C-statistics for the models was 0.79 for CFD and 0.68 for APACHE II. Integrated discrimination improvement (IDI) analyses showed that CFD and CFD+APACHE II score models had better discriminatory ability than APACHE II score alone. Conclusions CFD level assessed by a new, simple fluorometric-assay is an accurate predictor of acute mortality among ICU patients with severe sepsis. Comparison of CFD to APACHE II score and Procalcitonin (PCT), suggests that CFD has the potential to improve clinical decision making. PMID:24955978

Association of Delayed Antimicrobial Therapy with One-Year Mortality in Pediatric Sepsis.

PubMed

Han, Moonjoo; Fitzgerald, Julie C; Balamuth, Fran; Keele, Luke; Alpern, Elizabeth R; Lavelle, Jane; Chilutti, Marianne; Grundmeier, Robert W; Nadkarni, Vinay M; Thomas, Neal J; Weiss, Scott L

2017-07-01

Delayed antimicrobial therapy in sepsis is associated with increased hospital mortality, but the impact of antimicrobial timing on long-term outcomes is unknown. We tested the hypothesis that hourly delays to antimicrobial therapy are associated with 1-year mortality in pediatric severe sepsis. Retrospective observational study. Quaternary academic pediatric intensive care unit (PICU) from February 1, 2012 to June 30, 2013. One hundred sixty patients aged ≤21 years treated for severe sepsis. None. We tested the association of hourly delays from sepsis recognition to antimicrobial administration with 1-year mortality using multivariable Cox and logistic regression. Overall 1-year mortality was 24% (39 patients), of whom 46% died after index PICU discharge. Median time from sepsis recognition to antimicrobial therapy was 137 min (IQR 65-287). After adjusting for severity of illness and comorbid conditions, hourly delays up to 3 h were not associated with 1-year mortality. However, increased 1-year mortality was evident in patients who received antimicrobials ≤1 h (aOR 3.8, 95% CI 1.2, 11.7) or >3 h (aOR 3.5, 95% CI 1.3, 9.8) compared with patients who received antimicrobials within 1 to 3 h from sepsis recognition. For the subset of patients who survived index PICU admission, antimicrobial therapy ≤1 h was also associated with increased 1-year mortality (aOR 5.5, 95% CI 1.1, 27.4), while antimicrobial therapy >3 h was not associated with 1-year mortality (aOR 2.2, 95% CI 0.5, 11.0). Hourly delays to antimicrobial therapy, up to 3 h, were not associated with 1-year mortality in pediatric severe sepsis in this study. The finding that antimicrobial therapy ≤1 h from sepsis recognition was associated with increased 1-year mortality should be regarded as hypothesis-generating for future studies.

Development of an e-learning package for sepsis care.

PubMed

Davis, Anna; Henderson, James; Langmack, Gill

Severe sepsis is a major cause of morbidity and mortality in the UK. This article describes the collaborative development and implementation of an interactive online learning package to understand the key role nurses have in recognising and then starting to apply the Sepsis Six care bundle in clinical practice. The e-learning package, developed in a UK teaching hospital, uses a case study approach to address the knowledge that is required to be able to recognise sepsis, to understand the processes that occur and the ongoing care and treatment required. The package is relevant to final-year student nurses, newly registered nurses in preceptorship and other health professionals involved in assessing and treating patients who may be developing sepsis.

[Predictive value of early phrase echocardiography and cardiac biological markers in patients with severe sepsis: a five-year single-center retrospective study].

PubMed

Zang, Xuefeng; Chen, Wei; Sheng, Bo; Zhao, Lei; Gu, Xuyun; Zhen, Jie; Liu, Ping

2018-04-01

To assess the predictive value of early phrase echocardiography and cardiac biomarkers in patients with severe sepsis. A retrospective analysis of severe septic patients (patients with acute coronary syndrome and end stage renal disease were excluded) in department of intensive care unit of Capital Medical University Affiliated Beijing Shijitan Hospital from January 2013 to December 2017 was conducted. The acute physiology and chronic health evaluation II (APACHE II) score, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI), myoglobin (MYO), creatine kinase (CK), MB isoenzyme of creatine kinase (CK-MB) within 6 hours after admission, and bedside echocardiography indexes [left ventricular ejection fraction (LVEF), the ratio of the peak blood flow velocity in the early stage of the mitral valve and the peak blood flow rate of the mitral valve (E/A ratio)] within 6 hours after diagnosis were recorded. The differences of indexes between patients with decreased contractile function (LVEF < 0.50) group and normal group, and the difference between dead group and survival group within 28-day were compared. Receiver operating characteristic (ROC) curve and Logistic regression analysis were conducted to assess the early detected prognostic value in severe sepsis patients. (1) A total of 316 patients were enrolled in the survey period. Decreased cardiac systolic function (LVEF < 0.50) was found in 89 cases (28.2%), and cardiac diastolic function impaired (E/A ratio < 1) in 269 cases (85.1%); while 79 cases (25.0%) had both systolic function and diastolic function impairment. (2) NT-proBNP and cTnI were statistically different between cardiac systolic function impaired group and normal group. Further Logistic regression analysis showed that only NT-proBNP was significantly correlated with LVEF [β=-1.311, odds ratio (OR) = 0.269, P < 0.001]. (3) Eighty-two of 316 cases were died in 28-day, and the 28-day mortality rate was 25.9%. Compared

Extracorporeal blood purification therapy for sepsis and systemic inflammation: its biological rationale.

PubMed

Bellomo, R; Baldwin, I; Ronco, C

2001-01-01

EBPTs represent a promising new approach to the adjuvant treatment of severe sepsis, septic shock and MODS. Their technology is rapidly evolving and pilot animal and human studies are now taking place to prepare the territory for the first large randomized controlled trial. The rationale for EBPT is reasonable and the initial data are encouraging. The correct technology and molecular targeting, however, are still being explored. Once the best technology has been determined, it is likely that phase II and phase III trials will be performed to test the hypothesis that these therapies can indeed alter mortality in severe inflammatory multiorgan dysfunction.

Application of the new Sepsis-3 definition in a cohort of patients with severe sepsis and septic shock admitted to Intensive Care Unit from the Emergency Department.

PubMed

García-Gigorro, Renata; Molina-Collado, Zaira; Sáez-de la Fuente, Ignacio; Sanchez-Izquierdo, José Ángel; Montejo González, Juan Carlos

2018-04-18

After the publication of the new definition for sepsis and septic shock, our objective is to analyse the evolution of patients admitted to ICU with an infection process using the previous and new recommendations. This is a sub-analysis of a previous observational prospective study. We included 98 patients admitted to ICU from the emergency department due to infection during an 18-month period. We studied the clinical evolution during ICU admission and hospital mortality. According to Sepsis-2 definition, 78% percent had septic shock and using Sepsis-3 criteria, 52%; hospital mortality was 29 and 41%, respectively. The RR of hospital mortality of septic shock was 10.3 (95% CI: 2.8-37.5) compared to patients without shock. The 30-day probability survival of patients with sepsis and septic shock were 78% and 68%, respectively (long rank < 0.001). In our experience, the incorporation of the SOFA score and lactate levels to the new definition could help improve the evaluation of risk of hospital death. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Heart-rate variability depression in porcine peritonitis-induced sepsis without organ failure.

PubMed

Jarkovska, Dagmar; Valesova, Lenka; Chvojka, Jiri; Benes, Jan; Danihel, Vojtech; Sviglerova, Jitka; Nalos, Lukas; Matejovic, Martin; Stengl, Milan

2017-05-01

Depression of heart-rate variability (HRV) in conditions of systemic inflammation has been shown in both patients and experimental animal models and HRV has been suggested as an early indicator of sepsis. The sensitivity of HRV-derived parameters to the severity of sepsis, however, remains unclear. In this study we modified the clinically relevant porcine model of peritonitis-induced sepsis in order to avoid the development of organ failure and to test the sensitivity of HRV to such non-severe conditions. In 11 anesthetized, mechanically ventilated and instrumented domestic pigs of both sexes, sepsis was induced by fecal peritonitis. The dose of feces was adjusted and antibiotic therapy was administered to avoid multiorgan failure. Experimental subjects were screened for 40 h from the induction of sepsis. In all septic animals, sepsis with hyperdynamic circulation and increased plasma levels of inflammatory mediators developed within 12 h from the induction of peritonitis. The sepsis did not progress to multiorgan failure and there was no spontaneous death during the experiment despite a modest requirement for vasopressor therapy in most animals (9/11). A pronounced reduction of HRV and elevation of heart rate developed quickly (within 5 h, time constant of 1.97 ± 0.80 h for HRV parameter TINN) upon the induction of sepsis and were maintained throughout the experiment. The frequency domain analysis revealed a decrease in the high-frequency component. The reduction of HRV parameters and elevation of heart rate preceded sepsis-associated hemodynamic changes by several hours (time constant of 11.28 ± 2.07 h for systemic vascular resistance decline). A pronounced and fast reduction of HRV occurred in the setting of a moderate experimental porcine sepsis without organ failure. Inhibition of parasympathetic cardiac signaling probably represents the main mechanism of HRV reduction in sepsis. The sensitivity of HRV to systemic inflammation may allow

Serum decoy receptor 3, a potential new biomarker for sepsis.

PubMed

Hou, Yan-Qiang; Xu, Ping; Zhang, Mei; Han, Deping; Peng, Liang; Liang, Dong-Yu; Yang, Shanmin; Zhang, Zhenhuan; Hong, Jinsheng; Lou, Xiao-Li; Zhang, Lurong; Kim, Sunghee

2012-04-11

Sepsis, a common deadly systemic infection caused by a variety of pathogens, has some clinical symptoms similar to the systemic inflammatory response syndrome (SIRS), a whole-body non-infectious inflammatory reaction to severe insults, such as burn, trauma, hypotensive shock and so on. Treatment of sepsis depends mainly on anti-microbial, while remedy for SIRS might require steroids that could possibly enhance the spread of microbes. Unfortunately, it is very difficult to distinguish these two completely different serious conditions without blood culture, which takes days to grow and identify causative pathogens. We examined a biomarker, serum decoy receptor 3 (DcR3), was evaluated for its utility in the differential diagnosis between sepsis and SIRS. Serum DcR3 level in 118 healthy controls, 24 sepsis patients and 43 SIRS patients, was quantitatively measured by enzyme-linked immunosorbent assay (ELISA). The serum DcR3 was significantly increased in sepsis patients compared with SIRS patients and healthy controls (6.11±2.58 ng/ml vs 2.62±1.46 ng/ml, and 0.91±0.56 ng/ml, respectively, p<0.001). The areas under the receiver operating characteristic curve of DcR3 for the normal vs. SIRS, normal vs. sepsis and SIRS vs. sepsis were 0.910 (0.870-0.950), 0.992 (0.984-1.000) and 0.896 (0.820-0.973), respectively. In addition, the DcR3 exhibited a positive correlation coefficient with APACHE II score, a most commonly used index for the severity of sepsis (r=0.556, p=0.005). The serum DcR3 has a potential to serve as a new biomarker for sepsis with its high specificity and sensitivity. Copyright © 2012 Elsevier B.V. All rights reserved.