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Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients.

ABSTRACT: BACKGROUND:Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007. OBJECTIVES:We assessed the benefits and harms of APC for patients with severe sepsis or septic shock. SEARCH METHODS:We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2010 to June 2012); EMBASE (2010 to June 2012); BIOSIS (1965 to June 2012); CINAHL (1982 to June 2012) and LILACS (1982 to June 2012). There was no language restriction. SELECTION CRITERIA:We included randomized clinical trials assessing the effects of APC for severe sepsis or septic shock in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28 and at the end of study follow up, and hospital mortality as the primary outcomes. DATA COLLECTION AND ANALYSIS:We independently performed trial selection, risk of bias assessment, and data extraction in duplicate. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model. MAIN RESULTS:We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (780/3435 (22.7%) versus 767/3346 (22.9%); RR 1.00, 95% confidence interval (CI) 0.86 to 1.16; I(2) = 56%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I(2) = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I(2) = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I(2) = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes. AUTHORS' CONCLUSIONS:This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.

SUBMITTER: Marti-Carvajal AJ

PROVIDER: S-EPMC6464614 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients.

Martí-Carvajal Arturo J AJ Solà Ivan I Gluud Christian C Lathyris Dimitrios D Cardona Andrés Felipe AF

The Cochrane database of systematic reviews 20121212

<h4>Background</h4>Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007.<h4>Objectives</h4>We assessed the benefits and harms of APC for patients with severe sepsis or septic shock.<h4>Search methods</h4>We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2 ...[more]

PMID: 23235609

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Project description:BackgroundProspective studies on the incidence of VTE during severe sepsis and septic shock remain absent, hindering efficacy assessments regarding VTE prevention strategies in sepsis.MethodsWe prospectively studied 113 consecutively enrolled patients in the ICU with severe sepsis and septic shock at three hospitals. All patients provided informed consent. VTE thromboprophylaxis was recorded for all patients. Patients underwent ultrasonography and were followed for VTE prior to ICU discharge. All-cause 28-day mortality was recorded. Variables from univariate analyses that were associated with VTE (including central venous catheter [CVC] insertion, age, length of stay, and mechanical ventilation) were included in a multivariable logistic regression analysis using backward stepwise elimination to determine VTE predictors.ResultsMean APACHE (Acute Physiology and Chronic Health Evaluation) II score was 18.2 ± 7.0, and age was 50 ± 18 years. Despite all patients receiving guideline-recommended thromboprophylaxis, the incidence of VTE was 37.2% (95% CI, 28.3-46.8). Most VTE events were clinically significant (defined as pulmonary embolism, proximal DVT, and/or symptomatic distal DVT) and associated with an increased length of stay (18.2 ± 9.9 days vs 13.4 ± 11.5 days, P < .05). Mortality was higher in patients with acute VTE but did not reach statistical significance. Insertion of a CVC and longer mechanical ventilation duration were significant VTE risk factors. VTE incidence did not differ by thromboprophylaxis type.ConclusionsTo our knowledge this is the first multicenter prospective study to identify a high incidence of VTE in patients with severe sepsis and septic shock, despite the use of universal, guideline-recommended thromboprophylaxis. Our findings suggest that the systemic inflammatory milieu of sepsis may uniquely predispose patients with sepsis to VTE. More effective VTE prevention strategies are necessary in patients with sepsis.Trial registryClinicalTrials.gov; No.: NCT02353910; URL: www.clinicaltrials.gov.

Project description:ObjectivesThis study aimed to conduct a comprehensive and updated systematic review with network meta-analysis (NMA) to assess the outcome benefits of various blood purification modalities for adult patients with severe infection or sepsis.Data sourcesWe conducted a search of PubMed, MEDLINE, clinical trial registries, Cochrane Library, and Embase databases with no language restrictions.Study selectionOnly randomized controlled trials (RCTs) were selected.Data extractionThe primary outcome was overall mortality. The secondary outcomes were the length of mechanical ventilation (MV) days and ICU stay, incidence of acute kidney injury (AKI), and kidney replacement therapy requirement.Data synthesisWe included a total of 60 RCTs with 4,595 participants, comparing 16 blood purification modalities with 17 interventions. Polymyxin-B hemoperfusion (relative risk [RR]: 0.70; 95% CI, 0.57-0.86) and plasma exchange (RR: 0.61; 95% CI, 0.42-0.91) were associated with low mortality (very low and low certainty of evidence, respectively). Because of the presence of high clinical heterogeneity and intransitivity, the potential benefit of polymyxin-B hemoperfusion remained inconclusive. The analysis of secondary outcomes was limited by the scarcity of available studies. HA330 with high-volume continuous venovenous hemofiltration (CVVH), HA330, and standard-volume CVVH were associated with shorter ICU stay. HA330 with high-volume CVVH, HA330, and standard-volume CVVH were beneficial in reducing MV days. None of the interventions showed a significant reduction in the incidence of AKI or the need for kidney replacement therapy.ConclusionsOur NMA suggests that plasma exchange and polymyxin-B hemoperfusion may provide potential benefits for adult patients with severe infection or sepsis/septic shock when compared with standard care alone, but most comparisons were based on low or very low certainty evidence. The therapeutic effect of polymyxin-B hemoperfusion remains uncertain. Further RCTs are required to identify the specific patient population that may benefit from extracorporeal blood purification.

Project description:ObjectivesRapid fluid resuscitation has become standard in sepsis care, despite "low-quality" evidence and absence of guidelines for populations "at risk" for volume overload. Our objectives include as follows: 1) identify predictors of reaching a 30 mL/kg crystalloid bolus within 3 hours of sepsis onset (30by3); 2) assess the impact of 30by3 and fluid dosing on clinical outcomes; 3) examine differences in perceived "at-risk" volume-sensitive populations, including end-stage renal disease, heart failure, obesity, advanced age, or with documentation of volume "overload" by bedside examination.DesignRetrospective cohort study. All outcome analyses controlled for sex, end-stage renal disease, heart failure, sepsis severity (severe sepsis vs septic shock), obesity, Mortality in Emergency Department Sepsis score, and time to antibiotics.SettingUrban, tertiary care center between January 1, 2014, and May 31, 2017.PatientsEmergency Department treated adults (age ≥18 yr; n = 1,032) with severe sepsis or septic shock.InterventionsAdministration of IV fluids by bolus.Measurements and main resultsIn total, 509 patients received 30by3 (49.3%). Overall mortality was 17.1% (n = 176), with 20.4% mortality in the shock group. Patients who were elderly (odds ratio, 0.62; 95% CI, 0.46-0.83), male (odds ratio, 0.66; CI, 0.49-0.87), obese (odds ratio, 0.18; CI, 0.13-0.25), or with end-stage renal disease (odds ratio, 0.23; CI, 0.13-0.40), heart failure (odds ratio, 0.42; CI, 0.29-0.60), or documented volume "overload" (odds ratio, 0.30; CI, 0.20-0.45) were less likely to achieve 30by3. Failure to meet 30by3 had increased odds of mortality (odds ratio, 1.52; CI, 1.03-2.24), delayed hypotension (odds ratio, 1.42; CI, 1.02-1.99), and increased ICU stay (~2 d) (β = 2.0; CI, 0.5-3.6), without differential effects for "at-risk" groups. Higher fluid volumes administered by 3 hours correlated with decreased mortality, with a plateau effect between 35 and 45 mL/kg (p < 0.05).ConclusionsFailure to reach 30by3 was associated with increased odds of in-hospital mortality, irrespective of comorbidities. Predictors of inadequate resuscitation can be identified, potentially leading to interventions to improve survival. These findings are retrospective and require future validation.

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Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients.

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Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients.

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