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      Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis

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          Abstract

          Introduction

          There are approximately 19 million new cases of sepsis worldwide each year. Among them, more than one quarter of patients die. We aimed to assess the effects of heparin on short-term mortality in adult patients with sepsis and severe sepsis.

          Methods

          We searched electronic databases (Medline, Embase, and Cochrane Library databases; the Cochrane Controlled Trials Register) and conference proceedings (Web of Knowledge (Conference Proceedings Citation Index - Science, Conference Proceedings Citation Index - Social Sciences & Humanities)) from inception to July 2014, expert contacts and relevant websites. Controlled trials of heparin versus placebo in sepsis or severe sepsis were identified. In total two reviewers independently assessed eligibility, and four authors independently extracted data; consensus was reached by conference. We used the chi-square test and I 2 to assess statistical heterogeneity ( P <0.05). The primary analysis was based on the fixed-effect model to produce pooled odds ratios with 95% confidence intervals.

          Results

          A total of nine publications were included in the meta-analysis. Heparin decreased 28-day mortality (n = 3,482, OR = 0.656, 95% CI = 0.562 to 0.765, P <0.0001). According to the meta-analysis of 28-day mortality, heterogeneity was not found among the eight randomized clinical trials (RCTs) (I 2 = 0.0%). Heparin had no effect on bleeding events in sepsis (seven RCTs, n = 2,726; OR = 1.063; 95% CI = 0.834 to 1.355; P = 0.623; and I 2 = 20.9%). Subgroup analysis demonstrated that the sample size may be a source of heterogeneity, but experimental design was not.

          Conclusions

          Heparin may reduce 28-day mortality in patients with severe sepsis, at the same time, there was no increase in the risk of bleeding in the heparin group. We recommend the use of heparin for sepsis and severe sepsis.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13054-014-0563-4) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          The hazards of scoring the quality of clinical trials for meta-analysis.

          Peter Jüni (1999)
          Although it is widely recommended that clinical trials undergo some type of quality review, the number and variety of quality assessment scales that exist make it unclear how to achieve the best assessment. To determine whether the type of quality assessment scale used affects the conclusions of meta-analytic studies. Meta-analysis of 17 trials comparing low-molecular-weight heparin (LMWH) with standard heparin for prevention of postoperative thrombosis using 25 different scales to identify high-quality trials. The association between treatment effect and summary scores and the association with 3 key domains (concealment of treatment allocation, blinding of outcome assessment, and handling of withdrawals) were examined in regression models. Pooled relative risks of deep vein thrombosis with LMWH vs standard heparin in high-quality vs low-quality trials as determined by 25 quality scales. Pooled relative risks from high-quality trials ranged from 0.63 (95% confidence interval [CI], 0.44-0.90) to 0.90 (95% CI, 0.67-1.21) vs 0.52 (95% CI, 0.24-1.09) to 1.13 (95% CI, 0.70-1.82) for low-quality trials. For 6 scales, relative risks of high-quality trials were close to unity, indicating that LMWH was not significantly superior to standard heparin, whereas low-quality trials showed better protection with LMWH (P<.05). Seven scales showed the opposite: high quality trials showed an effect whereas low quality trials did not. For the remaining 12 scales, effect estimates were similar in the 2 quality strata. In regression analysis, summary quality scores were not significantly associated with treatment effects. There was no significant association of treatment effects with allocation concealment and handling of withdrawals. Open outcome assessment, however, influenced effect size with the effect of LMWH, on average, being exaggerated by 35% (95% CI, 1%-57%; P= .046). Our data indicate that the use of summary scores to identify trials of high quality is problematic. Relevant methodological aspects should be assessed individually and their influence on effect sizes explored.
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            Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.

            B Warren, A. Eid, P Singer … (2001)
            Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients. To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock. Double-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000. A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin). All-cause mortality 28 days after initiation of study medication. Overall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P =.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n = 698), the 28-day mortality was nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P =.08). This trend became significant after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo group; P =.03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001). High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.
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              Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis.

              John Victor Peter, Preeta John, Petra Graham … (2008)
              To systematically review the efficacy of steroids in the prevention of acute respiratory distress syndrome (ARDS) in critically ill adults, and treatment for established ARDS. Search of randomised controlled trials (1966-April 2007) of PubMed, Cochrane central register of controlled trials, Cochrane database of systematic reviews, American College of Physicians Journal Club, health technology assessment database, and database of abstracts of reviews of effects. Two investigators independently assessed trials for inclusion and extracted data into standardised forms; differences were resolved by consensus. Steroid efficacy was assessed through a Bayesian hierarchical model for comparing the odds of developing ARDS and mortality (both expressed as odds ratio with 95% credible interval) and duration of ventilator free days, assessed as mean difference. Bayesian outcome probabilities were calculated as the probability that the odds ratio would be > or =1 or the probability that the mean difference would be > or =0. Nine randomised trials using variable dose and duration of steroids were identified. Preventive steroids (four studies) were associated with a trend to increase both the odds of patients developing ARDS (odds ratio 1.55, 95% credible interval 0.58 to 4.05; P(odds ratio > or =1)=86.6%), and the risk of mortality in those who subsequently developed ARDS (three studies, odds ratio 1.52, 95% credible interval 0.30 to 5.94; P(odds ratio > or =1)=72.8%). Steroid administration after onset of ARDS (five studies) was associated with a trend towards reduction in mortality (odds ratio 0.62, 95% credible interval 0.23 to 1.26; P(odds ratio > or =1)=6.8%). Steroid therapy increased the number of ventilator free days compared with controls (three studies, mean difference 4.05 days, 95% credible interval 0.22 to 8.71; P(mean difference > or =0)=97.9%). Steroids were not associated with increase in risk of infection. A definitive role of corticosteroids in the treatment of ARDS in adults is not established. A possibility of reduced mortality and increased ventilator free days with steroids started after the onset of ARDS was suggested. Preventive steroids possibly increase the incidence of ARDS in critically ill adults.
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                Author and article information

                Contributors
                Changsong Wang: changsongwang@aliyun.com
                Chunjie Chi: ccjnzb0602@163.com
                Lei Guo: 57077184@qq.com
                Xiaoyang Wang: 851787303@qq.com
                Libo Guo: 780214870@qq.com
                Jiaxiao Sun: 434924071@qq.com
                Bo Sun: 774006208@qq.com
                Shanshan Liu: nobutfree@126.com
                Xuenan Chang: 794417564@qq.com
                Enyou Li: enyouli@aliyun.com
                Journal
                Journal ID (nlm-ta): Crit Care
                Title: Critical Care
                Publisher: BioMed Central (London )
                ISSN (Print): 1364-8535
                ISSN (Electronic): 1466-609X
                Publication date (Electronic): 16 October 2014
                Publication date PMC-release: 16 October 2014
                Publication date (Print): 2014
                Volume: 18
                Issue: 5
                Electronic Location Identifier: 563
                Affiliations
                [ ]Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, No 23 Youzheng Street, Nangang District, Harbin, Heilongjiang 150001 China
                [ ]Department of Anesthesiology, First Affiliated Hospital of Quan Zhou, No. 151 Yanjiang West Road, Yuexiu, Quan Zhou, Guangdong China
                [ ]Department of Anesthesiology, Tianjin Huanhu Hospital, No. 122 Qixiangtai Road, Hexi, Tian Jin 300060 China
                Article
                Publisher ID: 563
                DOI: 10.1186/s13054-014-0563-4
                PMC ID: 4213495
                PubMed ID: 25318353
                SO-VID: debc1b48-3c59-4886-a932-990a66536134
                Copyright © © Wang et al.; licensee BioMed Central Ltd. 2014
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 25 April 2014
                Date accepted : 1 October 2014
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2014

                ScienceOpen disciplines: Emergency medicine & Trauma
                Data availability:
                ScienceOpen disciplines: Emergency medicine & Trauma

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