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Heparin Therapy Reduces 28-Day Mortality in Adult Severe Sepsis

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Heparin Therapy Reduces 28-Day Mortality in Adult Severe Sepsis Wang et al. Critical Care 2014, 18:563 http://ccforum.com/content/18/5/563 RESEARCH Open Access Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis Changsong Wang1†, Chunjie Chi1†, Lei Guo1, Xiaoyang Wang1, Libo Guo1, Jiaxiao Sun2, Bo Sun1, Shanshan Liu1, Xuenan Chang3 and Enyou Li1* 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 I2 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) (I2 = 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 I2 = 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. Introduction found that lower mortality among sepsis patients may be There are approximately 19 million new cases of sepsis related to the use of heparin, steroids, and vasoactive worldwide each year. Among them, more than one quar- drugs [3], which inspired many researchers to evaluate ter of patients die. In addition, there is an upward trend heparin for sepsis treatment. Therefore, many clinical in sepsis incidence; sepsis and septic shock have become studies have been conducted since that first report. Cur- serious health problems [1,2]. Heparin was first applied rently, the efficacy and safety of heparin in sepsis patients in the treatment of sepsis in 1966. By evaluating a novel remain controversial, with some authors suggesting that therapeutic concept in clinical practice, Martinez et al. heparin may reduce 28-day mortality [4,5] and others reporting no effect on 28-day mortality [6-9]. We con- ducted a meta-analysis of studies on heparin treatment for * Correspondence: [email protected] sepsis to evaluate the effect of heparin on 28-day mortality †Equal contributors and the occurrence of bleeding events in patients with 1Department of Anesthesiology, First Affiliated Hospital of Harbin Medical sepsis. University, No 23 Youzheng Street, Nangang District, Harbin, Heilongjiang 150001, China Full list of author information is available at the end of the article © 2014 Wang et al.; licensee BioMed Central Ltd. 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. Wang et al. Critical Care 2014, 18:563 Page 2 of 9 http://ccforum.com/content/18/5/563 Methods Central Register of Controlled Trials, and Web of Know- Search strategy for identification of studies ledge (Conference Proceedings Citation Index - Science, We conducted a systematic review and several meta- Conference Proceedings Citation Index - Social Sciences analyses of the existing literature according to the & Humanities). We did not restrict our search based on methods recommended in the PRISMA statement for language or year of publication. The last search update reporting systematic reviews and meta-analyses of stud- was July 2014. Additionally, we manually searched the ies that evaluate healthcare interventions (Figure 1). No Index Medicus of randomized clinical trials (RCTs), meta- institutional review board (IRB) approval or consents analyses, and systematic reviews for studies that were were needed for this systematic review because it evalu- missed in the initial electronic search. The search strategy ated published studies. identified 1,738 studies. Two literature review groups con- Our investigators were divided into four groups. CW ducted the literature exclusion; 66 studies were included was primarily responsible for the literature search group for potential interest. (CW and LG). JS and XW were responsible for the two literature review groups (JS, XW, LG, and XC). The tri- Inclusion and exclusion criteria als were identified by electronic and manual searches. The literature inclusion and exclusion procedures were The electronic searches were performed by two authors performed independently by two literature review groups (CW and LG) who independently searched the Medline, (XW and XC; LG and EL). We excluded review, retro- Embase, and Cochrane Library databases, the Cochrane spective analyses, repeated literature reports, and repeated Figure 1 Flow diagram of the literature search. Wang et al. Critical Care 2014, 18:563 Page 3 of 9 http://ccforum.com/content/18/5/563 experiments (the same experiment analyzed and evaluated who were treated with heparin. After the extracted data in different literature reports); purely physiological studies were reviewed and verified by different study groups, (for example, Effect of recombinant activated protein C and Stata software (Version 12.0; StataCorp LP, College low-dose heparin on neutrophil-endothelial cell interactions Station, TX, USA) was used for statistical analysis. The in septic shock [10]); imaging studies; pediatric studies; Cochrane Handbook of Systematic Reviews notes that studies on medications other than heparin; and studies the most commonly encountered effect measures used without a control group (see Table S1 in Additional file 1). in clinical trials with dichotomous data are odds ratio If data were missing, the literature search group contacted (OR) and relative risk (RR). Both are entirely valid ways the authors for the relevant data. Subsequently, the two of describing a treatment. At the same time, because the study review groups performed the initial verification. mortality was calculated over different time points in A disagreement occurred for two studies [5,9], which most study designs, the hazard ratio (HR) is a more were eventually excluded after a discussion among all appropriate parameter for mortality calculations [13]. of the authors. However, the HR may suffer relatively greater bias due to internal variability in different studies. As the value of Study selection and data abstraction the HR is considered closer to the OR, the authors chose The data extraction strategy was discussed and designed ORs and 95% confidence intervals (CIs) as approximate by two authors (CW and CC). After all of the authors parameters to evaluate the effect of heparin on 28-day had discussed and reviewed the strategy, the correspond- mortality and bleeding events in septic patients [14,15]. ing author approved the final version of the study design Between-study heterogeneity was assessed using an I2 strategy. The process yielded nine published studies. statistic (25% is defined as low heterogeneity, 50% as Two groups of researchers independently conducted a moderate heterogeneity, and 75% as high heterogeneity; second round of data extraction from the literature. Key significant heterogeneity is considered if I2 is greater data were 28-day mortality and bleeding events. If the than 50%) [16]. The fixed-effect model was applied if no relevant data were missing or ambiguous, we contacted or low significant heterogeneity was present, and pooled the authors for clarification. After the two separate lit- ORs were estimated using the Mantel-Haenszel method erature review groups conducted the data extraction, the [17]. We performed a Z significance test on pooled ORs. data were verified. If there was an inconsistency, the data Subgroup analysis was performed on bleeding events ac- extraction was repeated until a consensus was reached. cording to the sample size (that is, <100 or >100) and randomization method (that is, NRCT or RCT) of each Quality assessment study. We also assessed publication bias and small study Quality assessments were performed separately by the two bias. The Egger test was usually applied for continuous literature review groups. Studies that received inconsistent data analysis. However, the response variables of this scores were scored again by all of the authors. The quality study were dichotomous variables. Therefore,
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