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Meta-Analysis
. 2013 Feb 15:346:f839.
doi: 10.1136/bmj.f839.

Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis

Nicolai Haase  1 , Anders Perner, Louise Inkeri Hennings, Martin Siegemund, Bo Lauridsen, Mik Wetterslev, Jørn Wetterslev
Affiliations
Meta-Analysis

Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis

Nicolai Haase et al. BMJ. .

Abstract

Objective: To assess the effects of fluid therapy with hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin on mortality, kidney injury, bleeding, and serious adverse events in patients with sepsis.

Design: Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.

Data sources: Cochrane Library, Medline, Embase, Biosis Previews, Science Citation Index Expanded, CINAHL, Current Controlled Trials, Clinicaltrials.gov, and Centerwatch to September 2012; hand search of reference lists and other systematic reviews; contact with authors and relevant pharmaceutical companies.

Study selection: Eligible trials were randomised clinical trials comparing hydroxyethyl starch 130/0.38-0.45 with either crystalloid or human albumin in patients with sepsis. Published and unpublished trials were included irrespective of language and predefined outcomes.

Data extraction: Two reviewers independently assessed studies for inclusion and extracted data on methods, interventions, outcomes, and risk of bias. Risk ratios and mean differences with 95% confidence intervals were estimated with fixed and random effects models.

Results: Nine trials that randomised 3456 patients with sepsis were included. Overall, hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin did not affect the relative risk of death (1.04, 95% confidence interval 0.89 to 1.22, 3414 patients, eight trials), but in the predefined analysis of trials with low risk of bias the relative risk of death was 1.11 (1.00 to 1.23, trial sequential analysis (TSA) adjusted 95% confidence interval 0.95 to 1.29, 3016 patients, four trials). In the hydroxyethyl starch group, renal replacement therapy was used more (1.36, 1.08 to 1.72, TSA adjusted 1.03 to 1.80, 1311 patients, five trials), and the relative risk of acute kidney injury was 1.18 (0.99 to 1.40, TSA adjusted 0.90 to 1.54, 994 patients, four trials). More patients in the hydroxyethyl starch group were transfused with red blood cells (1.29, 1.13 to 1.48, TSA adjusted 1.10 to 1.51, 973 patients, three trials), and more patients had serious adverse events (1.30, 1.02 to 1.67, TSA adjusted 0.93 to 1.83, 1069 patients, four trials). The transfused volume of red blood cells did not differ between the groups (mean difference 65 mL, 95% confidence interval -20 to 149 mL, three trials).

Conclusion: In conventional meta-analyses including recent trial data, hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin increased the use of renal replacement therapy and transfusion with red blood cells, and resulted in more serious adverse events in patients with sepsis. It seems unlikely that hydroxyethyl starch 130/0.38-0.45 provides overall clinical benefit for patients with sepsis.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: AP was principal investigator for the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial and NH and JW were members of the steering committee. The 6S trial was funded by the Danish Research Council, the Rigshospitalet Research Council, and the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (the ACTA foundation). B Braun Melsungen delivered trial fluid to all sites free of charge. Neither the funders nor B Braun Melsungen had an influence on the protocol, trial conduct, data analyses, or reporting of the 6S trial. AP is head of research in his intensive care unit, which receives research funds from Fresenius Kabi and BioPorto. B Braun Melsungen has covered his travel expenses for presenting 6S data at the German Anaesthetic Congress 2012. MS was principal investigator for the Basel starch evaluation in sepsis (BaSES) trial. The BaSES trial was funded by the Department of Anaesthesia and Intensive Care of the University Hospital Basel. Fresenius Kabi delivered study fluids for free and paid for the packaging and blinding process. A signed contract between Fresenius Kabi and MS stated that MS was free to publish all data without influence from Fresenius Kabi. Fresenius Kabi covered travel expenses for MS’s participation in meetings about fluid resuscitation.

Figures

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Fig 1 Flow of papers through review. Each of the 32 excluded randomised clinical trials may have more than one reason for exclusion
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Fig 2 Forest plot of all cause mortality in relation to risk of bias in trials. Size of squares for risk ratio reflects weight of trial in pooled analyses. Horizontal bars represent 95% confidence intervals
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Fig 3 Trial sequential analysis of mortality in four trials with low risk of bias. A diversity adjusted information size of 6237 patients was calculated using α=0.05 (two sided), β=0.20 (power 80%), D2=0%, an anticipated relative risk increase of 11%, and an event proportion of 30% in the control arm. The blue cumulative z curve was constructed using a random effects model
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Fig 4 Forest plot of renal replacement therapy. Size of squares for risk ratio reflects weight of trial in pooled analyses. Horizontal bars represent 95% confidence intervals
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Fig 5 Trial sequential analysis of renal replacement therapy. A diversity adjusted information size of 1654 patients was calculated using α=0.05 (two sided), β=0.20 (power 80%), D2=0%, an anticipated relative risk increase of 35% and an event proportion of 15% in the control arm. The blue cumulative z curve was constructed using a fixed effects model. Trials with no events were included in the analysis with an empirical continuity correction of 0.01
See this image and copyright information in PMC

Comment in

References

    1. Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, et al. Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units. Crit Care 2010;14:R185. - PMC - PubMed
    1. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125-39. - PubMed
    1. Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911-6. - PubMed
    1. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg 2011;112:635-45. - PubMed
    1. Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function. Cochrane Database Syst Rev 2010;(1):CD007594. - PubMed

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