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

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f839 (Published 15 February 2013) Cite this as: BMJ 2013;346:f839
  1. Nicolai Haase, physician1,
  2. Anders Perner, professor1,
  3. Louise Inkeri Hennings, physician1,
  4. Martin Siegemund, professor2,
  5. Bo Lauridsen, physician1,
  6. Mik Wetterslev, medical student1,
  7. Jørn Wetterslev, chief physician3
  1. 1Department of Intensive Care, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
  2. 2Department of Anaesthesia, Intensive Care and Rescue Medicine, Baden State Hospital AG, Baden, Switzerland
  3. 3Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 3, DK-2200 Copenhagen, Denmark
  1. Correspondence to: N Haase nicolai.haase{at}rh.regionh.dk
  • Accepted 30 January 2013

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 Published and unpublished trials were included irrespective of language and predefined outcomes.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.

Footnotes

  • We thank Sarah Klingenberg, search coordinator for the Cochrane Hepato-Biliary Group, for performing the literature search; Xia Yun for evaluating references in Chinese and extracting data from two Chinese articles included in the review; Dimitrenka Nikolova, Copenhagen Trial Unit, for evaluating four papers in Russian; Naoya Sakamoto for evaluating one paper in Japanese; and Arnaldo Dubin, Petr Svoboda, and Martin Westphal for providing data for this systematic review. The trial protocol was registered through PROSPERO (registration No CRD42011001762).

  • Contributors: NH developed the protocol, was responsible for the searches, selected trials, extracted data, assessed the risk of bias of trials, did the data analysis, and developed the final review. AP developed the protocol, analysed data, and developed the final review. LIH developed the protocol, selected trials, extracted data, assessed the risk of bias of trials, and developed the final review. MS extracted data, assessed the risk of bias of trials, and developed the final review. BL and MW developed the protocol, selected trials, and developed the final review. JW developed the initial idea for the review, developed the protocol, selected trials, advised on statistical methods, analysed data, and developed the final review. All authors read and approved the final manuscript. NH and JW are the guarantors.

  • 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.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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