Research Article| Volume 151, ISSUE 3, P333-341, September 15, 2011

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Hypothermia after cardiac arrest should be further evaluated—A systematic review of randomised trials with meta-analysis and trial sequential analysis

  • Niklas Nielsen
    Corresponding author. Department of Anaesthesia and Intensive Care, Helsingborg Hospital, S. Vallgatan 5, S-251 87 Helsingborg, Sweden. Tel.: +46 42 4061000.
    Department of Clinical Sciences, Section of Anesthesia and Intensive Care, Lund University, S-221 85 Lund, Sweden and Department of Anesthesia and Intensive Care, Helsingborg Hospital, S-251 87 Helsingborg, Sweden
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  • Hans Friberg
    Department of Clinical Sciences, Section of Anesthesia and Intensive Care, Lund University, S-221 85 Lund, Sweden and Department of Emergency Medicine, Lund University Hospital, S-221 85 Lund, Sweden
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  • Christian Gluud
    Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
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  • Johan Herlitz
    Department of Cardiology, Sahlgrenska University Hospital, S-413 19 Gothenburg, Sweden
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  • Jørn Wetterslev
    Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
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      Guidelines recommend mild induced hypothermia (MIH) to reduce mortality and neurological impairment after out-of-hospital cardiac arrest. Our objective was to systematically evaluate the evidence for MIH taking into consideration the risks of systematic and random error and to GRADE the evidence.


      Systematic review with meta-analysis and trial sequential analysis of randomised trials evaluating MIH after cardiac arrest in adults. We searched CENTRAL, MEDLINE, and EMBASE databases until May 2009. Retrieved trials were evaluated with Cochrane methodology. Meta-analytic estimates were calculated with random- and fixed-effects models and random errors were evaluated with trial sequential analysis (TSA).


      Five randomised trials (478 patients) were included. All trials had substantial risk of bias. The relative risk (RR) for death was 0.84 (95% confidence interval (CI) 0.70 to 1.01) and for poor neurological outcome 0.78 (95% CI 0.64 to 0.95). For the two trials with least risk of bias the RR for death was 0.92 (95% CI 0.56 to 1.51) and for poor neurological outcome 0.92 (95% confidence interval 0.56 to 1.50). TSA indicated lack of firm evidence for a beneficial effect. The substantial risk of bias and concerns with directness rated down the quality of the evidence to low.


      Evidence regarding MIH after out-of-hospital cardiac arrest is still inconclusive and associated with non-negligible risks of systematic and random errors. Using GRADE-methodology, we conclude that the quality of evidence is low. Our findings demonstrate that clinical equipoise exists and that large well-designed randomised trials with low risk of bias are needed.


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