A188E. Sample size in hypothermia randomized controlled trials

[Versión en español]

Until recently, only five randomized clinical trials (RCTs ) had been published on the effectiveness of induced hypothermia in recovered cardiac arrest, one of them only in abstract form. They were small size (figure), and suffered from methodological limitations. Two previous meta-analysis, carried out on four [1] and five [2] of these RCT concluded that hypothermia decreased mortality and increased the likelihood of brain function recovery, not taking into account the uncertainty arising from the limited available evidence, as shown in a third meta-analysis [3]. Empiric studies have shown that disregarding the inaccuracy derived from a small sample size in relation to the magnitude of the therapeutic effect can be misleading in many meta-analysis [4], and erroneously inform clinical practice guidelines.
Recently a new randomized clinical trial [5] on hypothermia in cardiac arrest has been published [5], which, besides being less prone to bias and more consistent with current standards of therapy than previous, includes many more patients, changing the sign of the summarized evidence [6]. Nielsen study alone provides twice as many patients than all previous studies combined. The most recent clinical trial (Nielsen 2013) includes almost four times more patients than the previous largest (HACA 2002). The total number of patients included now in the updated meta-analysis has been tripled by Nielsen study (Figure).

Eduardo Palencia Herrejón, Hospital Universitario Infanta Leonor, Madrid.
Domingo Díaz Díaz, Hospital Universitario Infanta Leonor, Madrid.
Ramón Díaz-Alersi, Hospital Universitario Puerto Real, Cádiz.
Ferran Roche Campo, Hospital Verge de la Cinta, Tortosa (Tarragona).
© REMI, http://medicina-intensiva.com. Enero 2014.


  1. Systematic review of randomized controlled trials of therapeutic hypothermia as a neuroprotectant in post cardiac arrest patients. Cheung KW, Green RS, Magee KD. CJEM 2006; 8: 329-337. [PubMed]
  2. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Arrich J, Holzer M, Herkner H, Mullner M. Cochrane Database Syst Rev 2009; 4: CD004128. [PubMed]
  3. Hypothermia after cardiac arrest should be further evaluated--a systematic review of randomised trials with meta-analysis and trial sequential analysis. Nielsen N, Friberg H, Gluud C, Herlitz J, Wetterslev J. International journal of cardiology 2011; 151: 333-341. [PubMed]
  4. Random error in cardiovascular meta-analyses: how common are false positive and false negative results? AlBalawi Z, McAlister FA, Thorlund K, Wong M, Wetterslev J. Int J Cardiol 2013; 168: 1102-1107. [PubMed] [REMI]
  5. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Aneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Køber L, Langørgen J, Lilja G, Møller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H; the TTM Trial Investigators. N Engl J Med 2013. [PubMed] [REMI]
  6. Palencia Herrejón E. Papel de la hipotermia tras la parada cardiaca: metaanálisis de ensayos clínicos. [REMI 2013; 13(12): A183


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