Is It Still Cool to Cool? Interpreting the Latest Hypothermia for Cardiac Arrest Trial: March 2014 Annals of Emergency Medicine Journal Club

Abstract

1.The authors reference 2 previous trials2,3 that compared therapeutic hypothermia (32°C to 34°C [89.6F to 93.2F] for 12 to 24 hours) with standard treatment and “showed a significant improvement in neurologic function and survival with therapeutic hypothermia.”1AWhat was the treatment effect in the previous 2 studies? What percentage of patients had neurologically intact survival? How many patients would one need to treat with hypothermia to produce 1 additional neurologically intact patient?BThere is good evidence that the presence of an initial shockable rhythm greatly enhances the probability of survival from cardiac arrest. Have any randomized trials demonstrated an improvement in neurologic outcomes in patients whose initial rhythm was pulseless electrical activity or asystole?2.Previous studies have reported deleterious effects when patients recovering from an out-of-hospital cardiac arrest develop fever,1,4,5 leading authors to question whether reported benefits are due to hypothermia or prevention of hyperthermia.1 The authors conducted a multicenter, international trial that randomized unconscious adults, who had return of spontaneous circulation after out-of-hospital cardiac arrest, to either 33°C or 36°C (91.4F or 96.8F) temperature target.AThe current recommendation by many expert consensus groups is to cool out-of-hospital cardiac arrest victims to 32°C to 34°C (89.6F to 93.2F) after ventricular fibrillation and possibly other rhythms. The authors did not follow this recommendation for one of the arms of the study. Do you believe there was equipoise? Discuss the importance of equipoise in clinical research.BCould this trial have been performed in the United States? What additional requirements would the investigators have to complete to receive institutional review board approval for exception from informed consent?CThe authors note the inability to blind the critical care practitioners; however, they were able to blind the assessors providing follow-up neurologic examination. Were the methods used to eliminate the risk of critical care provider bias sufficient?3.The authors examined the primary outcome of survival time and followed patients up to the end of the trial (ie, 180 days after the enrollment of the last patient) and powered the study to this outcome.AThe trial was designed as a superiority trial to detect a 20% reduction in the hazard ratio for death with hypothermia at 33°C (91.4F) versus a control group at 36°C (96.8F). Was the study appropriately powered for this outcome?BHow would the power calculations change if the study design were a noninferiority trial of relative normothermia at 36°C (96.8F) versus hypothermia at 33°C (91.4F)?CWhat were the secondary outcomes? Discuss the advantages and disadvantages of using composite outcomes in medical research.DTherapeutic hypothermia causes many physiologic changes and potential dangers to the patient. Therefore, the authors also collected the incidence of predefined serious adverse events up to day 7 in the ICU. Which specific adverse events did they collect? Do you think these adverse events and 7-day interval were sufficient? If not, what other events or intervals might you have chosen?ETo evaluate neurologic outcomes, the authors used the Cerebral Performance Category (CPC) and the modified Rankin score (mRS). For scores to be effective, they should be already validated. Have these 2 scores been previously validated? Are there other scores that the authors could have used?4.For analysis of their results, hazard ratios were used for the analysis of the primary outcome (end-of-trial mortality), but risk ratios were used to analyze the secondary outcomes (CPC score, mRS). What are the differences between hazard ratios and risk ratios? Why did the authors use different tests to analyze their primary and secondary outcomes?5.If you were creating a cardiac arrest protocol in your hospital, what would you set for the target temperature? Do you think the temperature or the protocol is more important for survival?