Prehospital therapeutic hypothermia in cardiac arrest: will there ever be evidence?
© BioMed Central Ltd 2008
Published: 9 April 2008
Bruel and colleagues nicely demonstrate that the infusion of 2 l cold saline during resuscitation is a feasible, effective, and safe measure to induce therapeutic hypothermia in out-of-hospital cardiac arrest . Therapeutic hypothermia was induced in 33 eligible advanced life support patients before primary survival was foreseeable, and was continued in 11 patients after intensive care unit admission. The authors conclude that a large randomised trial should be performed.
The design of future trials on therapeutic hypothermia, however, seems challenged by the fact that withholding this treatment in a control arm might be considered unjustifiable from an ethical point of view. In the prehospital setting, such a trial would require a large number of study patients to demonstrate an additional benefit. This is due to the fact that both a spontaneous decline in body core temperature occurs, especially in the no-flow and low-flow phase, and that the overall gain of time (typically around 45 min) may be considered marginal against the background of most published data, indicating that target temperatures cannot be reached until about 6 to 8 hours later [2, 3]. Given the optimistic view that prehospital cooling increases the number of favourable neurological outcomes from 55%  to 60%, about 750 patients would have to be included in a given randomised trial.
Nevertheless, although we totally agree with Bruel and colleagues that the intervention is safe and feasible, and that a clear biological rationale for the earliest possible induction of therapeutic hypothermia exists [2–5], we doubt that a prospective randomised trial on additional prehospital cooling is feasible and justifiable. We may have reached another boundary of evidence-based medicine.
Cédric Bruel, Jean-Jacques Parienti, William Marie, Xavier Arrot, Cédric Daubin, Damien Du Cheyron, Massimo Massetti and Pierre Charbonneau
We would like to thank Schefold and colleagues for their interest in our article . Two issues are discussed in their correspondence. First, they questioned the ethical rationale of a randomised study in which the control group would not receive out-of-hospital therapeutic hypothermia (which is not yet standard practice) . We believe the findings of our small pilot feasibility study should not be overinterpreted, particularly regarding safety issues, because we presented no control group. For this reason, it is our view that the potential benefit in terms of neurologic outcome, if any, should be evaluated in a randomised controlled study.
The second issue raised by Schefold and colleagues is the small effect size and thus the large sample size required to demonstrate significant improvements. Recent animal models by Nozari and colleagues  and Zhao and colleagues  demonstrate the benefit on survival if hypothermia is induced during cardiopulmonary resuscitation. This finding supports the concept that postresuscitation injury processes begin immediately after the return of spontaneous circulation, and that cooling during advanced life support may serve as a useful therapeutic approach to improve survival.
Although we do not share Schefold and colleagues' opinion that the gain of time on cerebral disease is marginal , we agree that the potential improvement would be small, in terms of clinical outcome. For this reason, a multicentre international randomised study may be necessary.
- Bruel C, Parienti JJ, Marie W, Arrot X, Daubin C, Du Cheyron D, Massetti M, Charbonneau P: Mild hypothermia during advanced life support: a preliminary study in out-of-hospital cardiac arrest. Crit Care. 2008, 12: R31-10.1186/cc6809.PubMedPubMed CentralView ArticleGoogle Scholar
- Froehler MT, Geocadin RG: Hypothermia for neuroprotection after cardiac arrest: mechanisms, clinical trials and patient care. J Neurol Sci. 2007, 261: 118-126. 10.1016/j.jns.2007.04.042.PubMedView ArticleGoogle Scholar
- Schefold JC, Storm C, Joerres A, Hasper D: Mild therapeutic hypothermia after cardiac arrest and the risk of bleeding in patients with acute myocardial infarction. Int J Cardiol. 2008 [Epub ahead of print].Google Scholar
- Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002, 346: 549-556. 10.1056/NEJMoa012689.View ArticleGoogle Scholar
- Storm C, Schefold JC, Nibbe L, Martens F, Krueger A, Oppert M, Joerres A, Hasper D: Therapeutic hypothermia after cardiac arrest – the implementation of the ILCOR guidelines in clinical routine is possible! [Letter.]. Crit Care. 2006, 10: 425-10.1186/cc4772.PubMedPubMed CentralView ArticleGoogle Scholar
- Nolan JP, Deakin CD, Soar J, Böttiger BW, Smith G: European Resuscitation Council Guidelines for Resuscitation 2005: Section 4. Adult advanced life support. Resuscitation. 2005, 67 (Suppl 1): S39-S86. 10.1016/j.resuscitation.2005.10.009.PubMedView ArticleGoogle Scholar
- Nozari A, Safar P, Stezoski SW, Wu X, Kostelnik S, Radovsky A, Tisherman S, Kochanek PM: Critical time window for intra-arrest cooling with cold saline flush in a dog model of cardiopulmonary resuscitation. Circulation. 2006, 113: 2690-2696. 10.1161/CIRCULATIONAHA.106.613349.PubMedView ArticleGoogle Scholar
- Zhao D, Abella BS, Beiser DG, Alvarado JP, Wang H, Hamann KJ, Vanden Hoek TL, Becker LB: Intra-arrest cooling with delayed reperfusion yields higher survival than earlier normothermic resuscitation in a mouse model of cardiac arrest. Resuscitation. 2008, 77: 242-249. 10.1016/j.resuscitation.2007.10.015.PubMedPubMed CentralView ArticleGoogle Scholar
- Saver JL: Time is brain – quantified. Stroke. 2006, 37: 263-266. 10.1161/01.STR.0000196957.55928.ab.PubMedView ArticleGoogle Scholar