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Journal Scan: Therapeutic Hypothermia Heating Up the Debate

Chiem, Alan MD; Lovato, Luis MD

doi: 10.1097/01.EEM.0000446055.34736.0e
Journal Scan

Dr. Chiem is an assistant professor of emergency medicine at the David Geffen School of Medicine at UCLA and the director of emergency ultrasound at Olive View/UCLA Medical Center. Luis Lovato, MD, serves as the medical editor of Journal Scan, and is an associate professor at the David Geffen School of Medicine at UCLA, the ED director of clinical practice at Olive View-UCLA Medical Center, and the co-chair for the Emergency Medicine Best Practices Committee for the Los Angeles County Department of Health Services.







Emergency physicians as resuscitation team leaders are experts at achieving post-arrest return of spontaneous circulation. Unfortunately, bringing back a pulse does not equate to meaningful recovery.

Post-arrest brain injury is the most important part of the post-cardiac arrest syndrome (Resuscitation 2008;79[3]:350), causing the majority of post-arrest deaths. (Intensive Care Med 2004;30[11]:2126.) Mechanisms are not well understood but potentially include disruption of cerebral auto-regulation, microcirculatory thrombosis, activation of apoptosis, and the advent of cerebral edema. Post-cardiac arrest syndrome management includes maintaining airway protection, cerebral perfusion, and normocarbia and preventing hyperglycemia and hyperoxia.

The most successful intervention over the past 50 years to improve post-arrest return of spontaneous circulation (ROSC) survival to discharge with good neurological function is targeted temperature management (TTM), widely known as “therapeutic hypothermia.” (N Engl J Med 2002;346[8]:549; 2002;346[8]:557.) It is still unclear how TTM results in benefit; proposed mechanisms include reducing reperfusion free-radical formation and limiting ischemic damage by lowering metabolic demand. (Front Biosci 2007;12[3]:816.) A recent systematic review of four randomized clinical trials (n=481) concluded that TTM was associated with improved neurologic outcome (RR 1.55, 95% CI, 1.22-1.96) and improved survival to discharge (RR 1.35, 95% CI, 1.10-1.65). (Cochrane Database Syst Rev 2012 Sep 12;9:CD004128.)

Current TTM recommendations based on these data target a post-ROSC temperature range of 32°C-34°C for at least six to 12 hours using methods ranging from inexpensive icepacks to high-tech commercial products that regulate and monitor temperature in real time. Magnesium, benzodiazepines, or paralytics are often used to minimize shivering. Maintaining cooling requires serial monitoring and adjustment of core temperature. Finally, rewarming takes place at a rate of 0.25°C-0.5°C per hour until patients become normothermic.

Debate still exists not only about target temperatures in TTM but also its purported benefits overall. Whole body hypothermia has been associated with increased coagulopathy, myocardial dysfunction, and arrhythmia and decreased drug metabolism and immune function. TTM can also confound neurological prognostication. (N Engl J Med 2009;361[6]:605.)

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Target Temperature Management at 33°C versus 36°C after Cardiac Arrest

Nielsen N, Wetterslev J, et al

N Engl J Med


This international multicenter clinical trial enrolled 939 patients with ROSC after out-of-hospital cardiac arrest, randomizing each to either a 33°C or 36°C target body temperature for a 36-hour period. Subsequently, unconscious patients were maintained below 37.5°C. Fifteen percent of subjects died, and 48 percent regained consciousness before a study-defined neurologic assessment. The remaining third of subjects (34%) underwent extensive blinded neuro-prognostic evaluation, and 60 percent in each group had withdrawal or no escalation of care. Subjects were then followed for at least 180 days.

The overall mortality rate in each group at the end of the trial was equivalent: 50 percent in the 33°C group and 48 percent in the 36°C group (RR 1.06, 95% CI, 0.89-1.28; p=0.51). Composite measure of poor neurological performance and death at 180 days was also comparable with 47 percent of subjects in both arms having a cerebral performance category of 1 or 2 (RR 1.02, 95% CI, 0.88 to 1.16; p=0.78). No differences in the rate of infection, bleeding, arrhythmia, or seizure were seen between the groups.

The study had several key strengths to keep in mind. It was a well-coordinated international study involving 36 ICUs in eight European countries and Australia. The sample size (n=939) was more than twice the number of total patients combined in the prior randomized clinical trials that defined current TTM standards. Finally, strict predefined criteria for brain death were used to evaluate withdrawal of life-sustaining treatment. This is an important advantage over prior studies because the proportion of those patients clearly affects mortality.

The authors also pointed out some weaknesses, including that treatment teams were not blinded to treatment group (although study assessment teams were) and that a substantial proportion of eligible patients were not enrolled because of a more stringent surrogate consent requirement in one of the participating countries. Core body temperature control was imprecise, with more than 1°C variation seen in both study arms, which could lead to misclassification bias. The authors also did not do a predefined analysis of potential subgroups that may benefit from a lower temperature target.

This study represents the largest randomized controlled trial to date evaluating targeted temperature management of post-cardiac arrest patients, which demonstrated no difference in mortality or neurological outcome between 33°C and 36°C groups. These results are certain to have an effect on future post-arrest ROSC recommendations for when to initiate therapeutic hypothermia and on increasing target temperature goals to a more physiologic range.

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  • Read an abstract of the New England Journal of Medicine article, “Target Temperature Management at 33°C versus 36°C after Cardiac Arrest,” at
  • Read all of Dr. Lovato's past columns at
  • Comments about this article? Write to EMN at
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