Source: Arrich J, Holzer M, Herkner H, Müllner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database of Systematic Reviews 2009.
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. New England Journal of Medicine 2002;346(8):557–63.
Hypothermia after Cardiac Arrest Study Group (HACA). Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. New England Journal of Medicine 2002;346(8):549–56.
Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001;51(3):275–81.
Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. New England Journal of Medicine. 2014; 269:2197-206
Efficacy Endpoints: Neurologic recovery (best outcome while in hospital, as measured by cerebral performance categories), survival to hospital discharge
Harm Endpoints: Bleeding, pneumonia, sepsis, pulmonary edema, cardiac dysrhythmias
Narrative: After the return of spontaneous circulation following cardiac arrest, neurologic injury may occur in the process of reperfusion. Past investigations have suggested that the induction of hypothermia in initially comatose survivors can help mitigate this injury through several potential mechanisms, including reduction of free radical and neurotransmitter-mediated neuron damage, improved cerebral microcirculation, and protection of the blood-brain barrier. The Cochrane review included five randomized trials and excluded two from data pooling, one because of limited information and the other because it utilized hemofiltration as a means of hypothermia. The remaining three trials comprised 195 comatose subjects treated with mild hypothermia (32-34˚C) and 188 controls. All trials utilized external cooling. Pooled analysis of these trials revealed a relative risk of 1.55 (95% CI 1.22-1.96) for good neurologic outcome overall, and relative risk of 1.35 (95% CI 1.1-1.65) for survival to hospital discharge when considered alone. The NNT for these pooled outcomes were 5 and 7, respectively.
Adverse events were addressed in each of the 3 studies, though none were powered to detect differences. These adverse events included, but were not limited to, pneumonia, bleeding, need for transfusion, sepsis, pulmonary edema, lethal arrhythmias, and renal failure. There were no statistically significant differences between treatment groups.
More recently, a targeted temperature approach was published in 2013 in the NEJM. This international, randomized controlled study enrolled adult patients with a cardiac arrest of presumed cardiac cause. These patients were randomized to a 33˚C versus a 36˚C cooling protocol with a primary outcome of survival until the end of the trial and secondary outcomes of neurological function and complications. Part of the premise of this study was that avoidance of the febrile state may accord much of the neurologically intact survival benefit. This study was more than triple the size of the original 2002 NEJM HACA study with 939 patients and used neuroprognostication in determining when to withdraw care; this is the first time this concept was used in a therapeutic hypothermia study. The study found no difference in the primary outcome between the two groups (50% versus 48% for 33˚C and 36˚C, respectively, p=0.51). The secondary outcomes had no statistically significant difference. This study did not show a statistical difference in adverse events between the groups.
Caveats: Only three trials were pertinent for inclusion, one of which was a small feasibility trial. There was substantial clinical heterogeneity among the trials, although the survival and neurologic outcome results were statistically homogenous as measured by the I2 statistic. In addition, Bernard and HACA focused on patients with ventricular arrhythmias as their first observed cardiac rhythm, while Hachimi-Idrissi only examined patients with initial asystole/PEA. The inclusion of subjects with an initial rhythm other than ventricular arrhythmia remains a subject of ongoing debate and this third trial that enrolled such subjects was the smallest (n=33), thus it is unclear the degree to which this can be considered evidence in support of this practice. Patients also reached target temperature at different times (2 hours vs. 8 hours) and average duration of cooling varied significantly (3 hours vs. 24 hours).
Finally, we chose not to report improvement in neurologic outcome and survival to discharge as separate outcomes (as the Cochrane review did) because neurologically intact survival is clinically relevant and includes overall survival. Improved neurologic outcome in survivors treated with a hypothermia protocol versus control survivors was not individually tested, is not distinguishable in the reported studies, and would require larger studies.
Author: Seth Gemme, MD, Brandon Maughan, MD and Anthony M. Napoli, MD FACEP
Published/Updated: August 20, 2015
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