The remarkable career of leptin: from antidote to obesity to mediator of lung inflammation.

490 www.ccmjournal. org February 2014 • Volume 42 • Number 2 δPKC can induce apoptosis. δPKC may further damage mitochondria directly (11). Although the findings of the study by Suh et al (8) are important, both in terms of the basic science of cerebral ischemia/reperfusion and the clinical application of therapeutic hypothermia, the model does have some important limitations. First, the model does not include long-term functional or histopathologic outcome. The histopathologic findings at 60 hours may not correlate with functional outcome. Second, and perhaps more importantly, since the outcome was observed within hours of rewarming, one possible explanation for the results is that more prolonged hypothermia merely delays the inevitable neuronal death and neurologic dysfunction. Third, Suh et al (8) utilized a volatile anesthetic agent throughout the experiment, which may have impacted hemodynamics and would not have been used clinically. The other downside of using such an agent is its potential impact on the mechanisms of neurologic dysfunction after cardiac arrest (12). Using animal models with robust clinically relevant insults and outcome measures, in theory, one could determine the optimal depth and duration of hypothermia for a variety of controlled ischemic insults. The clinical problem, however, is that the exact nature of the insult is never completely known. Although clinicians could suspect that one patient’s insult was worse than another and therefore treat the former patient with more prolonged hypothermia, this approach would be arbitrary and impossible to study or standardize. Ideally, researchers will develop markers of cerebral injury that could be used to titrate both the depth and duration of hypothermia. There is good data to suggest that therapeutic hypothermia is beneficial for comatose survivors of cardiac arrest. Whether or not more is better is yet to be determined. REFERENCES 1. Nichol G, Thomas E, Callaway CW, et al; Resuscitation Outcomes Consortium Investigators: Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008; 300:1423–1431 2. The 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 3. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557–563 4. Peberdy MA, Callaway CW, Neumar RW, et al; American Heart Association: Part 9: Post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S768–S786 5. Ravitch MM, Lane R, Safar P, et al: Lightning stroke. Report of a case with recovery after cardiac massage and prolonged artificial respiration. N Engl J Med 1961; 264:36–38 6. Che D, Li L, Kopil CM, et al: Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Crit Care Med 2011; 39:1423–1430 7. Guenther U, Varelmann D, Putensen C, et al: Extended therapeutic hypothermia for several days during extracorporeal membrane-oxygenation after drowning and cardiac arrest: Two cases of survival with no neurological sequelae. Resuscitation 2009; 80:379–381 8. Suh GJ, Kwon WY, Kim KS, et al: Prolonged Therapeutic Hypothermia Is More Effective in Attenuating Brain Apoptosis in a Swine Cardiac Arrest Model. Crit Care Med 2014; 42:e132 –e142 9. Bright R, Raval AP, Dembner JM, et al: Protein kinase C delta mediates cerebral reperfusion injury in vivo. J Neurosci 2004; 24:6880–6888 10. Zhao H, Yenari MA, Sapolsky RM, et al: Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome C release. Stroke 2004; 35:572–577 11. Raval AP, Dave KR, Prado R, et al: Protein kinase C delta cleavage initiates an aberrant signal transduction pathway after cardiac arrest and oxygen glucose deprivation. J Cereb Blood Flow Metab 2005; 25:730–741 12. Matchett GA, Allard MW, Martin RD, et al: Neuroprotective effect of volatile anesthetic agents: Molecular mechanisms. Neurol Res 2009; 31:128–134