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Bakken Lecture: The brain, the heart, and therapeutic hypothermia

April 1, 2009|Cleveland Clinic Journal of Medicine
Patrick M. Kochanek, MD
Author and Disclosure Information

Patrick M. Kochanek, MD
Department of Critical Care Medicine, Department of Pediatrics, Safar Center for Resuscitation Research, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA

Correspondence: Patrick M. Kochanek, MD, Director, Safar Center for Resuscitation Research; Professor and Vice Chairman, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3434 Fifth Avenue, Pittsburgh, PA 15260; kochanekpm@ccm.upmc.edu

Dr. Kochanek reported that he has no financial interests or relationships that pose a potential conflict of interest with this article.

Dr. Kochanek is a co-holder of the patent on the Emergency Preservation and Resuscitation Method. He is supported by grants from the National Institutes of Health (NS38087, NS30318, HD04686), the United States Army (PRMRP PR054755 W81XWH-06-1-0247), the Defense Advanced Research Projects Agency, the Centers for Disease Control and Prevention, and the Laerdal Foundation.

ABSTRACT

Therapeutic hypothermia in acute resuscitation medicine has a long history, but its currently recommended use dates back to work in the mid-1960s by the late Dr. Peter Safar and colleagues. Compared with normothermia, mild therapeutic hypothermia, induced right after restoration of spontaneous circulation in comatose survivors of cardiac arrest, leads to 1 additional patient with intact neurological outcome for every 6 patients treated. Demonstrating benefit from therapeutic hypothermia in other acute neurological insults, such as traumatic brain injury, has been more difficult. Current research to optimize the benefits of mild therapeutic hypothermia in cardiac arrest is focused on hypothermia’s profound effects on drug metabolism, determining the best anesthetics and sedatives to use with cooling, and identifying compounds that may promote induction of hypothermia or create a poikilothermic state. Future applications of therapeutic hypothermia may include induction of emergency preservation and resuscitation to buy time for damage-control surgery in patients with exsanguination cardiac arrest.

FUTURISTIC APPLICATIONS OF THERAPEUTIC HYPOTHERMIA

Emergency preservation and resuscitation

Exsanguination cardiac arrest is one of the most refractory types of cardiac arrest, with mortality rates generally greater than 95%.31 Obviously, therapies such as CPR are ineffective in the absence of an adequate circulating blood volume.

Figure 2. Schematic of aortic cold flush for the induction of emergency preservation and resuscitation (EPR) to rapidly create a transient state of hypothermic preservation in otherwise lethally injured victims of exsanguination cardiac arrest. After damage-control surgery, resuscitation is performed via cardiopulmonary bypass (see text for details).
In 1984, Dr. Peter Safar and military expert Col Ronald Bellamy pioneered a new approach to exsanguination cardiac arrest that they called suspended animation for delayed resuscitation. The concept was a logical one—namely, in the setting of otherwise lethal trauma-induced exsanguination cardiac arrest, a transient state of preservation would be induced to buy time for damage-control surgery, and then a delayed resuscitation would be carried out using cardiopulmonary bypass. Our center has worked on this concept since 1988 in studies funded initially by the US Navy and later by the US Congress. Ultimately, we coined the phrase emergency preservation and resuscitation (EPR) for this method. Using a canine model of exsanguination cardiac arrest, we first demonstrated the feasibility of this approach by inducing a state of preservation via an aortic flush of iced saline.32 A schematic of the protocol is presented in Figure 2.

In initial reports,32–34 we targeted relatively brief insults ranging from 15 to 60 minutes. We determined that for insults at or beyond 60 minutes, profound levels of hypothermia (tympanic temperature of ~10°C) were most effective.34 In subsequent studies, we demonstrated that pharmacologic adjuncts to hypothermia were relatively ineffective. Indeed, only one agent, the brain-penetrating antioxidant Tempol, enhanced the efficacy of profound hypothermia.35 We also demonstrated that the prolonged use (36 to 48 hours) of mild hypothermia after the acute application of EPR further enhanced neurological outcomes as compared with more rapid rewarming.36 Similarly, unlike drugs, the addition of energy substrates (namely, dissolved oxygen and 2.5% dextrose) to the flush facilitated the ability to achieve remarkably long EPR durations in experimental exsanguination cardiac arrest—as long as 3 hours of preservation at approximately 10°C.37 These findings could also have important implications for optimizing conventional use of deep hypothermia circulatory arrest in cardiac or neurological surgery. We also have recently developed a rat model of EPR using a miniaturized cardiopulmonary bypass system. It is used to screen novel therapeutic adjuncts to EPR and to study mechanisms of neuroprotection in this special paradigm.38,39

Two other investigative teams, one at Harvard University and another at the Vienna General Hospital, have also been exploring the use of EPR-related technologies—and observing similar success. Alam et al40 have used a low-flow EPR approach in pigs to facilitate damage-control surgery after otherwise lethal traumatic insults. Janata et al41 have successfully used EPR in the setting of refractory normovolemic cardiac arrest, simulating the typical cardiac arrest victim who cannot be resuscitated in either the field or the emergency department.

Finally, the EPR concept recently received funding to proceed to a clinical trial in civilian trauma. The study, to be led by Dr. Samuel Tisherman, one of the pioneers of this approach at the Safar Center, will include several trauma centers in the United States and target otherwise lethally injured trauma victims with exsanguination cardiac arrest.

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