A new generation of therapeutic hypothermia: Using a warm syringe to cool*

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Since the development of modern cardiopulmonary resuscitation (CPR), the overall survival from cardiac arrest resuscitation and quality of life after survival has been dismal. This overall poor outcome is a consequence of a complex multisystems injury that has been recently described as the postcardiac arrest syndrome (1). As part of the postcardiac arrest syndrome, postarrest brain injury has been a major determinant of survival and quality of life after resuscitation. Research in the area of pathophysiology and neuroprotective therapies for brain injury after successful CPR is rich in basic and preclinical experimental success. Yet, a multitude of translational and clinical trials of neuroprotective strategies in resuscitated patients failed to show outcome benefits. The only exception was therapeutic hypothermia. Backed with bedside experience, bench research, and clinical trials, therapeutic hypothermia showed not only survival benefit but also ameliorated neurologic injury to improve the quality of life in cardiac arrest survivors (1–4). The success of therapeutic hypothermia is gaining wider acceptance and has become part of the 2010 postcardiac arrest management guidelines of the American Heart Association (5).Currently, the implementation of therapeutic hypothermia includes physical and mechanical methods, including surface cooling and intravascular cooling. Although survival to hospital discharge and neurologic function up to 1 yr later was equal with both methods (6), they both have limitations, including the need for technical expertise and elaborate set-up, many hours to achieve the target temperature, and the occurrence of shivering, which can be counterproductive. Furthermore, each has specific side effects, such as hyperglycemia in surface cooling and hypomagnesemia in intravascular cooling (6). Intravascular cooling has a higher incidence of deep vein thrombosis (7), although surface cooling may have higher risk of skin injury in certain patients (8). An added approach to these methods includes the administration of ice-cold saline through a peripheral line immediately after resuscitation to hasten reaching target temperatures that may provide added outcome benefit (9).As we learn more about the real-world benefits and challenges of therapeutic hypothermia, it has sparked many questions and controversies, including the mechanism of how it works, how to deliver it, what the ideal temperature is, and who the best candidates are for therapy (10–12). As we continue to further develop therapeutic hypothermia, we may start its evolution by imagining that instead of laboriously inserting a cooling catheter into a central vein, applying sticky pads to the skin, transporting a refrigeration unit to a resuscitation site, or carrying loads of ice packs to patients after successful CPR, what if one could induce mild therapeutic hypothermia by simply administering a medication via a syringe into a peripheral vein? Now imagine paramedics administering such a medication intravenously immediately after resuscitating a patient in the field, or physicians in hospital code teams administering the same medication immediately after return of circulation.In this issue of Critical Care Medicine, Dr. Weng et al (13) demonstrate how cholecystokinin octapeptide (CCK8) can induce mild hypothermia while also improving outcome in rats undergoing CPR after cardiac arrest. Weng et al chose to test CCK8 because of its long-known ability to induce hypothermia when injected peripherally (14, 15), its anti-inflammatory properties (16, 17), and its ability to optimize neurologic and cardiac function (18, 19). After inducing ventricular fibrillation in rats, they resuscitated rats by CPR and peripherally administered either CCK8 or saline into rats 30 mins after resuscitation. While controlling for the ambient temperature and heat exposure, they injected rats with CCK8, which gradually lowered their core temperature to 34.8°C.

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