Clinical applications of targeted temperature management

Abstract

Targeted temperature management (TTM) has been investigated experimentally and used clinically for over 100 years. The initial rationale for the clinical application of TTM, historically referred to as therapeutic hypothermia, was to decrease the metabolic rate, allowing the injured brain time to heal. Subsequent research demonstrated the temperature dependence of diverse cellular mechanisms including endothelial dysfunction, production of reactive oxygen species, and apoptosis. Consequently, modern use of TTM centers on neuroprotection following focal or global neurologic injury. Despite a solid basic science rationale for applying TTM in a variety of disease processes, including cardiac arrest, traumatic brain injury, ischemic stroke, neonatal ischemic encephalopathy, sepsis-induced encephalopathy, and hepatic encephalopathy, human efficacy data are limited and vary greatly from disease to disease. Ten years ago, two landmark investigations yielded high-quality data supporting the application of TTM in comatose survivors of out-of-hospital cardiac arrest. Additionally, TTM has been demonstrated to improve outcomes for neonatal patients with anoxic brain injury secondary to hypoxic ischemic encephalopathy. Trials are currently under way, or have yielded conflicting results in, examining the utility of TTM for the treatment of ischemic stroke, traumatic brain injury, and acute myocardial infarction. In this review, we place TTM in historic context, discuss the pathophysiologic rationale for its use, review the general concept of a TTM protocol for the management of brain injury, address some of the common side effects encountered when lowering human body temperature, and examine the data for its use in diverse disease conditions with in-depth examination of TTM for postarrest care and pediatric applications.

Figure 1.

Time course of neuronal injury mechanisms during and after cardiac arrest and the different phases during which injury occurs. The shapes of the individual curves schematically depict the severity and duration of injury during each phase. ROSC = return of spontaneous circulation.

Figure 2.

Phases of targeted temperature management (TTM). An example of a temperature curve for a patient undergoing TTM postcardiac arrest, demonstrating initiation of cooling shortly after ROSC, temperature drop during the induction phase, slight variability around target temperature during the maintenance phase, and gradual increase in temperature during controlled rewarming phase. The patient was a 69-year-old woman who had an out-of-hospital ventricular fibrillation arrest treated with defibrillation and epinephrine with ROSC 16 min after arrest. She was comatose on arrival and a rapid decision was made to initiate therapeutic hypothermia. T = temperature. See Figure 1 legend for expansion of other abbreviation.

Figure 3.

TTM-induced physiologic changes and resuscitation opportunities. Phase-specific physiologic findings have been observed in patients undergoing TTM and reported in multiple studies. These physiologic changes provide resuscitation opportunities but also may be detrimental to the patient’s outcome if not anticipated and appropriately managed. See Figure 2 legend for expansion of abbreviation.