The incidence of out-of-hospital sudden cardiac arrest (OHCA) in industrial countries is reported to be between 35.7 and 128.3 cases per 100,000, with a mean of 62 cases per year. [6] This translates into approximately 300,000 people in the United States and about the same number in Europe each year. Despite nearly 40 years of prehospital advanced life support, the survival rate of OHCA is very poor. [7] Less than half of victims who develop return of spontaneous circulation (ROSC) survive to leave the hospital alive, and the cause of death is anoxic brain injury in most patients with ROSC who die within one month of the cardiac arrest. Inducing mild therapeutic hypothermia in selected patients surviving OHCA has a major impact on long-term neurologically intact survival and may prove to be one of the most important clinical advancements in the science of resuscitation.

Some early great physicians, including Hippocrates, recognized the utility of hypothermia in attenuating injury. [8] The concept has experienced periodic reemergence in the medical literature, and recent studies of the modality date back mostly to the 1950s. In 1954, Hegnauer and D'Amato demonstrated decreased oxygen consumption in hypothermic dogs, [9] and the study by Benson et al of hypothermia after cardiac arrest in humans [10] demonstrated decreased mortality.

Until relatively recently, evidence for targeted temperature management (TTM) has lacked sufficient weight and the advisory panel support that thereby follows to propel it into common practice. Despite its 2005 inclusion in American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care, and 2003 advisory statements by the International Liaison Committee on Resuscitation (ILCOR) and the European Resuscitation Council (ERC), TTM is largely misunderstood and inconsistently applied. [11, 12, 13] The 2015 guidelines have modified the specific temperature range and duration of TTM on the basis of several more recent studies. [2]

A 2011 meta-analysis of randomized controlled trials found that TTM with conventional cooling methods improves both survival and neurologic outcomes at hospital discharge for patients who experienced cardiac arrest. [14]

In a retrospective cohort study covering 7 years that assessed the impact of TTM on early repolarization (ER) in survivors of cardiac arrest attributed to idiopathic ventricular fibrillation (ID-VF) compared with a control group who experienced coronary artery disease-related VF (CAD-VF), Williams et al found that hypothermia increased the prevalence and mean amplitude of ER in cardiac arrest survivors. [15] ER occurred in all survivors of ID-VF (100%) compared with over two third of survivors of CAD-VF (67%); TTM increased ER amplitude only in CAD-VF survivors. [15]

Two early studies demonstrated improved survival and neurological outcomes with induction of mild therapeutic hypothermia for comatose survivors of OHCA. The Hypothermia after Cardiac Arrest Study Group showed that, when applied to unconscious OHCA patients with ROSC (n=274), mild hypothermia (cooling to 32ºC-34ºC) provided significant improvement in functional recovery at hospital discharge (55% vs 39%; number needed to treat [NNT] = 6) and lower 6-month mortality rate when compared with patients who were not cooled (41% vs 55%) (NNT = 7). [16]

The NNT is very low and comparable to other important emergent treatments such as cardiac catheterization for acute coronary syndrome. [17] Bernard examined endpoint of survival to hospital discharge to home or a rehabilitation facility (good outcome) in 77 patients and demonstrated 49% in the hypothermia group compared with 26% in the normothermic group, finding an NNT of 4.5 for death and severe disability. [18]

After studying 133 comatose patients who experienced after OHCA and were treated with TTM, Kragholm et al found that one year later, most patients who were able to work prior to cardiac arrest were able to return to work. [19]

In a prospective, observational study that investigated the rate of good neurologic outcome based on the duration of resuscitation efforts in 86 OHCA) patients treated with TTM, Kim et al reported a median downtime of 18.5 minutes, with 33 patients (38.0%) having a good neurologic outcome. [20] Good neurologic outcomes were greatest when downtime was shortest: 62.5% at 10 minutes or less, 37% at 11-20 minutes, 25% at 21-30 minutes, and 21.7% at longer than 30 minutes. Interestingly, nearly one quarter of patients (22.9%) had a good neurologic outcome even with downtown longer than 20 minutes, a percentage that increased to 37.5% in patients with an initial shockable rhythm. [20]

A 2013 randomized control trial suggested no change in neurologic outcome and survival at 6 months in OHCA for 33ºC and 36ºC, followed by avoidance of fever for 72 hours. [21] Both groups in the study received some form of temperature management. The investigators found no difference in mortality and no difference in neurologic outcome between the groups. However, unlike the Bernard study, this trial included arrest other than VF/pVT OHCA. [21] Currently, advanced cardiac life support (ACLS) guidelines state that a temperature between 33ºC and 36ºC is recommended for at least 24 hours after achieving the target temperature. [2]

In a more recent systematic review and meta-analysis (2000-2016) that evaluated the effects of TTM on mortality and neurologic outcome, investigators found low-quality evidence supporting in-hospital initiation and maintenance of TTM at 32ºC-36ºC among adult OHCA survivors with an initial shockable rhythm for 18-24 hours. [22] There was no benefit of TTM for survivors of in-hospital cardiact arrest nor for those of OHCA with a nonshockable rhythm. In addition, there was no difference between endovascular and surface cooling TTM systems, and no benefit of adding feedback control to TTM systems. Moderate quality evidence also revealed no benefit for initiating prehospital TTM. [22]

In a multicenter retrospective study (2008-2013) that evaluated 1-year functional outcome (32ºC-34ºC) in 101 patients following intraoperative cardiac arrest (IOCA), Constant et al noted that less than one third (29.7%) received TTM. [23] Patients treated with TTM had an increased risk of infection but not with hemorrhage, arrhythmia, or metabolic/electrolyte disorders; TTM was not an independent prognosticator of 1-year favorable functional outcome after IOCA. [23]

Literature primarily evaluating different durations of TTM are lacking, as most studies maintain temperatures for at least 24 hours, with some longer (36 hours), followed by slow return to normothermia. Temperature sensitivity of the central nervous system following cardiac arrest can last as long as coma is present, and the duration of the TTM upper limit is unknown. [2]

TTM may also confer benefits to patients experiencing cardiac arrest in other clinical environments, [24] patients with hemorrhagic shock, [25] and patients with other forms of severe brain injury. [26, 27, 28, 29] Currently, at least 19 clinical trials are underway and focus principally on ROSC, traumatic brain injury, stroke, neonatal hypoxic-ischemic encephalopathy, and medical device safety. [30] Currently, no evidence supports using this modality for stroke. [31]

The process of selecting patients and initiating therapy is not complex. The ERC states that hypothermia is "safe and effective even if there is lack of experience." [32] The practice has been successfully applied in the academic tertiary care environment and in the community hospital setting, and it has been successfully implemented in the prehospital environment. [33, 34, 35, 36]

Implementation of hypothermia does require planning, education, and integration of multiple services within an institution. The basic framework for clinical protocols are well established, and institutions interested in establishing protocols may find a substantial amount of prior art in the literature (see hypothermia protocols).

Summary of 2015 AHA guidelines for CPR and emergency cardiovascular care regarding the use of hypothermia

Note the following [2] :

Induce hypothermia for unconscious adult patients with return of spontaneous circulation (ROSC) after OHCA when the initial rhythm was VF or pVT (class I, level of evidence: B-R)

Similar therapy may be beneficial for patients with non-VF/non-pVT (nonshockable) OHCA or with in-hospital arrest (class I, level of evidence: C-EO)

The temperature should be maintained between 32ºC and 36ºC (class I, level of evidence: B-R)

It is reasonable to maintain TTM for at least 24 hours (class IIa, level of evidence: C-EO)

Routine prehospital cooling of patients with ROSC with IV rapid infusion is not advised (class III: no benefit; level of evidence A)

It is reasonable to prevent fever in comatose patients after TTM (class IIb, level of evidence C-LD)

Hemodynamically stable patients with spontaneous mild hypothermia (>33°C) after resuscitation from cardiac arrest should not be actively rewarmed

Take home points

Note the following: