Therapeutic hypothermia is not dead, but hibernating!
Article information
Therapeutic hypothermia (TH) began to be recommended as a treatment for comatose post–cardiac arrest resuscitation patients in 2003. Numerous laboratory studies have shown that post-resuscitation cooling can significantly reduce the severities of ischemia/reperfusion injuries that can damage the brain following cardiac arrest. Two landmark clinical studies, in which post-resuscitation patients were cooled to 32 to 34 °C and maintained at that level for 12 to 24 hours, reported that TH yielded significant improvements in survival and neurological recoveries [1,2]. These and other studies led to a broad acceptance of this treatment, leading to the addition of TH to the 2003 guidelines issued by the International Liaison Committee on Resuscitation (ILCOR) [3]. However, in 2013, a large randomized clinical trial which is often referred to as the “TTM Study” [4], reported that using targeted temperature management (TTM) to cool post-resuscitation patients to 33 °C yielded no better outcomes than did maintaining patients at 36 °C. Based largely on this study, the 2015 ILCOR treatment guidelines were revised to recommend a target temperature of 32 to 36 °C [5]. In 2021 the TTM2 Study was published, which reported that post-resuscitation patients cooled to 33 °C had similar outcomes to those who simply received fever prevention (core temperature, ≤37.8 °C) [6]. In that same year ILCOR issued draft guidelines that recommended keeping comatose post-resuscitation patients below 37.5 °C, stating that it was not clear whether some cardiac arrest patients might benefit from targeting hypothermia at 32 to 34 °C
Some recent publications, including those by Taccone et al. [7] and Spears and Greer [8], have concluded that TH of 32 to 34 °C is ineffective in improving outcomes in sudden cardiac death patients. However, this conclusion has three major flaws:
(1) It is predominantly based on the TTM and TTM2 studies, which used extremely slow cooling procedures, taking 5 to 10 hours after return of spontaneous circulation (ROSC) to reach target TH. Such late cooling does not have the ability to significantly impact the biochemical mechanisms of reperfusion injury that occur over the first 4 hours after ROSC.
(2) Enrollment in the above cited studies occurred hours after ROSC. With similar logic as above, delayed therapeutic interventions in critical conditions do not work. Hypoglycemia treatment delayed for as little as an hour simply results in a dead or brain damaged patient. It would be expected that delays in TH implementation would have similar results.
(3) The typical patient treated in the TTM trials received cardiopulmonary resuscitation (CPR) with 1 minute of collapse. Such early CPR reduces the potential for serious brain injury, reducing the need to administer TH.
Several reviews of TH have been published, including a comprehensive paper by Callaway [9], to explain the inconsistent results in studies of TH. This publication discussed many of the variables which impact the effectiveness of the treatment. From a broad perspective, the primary variables are the physiological state of the patient and the timing, depth, and duration of cooling. In consideration of these reviews, the 2024 treatment guidelines from the American Heart Association have left a more open range of target temperatures of 32 to 37.5 °C [10].
The delay from collapse to CPR is a critical variable. Previous clinical research has found that patients surviving cardiac arrest typically receive CPR within 3.6±2.5 minutes of collapse, while those not surviving receive CPR within 6.1±3.3 minutes of collapse [11]. Patients having extended delays to CPR are most likely to be at risk of injury, and are most likely to benefit from TH. Paradoxically, the patients having the greatest levels of injury also cool most quickly, due to a loss of active thermoregulatory mechanisms [12]. This complicates retrospective analyses which seek to link timing of cooling to outcomes [13].
The ability of rapid post-resuscitation TH to prevent injuries after long delays in CPR has been demonstrated in several laboratory studies. One such study found that eight of eight swine subjected to 10-minutes of untreated cardiac arrest achieved full recoveries after they were cooled to 33 °C within 1 hour of resuscitation and then maintained at that temperature for 14 hours [14]. In this same study, only one of eight animals randomized to normothermic recovery achieved full recovery.
CLINICAL STUDIES SUPPORTING RAPID COOLING
The lack of focus on the critical importance of early and rapid TH neglects those human clinical studies of rapid TH induction methods (<60 minutes from cooling initiation to TH target [15]). A meta-analysis of 4,700 human patients from 13 studies, including both observational and randomized studies, compared slow cooling to rapid cooling and reported that patients had the best recoveries when fast cooling methods (other than intravenous cold fluids) were used and 34 °C was reached 2.5 hours after ROSC [16]; the analysis found that 80% of the rapidly cooled patients recovered to Cerebral Performance Category (CPC) [17] ≤2, while only 57% of patients recovered to CPC ≤2 when the time to 34 °C was 4.9 hours. A more recently published meta-analysis of 4,058 subjects from nine randomized controlled trials found that neurological recoveries of patients resuscitated from shockable rhythms were best when cooling to 32 to 34 °C was initiated within the first 2 hours after resuscitation (<2 hours: relative risk, 0.74; 95% confidence interval, 0.60–0.91) [18].
TIME WINDOW AND KEY MECHANISMS FOR TH
The favorable results obtained with rapid cooling in humans are also supported by laboratory studies of animal models of cardiac arrest, ischemic stroke, and heart attack (acute myocardial infarction). A meta-analysis of 102 animal studies, in which TH was applied either before or soon after ROSC, showed benefits in terms of behavioral outcomes and histological results versus normothermic controls [19]. In fact, the benefits were greatest when cooling was initiated before resuscitation. In a rat model of post-resuscitation cooling (33 °C maintained for 24 hours) the numerically best neurological protection was achieved when TH was provided within 2 hours of ROSC and the benefit was diminished when the delay exceeded 4 hours [20]. Ultimately, any benefit was abolished if the delay was 8 hours. It would be expected that randomized clinical studies in which TH implementation occurred 6 hours or longer after ROSC, as cited by Taccone et al. [7] and Spears and Greer [8], would find little difference between treatment groups.
For TH to be effective in the brain it must influence multiple mechanisms of injury. For example, it must rapidly interdict the cascade of intracellular apoptosis triggered by reperfusion of warm oxygenated blood. In the brain, apoptosis is signaled by glutamate from the brain cells first affected to their neighboring neurons, and which over hours will destroy the brain by way of caspase-driven apoptosis; TH has been shown to diminish glutamate excitoxicity [21] and it prevents apoptosis by inhibiting the caspase pathway [22]. One of the other mechanisms of ischemia-related neuronal injury is the development of post-reperfusion no-reflow [23], which can account for more neuronal death than the pre-reperfusion ischemic period. In the arteries, TH inhibits the expression of matrix metalloproteinases [24], securing the integrity of the vascular walls [25], and protecting the blood brain barrier [26]. Without early TH, the severity of no-reflow increases progressively over the first 5 hours after reperfusion [23]. Prompt induction of TH has been found to provide a 92% reduction in no-reflow [27] in an acute myocardial infarction model. Delayed cooling misses the window for impacting the above and most other mechanisms of cellular injury.
The progression of reperfusion injury through the brain begins within minutes after reperfusion and progresses continually through its phases to ever more irreversible injuries by 6 hours post reperfusion [28]. Moderate hypothermia (32–34 °C) suppresses most, if not all, of the mechanisms of reperfusion injury [29]. The earlier this level of hypothermia can be reached, the less brain damage will result [20]. The timing of several key biochemical events which can impact the degree of neuronal loss support this (Table 1) [20,23,27,29,30]. All of these can be favorably impacted by cooling of sufficient speed, depth, and duration.
Time course of reperfusion injuries
In our prior meta-analysis, rapidly cooled post–ventricular tachycardia/ventricular fibrillation patients who reached 34 °C by 2.5 hours after ROSC had good outcomes more frequently than similar patients who failed to reach 34 °C until 4.9 hours after ROSC [16]. These findings raise the question, what biochemical mechanisms are at work in the first few hours after ROSC that could account for the worsened outcomes associated with delayed cooling? Loss of mitochondrial calcium buffering capacity (mCBC) and activation of caspases in the cortex (both at 4 hours) may be important factors (Table 1) [20,23,27,29,30]. In normothermic mice subjected to ischemia/reperfusion, mCBC drops profoundly at 4 hours post-reperfusion, and this is followed by loss of mitochondrial energy production at 4 to 6 hours [30]. However, early post-reperfusion hypothermia (ideally 32 °C achieved well before the 4-hour mark) protects mCBC and mitochondrial function, significantly reducing the incidence of neuronal death. Caspase-3 activation in the cortex at 4-hours post-reperfusion normally leads directly to destruction of mitochondrial DNA and apoptosis [24]; caspase-3 activation is inhibited by hypothermia of 33 °C [23], but this temperature level must be achieved before the 4-hour mark to provide meaningful protection. There are certainly other mechanisms at work in this timeframe, and these should be considered as well.
Some researchers are trying to improve the efficacy of TH by prolonging the hypothermic maintenance phase [31], but the evidence supporting that approach is less substantial than that supporting the use of faster cooling induction methods. The use of pre-reperfusion cooling may provide the greatest protection. Better than an 80% reduction in post-ischemic infarct size has been reported in animal models of ischemic stroke [32] and acute myocardial infarction [27]. Most impressively, the use of intra–cardiac arrest hypothermia has been shown to provide full protection in animal models [33], humans undergoing cardiac surgery [34], and in victims of rapid-onset accidental hypothermia [35].
Expert opinions on TH for post-resuscitation patients appear to be swinging back in favor of earlier, deeper cooling. A Cochrane review updated in 2023 by Arrich et al. [36] reinforced the support for this, as do the recently updated European Treatment Recommendations (2024) [37], which state, “clinicians should consider hypothermia in the range of 32 to 34 °C in all adults after cardiac arrest as soon as feasible, and to maintain this temperature range for at least 24 h[ours].”
While slower cooling methods appear to offer some protection from neurologic injuries in certain post-arrest patients, more rapid cooling induction methods, such as convective-immersion surface cooling (3.5 C°/min cooling rate) [5], nasal cooling (0.77 C°/min cooling rate) [38], and ice packs (0.9 C°/min cooling rate) [2], may offer more protection. These should be further evaluated in humans in randomized prospective studies. It is time to embrace and further explore rapid TH induction to optimize the recovery of patients suffering from cardiac arrest, myocardial infarction, and ischemic stroke.
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Conflicts of interest
Robert J. Freedman Jr. and Robert B. Schock are co-founders of Life Recovery Systems (Alexandria, LA, USA), and own stock in the company. W. Frank Peacock is an Editorial Board member of Clinical and Experimental Emergency Medicine, but was not involved in the peer reviewer selection, evaluation, or decision process of this article. The authors have no other conflicts of interest to declare.
Funding
The authors received no financial support for this study.
Data availability
Data sharing is not applicable as no new data were created or analyzed in this study.