Controversies Surrounding Targeted Temperature Management (TTM) in Cardiac Arrest

Hypothermia refers to a condition where the body temperature is equal to or less than 36°C. Normothermia is when the body temperature falls within the range of 36-37.5°C. Fever is a condition where the body temperature is equal to or greater than 38.3°C.

The mechanism behind targeted temperature management (TTM) involves reducing the body's metabolic rate, which can have various physiological benefits. One such benefit is a reduction in lactate accumulation, which can lead to neuronal cell death. TTM may also decrease the release of excitatory neurotransmitters, such as aspartate and glutamate, that are related to neuronal death. Animal studies have shown that mild to moderate hypothermia can reduce the release of these neurotransmitters. Additionally, inflammation and free radical production can occur following reperfusion, not just global ischemia. By reducing the metabolic rate and limiting the body's need for energy, TTM may also help to reduce inflammation and free radical production, thereby promoting better overall patient outcomes.

Based on the early single-center randomized controlled trials (RCT) targeting 32-34°C by Bernard, et al. and the multicenter randomized trial by the Hypothermia After Cardiac Arrest (HACA) trial group, TTM was found to be associated with an increase of survival with good neurologic outcome in patients presenting with an out of hospital cardiac arrest (OHCA) with shockable rhythms. In addition, HACA trial revealed that TTM reduces 6-month mortality.

The TTM-1 trial published in 2013 was a multicenter RCT that evaluated out-of-hospital cardiac arrest (OHCA) patients who remained comatose post-ROSC and compared 33°C to 36°C, excluding patients with unwitnessed arrests and those in asystole (evaluating arrests of assumed cardiac origin). Approximately 80% of patients had an initial shockable rhythm with a median time to BLS occurring in 1 minute, time to ACLS within 10 minutes, and ROSC within 25 minutes. The control group of 36°C underwent active control of temperature, and management of cooling was done in both groups at the site’s discretion. TTM to 33°C was not associated with a statistically significant improvement in mortality, composite of death or poor neurologic function, or total complications compared to 36°C.

Based on these trials, the American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR) 2015 guidelines were updated to recommend maintaining temperatures between 32°C and 36°C in the immediate post-arrest period.

The TTM-2 trial published in 2021 was a multicenter RCT that evaluated OHCA patients who remained comatose post-ROSC and compared 32°C to 37.5°C, excluding patients with unwitnessed arrests and those in asystole (evaluating arrests of assumed cardiac origin). The trial found no difference in the primary outcome of mortality at six months or secondary outcome of neurologic function at six months. TTM-2 sought to add to the original trial on evaluation of whether prevention of fevers would result in similar outcomes.

In contrast to previous studies TTM-2 demonstrated that TTM is not a benign treatment and that 32°C was associated with an increased risk of arrythmias resulting in hemodynamic compromise. Overall, based on the inability to reproduce the mortality benefit of hypothermia in larger, multi-center trials, the literature would support TTM to maintain normothermia and prevent fevers in the post-arrest comatose patient with a shockable rhythm.

Many prior trials evaluating TTM were done in shockable rhythms, however two trials (HYPERION in 2019, and Wolfrum et al, in 2022) evaluated the use of TTM in primarily non-shockable rhythm populations. HYPERION compared 33°C to 37°C in both OHCA and in-hospital cardiac arrest patients (IHCA) with a primary outcome of favorable neurologic outcome at 90 days. The trial concluded a statistically significant increase in survival with good neurologic outcome 10.2% versus 5.7% (HR 4.5 (0.1-8.9)) in 33°C compared to 37°C. There was no difference in death at 90 days across the groups. Some limitations to this conclusion were, that patients in the 37°C arm had temperature spikes over 38°C, there was a narrow inclusion time (limiting extrapolation), and a wide confidence window with a fragility index of 1.

The follow-up study evaluating TTM in specifically IHCA patients using 32-34°C compared to normothermia at 37.5°C found no difference in the primary outcome of all-cause mortality or favorable functional outcome at 180 days.

Based on the fragility index and large confidence interval in the trial supporting a potential survival with positive neurologic function and repeat studies showing no difference, prevention of fevers and maintenance of 37.5°C should be pursued in post-arrest patients with non-shockable rhythms similar to the strategy utilized for shockable rhythms.

Early trials suggesting mortality and neurological benefits of TTM of 32-34°C had limitations that included a high incidence of fever in the control group and nonblinded neurological prognostication of patient were unable to be replicated with larger blinded randomized control trials such as TTM-1 and TTM-2 emphasizing the importance of fever avoidance in the post arrest period. Limiting the degree of targeted temperature management can also limit complications associated with TTM including but not limited to shivering and cardiac arrythmias.