Recent Clinical Evidence on Post-Arrest TTM

The accumulated post-arrest care literature makes clear that careful fever avoidance following resuscitation is essential. But the question remains, is there ever an explicit indication for hypothermia to 33 degrees Celsius, based on the earlier trials and the strong laboratory evidence supporting this more aggressive form of temperature control? Growing evidence suggests that there may be utility for TTM in the sicker phenotype of arrest patients. Several recent studies yield insights into this hypothesis:

In a single site retrospective cohort study, Callaway et al demonstrated that TTM efficacy may be impacted by arrest severity.10 In this observational study of 911 American post-arrest patients, sicker patients (PCAC greater than or equal to 3) had improved outcomes when treated at 33 degrees Celsius while less sick patients (PCAC less than or equal to 2) had better outcomes when treated at 36 degrees Celsius. This finding is consistent with the large animal model literature on post-arrest TTM, where a dose effect relationship of TTM is related to arrest model severity.

In a multisite retrospective cohort study, a study by Nishikimi, et al., adds to the hypothesis that TTM efficacy is dependent on arrest severity.¹¹ Similar to the Callaway study, this study of 1,111 Japanese patients replicated the finding that low-severity post-arrest patients did not benefit from hypothermia while patients with moderate-severity arrests significantly benefited from hypothermia. Adding nuance, this study also showed that the highest-severity arrests did not benefit from hypothermia. While TTM may attenuate injury, it does not reverse it, so it is unsurprising to discover a profoundly injured subset of patients who do not benefit from TTM. In summary, this study shows that there is a subset of post-arrest patients who experience neither too much, nor too little injury and are therefore disposed to benefit from expeditious hypothermic intervention.

Several studies have shown that after TTM1 (2013), in cases where hospitals changed post-arrest temperature targets from 33 degrees Celsius to 36 degrees Celsius, patients had an concomitant increase in fever, poor neurological outcomes and increased mortality.^12–13 These are challenging studies to draw definitive conclusions from, however they suggest that some of these post-TTM1 patients who were cooled to 36 degrees Celsius did worse, supporting the notion that there exists a subset of patients who benefit from cooling to 33 degrees Celsius.

There is a current vigorous debate regarding post-arrest TTM. Who should receive it? At what dose? For how long? There are a number of trials in progress that may help address these questions; notably, ICECAP, IH-TTM, and PRINCESS-2, each focusing on different aspects of TTM dosing and timing. Until then, we propose that it’s worth considering mild hypothermia (33 degrees Celsius) in our sickest post-arrest patients, while avoiding fever in every patient resuscitated from cardiac arrest.