TEMPERATURE INTERVENTION

Active temperature management was established as an intervention to reduce brain injury after cardiac arrest and was based on animal data, clinical observations and the results of phase-2 trials from 2002. 

In a 950-patient trial (TTM1) we showed similar survival, functional status, quality of life and cognitive impairment for TTM to 33°C or 36°C. The TTM1 had wide confidence limits which encompassed both clinically significant benefit and harm of the interventions. 

In the TTM2-trial we randomized 1900 patients to TTM at 33°C or to a TTM-strategy to maintain normothermia with active treatment of fever (defined as a core body temperature ≥37.8°C). As the results were neutral and almost identical to TTM1, TTM2 strongly reinforced the TTM1-results, confirming that cooling to subnormal temperatures does not provide benefit compared with targeting normothermia and avoiding fever. This was also supported by an individual patient data meta-analysis of TTM1 and TTM2.  

Fever after cardiac arrest has been suggested as a risk factor for death, but guideline recommendations to treat fever are based on non-randomized studies, and it is not known whether there is a causal and modifiable relationship. It remains to be determined if fever is harmful for a neurologically impaired patient or if it is merely an epiphenomenon, and if active fever prevention is beneficial or harmful.  

In a systematic review by our group, a meta-analysis of all-cause mortality did not find any evidence suggesting a beneficial effect of fever interventions versus no fever interventions, RR 0.98; 95 % CI 0.94 – 1.03; I2 = 6.37 %; p = 0.38, (based on 16 trials, evidence of moderate certainty). 

Currently, international guidelines recommend active prevention of fever, despite limited supporting evidence. Therefore, the primary outstanding question regarding TTM after out-of-hospital cardiac arrest is whether early fever management with temperature management devices is beneficial, and this will be studied as one of the interventions in the STEPCARE-trial.