The STEPCARE-trial is designed with three major arms of interventions; targeted temperature management (TTM), mean arterial pressure (MAP) and sedation.
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.