Hypothermia versus normothermia after out-of-hospital cardiac arrest
Dankiewicz J, Cronberg T, Lilja G, et al. N Engl J Med. 2021;384(24):2283-2294.
Targeted temperature management (TTM) or therapeutic hypothermia continues to be included in society guidelines for the treatment of comatose patients after resuscitation for out-of-hospital cardiac arrest (OHCA), despite very poor evidence. The initial 2 trials of this modality, from 2002, had very high risk of bias and did not attempt to maintain body temperature in the normal range but allowed fever in the control group. However, good evidence indicates that fever is bad for the recovering brain. These studies are countered by only 1 large trial on the topic that found no benefit of TTM. However, in that trial, the unplanned subgroup of people with initial nonshockable rhythm showed a small but statically very unsteady hint toward improved outcomes for hypothermia. A more recent small trial of patients with initial nonshockable rhythm has also shown benefits of hypothermia compared with a controlled temperature of 36-37 °C, but the findings were marginal, and if a single case had been reclassified from a good outcome to a bad outcome, the results would have been insignificant.
This was a massive and highly anticipated international, investigator-initiated study that aimed to reduce ambiguity.
Patients were randomized 1:1 to targeted hypothermia (33 °C) or normothermia (<37.5 °C) for 40 hours. The eligibility criteria included OHCA with a presumed cardiac etiology (no traumatic brain injury) irrespective of the initial rhythm (shockable or not). The patients were required to be comatose and to have sustained return of spontaneous circulation (ROSC) for at least 20 minutes before the initiation of temperature-control measures. The patients were excluded if they were not randomized within 3 hours.
The key outcomes were death at 6 months and survival with poor neurologic outcomes at 6 months (Modified Rankin Scale score 4-6). Adverse events were also collected. Outcomes were judged by a blinded assessor, but otherwise the trial was unblinded. Several subgroup analyses were planned including participants with initial nonshockable rhythms.
A total of 1,861 patients were enrolled (twice the number in the previous large study and 5 times the number in initial trials). The mean age was 64; 80% were men; 91% had cardiac arrest, >80% had bystander CPR performed, and 72% had an initial shockable rhythm. Many of these measures are good prognostic indicators.
The results indicated that therapeutic hypothermia did not work at all: 50% of the hypothermia group was alive at 6 months vs 48% of the normothermia group (nonsignificant). In terms of the functional outcomes, 55% of the hypothermia group had poor outcomes, compared with 55% of the normothermia group. The results across the subgroups, including those of patients with initial shockable rhythm, early ROSC vs late ROSC, and a post-ROSC shock state, were all identical. The only significant difference was a higher incidence of arrhythmias in the hypothermia group.
The survival curves were superimposed throughout the study period.
For good measure, the authors provide the temperature curves of the 2 groups to demonstrate that the people assigned to hypothermia actually got cold.
Overall, the study design is very strong. This study is by far the largest on the topic and has a very low risk of bias. The evidence clearly refutes the notion that hypothermia is good for post-ROSC patients, and indicates that the practice should be dropped unless and until new high-quality evidence emerges.
EDITOR’S COMMENTARY: This extraordinarily large and well-conducted study plainly shows that therapeutic hypothermia is not beneficial for resuscitated, comatose patients with OHCA of presumed cardiac origin, regardless of initial rhythm. Providers should still keep patients within the normothermic range and treat hyperthermia, but cooling measures are not necessary.