Comatose out-of-hospital cardiac arrest (OHCA) survivors fared no better on targeted temperature management (TTM) than standard care for avoiding fever in the ICU, according to the TTM2 trial.
There was no significant difference between the 50% incidence of all-cause death at 6 months among patients randomized to targeted hypothermia at 33°C (91.4°F) and the 48% rate for peers kept in normothermia at 37.5°C (99.5°F) or less (RR 1.04, 95% CI 0.94-1.14), reported Niklas Nielsen, MD, PhD, of Helsingborg Hospital, Sweden, and colleagues.
In addition, hypothermia and normothermia were associated with similar functional outcomes at 6 months, with 55% of each treatment group experiencing moderately severe disability or worse per the modified Rankin scale (RR 1.00, 95% CI 0.92-1.09), they reported in the New England Journal of Medicine.
Study findings persisted across prespecified subgroups, and also are consistent with the previous TTM trial. In that 2013 study, investigators had compared therapeutic hypothermia at 33°C versus 36°C (96.8°F) and found the lower target to make no difference in survival or neurological outcomes after OHCA.
“The combined results of the two trials imply a low likelihood of any meaningful clinical improvement with hypothermia as compared with normothermia, since 36°C may be considered to be the lower boundary of normothermia,” Nielsen’s group suggested.
Another group had recently reported even more aggressive hypothermia, targeted to 31°C (87.8°F), to be a flop for comatose survivors of OHCA.
Guidelines currently recommend TTM with a constant target between 32°C and 36°C despite the overall low quality of supporting evidence in the literature.
“Our results contrast with findings of practice-changing trials published in 2002 in which a benefit of hypothermia was reported,” the TTM2 group asserted, noting that the strengths of their trial include the lower risks of bias and random error given a sample size that was five times as large as the earlier trials combined.
TTM2 was an open-label trial conducted at sites in Europe, Australia, and the U.S. There were 1,900 adult survivors of OHCA, of presumed cardiac or unknown cause, enrolled in 2017-2020.
Patients randomized to targeted hypothermia were immediately cooled with a surface or intravascular temperature-management device to a target temperature of 33°C. This target was maintained until 28 hours after randomization, followed by rewarming to 37°C (98.6°F) in hourly increments of one third of a degree.
The control group assigned targeted normothermia was kept at a temperature of 37.5°C or less with conservative and pharmacologic measures. However, 46% of this study arm experienced fever (≥37.8°C or 100.0°F) and subsequently received surface or intravascular cooling therapies targeting 37.5°C.
After the 40-hour assigned intervention, ICU care was otherwise the same for the two groups.
Hypothermia and normothermia groups were well balanced in baseline characteristics, with a mean age of 64 and four out of five participants being men.
Over half of patients had had their cardiac arrest at home. Over 90% had bystander-witnessed cardiac arrest, and about 80% received bystander CPR. The initial rhythm was shockable in about three-quarters.
It took a median of 25 minutes from cardiac arrest to sustained return of spontaneous circulation, and 135 minutes from cardiac arrest to randomization. Recipients of targeted hypothermia reached 33°C at approximately 7 hours after randomization.
It is possible that timely initiation of hypothermia may play a role in its potential benefits, Nielsen and colleagues acknowledged.
“Since all participating sites in our trial had previous experience with the use of hypothermia, and a large percentage of the patients in our trial underwent randomization at cardiac arrest centers, the cooling rates we observed were probably faster than those that are feasible in current clinical practice,” they noted.
The investigators reported hypothermia to be associated with excess arrhythmias resulting in hemodynamic compromise (24% vs 17% with normothermia, P<0.001).
The open-label nature of TTM2 was a major limitation of the trial: Despite physicians being blinded when assessing neurologic outcomes, ICU staff had been aware of the assigned target temperatures.
Furthermore, the trial protocol may not reflect usual clinical practice, and the authors did not test a control group with no temperature management at all. Study results may also not be generalizable to other presentations of cardiac arrest, Nielsen’s group cautioned.
The trial was supported by the Swedish Research Council, Swedish Heart–Lung Foundation, Stig and Ragna Gorthon Foundation, Knutsson Foundation, Laerdal Foundation, Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research, Region Skåne, and the Swedish National Health Service.
Nielsen disclosed receiving lecture fees from Bard Medical and consulting fees from BrainCool.