In 2013, a large international randomized control trial (TTM trial) studied 950 unconscious adults after out-of-hospital cardiac arrest (OHCA) to determine whether there was a potential patient benefit in inducing a target temperature of 33°C versus 36°C. The primary outcome measure was all-cause mortality at 6 months which showed no significant difference in the hypothermia group and the normothermia group (50% vs. 48%). Using the modified Rankin scale to adjust for disability, the comparable mortality rate showed no difference (52% vs 52%). The composite endpoint of neurological function or death did not differ between the two groups.
In 2021, the TTM2 trial compared targeted hypothermia of 33°C versus normothermia of ≤37.5°C and found that the death rate at 6 months was not significantly different between the two groups (50% vs. 48%). This mirrors the results of the 2013 study. The 2021 study also showed that the level of moderately severe disability (Rankin scale ≥4) was not significantly different between either group (55% vs. 55%) [8].
In an individual patient data meta-analysis published in NEJM Evidence on June 15, 2022, the investigators tried to answer the question of whether hypothermia at 33°C decreases 6-month mortality compared with normothermia after out-of-hospital cardiac arrest or not?
The study included patients from both the TTM and TTM2 trials as discussed above. A total of 2800 patients were included in the study with 1403 patients in the hypothermia group (target temperature of 33°C), and 1397 patients in the normothermia group (target temperature of 36°C in the TTM trial and <37.8°C in TTM2 trial). The primary outcome was 6-month mortality of all causes, and the secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. The predefined study subgroups that were tested for interaction with the intervention as follows:
Age (older or younger than the median),
Sex (female or male).
Initial cardiac rhythm (shockable or nonshockable).
Time to return of spontaneous circulation (above or below the median).
Circulatory shock on admission (presence or absence).
The results of the study showed that 6-month mortality rate was not significantly different in the hypothermia group compared to the normothermia group (49.4% vs. 47.9%, relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). The incidence of a poor functional outcome was not significantly different in the hypothermia group compared to the normothermia group (54.3% vs. 54.0%, relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). There was no evidence of improved outcomes in any of the predefined subgroups, including type of rhythm. The study also suggested potential harm in hypothermia patients who had received bystander cardiopulmonary resuscitation signaled by a higher mortality rate and potential benefit in hypothermia patients with no bystander cardiopulmonary resuscitation.
This meta-analysis using sequential analysis is a well-designed study with good power. This analysis revealed that we can reject the hypotheses of a relative risk benefit of hypothermia as subtle as 10% for mortality and 8% for poor functional outcome. Furthermore, Bayesian analysis of the study based on mortality and poor functional outcome suggests hypothermia is more likely to lead to no benefit than benefit. The study does not rule out a benefit in controlling the temperature between 36-37.8°C, and this could be investigated further in the future. In the TTM and TTM2 studies, temperature control devices were utilized (100% in the control group of the TTM trial and 46% in the TTM2 trial).
In conclusion, the study shows that hypothermia at 33°C does not reduce 6-month mortality and does not improve 6-month neurological outcome compared to normothermia. This high level evidence provides support to using device-controlled normothermia in patients with out-of-hospital cardiac arrest.
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