Differentiated effect of hypothermia versus normothermia after cardiac arrest by neurological status and clinical correlates of ischemic burden.

Overall six-month mortality was similar between the 33 °C group and the controlled normothermia group in the pooled TTM and TTM2 population.

• All 2789 adult OHCA patients from the trials' primary analyses were included.
• Death occurred in 49.4% of patients in the 33 °C group and in 47.9% in the controlled normothermia group.
• Median age was 65 years (IQR 56-73) and 79.9% of participants were male.

Individualized treatment effects on six-month mortality, estimated from ischemic burden correlates and initial neurological findings, showed minimal variation, and no significant heterogeneity of treatment effect was found.

• Effect-based machine learning (causal forests and Bayesian additive regression trees, BART) was applied to the TTM and TTM2 trials.
• Predictors included ischemia duration, prehospital factors, and neurological examination findings at hospital admission.
• No significant heterogeneity was identified across all methods and analysis populations (within each trial and pooled).

In the pooled analysis, the estimated range of conditional mean mortality risk differences between temperature strategies was narrow and centered near zero.

• Causal forest estimates ranged from -1.2% to 2.1% (p = 0.99).
• BART estimates ranged from -0.5% to 1.5%.
• BART posterior probabilities for hypothermia benefit ranged from 42% to 53%, indicating no clear benefit in any subset.

Treatment effect modifier variable importance parameter (TEM-VIP) analysis did not identify baseline variables with meaningful effect modification.

• TEM-VIP ranked baseline variables most likely to modify the treatment effect.
• Absolute subgroup estimates in TEM-VIP analysis were small and non-significant.

Findings for the secondary outcome of poor functional outcome (modified Rankin scale 4-6) at six months were consistent with the mortality findings.

• Poor functional outcome was defined as modified Rankin scale score 4-6.
• No detectable heterogeneity of treatment effect was reported for this outcome.

The study's conclusion is that available clinical correlates of ischemic burden and initial neurological findings do not identify patients who respond differently to 33 °C versus normothermia.

• The analysis was motivated by the hypothesis that patients with differing ischemic burden or early neurological injury might respond differently to temperature targets.
• Primary analyses evaluated heterogeneity within each trial; secondary analyses pooled all participants.
• Estimated variation in treatment effect was minimal.