Heterogeneous Treatment Effect for Targeted Temperature Management After Cardiac Arrest: A Causal Machine Learning Analysis
Journal:
medRxiv
Published Date:
May 6, 2026
Abstract
ABSTRACT Objectives: To determine whether heterogeneous treatment effects (HTE) explain the inconclusive results of targeted temperature management (TTM) trials after cardiac arrest, using causal machine learning across four datasets. Design: Secondary analysis of one multicenter RCT and three observational ICU cohorts using S-learner and forest-based R-learner models to estimate conditional average treatment effects (CATE). Setting: Twenty-six French ICUs (HYPERION), approximately 200 U.S. ICUs (eICU-CRD), Johns Hopkins Hospital (PMAP), and Beth Israel Deaconess Medical Center (MIMIC-IV). Patients: Adults (>=18 years) with cardiac arrest; 4,507 patients across the four datasets, of whom 1,814 (40.2%) received TTM. Interventions: TTM as administered clinically or per HYPERION protocol. Ascertainment: randomization (HYPERION), treatment documentation (eICU-CRD), sustained hypothermia <36C for >12 hours (PMAP), or documented cooling device use >=12 hours (MIMIC-IV). Measurements and Main Results: The primary outcome was hospital mortality; the secondary outcome was favorable neurologic function (Cerebral Performance Category 1-2 at 90 days for HYPERION; last motor Glasgow Coma Scale = 6 for observational cohorts). Three S-learner models (XGBoost, neural network, Bayesian Additive Regression Trees) and one forest-based R-learner (CausalForestDML) estimated CATE. HTE was assessed by likelihood-ratio tests for CATExtreatment interaction, CausalForestDML 95% confidence intervals, Group Average Treatment Effects (GATES) across CATE quintiles, and SHAP feature importance. S-learner discrimination was adequate (AUROC 0.72-0.82). No model showed a significant CATExTTM interaction in any dataset (all p > 0.05). Individual CATE confidence intervals uniformly crossed zero, and GATES showed no monotonic gradient of benefit across quintiles in any dataset. Conclusions: Across four diverse datasets and multiple causal machine-learning approaches, we found no evidence of heterogeneous treatment effects for TTM after cardiac arrest. The inconclusive findings of TTM trials are unlikely explained by differential effects in identifiable subgroups defined by routinely available clinical features.
