Differentiated effect of hypothermia versus normothermia after cardiac arrest by neurological status and clinical correlates of ischemic burden.
30 affiliations
- 1Anesthesiology and Intensive Care, Department of Clinical Sciences Helsingborg, Lund University, Svartbrödragränden 3, Helsingborg, 251 87, Sweden. [email protected].
- 2Department of Intensive and Perioperative Care, Skåne University Hospital, Malmö, Sweden. [email protected].
- 3Cardiology and Critical Care Medicine, McGill University Health Centre, McGill University, Montréal, Canada.
- 4Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Canada.
- 5Neurology and Rehabilitation Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
- 6Department of Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden.
- 7Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, WI, USA.
- 8Cardiology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
- 9Department of Cardiology, Skåne University Hospital, Lund, Sweden.
- 10Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
- 11Department of Neurology, Skåne University Hospital, Lund, Sweden.
- 12Adult Critical Care Unit, University Hospital of Wales, Cardiff, UK.
- 13Division of Intensive Care Medicine, HOCH Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
- 14Intensive Care Unit, Liverpool Hospital, Sydney, Australia.
- 15South Western Sydney Clinical School, University of New South Wales, Sydney, Australia.
- 16Institute of Intensive Care Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
- 17Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.
- 18Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
- 19Department of Intensive Care, Amsterdam Neurosciences, Amsterdam University Medical Center, Amsterdam, The Netherlands.
- 20Department of Anesthesia and Intensive Care Medicine, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.
- 21Department of Health, Medicine and Life Sciences, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
- 22Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
- 23Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark.
- 24Department of Cardiology, The Heart Center, Copenhagen University Hospital, Copenhagen, Denmark.
- 25Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
- 26Anesthesia and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
- 27Department of Biostatistics, Epidemiology and Informatics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 28Anesthesiology and Intensive Care, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
- 29Department of Intensive and Perioperative Care, Skåne University Hospital, Lund, Sweden.
- 30Cardiology and Critical Care Medicine, University of Toronto, Toronto, Canada.
Abstract
Introduction
The optimal temperature target after out-of-hospital cardiac arrest (OHCA) remains uncertain, as major randomized trials have not demonstrated a clear benefit of lower-target hypothermia compared with normothermia. Despite this, patients with differing degrees of ischemic burden or early neurological injury may hypothetically respond differently to temperature targets, raising the possibility of heterogeneous treatment effects. This study aimed to determine whether outcomes differ after OHCA with 33 °C versus controlled normothermia (36.0-37.7 °C) according to correlates of ischemic burden and neurological findings at hospital admission.Methods
This secondary analysis of the TTM and TTM2 trials employed effect-based machine learning to probe for heterogeneous treatment effects. Causal forests and Bayesian additive regression trees (BART) estimated individualized treatment effects (ITE) based on ischemia duration, prehospital factors, and neurological examination findings at hospital admission. Treatment effect modifier variable importance parameter (TEM-VIP) analysis ranked the baseline variables most likely to modify effect. The primary outcome was six-month all-cause mortality, and the secondary outcome was poor functional outcome (modified Rankin scale score 4-6). Primary analyses evaluated potential heterogeneity within each trial, while secondary analyses pooled all participants.Measurements and main results
All 2789 adult OHCA patients from the trials' primary analyses were included (median age 65 years (IQR 56-73), 79.9% male). Death occurred in 49.4% of patients in the 33 °C group, and in 47.9% in the controlled normothermia group. Variation in six-month mortality ITEs estimated from ischemic burden correlates and initial neurological findings was minimal, and no significant heterogeneity of treatment effect was identified across all methods and analysis populations. In the pooled analysis, estimated conditional mean mortality risk difference ranged from - 1.2% to 2.1% in causal forest (p = 0.99), and from - 0.5% to 1.5% in BART, with posterior probabilities for hypothermia benefit ranging from 42% to 53%. Absolute subgroup estimates in TEM-VIP analysis were small and non-significant. Results were consistent for the six-month functional outcome.Conclusions
Among TTM and TTM2 participants randomized to 33 °C versus controlled normothermia post-OHCA, no evidence of detectable heterogeneity of treatment effect based on available clinical correlates of ischemic burden or initial neurological findings was identified, with minimal estimated variation in treatment effect.
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BibTeX
@article{lileikyte2026differentiated,
title = {{Differentiated effect of hypothermia versus normothermia after cardiac arrest by neurological status and clinical correlates of ischemic burden.}},
author = {Gabriele Lileikyte and Lucas L Marinho and Ying Lu and Philippe Boileau and Marion Moseby-Knappe and Alexandra Spicer and Josef Dankiewicz and Gisela Lilja and Matt P Wise and Claudia Schrag and Anders Aneman and Matthias Haenggi and Anders M Grejs and Janneke Horn and Pascal Stammet and Janus C Jakobsen and Jesper Kjaergaard and Christian Rylander and Michael O Harhay and Matthew M Churpek and Niklas Nielsen and Patrick R Lawler},
journal = {Critical care (London, England)},
year = {2026},
month = nov,
doi = {10.1186/s13054-026-06414-x},
url = {https://europepmc.org/article/MED/42972430},
note = {CC BY},
}
RIS
TY - JOUR
TI - Differentiated effect of hypothermia versus normothermia after cardiac arrest by neurological status and clinical correlates of ischemic burden.
AU - Gabriele Lileikyte
AU - Lucas L Marinho
AU - Ying Lu
AU - Philippe Boileau
AU - Marion Moseby-Knappe
AU - Alexandra Spicer
AU - Josef Dankiewicz
AU - Gisela Lilja
AU - Matt P Wise
AU - Claudia Schrag
AU - Anders Aneman
AU - Matthias Haenggi
AU - Anders M Grejs
AU - Janneke Horn
AU - Pascal Stammet
AU - Janus C Jakobsen
AU - Jesper Kjaergaard
AU - Christian Rylander
AU - Michael O Harhay
AU - Matthew M Churpek
AU - Niklas Nielsen
AU - Patrick R Lawler
PY - 2026
DA - 2026/11/02
JO - Critical care (London, England)
DO - 10.1186/s13054-026-06414-x
UR - https://europepmc.org/article/MED/42972430
AB - Introduction The optimal temperature target after out-of-hospital cardiac arrest (OHCA) remains uncertain, as major randomized trials have not demonstrated a clear benefit of lower-target hypothermia compared with normothermia. Despite this, patients with differing degrees of ischemic burden or early neurological injury may hypothetically respond differently to temperature targets, raising the possibility of heterogeneous treatment effects. This study aimed to determine whether outcomes differ after OHCA with 33 °C versus controlled normothermia (36.0-37.7 °C) according to correlates of ischemic burden and neurological findings at hospital admission.Methods This secondary analysis of the TTM and TTM2 trials employed effect-based machine learning to probe for heterogeneous treatment effects. Causal forests and Bayesian additive regression trees (BART) estimated individualized treatment effects (ITE) based on ischemia duration, prehospital factors, and neurological examination findings at hospital admission. Treatment effect modifier variable importance parameter (TEM-VIP) analysis ranked the baseline variables most likely to modify effect. The primary outcome was six-month all-cause mortality, and the secondary outcome was poor functional outcome (modified Rankin scale score 4-6). Primary analyses evaluated potential heterogeneity within each trial, while secondary analyses pooled all participants.Measurements and main results All 2789 adult OHCA patients from the trials' primary analyses were included (median age 65 years (IQR 56-73), 79.9% male). Death occurred in 49.4% of patients in the 33 °C group, and in 47.9% in the controlled normothermia group. Variation in six-month mortality ITEs estimated from ischemic burden correlates and initial neurological findings was minimal, and no significant heterogeneity of treatment effect was identified across all methods and analysis populations. In the pooled analysis, estimated conditional mean mortality risk difference ranged from - 1.2% to 2.1% in causal forest (p = 0.99), and from - 0.5% to 1.5% in BART, with posterior probabilities for hypothermia benefit ranging from 42% to 53%. Absolute subgroup estimates in TEM-VIP analysis were small and non-significant. Results were consistent for the six-month functional outcome.Conclusions Among TTM and TTM2 participants randomized to 33 °C versus controlled normothermia post-OHCA, no evidence of detectable heterogeneity of treatment effect based on available clinical correlates of ischemic burden or initial neurological findings was identified, with minimal estimated variation in treatment effect.
SN - 1364-8535
SN - 1466-609X
ER -