{
  "abstract": "Introduction\n\nThe 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\n\nThis 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\n\nAll 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\n\nAmong 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.",
  "abstract_shown": true,
  "affiliations": [
    "Anesthesiology and Intensive Care, Department of Clinical Sciences Helsingborg, Lund University, Svartbrödragränden 3, Helsingborg, 251 87, Sweden. gabriele.lileikyte@med.lu.se.",
    "Department of Intensive and Perioperative Care, Skåne University Hospital, Malmö, Sweden. gabriele.lileikyte@med.lu.se.",
    "Cardiology and Critical Care Medicine, McGill University Health Centre, McGill University, Montréal, Canada.",
    "Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Canada.",
    "Neurology and Rehabilitation Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.",
    "Department of Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden.",
    "Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, WI, USA.",
    "Cardiology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.",
    "Department of Cardiology, Skåne University Hospital, Lund, Sweden.",
    "Neurology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.",
    "Department of Neurology, Skåne University Hospital, Lund, Sweden.",
    "Adult Critical Care Unit, University Hospital of Wales, Cardiff, UK.",
    "Division of Intensive Care Medicine, HOCH Cantonal Hospital St. Gallen, St. Gallen, Switzerland.",
    "Intensive Care Unit, Liverpool Hospital, Sydney, Australia.",
    "South Western Sydney Clinical School, University of New South Wales, Sydney, Australia.",
    "Institute of Intensive Care Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland.",
    "Department of Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.",
    "Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.",
    "Department of Intensive Care, Amsterdam Neurosciences, Amsterdam University Medical Center, Amsterdam, The Netherlands.",
    "Department of Anesthesia and Intensive Care Medicine, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg.",
    "Department of Health, Medicine and Life Sciences, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.",
    "Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.",
    "Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Copenhagen, Denmark.",
    "Department of Cardiology, The Heart Center, Copenhagen University Hospital, Copenhagen, Denmark.",
    "Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.",
    "Anesthesia and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.",
    "Department of Biostatistics, Epidemiology and Informatics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.",
    "Anesthesiology and Intensive Care, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.",
    "Department of Intensive and Perioperative Care, Skåne University Hospital, Lund, Sweden.",
    "Cardiology and Critical Care Medicine, University of Toronto, Toronto, Canada."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Gabriele Lileikyte",
      "orcid": "0000-0002-6778-6269"
    },
    {
      "affs": [
        2
      ],
      "name": "Lucas L Marinho"
    },
    {
      "affs": [
        2
      ],
      "name": "Ying Lu"
    },
    {
      "affs": [
        3
      ],
      "name": "Philippe Boileau"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Marion Moseby-Knappe"
    },
    {
      "affs": [
        6
      ],
      "name": "Alexandra Spicer"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Josef Dankiewicz"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Gisela Lilja"
    },
    {
      "affs": [
        11
      ],
      "name": "Matt P Wise"
    },
    {
      "affs": [
        12
      ],
      "name": "Claudia Schrag"
    },
    {
      "affs": [
        13,
        14
      ],
      "name": "Anders Aneman"
    },
    {
      "affs": [
        15
      ],
      "name": "Matthias Haenggi"
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    {
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        16,
        17
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      "name": "Anders M Grejs"
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    {
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        18
      ],
      "name": "Janneke Horn"
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    {
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        19,
        20
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      "name": "Pascal Stammet"
    },
    {
      "affs": [
        21,
        22
      ],
      "name": "Janus C Jakobsen"
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    {
      "affs": [
        23,
        24
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      "name": "Jesper Kjaergaard"
    },
    {
      "affs": [
        25
      ],
      "name": "Christian Rylander"
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    {
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        26
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      "name": "Michael O Harhay"
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    {
      "affs": [
        6
      ],
      "name": "Matthew M Churpek"
    },
    {
      "affs": [
        27,
        28
      ],
      "name": "Niklas Nielsen"
    },
    {
      "affs": [
        2,
        29
      ],
      "name": "Patrick R Lawler"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/erxnyzqkvg7cz.bib",
  "cited_by": 0,
  "doi": "10.1186/s13054-026-06414-x",
  "fulltext_url": "https://europepmc.org/articles/PMC13729339",
  "id": "erxnyzqkvg7cz",
  "issns": [
    "1364-8535",
    "1466-609X"
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  "landing_url": "https://europepmc.org/article/MED/42972430",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
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      "2711|Cardiac Arrest and Resuscitation"
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  "pdf_url": "https://europepmc.org/articles/PMC13729339?pdf=render",
  "pmcid": "PMC13729339",
  "pmid": "42972430",
  "published": "2026-11-02",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/erxnyzqkvg7cz.ris",
  "sources": [
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      "first_seen": "2026-11-04T15:20:47Z",
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      "url": "https://europepmc.org/article/MED/42972430"
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      "native_id": "PMC13729339",
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  "subjects": [
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      "field": "medicine",
      "origin": "openalex:2711|Cardiac Arrest and Resuscitation",
      "subfield": "general"
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  ],
  "title": "Differentiated effect of hypothermia versus normothermia after cardiac arrest by neurological status and clinical correlates of ischemic burden.",
  "title_text": "Differentiated effect of hypothermia versus normothermia after cardiac arrest by neurological status and clinical correlates of ischemic burden.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:07Z",
  "url": "https://research.draconitic.com/paper/erxnyzqkvg7cz",
  "venue": "Critical care (London, England)",
  "versions": []
}