IMPORTANCE: International guidelines recommend body temperature control below 37.8 °C in unconscious patients with out-of-hospital cardiac arrest (OHCA); however, a target temperature of 33 °C might lead to better outcomes when the initial rhythm is nonshockable. OBJECTIVE: To assess whether hypothermia at 33 °C increases survival and improves function when compared with controlled normothermia in unconscious adults resuscitated from OHCA with initial nonshockable rhythm. DATA SOURCES: Individual patient data meta-analysis of 2 multicenter, randomized clinical trials (Targeted Normothermia after Out-of-Hospital Cardiac Arrest [TTM2; NCT02908308] and HYPERION [NCT01994772]) with blinded outcome assessors. Unconscious patients with OHCA and an initial nonshockable rhythm were eligible for the final analysis. STUDY SELECTION: The study cohorts had similar inclusion and exclusion criteria. Patients were randomized to hypothermia (target temperature 33 °C) or normothermia (target temperature 36.5 to 37.7 °C), according to different study protocols, for at least 24 hours. Additional analyses of mortality and unfavorable functional outcome were performed according to age, sex, initial rhythm, presence or absence of shock on admission, time to return of spontaneous circulation, lactate levels on admission, and the cardiac arrest hospital prognosis score. DATA EXTRACTION AND SYNTHESIS: Only patients who experienced OHCA and had a nonshockable rhythm with all causes of cardiac arrest were included. Variables from the 2 studies were available from the original data sets and pooled into a unique database and analyzed. Clinical outcomes were harmonized into a single file, which was checked for accuracy of numbers, distributions, and categories. The last day of follow-up from arrest was recorded for each patient. Adjustment for primary outcome and functional outcome was performed using age, gender, time to return of spontaneous circulation, and bystander cardiopulmonary resuscitation. MAIN OUTCOMES AND MEASURES: The primary outcome was mortality at 3 months; secondary outcomes included unfavorable functional outcome at 3 to 6 months, defined as a Cerebral Performance Category score of 3 to 5. RESULTS: A total of 912 patients were included, 490 from the TTM2 trial and 422 from the HYPERION trial. Of those, 442 had been assigned to hypothermia (48.4%; mean age, 65.5 years; 287 males [64.9%]) and 470 to normothermia (51.6%; mean age, 65.6 years; 327 males [69.6%]); 571 patients had a first monitored rhythm of asystole (62.6%) and 503 a presumed noncardiac cause of arrest (55.2%). At 3 months, 354 of 442 patients in the hypothermia group (80.1%) and 386 of 470 patients in the normothermia group (82.1%) had died (relative risk [RR] with hypothermia, 1.04; 95% CI, 0.89-1.20; P = .63). On the last day of follow-up, 386 of 429 in the hypothermia group (90.0%) and 413 of 463 in the normothermia group (89.2%) had an unfavorable functional outcome (RR with hypothermia, 0.99; 95% CI, 0.87-1.15; P = .97). The association of hypothermia with death and functional outcome was consistent across the prespecified subgroups. CONCLUSIONS AND RELEVANCE: In this individual patient data meta-analysis, including unconscious survivors from OHCA with an initial nonshockable rhythm, hypothermia at 33 °C did not significantly improve survival or functional outcome.

2nd Department of Medicine Cardiovascular Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

Adult Critical Care University Hospital of Wales Cardiff United Kingdom

After ROSC Network

Anaesthesia and Intensive Care Department of Surgical Sciences Uppsala University Uppsala Sweden

Australian and New Zealand Intensive Care Research Centre Monash University Melbourne Victoria Australia

Cardiology Department Lund University Skåne University Hospital Lund Lund Sweden

Copenhagen Trial Unit Centre for Clinical Intervention Research The Capital Region Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Critical Care and Trauma Division George Institute for Global Health Sydney New South Wales Australia

Département de Médecine Intensive Réanimation CHU Angers Angers France

Department of Anaesthesia Southmead Hospital Bristol United Kingdom

Department of Anesthesia and Intensive Care Oslo University Hospital Rikshospitalet Oslo Norway

Department of Anesthesiology and Critical Care San Martino Policlinico Hospital IRCCS for Oncology and Neurosciences Department of Surgical Sciences and Integrated Diagnostics University of Genoa Genoa Italy

Department of Clinical Medicine Aarhus University Aarhus Denmark

Department of Clinical Sciences Anesthesiology and Intensive Care Lund University Lund Sweden

Department of Critical Care University of Melbourne Melbourne Victoria Australia

Department of Intensive Care Hôpital Universitaire de Bruxelles Brussels Belgium

Department of Intensive Care Medicine Aarhus University Hospital Aarhus Denmark

Department of Intensive Care Medicine Bern University Hospital University of Bern Bern Switzerland

Department of Intensive Care Medicine St George Hospital Kogarah New South Wales Australia

Department of Intensive Care Paris Cité University Cochin Hospital Paris France

Department of Intensive Care Wellington Regional Hospital Capital and Coast District Health Board Wellington New Zealand

Department of Regional Health Research The Faculty of Health Sciences University of Southern Denmark Odense Denmark

Department of Research and Education Lund University and Skåne University Hospital Lund Sweden

District Hospital Center Medical Surgical Intensive Care Unit La Roche sur Yon France

INSERM CIC 1402 groupe IS ALIVE Université de Poitiers Poitiers France

INSERM UMR 1260 Regenerative Nanomedicine Fédération de Médecine Translationnelle de Strasbourg Université de Strasbourg Strasbourg France

Médecine Intensive Réanimation CHU Lille Université de Lille Faculté de Médicine Lille France

Medecine Intensive Reanimation CHU Nantes Nantes France

Medical Intensive Care Unit Centre Hospitalier Régional d'Orléans Hôpital de la Source Orléans France

Medical Research Institute of New Zealand Wellington New Zealand

Medical Surgical Intensive Care Unit District Hospital Center Lorient France

Neurology Department of Clinical Sciences Lund University Lund Sweden

Neurology Department Skåne University Hospital Lund Sweden

Service de Médecine Intensive Réanimation Nouvel Hôpital Civil Hôpitaux universitaires de Strasbourg Strasbourg France

Skåne University Hospital Intensive and Perioperative Care Malmö Sweden

Université Paris Cité INSERM PARCC 75015 Paris France

JAMA Neurol. 2024 Feb 1;81(2):115-117. doi: 10.1001/jamaneurol.2023.4831. PubMed

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