IMPORTANCE: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. OBJECTIVES: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. DESIGN, SETTING, AND PARTICIPANTS: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. INTERVENTIONS: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). MAIN OUTCOMES AND MEASURES: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. RESULTS: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). CONCLUSIONS: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02908308.

2nd Department of Medicine Department of 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

Anesthesia and Critical Care San Martino Policlinico Hospital IRCCS for Oncology and Neurosciences Genoa Italy

Anesthesia and Intensive Care Department of Clinical Sciences Lund Lund University Skane University Hospital Malmö Sweden

Cardiac anesthesia and Intensive Care department Istituto Cardiocentro Ticino Lugano Switzerland

Cardiac Intensive Care Unit Haukeland University Hospital Bergen Norway

Cardiology Department of Clinical Sciences Lund Lund University Skane University Hospital Lund Sweden

Center for Resuscitation Sciences Department of Clinical Science and Education Södersjukhuset Karolinska Institutet Stockholm Sweden

Charité Universitätsmedizin Berlin coroporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Department of Neurology Berlin Germany

Clinical Studies Sweden Forum South Skane University Hospital Lund Sweden

Cochin University Hospital Paris France

Copenhagen Trial Unit Center for Clinical Intervention Research Copenhagen University Hospital Copenhagen Denmark

Critical Care Program The George Institute for Global Health and UNSW Sydney Sydney New South Wales Australia

Department of Anaesthesiology and Intensive Care Medicine Institute of Clinical Sciences Sahlgrenska Academy University of Gothenburg Sahlgrenska University Hospital Gothenburg Sweden

Department of Anesthesiology and Pain Medicine Inselspital Bern University Hospital University of Bern Bern Switzerland

Department of Anesthesiology Division of Emergencies and Critical Care Oslo University Hospital Rikshospitalet Oslo Norway

Department of Anesthesiology Sørlandet Hospital Arendal Norway

Department of Clinical Sciences Lund Anaesthesia and Intensive Care and Clinical Sciences Helsingborg Helsingborg Hospital Lund University Lund Sweden

Department of Intensive Care Austin Hospital Melbourne Victoria Australia

Department of Intensive Care Medicine and Department of Clinical Medicine Aarhus University Hospital Aarhus Denmark

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

Department of Neurology Rikshospitalet Oslo University Hospital Oslo Norway

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

Department of Surgical Sciences Anaesthesiology and Intensive Care Medicine Uppsala University Sweden

Department of Surgical Sciences and Integrated Diagnostics University of Genoa Genoa Italy

Essex Cardio Thoracic Centre Basildon Essex UK Thurrock University Hospitals Basildon United Kingdom

Function Perioperative Medicine and Intensive Care Karolinska University Hospital Stockholm Sweden

Hallands hospital Halmstad Sweden

Institute of Intensive Care Medicine University Hospital Zurich Zurich Switzerland

Intensive Care Department Kantonspital St Gallen St Gallen Switzerland

Intensive Care Unit Wellington hospital Wellington New Zealand

Malcolm Fisher Department of Intensive Care Royal North Shore Hospital Sydney New South Wales Australia

Manchester Foundation Trust Manchester United Kingdom

Medecine Intensive Reanimation CHU Nantes Nantes France

Medical Research Institute of New Zealand Wellington New Zealand

Medical surgical ICU and Inserm CIC 1435 Dupuytren University hospital Limoges France

MTRC Anglia Ruskin University Faculty of Health Education Medicine and Social Care Chelmsford Essex United Kingdom

Neurology Department of Clinical Sciences Lund Lund University Skane University Hospital Lund Sweden

Research Center for Emergency Medicine Emergency Department Aarhus University Hospital and Department of Clinical Medicine Aarhus University Aarhus Denmark

St George Hospital Clinical School The George institute for Global Health University of New South Wales Sydney New South Wales Australia

The 1st Department of Internal Medicine Cardioangiology Medical Faculty of Charles University in Hradec Králové and University Hospital Hradec Králové Hradec Králové Czech Republic

The Greater Manchester NIHR Clinical Research Network Manchester United Kingdom

University Hospitals Bristol and Weston NHS Trust Bristol United Kingdom

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ClinicalTrials.gov
NCT02908308