Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial

Gisela Lilja, Susann Ullén, Josef Dankiewicz, Hans Friberg, Helena Levin, Erik Blennow Nordström, Katarina Heimburg, Janus Christian Jakobsen, Marita Ahlqvist, Frances Bass, Jan Belohlavek, Roy Bjørkholt Olsen, Alain Cariou, Glenn Eastwood, Hans Rune Fanebust, Anders M Grejs, Lisa Grimmer, Naomi E Hammond, Jan Hovdenes, Juraj HreckoManuela Iten, Henriette Johansen, Thomas R Keeble, Hans Kirkegaard, Jean-Baptiste Lascarrou, Christoph Leithner, Mildred Eden Lesona, Anja Levis, Marco Mion, Marion Moseby-Knappe, Leanlove Navarra, Per Nordberg, Paolo Pelosi, Rachael Quayle, Christian Rylander, Helena Sandberg, Manoj Saxena, Claudia Schrag, Michal Siranec, Cassina Tiziano, Philippe Vignon, Pedro David Wendel-Garcia, Matt P Wise, Kim Wright, Niklas Nielsen, Tobias Cronberg


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.

TidsskriftJAMA Neurology
StatusE-pub ahead of print - 7 aug. 2023


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