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. 2023 Oct 1;80(10):1070-1079.
doi: 10.1001/jamaneurol.2023.2536.

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  1 , Susann Ullén  1 , Josef Dankiewicz  2 , Hans Friberg  3 , Helena Levin  3 , Erik Blennow Nordström  4 , Katarina Heimburg  4 , Janus Christian Jakobsen  5   6 , Marita Ahlqvist  7 , Frances Bass  8   9 , Jan Belohlavek  10 , Roy Bjørkholt Olsen  11 , Alain Cariou  12 , Glenn Eastwood  13 , Hans Rune Fanebust  14 , Anders M Grejs  15 , Lisa Grimmer  16 , Naomi E Hammond  8   9 , Jan Hovdenes  17 , Juraj Hrecko  18 , Manuela Iten  19 , Henriette Johansen  20 , Thomas R Keeble  21   22 , Hans Kirkegaard  23 , Jean-Baptiste Lascarrou  24 , Christoph Leithner  25 , Mildred Eden Lesona  26 , Anja Levis  19   27 , Marco Mion  21   22 , Marion Moseby-Knappe  4 , Leanlove Navarra  28 , Per Nordberg  29   30 , Paolo Pelosi  31   32 , Rachael Quayle  33   34 , Christian Rylander  35 , Helena Sandberg  36 , Manoj Saxena  37 , Claudia Schrag  38 , Michal Siranec  10 , Cassina Tiziano  39 , Philippe Vignon  40 , Pedro David Wendel-Garcia  41 , Matt P Wise  42 , Kim Wright  16 , Niklas Nielsen  43 , Tobias Cronberg  4
Affiliations

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 et al. JAMA Neurol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lilja reported grants from The Swedish Research Council (2016-00428), The Swedish Heart-Lung Foundation, The Gorthon Foundation, The Knutsson Foundation, the Hans-Gabriel and Alice Trolle-Wachtmeisters Foundation for Medical Research, the Skane County Council’s Research and Development Foundation, the Skane University Hospital Foundations; the Swedish National Health System, and the Laerdal Foundation during the conduct of the study. Dr Belohlavek reported consultant fees, lecture honoraria, and personal fees from Abiomed, Xenios, Resuscitec, AstraZeneca, Boehringer Ingelheim, and Getinge, outside the submitted work. Dr Cariou reported personal fees from Bard for lectures outside the submitted work. Dr Eastwood reported being a chief principal investigator of the TAME cardiac arrest trial (NCT03114033) that permitted coenrollment with the TTM2 trial. Dr Grejs reported nonfinancial support from BD to travel to the TTM2 hypothermia symposium outside the submitted work. Dr Hammond reported grants from the National Health and Medical Research Council of Australia Emerging Leader Grant (APP1196320) outside the submitted work. Dr Lascarrou reported personal fees from Zoll and BD, and grants from the French Ministry Health, Nantes University Hospital, and Agence BioMedecine outside the submitted work. Dr Rylander reported nonfinancial support from The Swedish Research Council (2016-00428) during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Flow Diagram of Inclusion
ECMO indicates extracorporeal membrane oxygenation; GOSE, Glasgow Outcome Scale Extended; MoCA, Montreal Cognitive Assessment; ROSC, return of spontaneous circulation; SDMT, Symbol Digit Modalities Test.
Figure 2.
Figure 2.. Functional Outcome Focusing on Societal Participation
By the Glasgow Outcome Scale Extended (GOSE) score for survivors with hypothermia (n = 415) and normothermia (n = 419) at 6 months after out-of-hospital cardiac arrest. Information for the GOSE score was reported by the participant (328 of 415 vs 320 of 419), relative (11 of 415 vs 15 of 419), participant and relative together (72 of 415 vs 77 of 419), or other (3 of 415 vs 5 of 419). Description of categories included GOSE score of 2, vegetative state (unconscious); GOSE score of 3, lower severe disability (dependent, needs frequent help); GOSE score of 4, upper severe disability (dependent, needs some help); GOSE score of 5, lower moderate disability (independent, unable to participate in 1 or more life roles); GOSE score of 6, upper moderate disability (independent, limited to participate in 1 or more life roles); GOSE score of 7; lower good recovery (independent, returned to normal life with some symptoms); and GOSE score of 8, upper good recovery (independent and a full return to normal life).
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References

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