Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial

Rupert F.G. Simpson, Josef Dankiewicz, Grigoris V. Karamasis, Paolo Pelosi, Matthias Haenggi, Paul J. Young, Janus Christian Jakobsen, Jonathan Bannard-Smith, Pedro D. Wendel-Garcia, Fabio Silvio Taccone, Per Nordberg, Matt P. Wise, Anders M. Grejs, Gisela Lilja, Roy Bjørkholt Olsen, Alain Cariou, Jean Baptiste Lascarrou, Manoj Saxena, Jan Hovdenes, Matthew ThomasHans Friberg, John R. Davies, Niklas Nielsen, Thomas R. Keeble*

*Corresponding author for this work

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Background: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. Methods: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4–6 on modified Rankin scale). Results: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84–1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80–1.26). Conclusions: Using a hospital’s average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.

Original languageEnglish
Article number356
JournalCritical Care
Number of pages8
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
Dr Young reports receiving lecture fees from Bard Medical. Dr Wise receives honoraria from Gilead and Fisher & Paykel for educational lectures. Dr Keeble reports receiving lecture fees from BD, and a research grant from Zoll. Dr Cariou received fees from Bard Medical. Professor Taccone receives lecture fees from BD and ZOLL. Professor Friberg is a scientific advisor TEQCool (Lund, Sweden).

Publisher Copyright:
© 2022, The Author(s).


  • Hypothermia
  • Out of hospital cardiac arrest
  • Temperature management
  • Time to target temperature
  • Fever/therapy
  • Cardiopulmonary Resuscitation
  • Cold Temperature
  • Humans
  • Hypothermia, Induced
  • Out-of-Hospital Cardiac Arrest/therapy
  • Treatment Outcome


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