52 in 52 – #5: TTM2

Welcome back to the “52 in 52” series. This collection of posts features recently published must-know articles. Our fifth post looks at the TTM2 trial and targeted temperature management.

Author: Brannon Inman (Chief Resident, Emergency Medicine Physician, San Antonio, TX) // Reviewed by: Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest



Clinical question:

Does targeted temperature management compared with targeted normothermia (avoiding fever) impact all-cause mortality in patients with ROSC after out of hospital cardiac arrest (OHCA)?


Study design:

  • Open-label international randomized controlled superiority clinical trial
    • Clinicians were not blinded, but outcome assessors were blinded
    • Primary outcome death from any cause at 6 months
  • Was co-enrolled with targeted therapeutic mild hypercapnia (TAME) trial
  • Block randomized based on site and TAME group allocation
  • Intention to treat analysis
  • Authors assessed death from any cause at 6 months as the primary outcome.




  • Included patients in 14 countries
  • Included adult (≥18 years) patients admitted to the hospital following OHCA of presumed cardiac or unknown cause.
  • Patients were unconscious and had > 20 minutes ROSC with signs of circulation
    • Coma defined as Full Outline of Unresponsiveness (FOUR) scale < 4
      • Components
        • Eye response
        • Motor response
        • Brain stem reflexes
        • Respiratory pattern
      • Had to have > 20 min of return of spontaneous circulation (ROSC) following resuscitation
  • Exclusion: unwitnessed cardiac arrest with asystole as initial rhythm, temperature < 30ºC on admission, required ECMO prior to ROSC, obvious/suspected pregnancy, ICH, severe COPD requiring long-term oxygen.



  • Hypothermia to 33ºC using cooled IVF and intravascular cooling devices with rewarming at 28 hours at a rate of 0.3ºC/hour for up to 40 hours up to 37ºC.



  • Enforced normothermia of 37.5ºC (goal 36.5ºC-37.7ºC). Patients at 37.8ºC received surface or intravascular cooling devices to maintain temperature of 37.5ºC.  This was maintained for 72 hours.



  • Outcomes assessed at 30 days, 180 days, and 24 month with face to face interview or telephone interview. Modified Rankin Score was assessed using structured interviews.
  • Primary outcome (death at 6 months)
    • 50% of hypothermia group, 48 % of normothermia group had died (RR 1.04, 95% CI 0.94-1.14)
  • Secondary outcome
    • Poor functional outcome (mRS 4-6) 55% in both groups
    • The only significant secondary outcome was arrhythmia causing hemodynamic compromise (24% in hypothermia, 15% in normothermia, RR 1.45, 95% CI 1.21-1.75)
  • Data on primary outcome lost/missing on 11 of original 1861 patients (5 in intervention arm, 6 in control)

*Excerpt from text


Take away:

  • Overall, trial demonstrated no difference in the primary outcome of all-cause mortality at 6 months between hypothermia and normothermia.
  • The methods were clear and well organized. There was also a clear separation between groups in specific target temperatures.
  • The sample size was large, reducing risk of random error in outcomes.
  • Groups were overall well balanced, though there was a male predominance.
  • Close to half of the patients in the normothermia group needed a cooling device due to avoid fever.
  • Co-enrollment of 20% patients in the TAME trial could confound the results.
  • There was not a third group of no temperature control.
  • Approximately 3 hours was needed to cool patients to goal temperature, owning to the logistical difficulties with rapid cooling.
  • There might still be a group of patients in whom rapid cooling benefits. Based on these data we do not know what that group is.


My take:

This is a well-constructed study that adds considerably to our knowledge of post-ROSC care and TTM. When not explicitly required by hospital protocol I will not be using hypothermia in comatose post-arrest patients. Rather, I will focus on optimizing cardiac arrest care and ensuring normothermia and preventing fever in the post-ROSC period. At the patient level, I will continue to follow guidelines and hospital policies. At the policy level, I would advocate against making hypothermia in ROSC patients a universal policy. In all likelihood a large chunk of the benefit from the initial TTM literature came from intensive beside care when compared to the control arm, which was better accounted for in this study.



  1. Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021;384(24):2283-2294. doi:10.1056/NEJMoa2100591

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