Critical Care, Critical Care Alert, Cardiology

Critical Care Alert: Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2 Trial)

Critical Care Alert

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.

Randomized trial to assess the beneficial and harmful effects of hypothermia vs normothermia and early treatment of fever in comatose patients after out-of-hospital cardiac arrest

Fever has been thought to be a risk factor for hypoxic-ischemic brain damage in patients post-cardiac arrest. Relatively small trials from the early 2000s showed significant mortality and functional benefits from targeted temperature management to 33℃ after return of spontaneous circulation (ROSC) in patients with shockable rhythms.1,2 Since then, targeted temperature management (TTM) has become a standard protocol in many institutions. In 2013, this dogma was brought into question by the larger TTM1 trial that showed similar outcomes in their hypothermia (33℃) and forced normothermia (36℃) groups.3 In 2019, a trial demonstrated a significant improvement in neurologic outcome but not mortality at 90 days in their hypothermia (33℃) arm after non-shockable arrest.4 Evidence surrounding the benefits of post-arrest hypothermia has been conflicting, but it continues to be the standard of care per international guidelines.


  • Open label-trial with blinded assessment of outcomes


  • ≥ 18 years of age
  • Admitted after out-of-hospital arrest from cardiac or unknown cause
    • Both shockable and non-shockable rhythms
  • > 20 minutes of spontaneous circulation after resuscitation
  • Unconscious, unable to obey verbal commands, and no verbal response to pain


  • Unwitnessed cardiac arrest with asystole as initial rhythm
  • ROSC to screening and randomization > 180 minutes
  • Temperature on admission of < 30℃
  • Extracorporeal Membrane Oxygenation prior to ROSC
  • Obvious or suspected pregnancy
  • Intracranial bleed
  • Long term home oxygen use secondary to severe pulmonary disease


  • Hypothermia group
    • Cooled with surface or intravascular device to 33℃ for 28 hours followed by gradual rewarming to 37℃ over 12 hours.
  • Normothermia
    • Maintained a temperature of 37.5℃ or less.
    • Cooled with a surface or intravascular device for temperatures greater than 37.8℃


  • Death from any cause at 6 months


  • Functional outcome at 6 months based on Rankin Score
  • Days alive and out of hospital until day 180
  • Health-related quality of life
  • Rate of adverse events

A total of 1850 patients were evaluated for the primary outcome 

Primary Outcome

  • There was no statistically significant difference in mortality at 6 months between the hypothermia and normothermia group (50% vs 48% respectively, relative risk (RR) with hypothermia of 1.04, p = 0.37)
  • The effect of the temperature intervention on death at 6 months was consistent across subgroups, including shockable and non-shockable rhythms.

Selected Secondary Outcomes

  • There was no statistically significant difference in the functional outcome between the two groups. (55% in both groups with “poor” functional outcomes. RR with hypothermia = 1.00)
  • The hypothermia group had increased risk of arrhythmia resulting in hemodynamic compromise compared to normothermia (24% vs 17%, p < 0.001)


  • Largest trial to date of targeted temperature management, spanning multiple countries
  • Hospitals with experience in cooling and considered cardiac arrest centers
  • Physicians performing neuroprognostication were blinded
  • Decisions to withdraw care were performed by a blinded physician at 96 hours, well after the intervention period
  • Investigators, authors, and statisticians were unaware of group assignments during analysis of data


  • No non-temperature regulated group
  • ICU staff members were aware of assigned target temperature
  • Use of a cooling device was used in 43% of the normothermic group patients (an uncommon type of fever control)
  • ⅕ of patients were also involved in TAME trial (targeted mild hypercapnia after resuscitated cardiac arrest)

EM Take-Aways
Historical evidence for the effectiveness of hypothermia to 33℃ post-arrest has been inconsistent at best. The new TTM2 trial demonstrates a low likelihood of meaningful clinical or mortality improvement with TTM. In fact, cooling to 33℃ may be harmful in some cases - more often requiring paralytics, increased risk of unstable arrhythmia, and longer average time on the vent.5

While preventing fever in post-ROSC patients may be beneficial, aggressive cooling to 33℃ seems unlikely to provide benefit, regardless of initial rhythm, contradicting previously touted studies.

New evidence from the TTM2 trial may move critical care and hospital protocols away from post-arrest hypothermia, but until then we recommend you follow your individual hospital protocols.


  1. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. N Engl J Med. 2002;346(8):549-556.
  2. Bernard SA, Gray TW, Buist MD, et al. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. N Engl J Med. 2002;346(8):557-563.
  3. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. N Engl J Med. 2013;369(23):2197-2206.
  4. Lascarrou J-B, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019;381(24):2327-2337.
  5. Farkas J. PulmCrit - A history of hypothermia for cardiac arrest, 2002-2021 (RIP). EMCrit Project. Published June 17, 2021. Accessed June 21, 2021.

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