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.
- 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
- 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)
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.
- Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. N Engl J Med. 2002;346(8):549-556.
- 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.
- 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.
- 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.
- Farkas J. PulmCrit - A history of hypothermia for cardiac arrest, 2002-2021 (RIP). EMCrit Project. Published June 17, 2021. Accessed June 21, 2021.