Therapeutic hypothermia after cardiac arrest is not new. It was a thing 5000 years ago in Egypt. Fast forward to the 20th century and the first clinical trial of therapeutic hypothermia after cardiac arrest in 1958 reported a 50% survival – pretty much the exact same survival rate reported in the recent TTM2 trial. And back in the early 2000’s therapeutic hypothermia was widespread: as soon as we’d achieved ROSC we’d go running for ice packs and cooled crystalloid, and get the ICU on board to set up for their cooling protocol. It was considered “standard of care”. We were all convinced that cooling them would not only save their lives but save their brains, so that they could think and talk and walk like they did before the cardiac arrest. The pathophysiology made sense, the main idea being that cerebral blood flow and oxygen consumption decreases, which preserves autoregulation and saves the brain from ischemic insult and edema.
But as science does with everything, evidence comes along and changes things. The famous TTM trial was published in 2013. It was a large RCT that showed no difference between a target temperature of 33 degrees and 36 degrees. Even though both groups were technically hypothermic, a few logs were taken off the fire of therapeutic hypothermia, and it was no longer considered “the standard”. This year, an even bigger RCT was published, the TTM2 trial, and we now have new guidelines from ILCOR. You would expect that we would have a clear answer after 5000 years of experimenting with therapeutic hypothermia on whether or not to cool patients after cardiac arrest. Well, not so clear.
In this Journal Jam podcast, special guest Dr. Mizuho Morrison joins Anton and Justin to clear up the muddy waters of therapeutic hypothermia with a deep dive into the world’s literature…
Podcast production by Justin Morgenstern and Anton Helman
Podcast editing and sound design by Anton Helman. Blog summary by Anton Helman, October 2021.
Cite this podcast as: Helman, A. Morgenstern, J. Morrison, M. Journal Jam 19 – Therapeutic Hypothermia after Cardiac Arrest – Mixed Evidence. Emergency Medicine Cases. October, 2021. https://emergencymedicinecases.com/journal-jam-therapeutic-hypothermia-cardiac-arrest.Accessed [date]
The original 2 RCTs in 2002 that made therapeutic hyperthermia “standard”
The Bernard trial, while showing an impressive improvement in the primary outcome of neurologic function well enough to be sent home or to a rehab facility (49% hypothermia group vs 26% in normothermia group), did not show a mortality benefit and had many weaknesses including: not randomized, selection bias, unblinded and included patients with fever.
The HACA RCT showed a 16% difference in 6 month functional neurologic status in the primary outcome (55% vs 39%), and 14% mortality benefit (41% vs 55%). This trial too suffered from selection bias, it was unblinded and included patients with fever.
The original TTM trial 2013: no difference between 33 and 36 degrees
This was a large RCT in 36 ICUs internationally that showed no difference in the primary outcome of mortality (50% vs 48%) and no difference in neurologic outcomes between cooling patients to 33 vs 36 degrees Celsius. This was a well-done RCT but suffered from very large confidence intervals and did not answer the question of whether cooling is any better than no cooling.
Timing of therapeutic hypothermia: prehospital RCTs – is earlier better?
3 pre-hospital RCTs totalling more than 2,000 adult patients showed no significant clinically improved outcomes with therapeutic hypothermia.
HYPERION RCT: therapeutic hypothermia in non-shockable rhythms
The HYPERION RCT randomized adult patients to 33 degrees Celsius vs 36.5 to 37.5 Celsius for 24 hours and found that survival with a favourable neurologic outcome at 90 days was 10.2% in the hypothermia group vs 5.7% in the normothermia group (absolute difference 4.5%), but no mortality benefit (81.3% vs 83.2%).
TTM2 RCT: no difference between 33 and 37.5 degrees
The recent TTM2 trail was a large international multi-center open-label RCT of 1861 comatose adult patients after out of hospital cardiac arrest regardless of initial rhythm. They excluded the sickest of the sick: those who had >3 hours of resususcihtion and those with an unwitnessed arrest who were asystole on presentation. They were randomized to a target temperature of 33 vs ≤37.5 degrees Celsius. The primary outcome was death from any cause at 6 months (48% versus 50%) and there was no difference in functional outcomes or quality of life. Dysrhythmias with hemodynamic instability were more common in the hypothermia group (24% vs 16%).
This RCT suffers from the same problems as previous RCTS: they did not include a control group without any temperature control. Additionally, some would argue that the patients in this study do not represent the patients we see in general EM practice very well (compared to most North American hospitals the TTM2 had 2 times the number of witnessed arrests, 2 times the number of bystander CPR, 3 times the frequency of shockable rhythms and about 3 times the survival to hospital discharge).
Update 2021: CAPTAIN CHILL (single-center, double-blind) randomized clinical trial of 367 comatose survivors of out-of-hospital cardiac arrest. Targeting moderate hypothermia (31 °C) for 24 hours, as opposed to mild hypothermia (32-36 °C; current guideline recommendation), did not reduce rate of death or poor neurologic outcomes at 180 days. Abstract
What about fever control? Does fever control improve outcomes?
While fever has been shown to be associated with bad outcomes in observational studies, there is no RCT level evidence that controlling fever is beneficial.
ILCOR guidelines on therapeutic hypothermia after cardiac arrest
The ILCOR guidelines came to similar conclusions as this review comparing hypothermia to normothermia or fever prevention:
No difference in survival to hospital discharge
No difference in favorable neurological outcome at hospital discharge or 30 days
No difference in survival to 90 or 180 days
No difference in favorable neurologic outcome at 90 or 180 days
ILCOR recommendations and suggestions:
Suggest actively prevent fever by targeting a temperature ≤ 37.5 for those patients who remain comatose after ROSC from cardiac arrest (weak recommendation, low certainty evidence).
Whether subpopulations of cardiac arrest patients may benefit from targeting hypothermia at 32-34oC remains uncertain.
Comatose patients with mild hypothermia after ROSC should not be actively warmed to achieve normothermia.
Recommend against the routine use of prehospital cooling with rapid infusion of large volumes of cold IV fluid immediately after ROSC (strong recommendation, moderate certainty evidence).
Suggest surface or endovascular temperature control techniques when temperature control is used in comatose patients after ROSC (weak recommendation, low certainty of evidence).
When a cooling device is used, suggest using a temperature control device that includes a feedback system based on continuous temperature monitoring to maintain the target temperature.
Suggest active prevention of fever for at least 72 hours in post-cardiac arrest patients who remain comatose (they acknowledge there are no RCTs to support this practice).
For Dr. Morgenstern’s, Dr. Morrison’s and Dr. Helman’s take home practical clinical application of these studies….please listen to the podcast.
Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. The New England journal of medicine. 2002; 346(8):557-63.
HACA – Hypothermia After Cardiac Arrest study group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. The New England journal of medicine. 2002; 346(8):549-56.
Bernard SA, Smith K, Cameron P, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010; 122(7):737-42.
Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. The New England journal of medicine. 2013; 369(23):2197-206.
Kim F, Nichol G, Maynard C, et al. Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial. JAMA. 2014; 311(1):45-52.
Nordberg P, Taccone FS, Truhlar A et al. Effect of Trans-Nasal Evaporative Intra-arrest Cooling on Functional Neurologic Outcome in Out-of-Hospital Cardiac Arrest: The PRINCESS Randomized Clinical Trial. JAMA. 2019 May 7;321(17):1677-1685.
Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. The New England journal of medicine. 2019; 381(24):2327-2337.
Young PJ, Bellomo R, Bernard GR, et al. Fever control in critically ill adults. An individual patient data meta-analysis of randomised controlled trials. Intensive care medicine. 2019; 45(4):468-476.
Dankiewicz J, Cronberg T, Lilja G, et al: TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.N Engl J Med. 2021 Jun 17;384(24):2283-2294.
Morrison LJ, Thoma B. Translating Targeted Temperature Management Trials into Postarrest Care. N Engl J Med. 2021 Jun 17;384(24):2344-2345.
Dr. Anton Helman is an Emergency Physician at North York General in Toronto. He is an Assistant Professor at the University of Toronto, Division of Emergency Medicine and the Education Innovation Lead at the Schwartz-Reisman Emergency Medicine Instititute. He is the founder, editor-in-chief and host of Emergency Medicine Cases.