TTM and ECMO – How low should you go?

In 2002, two landmark clinical trials published back-to-back in the New England Journal of Medicine (Bernard and HACA), building upon animal models that showed a neuroprotective benefit to hypothermia after cardiac arrest, set the bar for post-cardiac arrest care in the new millennium. Practice patterns changed rapidly as intensivists and hospital systems attempted to replicate their results, with greater than 50% of their patients in the 33C hypothermia arm of each trial achieving a good neurological outcome. In those halcyon days, the arguments were more about how to cool rather than to what temperature. ECMO was still in its infancy, although case reports began to emerge describing therapeutic hypothermia while on ECMO, and its safety. 

Then in 2013 Nielsen et al., released the infamous TTM trial concluding there was no difference in outcomes between cooling to 33C or 36C. Based on the results of just a single randomized controlled trial, a schism arose between clinicians. 

Proponents of 33C felt that the animal models and the physiology supported the lower temperature, and likely had a better neuroprotective benefit, and found flaws in the TTM trial including its inability to achieve the target temperature early enough, which some hypothesized may have negated the neuroprotective effect of TTM at lower temperatures. 

Proponents of 36C argued that the lower temperature of 33C was more difficult to achieve and that it put their patients at higher risks of bleeding, infection, and cardiac arrhythmias.

International guidelines published by the International Liaison Committee on Resuscitation (ILCOR) avoided the argument, recommending physicians choose a range from 32C-36C post-arrest.

Both groups, it appears so far, were somewhat mistaken. Several prospective and feasibility studies have shown the safety of TTM to 33C as well as therapeutic hypothermia with ECMO. And since the TTM trial in 2013 several retrospective analyses have come out purporting 33C over 36C. While valuable, they are retrospective analyses and are usually single center, covering a small non-representative slice of the population. On the other hand, 3 RCTs – two in children and one preliminary analysis in adults – have been published comparing 33C vs normothermia. One of these, by Pang et al., in 2016, was on 50 adults on ECMO. THAPCA-OH and THAPCA-IH were RCTs performed in children with OHCA and HICA respectively, and enrolled ~300 in each. All three RCTs showed no difference in safety, but also no benefit to neurological outcomes from cooling to a lower temperature. 

The conclusions that can be drawn from these trials are as follows:

Both 32-34C and normothermia are safe. In nearly all studies, there was no difference in complications between groups. This should not be a factor in the temperature decision.

Animal models and retrospective analyses typically show benefit for 33C, however all RCTs in adults and children comparing 32-34C vs active temperature control with fever avoidance (normothermia) showed no benefit between groups.

It seems that despite known physiologic mechanisms that make a good case for lower temperatures, the only benefit that has been shown in humans in randomized controlled trials is from strict fever avoidance, or normothermia.

Bibliography

Ao et al. 2000. Long-term mild hypothermia with extracorporeal lung and heart assist improves survival from prolonged cardiac arrest in dogs. Resuscitation.  48:163-174.

Bernard et al. 2002. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. N Engl J Med.  346(8):557-563.

The Hypothermia After Cardiac Arrest Study Group. 2002. Mild Therapeutic Hypothermia To Improve the Neurologic Outcome After Cardiac Arrest. N Engl J Med. 346(8):549-556.

Guenther et al. 2006. Extended therapeutic hypothermia for several days during extracorporeal membrane-oxygenation after drowning and cardiac arrest. Two cases of survival with no neurological sequelae. Resuscitation. 80:379-381.

Field, David on behalf of the NEST Study Collaborative Group. 2013. Neonatal ECMO Study of Temperature (NEST): A Randomized Controlled Trial. Pediatrics. 132(5):e1247.

Lou et al. 2015. Safety of therapeutic hypothermia in children on veno-arterial extracorporeal membrane oxygenation after cardiac surgery. Cardiology in the Young. 25:1367-1373.

Stub et al. 2015. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation. 86:88-94.

Moler et al. 2015. Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children. N Engl J Med.357(20):1898-1908.

Pang et al. 2016. Therapeutic hypothermia in adult patients receiving extracorporeal life support: early results of a randomized controlled study. Journal of Cardiothoracic Study. 11(43):1-5.

Kim et al. 2017. Extracorporeal Cardiopulmonary Resuscitation with Therapeutic Hypothermia for Prolonged Refractory In-hospital Cardiac Arrest. Korean Circ J. 47(6):969-948.

Pang et al. 2017. Therapeutic Hypothermia May Improve Neurological Outcomes in Extracorporeal Life Support for Adult Cardiac Arrest. Heart, Lung, and Circulation. 26:817-824.

Moler et al. 2017. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. N Engl J Med. 376(4):318-329.

Johnson et al. 2019. Targeted Temperature Management at 33 Versus 36 Degrees: A Retrospective Cohort Study. Crit Care Med. 48(3):362-369.