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Data Supporting Therapeutic Hypothermia for Cardiac Arrest Aren’t So Hot

By Ryan Patrick Radecki, MD, MS | on November 23, 2021 | 2 Comments
Pearls From the Medical Literature
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The idea of cooling survivors from cardiac arrest has a long and storied history. In perhaps the most famous, although fictional, example of the efficacy of hypothermia, a military hero named Steve Rodgers went into the ice during operations over the Arctic Ocean in 1945. After being successfully resuscitated nearly 66 years later, no cognitive or physical impairment was evident in this soldier also known as Captain America. Despite powerful fictional anecdotes such as this and others, the evidence guiding routine use of mild therapeutic hypothermia remains elusive.

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ACEP Now: Vol 40 – No 11 – November 2021

Research History

For nearly 20 years, controversy has followed, primarily from a prospective multicenter trial testing mild therapeutic hypothermia versus normothermia in survivors of out-of-hospital cardiac arrest.1 This prominent trial identified a risk ratio of 1.40 favoring good neurological outcome in the hypothermia group, along with a corresponding benefit on mortality. These data, among other studies and observational series, ultimately resulted in recommendations for mild therapeutic hypothermia entering into clinical guidelines.2

Following initial adoption of therapeutic hypothermia, the precise ideal temperature for hypothermia remained an open question. Subsequently, in 2013, the first Targeted Temperature Management (TTM) trial tested active temperature management of 33° C versus 36° C following cardiac arrest in a much larger trial population.3 This trial was unable to identify an advantage of 33° C over 36° C, adding substantial uncertainty regarding both implementation of and the fundamental principle of therapeutic hypothermia. Given this lack of observed difference between temperature targets, it became necessary to take a broader look at whether hypothermia conferred a benefit or simple avoidance of pyrexia.

Two additional trials served mainly to further muddy the issue. A trial testing therapeutic hypothermia against targeted normothermia in children provided inconclusive results but generally favored therapeutic hypothermia.4 Likewise, a trial in adults restricted solely to nonshockable rhythms tilted the balance of evidence incrementally toward therapeutic hypothermia.5

Latest Research

Finally, this August, the Targeted Temperature Management 2 (TTM2) trial was published, reexamining the fundamental question of the value of therapeutic hypothermia.6 Enrolling 1,900 patients in the largest trial addressing the question to date, study procedures tested 33°C and controlled rewarming against targeted normothermia and early treatment of pyrexia. The primary outcome was mortality at six months, along with secondary outcomes of functional outcome and other adverse events.

Like the TTM trial before it, this second iteration was unable to identify any advantage to therapeutic hypothermia for any patient-oriented outcome. Mortality at six months was similar, as was the proportion of patients with severe disability. Regardless of subgroup, including shockable and nonshockable rhythms, there was no further signal for potential benefit. Prespecified adverse outcomes while hospitalized were more common in the therapeutic hypothermia cohort, primarily manifesting as an excess of arrhythmias resulting in hemodynamic compromise.

Somehow, then, after 20 years of investing in cooling infrastructure, protocols, and research, we are back to nearly where we began and still with many outstanding questions. It is becoming clearly unlikely that therapeutic hypothermia, down to 33° C as implemented in these trials, provides a beneficial effect. Additionally, the biases in these trials virtually all favor the therapeutic hypothermia arm, considering their open-label nature. Clinicians and families are less likely to de-escalate care for patients randomized to an active intervention as compared to those in a control arm. Where possible, protocols and conservative withdrawal of care assessments aim to reduce early de-escalation, but this bias can only be minimized, not eliminated.

Additionally, it still is not possible to determine the benefit of active temperature management using intravascular or external devices versus simply aggressively treating pyrexia. Approximately half of the patients included in TTM2 had their temperatures actively managed with a device, leaving a knowledge gap regarding this intervention. Pyrexia is clearly associated with poorer outcomes following out-of-hospital cardiac arrest, but it remains unknown whether pyrexia may simply be treated or prevented via pharmacological methods.

Finally, the last major question raised by critics of trials of therapeutic hypothermia is about the rapidity with which patients attained target temperature. In TTM2, the median time from cardiac arrest to randomization was approximately two hours, and patients achieved core temperatures below 34° C approximately four hours later. It remains an open question whether cooling is achieved quickly enough to receive any therapeutic benefit from hypothermia. Prehospital trials using cold saline have achieved rapid cooling prior to hospital arrival but with concurrent adverse effects and no clear beneficial effect on hospital outcomes.7

We are nearly back at square one with respect to therapeutic hypothermia. Certainly, the routine use of therapeutic hypothermia under current protocols has little remaining justification. It would likewise be reasonable to discontinue routine use of active temperature management devices while awaiting further evidence of benefit. While the trends in medicine always tend to favor adoption rather than de-adoption of new practices, the time has likely come to fully reevaluate any role for therapeutic hypothermia.

Pages: 1 2 | Single Page

Topics: Cardiac ArrestCritical CareHypothermia

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About the Author

Ryan Patrick Radecki, MD, MS

Ryan Patrick Radecki, MD, MS, is an emergency physician and informatician with Christchurch Hospital in Christchurch, New Zealand. He is the Annals of Emergency Medicine podcast co-host and Journal Club editor and can be found on Twitter @emlitofnote.

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2 Responses to “Data Supporting Therapeutic Hypothermia for Cardiac Arrest Aren’t So Hot”

  1. December 13, 2021

    Douglas F. Kupas, MD, FACEP, FAEMS Reply

    I find this article to dangerously oversimplify the science behind hypothermia after cardiac arrest.

    The European TTM trials had significant weaknesses when comparing their study demographics with those of the average out-of-hospital cardiac arrests in most of the United States. (Maybe the OOHCAs in the authors country of New Zealand have different demographics that are biasing his interpretation?)The patients in TTM had incredibly high rates of bystander CPR, and the patients had very high rates of shockable initial rhythm – as well as other demographic differences from the US. Additionally, the time to cool patients was exceedingly long in the TTM trial which may have proven that “if you have delayed cooling, patients do no better than with no cooling”. The ongoing NIH funded ICECAP study requires cooling to target temperature within 4 hours of the 911 call – a huge difference from the leniency in cooling times in these TTM trials.

    I am most concerned about the conclusion of this overly simplistic ACEP Now article that suggests that we should stop cooling based upon this trade journal article. If we applied the current evidence for epinephrine in cardiac arrest to this same scrutiny, there is more support for hypothermia. Emergency and critical care physicians should use caution in using this ACEP article (and the TTM trials) by themselves to make an argument for major changes in the practice of cooling.

    • January 23, 2022

      Ryan Radecki Reply

      I think we probably agree more than we disagree on the science.

      You mention ICECAP and other ongoing efforts to determine new delivery approaches with potential benefits – as do I, in the concluding paragraphs.

      This summary should be construed, as you rightly note, to indicate the *current* approach – as likely reflected in the trial procedures – is unlikely to be of benefit to patients. I think we are actually arguing for the same thing – “major change in the practice of cooling”, and if evidence suggests greater alacrity is the beneficial element, that would be the change for which you argue.

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