How to do more, not less for post-cardiac arrest patients.
Background Information
Hypothermia is back in the headlines. Two studies introduced this therapy back in 2002, The Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with induced Hypothermia and The Hypothermia After Cardiac Arrest Trial (HACA).[1]
Although small, the HACA trial showed improved neurologic outcomes at six months when patients were cooled to 32-34oC.[2] After that, cooling patients to 33oC become standard therapy for out-of-hospital cardiac arrest at many institutions worldwide.[3] In 2013, the Targeted Temperature Management (TTM) Trial suggested no overall benefit between cooling patients to 33oC vs. 36oC.[4]
This left many institutions on their own to deciding the most appropriate temperature to target. Some institutions attempted 36oC only to find their outcomes worsened.[5,6] Most recently, the authors of the TTM Trial just came out with another study looking at the benefit of avoiding fever vs. targeting a specific temperature in these critically ill patients.
Study Design and Results
This was an international, multicenter randomized superiority trial that co-enrolled with the Targeted Therapeutic Mild Hypercapnia (TAME) trial. Patients were randomized into one of two groups: The hypothermia (intervention) group and the normothermia (control) group.
The intervention group achieved rapid targeted temperature management of 33oC via surface and intravascular cooling devices. While the control group had a trigger temperature of 37.8oC at which point they then received surface and intravascular cooling devices to aggressively maintain a temperature of 37.5oC for 72 hours after randomization.
The primary outcome was death from any cause at six months and some secondary outcomes included adverse events (i.e. arrhythmias, bleeding, pneumonia, sepsis, etc), poor functional outcome and number of days patients were alive and out of the hospital at six months.
A total of 1,861 patients were enrolled and divided between the two groups. The p-value for the primary outcome was 0.37 (not statistically significant). The only secondary outcomes to be statistically significant were arrhythmias causing hemodynamic compromise. Of note, the hypothermia intervention group required more paralytics and longer duration of mechanical ventilation than the normothermia group.
Strengths and Limitations
The methodology of this trial was impeccable. It checks off all the right boxes: Large sample size, high external validity, primary outcome with low risk of bias, equally balanced groups, minimal deviations from protocol, nearly complete follow-up and more.
A great feature of this study that arguably should be involved in all patient cases was neuro-prognostication performed at 96 hours by a physician unaware of the intervention assignments.
Each of these patients requires exceptionally tailored care as each case is different. While timely (and not too early) neuro-prognostication is required; it should not be the definitive end-goal that we as emergency physicians attempt to aggressively quantify. It’s important to note several limitations.
The patient population was extremely unique and factors regarding their cardiac arrest were also distinctive. Eighty percent of the patients in both groups were male and surprisingly over 75% of patients in both groups had bystander-CPR performed (a number far less in the United States).
Additionally, over 40% of patients, again in both groups, had STEMIs and went to the cardiac catherization lab. Keep in mind that due to inherent problems with blinding body-temperature, the clinicians involved were not blinded. Assessors of prognosis, participants, outcome assessors, statisticians and data managers all were blinded.
There was unfortunately no third group in this study to answer the question as to whether temperature management is better than no targeted temperature management. Lastly, a very thorough and protocolized critical care bundle of therapy was applied to all of these patients and this is not representative of current clinical practice at all institutions
Bottom Line
Following this evidence, it’s starting to become clear that cooling to 33oC may not lead to the improved clinical outcomes we once thought it did. Although the patient population was very different, cooling showed to have more harm than benefit. This does not necessarily mean that cooling should no longer be performed. In fact, we should be doing more, not less, for these patients.
There should be a greater vigilance on avoiding fever. More effort should be directed towards community CPR training, bystander CPR, early defibrillation and percutaneous coronary intervention access. More thorough and timelier neuro-prognostication needs to be performed. Lastly, having well designed post-cardiac arrest ICU bundles ensures we are providing the best possible care for these critically ill patients.
REFERENCES
- Bernard SA, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002 Feb 21; PMID: 11856794
- Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 Feb PMID: 11856793
- Dankiewicz J et al. Hypothermia Versus Normothermia After Out-Of-Hospital Cardiac Arrest. NEJM 2021. PMID: 34133859
- Nielsen N, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013 Dec 5. PMID: 24237006
- Johnson NJ, et al. Targeted Temperature Management at 33 Versus 36 Degrees: A Retrospective Cohort Study. Crit Care Med. Mar 2020. PMID: 31809279
- Bray JE, et al. Changing target temperature from 33°C to 36°C in the ICU management of out-of-hospital cardiac arrest: A before and after study. Resuscitation. Apr 2017 PMID: 28159575