RCT: In patients with coma after cardiac arrest with nonshockable rhythm, moderate hypothermia for 24 hours vs normothermia improved survival with favorable neurologic outcome at 90 d.
Lascarrou JB, Merdji H, Le Gouge A, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019 Oct 2. doi: 10.1056/NEJMoa1906661.

BACKGROUND: Moderate therapeutic hypothermia is currently recommended to improve neurologic outcomes in adults with persistent coma after resuscitated out-of-hospital cardiac arrest. However, the effectiveness of moderate therapeutic hypothermia in patients with nonshockable rhythms (asystole or pulseless electrical activity) is debated.

METHODS: We performed an open-label, randomized, controlled trial comparing moderate therapeutic hypothermia (33°C during the first 24 hours) with targeted normothermia (37°C) in patients with coma who had been admitted to the intensive care unit (ICU) after resuscitation from cardiac arrest with nonshockable rhythm. The primary outcome was survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the Cerebral Performance Category (CPC) scale (which ranges from 1 to 5, with higher scores indicating greater disability). We defined a favorable neurologic outcome as a CPC score of 1 or 2. Outcome assessment was blinded. Mortality and safety were also assessed.

RESULTS: From January 2014 through January 2018, a total of 584 patients from 25 ICUs underwent randomization, and 581 were included in the analysis (3 patients withdrew consent). On day 90, a total of 29 of 284 patients (10.2%) in the hypothermia group were alive with a CPC score of 1 or 2, as compared with 17 of 297 (5.7%) in the normothermia group (difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P = 0.04). Mortality at 90 days did not differ significantly between the hypothermia group and the normothermia group (81.3% and 83.2%, respectively; difference, -1.9 percentage points; 95% CI, -8.0 to 4.3). The incidence of prespecified adverse events did not differ significantly between groups.

CONCLUSIONS: Among patients with coma who had been resuscitated from cardiac arrest with nonshockable rhythm, moderate therapeutic hypothermia at 33°C for 24 hours led to a higher percentage of patients who survived with a favorable neurologic outcome at day 90 than was observed with targeted normothermia. (Funded by the French Ministry of Health and others; HYPERION ClinicalTrials.gov number, NCT01994772.).

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Comments from MORE raters

Emergency Medicine

In our ED, we have been doing therapeutic hypothermia for years. I`m glad to see it evaluated in a targeted way, as in this study. For non-shockable rhythm, this doubles the neurologically intact survival. The rate continues to be dismal, but this is an improvement.

This article adds to the literature about the role of TTM and whether to aim for a goal of mild hypothermia or normothermia. In this article, mild hypothermia had improvement of good CPC at 90 days compared with normothermia; however, mortality and other parameters were unchanged. Current literature is mixed in terms of outcome. More studies will be needed to confirm benefit before this becomes widely adopted.

In this RCT, the investigators found temperature management to a target of 33 degrees Centigrade improved neurologically intact survival in comatose out-of-hospital cardiac arrest survivors. Before this study, we generally extrapolated from trials focused on shockable rhythms and decided that the brain would not care about the mechanism of cardiac arrest. Notable is the high mortality (over 80% versus about 50% for shockable rhythms.) In addition, the finding was a bit fragile (the proportion of patients with CPC 3 was greater in the normothermia group, so misclassification here could be really impactful). Still, this is important and provides additional clinical evidence to back up previous guidelines that did not include randomized trials.

Hospital Doctor/Hospitalists

Hypothermia has been a way to improve neurologic outcomes in cardiac arrest. This study shows that in patients with non-shockable rhythms, hypothermia improves outcomes, at least in the 90-day outcome.

Clarification is needed about what factors are associated with better neurologic recovery. A major challenge is that hypothermia makes it less clear when one can say that a patient with hypoxic-ischemic brain injury is NOT recovering neurologically and can delay the transition to palliative care because of the greater uncertainty of the prognosis. Biggest takeaway for me is that mortality remains very likely irrespective of treatment assignment.

Intensivist/Critical Care

As a nephrologist interested in critical care medicine, the results definitely have great clinical implications.

Impactful article that extends evidence from shockable rhythm to non-shockable. Unsure of implications re 33 vs 36 degrees but great discussion points. Ubiquitous issue.

Internal Medicine

This is a very interesting and relevant study. Moderate therapeutic hypothermia is a well-established modality and routinely used as standard-of-care for patients with coma after successful resuscitation from cardiac arrest. This study successfully validated positive neurologic outcomes in patients with non-shockable-rhythm cardiac arrest. This study is very relevant to inpatient hospital medicine, general medicine, and intensive care.

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