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Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. doi: 10.1056/NEJMoa2100591. (Original study)

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty.

METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, =37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device.

RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score =4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups.

CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Discipline Area Score
Emergency Medicine 7 / 7
Cardiology 7 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Comments from MORE raters

Cardiology rater

This is an important paper. After early enthusiasm about the role of induced hypothermia after cardiac arrest, the emergence of new evidence such as this may again alter clinical practice.

Cardiology rater

Contrary to previous knowledge in patients with out-of-hospital cardiac arrest, targeted hypothermia was non-beneficial compared with normothermia, mostly due to an increased risk for arrhythmias in patients with hypothermia.

Emergency Medicine rater

Ultimately, this study provides important data that hypothermia compared with targeted normothermia does not reduce risk for death, but avoiding fever is paramount. This open-label trial randomized 1900 patients with coma from OHCA to targeted hypothermia followed by controlled rewarming versus normothermia (< 37.5C) with early treatment of fever. Surface cooling devices were used in 70% versus intravascular devices in 30%. Three quarters of patients had a shockable rhythm, and close to half of patients in the normothermia group received some cooling. Mortality and poor neurologic outcome did not differ between groups, and both groups had similar degree and duration of sedation. However, more arrhythmias resulting in hemodynamic compromise occurred in the hypothermia group (24% vs. 17%).

Emergency Medicine rater

Landmark paper. Unfortunately, it doesn't align with current guidelines and previous studies. Is this due to risk of bias in this trial or low certainty in the existing evidence? Contextualizing methods, study populations, and outcomes is critical to sort this out.

Emergency Medicine rater

This is a practice-changer.

Emergency Medicine rater

Very important article regarding post-arrest management. The methods can be debated (normothermia vs nontargeted normothermia), but requires us to question whether we should cool these patients.

Emergency Medicine rater

Like TTM, TTM2 showed no difference in outcomes (i.e. mortality, good functional outcome) between hypothermia and normothermia. This study is by far the largest of the RCTs looking at this question. Unlike the original 2002 article that showed benefit to TH (N Engl J Med 2002; 346:549-56), subgroups of either shockable or non-shockable rhythms had no difference in outcomes. Although there may be some bias as the authors state having a conservative approach in terms of withdrawing care (perhaps more so than in other studies), in many ways this likely represents a more realistic view of how TH would perform in the real world. Bottom line: investing in resources for a nontraumatic cardiac arrest TH program is not indicated and our health system will be keeping with normothermia as part of its TTM strategy.

Internal Medicine rater

We can point out some key elements. First, the comparison from previous clinical trials included in a systematic review and meta-analysis had a high risk of bias and random errors that benefited the hypothermia group. Second, this trial was stratified from a larger enrollment trial, TAME Cardiac Arrest Trial (Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest: A Phase III Multi-Centre Randomised Controlled Trial) that is still running, so we can expect further results. Third, these results contrast with trials published in 2002, as the authors wrote in the paper. The absence of a control group leaves a knowledge gap regarding the temperature, which we could analyse in past trials if they were included in a new systematic review. As seen in past clinical trials, the contrasting results again open the debate for a practice change in patients with coma after out-of-hospital cardiac arrest. This time in benefit of normothermia.
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