Effect of Moderate Hypothermia vs Normothermia on 30-Day Mortality in Patients With Cardiogenic Shock Receiving Venoarterial Extracorporeal Membrane Oxygenation: A Randomized Clinical Trial

Abstract

Importance: The optimal approach to the use of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiogenic shock is uncertain.

Objective: To determine whether early use of moderate hypothermia (33-34 °C) compared with strict normothermia (36-37 °C) improves mortality in patients with cardiogenic shock receiving venoarterial ECMO.

Design, setting, and participants: Randomized clinical trial of patients (who were eligible if they had been endotracheally intubated and were receiving venoarterial ECMO for cardiogenic shock for <6 hours) conducted in the intensive care units at 20 French cardiac shock care centers between October 2016 and July 2019. Of 786 eligible patients, 374 were randomized. Final follow-up occurred in November 2019.

Interventions: Early moderate hypothermia (33-34 °C; n = 168) for 24 hours or strict normothermia (36-37 °C; n = 166).

Main outcomes and measures: The primary outcome was mortality at 30 days. There were 31 secondary outcomes including mortality at days 7, 60, and 180; a composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at days 30, 60, and 180; and days without requiring a ventilator or kidney replacement therapy at days 30, 60, and 180. Adverse events included rates of severe bleeding, sepsis, and number of units of packed red blood cells transfused during venoarterial ECMO.

Results: Among the 374 patients who were randomized, 334 completed the trial (mean age, 58 [SD, 12] years; 24% women) and were included in the primary analysis. At 30 days, 71 patients (42%) in the moderate hypothermia group had died vs 84 patients (51%) in the normothermia group (adjusted odds ratio, 0.71 [95% CI, 0.45 to 1.13], P = .15; risk difference, -8.3% [95% CI, -16.3% to -0.3%]). For the composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at day 30, the adjusted odds ratio was 0.61 (95% CI, 0.39 to 0.96; P = .03) for the moderate hypothermia group compared with the normothermia group and the risk difference was -11.5% (95% CI, -23.2% to 0.2%). Of the 31 secondary outcomes, 30 were inconclusive. The incidence of moderate or severe bleeding was 41% in the moderate hypothermia group vs 42% in the normothermia group. The incidence of infections was 52% in both groups. The incidence of bacteremia was 20% in the moderate hypothermia group vs 30% in the normothermia group.

Conclusions and relevance: In this randomized clinical trial involving patients with refractory cardiogenic shock treated with venoarterial ECMO, early application of moderate hypothermia for 24 hours did not significantly increase survival compared with normothermia. However, because the 95% CI was wide and included a potentially important effect size, these findings should be considered inconclusive.

Trial registration: ClinicalTrials.gov Identifier: NCT02754193.

Figure 1.. Enrollment, Randomization, and Follow-up of Patients in the HYPO-ECMO Trial

ECMO indicates extracorporeal membrane oxygenation; HYPO-ECMO, Hypothermia During ECMO. ^aA patient may have been excluded based on 1 or more of the listed reasons. ^bDefined as a state of imminent death without any medical therapeutic option. ^cThe proper equipment was not available, a certified investigator was not on-site, or there was not enough time (>6 hours after ECMO). ^dVoluntary or accidental with cardiotoxic drugs (eg, β-blockers, calcium channel blockers).

Figure 2.. Core Body Temperatures Measured in the Intensive Care Unit During the First 96 Hours After Randomization

The middle line in the box plot represents the median observed esophageal core temperatures in the moderate hypothermia group (33-34 °C) and in the normothermia group (36-37 °C). The boxes represent the IQR. The whiskers extend to the most extreme observed values with 1.5 × IQR of the nearer quartile. The dots represent the observed values outside that range. Temperature control was initiated just after randomization but before admission to the intensive care unit (ICU), which explains the between-group differences in esophageal temperature at ICU admission. The median time from venoarterial extracorporeal membrane oxygenation to randomization was 3.0 hours (IQR, 1.7-4.5 hours). The median time from randomization to the first measured temperature was 30 minutes (IQR, 8-82 minutes).

Figure 3.. Kaplan-Meier Survival Estimates for the Primary Outcome of 30-Day Mortality in Patients Treated With Moderate Hypothermia or Normothermia

For the primary outcome of 30-day mortality, patients were observed for a median of 8 days (IQR, 8-30 days). HR indicates hazard ratio; OR, odds ratio.