Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest
Summary by Zil Patel DO, 2.5.23
https://www.nejm.org/doi/full/10.1056/NEJMoa2100591
Take Home Messages:
Targeted hypothermia did not lead to a lower incidence of death by 6 months compared to targeted normothermia
These results contrast with findings of practice-changing trials published in 2002 (The Hypothermia after Cardiac Arrest Study Group) in which a benefit of hypothermia was reported
Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group
The incidence of other adverse events did not differ significantly between the two groups.
Summary:
Background: Targeted temperature management (induced hypothermia to 33 degrees Celsius) has been utilized to prevent hypoxic-ischemic brain damage in patients with coma after cardiac arrest. However, evidence to support this has been inconclusive.
Study Design: Open-label trial with blinded assessment of outcomes.
Methods: Patients >/= 18 years of age who had been admitted for out-of-hospital cardiac arrest of presumed cardiac or unknown cause were screened. All patients were unconscious and eligible patients had >20 minutes of spontaneous circulation after achieving ROSC. Once screened, 1900 patients were enrolled and randomized at a 1:1 ratio to undergo hypothermia or normothermia for 40 hours.
Inclusion criteria:
- Out-of-hospital cardiac arrest of a presumed cardiac or unknown cause
- Sustained Return of spontaneous circulation (ROSC) - defined as 20 minutes with
signs of circulation without the need for chest compressions.
- Unconsciousness defined as not being able to obey verbal commands (FOUR-score motor response of <4) and no verbal response to pain after sustained ROSC.
- Eligible for intensive care without restrictions or limitations
- Inclusion within 180 minutes of ROSC
Exclusion criteria:
- Unwitnessed cardiac arrest with an initial rhythm of asystole
- Temperature on admission <30°C.
- On Extracorporeal Membrane Oxygenation prior to ROSC
- Obvious or suspected pregnancy
- Intracranial bleeding
- Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy
Those assigned to undergo hypothermia were cooled to 33°C for 28 hours, followed by gradual rewarming to 37°C, after which normothermia was maintained for 32 more hours if the patient remained comatose. Those who were selected for the normothermia group were maintained at a temperature of ~37.5°C. All patients were kept sedated during the intervention period.
At 96 hours after randomization, a physician who was blinded to the intervention assignments performed neurologic prognostication of the patients and determined whether criteria for likely poor neurological outcome were fulfilled. If the criteria were fulfilled, withdrawal of life-sustaining therapies was allowed, at the discretion of the physician.
- Primary outcome: death from any cause at 6 months
- Secondary outcome: poor functional status at 6 months (defined as a score of 4-6 on modified Rankin scale)
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. 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, as compared with 479 of 866 (55%) in the normothermia group. Outcomes were consistent in the pre-specified subgroups.
Discussion: Targeted hypothermia did not lead to a lower incidence of death by 6 months compared to targeted normothermia. Limitations of this study include not having a true control group without temperature management, ICU staff bias from being aware of the assigned intervention group, leaving concomitant care to the discretion of participating hospitals, and limiting the trial to out-of-hospital cardiac arrest only.