The IH-TTM trial is designed to determine whether survival with a favorable neurological outcome is improved by induced hypothermia at 33°C in comatose critically ill patients admitted after resuscitated in-hospital cardiac arrest (IHCA). Recent evidence suggests that targeted temperature management (TTM) at 33°C may provide no survival benefits compared to controlled normothermia in unselected patients with out-of-hospital cardiac arrest (OHCA). However, this evidence is relevant only to OHCA of presumed cardiac origin, chiefly witnessed and immediately followed by resuscitation efforts. Only scant data are available for cardiac arrest (CA) of other origins and for IHCA.
In a randomized clinical trial of patients with CA in an initial non-shockable rhythm, the subgroup with IHCA had significantly better outcomes when treated with TTM at 33°C versus controlled normothermia; nevertheless, the sample size was limited. Another randomized controlled trial done specifically in patients with IHCA failed to show benefits of TTM at 33°C compared to controlled normothermia but was underpowered. Thus, whether therapeutic hypothermia is indicated after IHCA remains unclear. IH-TTM will be the largest trial assessing TTM after IHCA.
IHCA (unwitnessed IHCA with initial asystole; these patients may still be eligible if visible or audible signs of life were witnessed within 10 minutes after IHCA (no-flow duration ≤10 minutes, in keeping with the non-inclusion criteria for HYPERION study).
Sustained ROSC (Return Of Spontaneous Circulation) defined as signs of circulation for 20 minutes without chest compressions
At least 1 mg of epinephrine
Coma defined as an inability to obey verbal commands (Glasgow Coma Scale motor response <6 or Full Outline of UnResponsiveness (FOUR) score motor response <4) after sustained ROSC
Temperature at admission <30°C
Obvious or suspected pregnancy
Intracranial bleeding
Dependent on others for activities of daily living before hospitalization
Parallel
Induced hypothermia at 33°C
Other interventionCooling and maintenance phase : The aim is to achieve the target temperature of 33±0.5°C within 60 minutes after randomization. The target temperature of 33±0.5°C and device setting of 33°C will be maintained until 28 hours after randomization. \- Rewarming: Normothermia will be restored by gradual rewarming at a rate of 0.2°C/h. \- After rewarming: After 40 hours, in those participants who are still comatose or sedated, normothermia (36.5-37.7°C) will be maintained until 72 hours after randomization, and active warming will be avoided.
Control normothermia
Other interventionParticipants whose initial temperature is below 33°C may be actively rewarmed to 36.5°-37.7°C, at which point active rewarming will be stopped and passive rewarming performed according to the latest guidelines. Participants whose initial temperature is above 33°C will not be actively rewarmed to normothermia. The goal will be to maintain temperature no higher than 37.8°C. After 40 hours, in those participants who are still comatose or sedated, normothermia (36.5-37.7°C) will be maintained until 72 hours after randomization, and active warming will be avoided.
To assess whether induced hypothermia (TTM at 33°C) is superior to targeted normothermia in providing a favorable neurological outcome, defined as a modified Rankin Scale (mRS) score of 0 to 3 at 6 months.
The primary endpoint is a favorable neurological outcome at 6 months, defined as an mRS score between 0 and 3.
All-cause mortality 2 months after randomization
Causes of death (refractory hemodynamic shock, life-support withdrawal for neurological reasons, life-support withdrawal due to comorbidities, respiratory failure, sudden cardiac death, brain death)
All-cause mortality 3 months after randomization
Causes of death (refractory hemodynamic shock, life-support withdrawal for neurological reasons, life-support withdrawal due to comorbidities, respiratory failure, sudden cardiac death, brain death)
All-cause mortality 4 months after randomization
Causes of death (refractory hemodynamic shock, life-support withdrawal for neurological reasons, life-support withdrawal due to comorbidities, respiratory failure, sudden cardiac death, brain death)
All-cause mortality 6 months after randomization
Causes of death (refractory hemodynamic shock, life-support withdrawal for neurological reasons, life-support withdrawal due to comorbidities, respiratory failure, sudden cardiac death, brain death)
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Nantes University Hospital
Lead sponsor
Erasme University Hospital
Collaborator
