Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest

Josef Dankiewicz, Tobias Cronberg, Gisela Lilja et el published a trial of normothermia vs hypothermia in out of hospital cardiac arrest in NEJM.

BACKGROUND

Targeted temperature management (TTM, therapeutic hypothermia) after cardiac arrest first came to use in clinical setting since the publication of two landmark articles in 2002(1,2). Earlier it was noted that persons who had cardiac arrest in cold temperatures had better neurological recovery than in warmer climates. Both the American Heart Association and European resuscitation counseling recommend targeted temperature management for out-of-hospital cardiac arrest and shockable rhythm. Trial comparing the level of targeted temperature management (33°C or 36°C) and the duration of this management (24 hours or 48 hours) have not indicated a dose effect.

WHAT

Open-label trial with blinded assessment of outcomes, of out of hospital presumed cardiac or unknown cause of cardiac arrest who were comatose. These were randomized to receive targeted temperature of 33 Celsius followed by controlled rewarming or targeted normothermia. 

WHERE

Various ICUs in USA, Europe, Australia and New Zealand.

PATIENTS

Adults (≥18 years of age) who had been admitted to the hospital after out-of-hospital cardiac arrest of a presumed cardiac or unknown cause, irrespective of the initial rhythm. All the patients were unconscious and not able to obey verbal commands (score of <4 on the Full Outline of Unresponsiveness [FOUR] scale.

A total of 1900 patients were enrolled between November 2017 and January 2020. Consent could not be obtained or was withdrawn in 37 patients, and 2 patients underwent randomization twice, resulting in an intention-to-treat population of 1861, of whom 930 were assigned to the hypothermia group and 931 to the normothermia group 

EXCLUSION

Interval from return of spontaneous circulation to screening of more than 180 minutes, unwitnessed cardiac arrest with asystole as the initial rhythm, and limitations in care. 

OUTCOMES

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.

PREDEFINED ADVERSE EVENTS

Pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device.

INTERVENTION

Temperature maintained at 33 degree Celsius for 28 hours, then rewarming in the hypothermia group, using a surface or intravascular temperature-management device. Total 40 hours. 

In normothermia group, a surface or intravascular temperature-management device used only if traditional methods failed. 

After 40 hours, a normothermic target (36.5°C to 37.7°C) was maintained until 72 hours after randomization in patients who remained sedated or comatose.

An independent physician performed neurological  assessment at 96 hours. 

RESULTS

At 6 months, 465 of 925 patients (50%) in the hypothermia group and 446 of 925 patients (48%) in the normothermia group had died (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P=0.37).

At 6 months, 488 of 881 patients (55%) in the hypothermia group and 479 of 866 patients (55%) in the normothermia group had a modified Rankin scale score of 4 to 6 (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09).

ADVERSE EVENTS

Arrhythmias resulting in hemodynamic compromise were more common in the hypothermia group than in the normothermia group (in 24% vs. 17%; P<0.001). There were no significant differences in other prespecified adverse events.

An intravascular device–related thrombosis in one patient in the hypothermia group and two patients in the normothermia group, and bradycardia with worsening hemodynamic function in one patient in the hypothermia group.

LIMITATIONS

  1. Similar care in both trial groups , except for the temperature intervention, which may not happen in real life.
  2. Staff members in the ICU were aware of the assigned target temperature.
  3.  No control group with no temperature management
  4. Trial only included out of hospital cardiac arrest
  5. One fifth patients also enrolled in TAME trial (Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest trial)

BOTTOMLINE

 For patients who are  comatose after out of  hospital cardiac  arrest,  temperature of 33° versus 37.5 does not make any difference,  but it does not mean that keeping normothermia does not help.  This trial did not compare  targeted temperature management verses usual care. 

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