Question:Does therapeutic hypothermia (33C for the first 24 hours) as compared to targeted normothermia (37C) improve neurologic outcomes in adults with persistent coma after cardiac arrest with nonshockable rhythm?

Primary outcome: favorable neurologic outcome (CPC Score of 1 or 2) at Day 90 

Methods:Multi-center, randomized controlled trial done in 25 ICUs in France 

N = 581 patients 

Patients randomized to therapeutic hypothermia arm or targeted normothermia arm.

• Therapeutic hypothermia: Cooled to 33C +/- 0.5C for 24 hours, then slowly rewarmedand maintained at 37 degrees +/- 0.5C for 24 hours
• Targeted normothermia: Maintained at 37C for 48 hours

Almost 13% of the hypothermia arm was unable to complete the cooling process for a variety of reasons.

Analysis

• Intention to treat analysis
• Day 90 from randomization, patients assigned a CPC Score (1 to 5) based on their neurologic status. A score of 1 or 2 was defined as a favorable neurologic outcome.
• CPC assessment was done by a single, blinded, psychologist over the phone

Results:

On Day 90

• Hypothermia group: 10.2% patients had CPC 1 or 2 
• Normothermia group: 5.7% patients had CPC 1 or 2

Difference: 4.5%, 95% CI (0.1 to 8.9, P = 0.04)

There was no statistically significant difference between groups in number of patients who died at 90 days, length of mechanical ventilation, or length of ICU stay.

Discussion:

Strengths

• Good randomization and blinding protocols
• Balanced patient characteristics in the control arm and the treatment arm
• The intention to treat analysis preserves randomization and increases confidence in the finding of a statistically significant result. Even with some of the hypothermia arm not completing the hypothermia protocol, the cooled patients still had statistically significantly improved neurologic outcomes.
• In addition to statistical significance, an absolute difference of 4.5% between groups in favor of the hypothermia arm suggests clinical significance as well

Weaknesses

• It took a significant amount of time from arrest to get patients to the targeted temperature in the hypothermia group - in many patients 7-8 hours. It is though that TTM is most effective in the hours immediately post-arrest, so we may be missing the most efficacious time period for TTM in this study.
• The fragility index of this study is 1: If a single patient was switched from a group of CPC Score 1 or 2 or CPC of 3-5, the results would not have been statistically significant. The CPC score has been shown to have inter-rater variability and may be somewhat subjective, especially if the assessment was performed over the phone.

References

Lascarrou J-B, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. October 2019. PMID: 31577396