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evident
Original paper
2021NEJMEmergency Medicine

TTM2

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest

RCTCardiac arrest

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Overview

After OHCA with coma, targeted hypothermia at 33 degrees C did not reduce 6-month death versus targeted normothermia with early fever treatment.

Clinical takeaway

TTM2 moved post-arrest care from routine hypothermia at 33 degrees C toward targeted normothermia with early fever treatment.

Key result

Six-month death was 50% with hypothermia vs 48% with normothermia (RR 1.04; p=0.37).

Practice impact

After OHCA with coma, prevent fever; do not routinely cool to 33 degrees C expecting a survival benefit.

Evidence

Study design

Open-label randomized trial with blinded outcome assessment comparing targeted hypothermia at 33 degrees C with targeted normothermia and early fever treatment.

Enrollment

1,900

Follow-up

Death from any cause and functional outcome at 6 months.

Geography

Not listed

Clinical question

Does targeted hypothermia at 33 degrees C reduce 6-month death compared with targeted normothermia and early fever treatment after out-of-hospital cardiac arrest?

Population

  • Comatose adults after out-of-hospital cardiac arrest of presumed cardiac or unknown cause.

Intervention

Targeted hypothermia at 33 degrees C, followed by controlled rewarming.

Comparator

Targeted normothermia with early treatment of fever (body temperature of 37.8 degrees C or higher).

Primary outcome

Death from any cause at 6 months.

Targeted hypothermia did not lower 6-month death compared with targeted normothermia and early fever treatment.

Relative risk / 1.04 / 95% CI 0.94-1.14 / p=0.37

Key results

  • Six-month death: 465 of 925 (50%) with hypothermia vs 446 of 925 (48%) with normothermia; RR 1.04 (95% CI 0.94-1.14; p=0.37).
  • Moderately severe disability or worse (modified Rankin scale score of 4 or higher) at 6 months was 55% in both groups; RR 1.00 (95% CI 0.92-1.09).
  • Outcomes were consistent in the prespecified subgroups.

Harms

  • Arrhythmia resulting in hemodynamic compromise was more common with hypothermia than with normothermia (24% vs 17%; p<0.001).
  • The incidence of other prespecified adverse events did not differ significantly between groups.

Clinical Use

Practice impact

  • After out-of-hospital cardiac arrest with coma, prevent fever rather than routinely targeting 33 degrees C.

Applicability

  • Most applicable to comatose adults resuscitated from out-of-hospital cardiac arrest of presumed cardiac or unknown cause.

Limitations

  • Temperature assignment was open-label, with blinded assessment of outcomes.
  • The trial compared hypothermia with active fever prevention, not with uncontrolled temperature.
  • Prespecified adverse events were limited to pneumonia, sepsis, bleeding, hemodynamically important arrhythmia, and device-related skin complications.

Common misinterpretations

  • TTM2 does not show that temperature control is unnecessary; the comparator treated fever early.
  • It does not compare hypothermia with no temperature management.

Related evidence

TTM - Earlier Trial

Citation

Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. N Engl J Med. 2021;384(24):2283-2294. doi:10.1056/NEJMoa2100591

In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia.