TTM

TTM Trial Investigators: Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

Nielsen et al for the TTM Trial Investigators. NEMJ 2013;369:2197-206

Clinical Question

  • In adults that suffer an out-of-hospitals (OOH) cardiac arrest of presumed cardiac cause, does induced therapeutic hypothermia targeting 36°C compared to 33°C reduce mortality or reduce neurological deficit?

Design

  • Randomised, controlled clinical trial
  • Single blinded

Setting

  • 36 intensive care units
  • Europe and Australia
  • November 2010 and January 2013

Population

  • Inclusion: adult patients who were unconscious (GCS < 8) on admission to hospital after OOH cardiac arrest of presumed cardiac cause.
  • Exclusion: > 6 hours from ROSC to enrolment screening, unwitnessed arrest with systole, hypothermia < 30°C, suspected or known intracranial haemorrhage.
  • 950 patients enrolled

Intervention

  • 28 hours of temperature management with a target of 36°C using invasive or surface cooling, followed by gradual warming to 37°C at 0.5°C per hour and avoidance of pyrexia for 72 hours from randomisation.
    • 4 patients did not receive this intervention as assigned

Control

  • 28 hours of temperature management with a target of 33°C using invasive or surface cooling, followed by gradual warming to 37°C at 0.5°C per hour and avoidance of pyrexia for 72 hours from randomisation
    • 3 patients did not receive this control as assigned

Outcome

  • Primary outcome: There was no difference in all-cause mortality through to the end of the trial (mean follow-up period was 256 days).
    • 48% had died in the 36°C group and 50% had died in the 33°C group.
    • The hazard ratio for death was 1.06 for cooling to 33°C (CI 0.89 to 1.28; p=0.51)
  • Secondary outcome: There were no differences between the groups regarding their neurological status (modified Rankin scale or Cerebral Performance Category).

Authors’ Conclusions

  • This trial does not provide evidence that targeting a body temperature of 33°C confers any benefit for unconscious patients admitted to the hospital after out-of-hospital cardiac arrest, as compared with targeting a body temperature of 36°C.

Strengths

  • Highly relevant clinical question
  • Well designed, pragmatic methodology
  • Objective outcomes assessed by blinded external physicians
  • Intention-to-treat analysis with minimal drop-out / loss-to-follow-up

Weaknesses

  • Not generalisable to arrests with long or unknown ‘down-time’
    • Unwitnessed arrests with systole as initial rhythm were excluded
    • 90% had bystander witness; 73% had bystander CPR
    • Median time to basic life support was 1 minute!
    • Median time to advanced life support was 9 and 10 minutes
    • Median time to ROSC was 25 minutes
  • Follow-up was relatively short-term; unclear if 36°C confers long-term neurological benefit or harm.
  • Wide confidence intervals: with 95% certainty, true hazard ratio for 33°C could be anywhere between 0.89 (strong benefit) and 1.28 (strong harm).

The Bottom Line

  • This trial has not shown any benefit of therapeutic hypothermia at 33°C over 36°C after OOH cardiac arrest. Not everyone agrees this is the same as “36°C is equivalent to 33°C”.
  • My conclusion: if cooling a patient to the conventional 33°C induces unwanted effects, aim for 36°C instead and it probably will make no difference to the patient’s outcome.

Links

Full text pdf not available without subscription / abstract / doi: 10.1056/NEJMoa1310519

Editorial or Commentaries

So many to choose!

Metadata

Summary author: @DuncanChambler
Summary date: 1 May 2014
Peer-review editor: @stevemathieu75 (DOI: at local institution we have opted for 36°C)

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