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
- 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?
- Randomised, controlled clinical trial
- Single blinded
- 36 intensive care units
- Europe and Australia
- November 2010 and January 2013
- 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
- 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
- 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
- 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).
- 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.
- 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
- 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.
Full text pdf not available without subscription / abstract / doi: 10.1056/NEJMoa1310519
Editorial or Commentaries
- Simon Carley at St Emlyn’s Blog: JC: What’s the target temperature for OOHCA cooling. St.Emlyn’s
- EmCrit Blog: Five Minutes with Jon Rittenberger on the TTM Trial
- Rittenburger. Temperature Management and Modern Post–Cardiac Arrest Care. NEMJ 2013;369:2262-3.
- ILCOR interim statement: Targeted temperature management following cardiac arrest: an update