Will longer (48 h) targeted temperature management (TTM) confer a statistically significant benefit compared to current (24 h) dose?
- The Hypothermia after Cardiac Arrest Study Group (HACA), 2002, showed that mild hypothermia (32–34°C for 24 h) in Out-of-Hospital Cardiac Arrest (OHCA) provided significant improvement in functional recovery after hospital discharge (55% vs. 39%). It also led to a lower 6-month mortality rate (41% vs. 55%)
- In 2013, TTM (Targeted Temperature Management of 33°C versus 36°C after OHCA) trial No difference between the two groups in overall mortality at the end of the trial or in the composite endpoint of poor neurologic function or death at 180 days was found.
- Current recommendations state that the patient’s temperature should be kept at a target of 32 C to 36 C for at least 24 hours.
- The optimal duration of cooling is still under debate.
- For newborns with anoxic-asphyxia brain injury, cooling periods of 72 hours were considered standard practice.
TTM for 48 h confers a statistically significant favourable neurological outcome as compared to the current 24 h dose.
Victims of out of hospital cardiac arrest who manifested sustained return of spontaneous circulation of more than 20 minutes and had a Glasgow coma score of more than 8.
355 adults with shockable or non-shockable rhythms in 10 European ICUS were randomized.
- The Time differentiated Therapeutic Hypothermia trial was a blinded-outcome-assessor, multicenter, randomized clinical trial conducted in 10 European ICUs.
- Patients were randomized to TTM at 33 c (+/- 1 c) for 24 hours (179 patients) or 48 hours (176 patients).
- Timing of the 24- or 48-hour duration started from the first point at which the core temperature was 34 c or lower.
- Rewarming was performed at a maximal rate of 0.5 c/h until 37 c was reached.
- All centers agreed to provide active treatment until 72 hours after normothermia except in patients with brain death or refractory shock with multiple organ dysfunctions.
Primary outcome: Favourable neurological outcome (cerebral performance categories score of 1 or 2) at 6 months.
Secondary outcomes: 6 months mortality and time to death.
- i) Primary outcome (favourable neurological outcome at 6 months):
In the 48-hour group (69%) and in the 24-hour group (64%). Absolute difference, 4.9%; relative risk, 1.08; 95% CI, 0.93-1.25; P = .33).
- ii) Mortality at 6 months:
In the 48-hour group (27%) and in the 24-hour group (34%). Relative risk, 0.81; 95%CI,0.59-1.11;P = .19).
iii) Adverse events:
Higher in the 48-hour group (97%) than in the 24-hour group (91%). Relative risk, 1.06; 95%CI, 1.01-1.12; P = .04).
- iv) ICU length of stay:
Longer in the 48-hour than in the 24-hour group(151 hours vs 117 hours; P < .001), but there was no significant difference in hospital length of stay
In unconscious survivors from out-of-hospital cardiac arrest who were admitted to the ICU, TTM for 48 hours did not significantly improve 6-month neurologic outcome compared with TTM for 24 hours.
- The first to explore whether longer durations of TTM improve patient outcomes.
- Centres enrolled > 98% of eligible OOHCA. Treating teams were unaware of allocation until randomization.
- Although it was not possible to blind treating teams to the intervention, assessors for 6-month outcomes were blinded to treatment allocation.
- The trial directly addressed the potential bias from withdrawal of life support by providing independent clinicians to conduct multimodal prognostic assessment at least 72 hours after cardiac arrest.
- The trial excludes the possibility that 48 hours of TTM results in outcomes that are 15% better or 5% worse than 24 hours of TTM. These bounds can guide the design of future trials.
- Size is the principal limitation of the trial. The study was powered to detect a 15% absolute difference (this effect size is comparable to the original effect of adding TTM to post arrest care). Nevertheless, this trial does exclude (with 95% CIs) the possibilities that 48 hours of TTM results in a more than 5% decrease in good outcome or a more than 14.8% increase in good outcome.
- The trial cannot exclude a 5% or 10% difference in good outcome, and such a difference might alter practice. Trials with binary outcomes will almost always require thousands of participants to detect such differences.
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