Targeted temperature management after cardiac arrest

Introduction
All patients with out-of-hospital cardiac arrest due to shockable rhythm should undergo TTM (32-36°C). This is a Neurocritical Care Society Clinical Performance Measure.

Trials
=== Hypothermia After Cardiac Arrest (HACA) trial (2002) === This blinded trial randomized 275 patients after out-of-hospital shockable-rhythm cardiac arrest to TTM to goal 32-34°C with external cooling vs. conventional hospital bed with plan to maintain normothermia. The primary favorable outcome was defined as a Cerebral Performance Category (CPC) score of 1 or 2. At 6 months, 55% of TTM patients had a favorable outcome while only 39% of normothermia patients did (RR 1.40, 95% CI 1.08-1.81), for a number needed to treat (NNT) of ~6 to achieve a good outcome. TTM also conferred a mortality benefit, with 41% of patients dead at 6 months compared with 55% in the normothermia group (RR 0.74, 95% CI 0.58-0.95) for a NNT of ~7 to prevent one death. The TTM group had numerically more bleeding, pneumonia, and sepsis, but these did not reach statistical significance.

One criticism of this trial is that the normothermia patients actually were somewhat febrile, with an average temperature greater than 37°C.

=== Bernard et al. trial (2002) === This was a quasi-randomized trial, with patients assigned to one group or the other based on the day of the month of presentation. The trial included 77 patients after out-of-hospital shockable-rhythm cardiac arrest randomized to TTM (goal temp 33°C with external ice packs to normothermia targeting temp 37°C. Good outcome was defined as discharge home or to a rehabilitation facility, which was achieved in 49% of the TTM group and 26% of the normothermia group, for a NNT of ~4 and aOR of 5.25 (95% CI 1.47-18.76). There was no difference in mortality.

=== Targeted Temperature Management 33°C versus 36°C after Out-of-Hospital Cardiac Arrest (TTM) trial (2013) === There was concern that the HACA study was positive not because the TTM group actually had benefit, but that the normothermia group was febrile, and perhaps fever control was actually all that was needed and not actually hypothermia. This trial randomized patients with out-of-hospital shockable-rhythm cardiac arrest to 33°C versus 36°C, all controlled with TTM. It was much larger than the prior trials, and randomized a total of 950 patients. Fever was appropriately avoided in the 36°C group. They found no difference in the primary outcome of mortality (33°C 50% vs. 36°C 48%, HR 1.06 (95% CI 0.89-1.28), or in functional outcome measured by CPC score or mRS, between the two groups.

Major criticisms:
 * There was was on average only 1 minute between cardiac arrest to the start of basic life support, with 73% of patients having bystander CPR. This likely selected for a population with less brain injury, who may be less likely to benefit from TTM.
 * They took approximately 10 hours on average to achieve target temperature.

=== Therapeutic Hypothermia after Cardiac Arrest in Nonshockable Rhythm (HYPERION) trial (2019) === As prior studies exclusively (HACA, Bernard et al.) or primarily (TTM) studied only shockable rhythms, the HYPERION trial set out to evaluate TTM in non-shockable rhythms. They randomized patients with nonshockable-rhythm cardiac arrest to 33°C vs. 37°C. In total they studied 541 patients and achieved goal temperature within 6 hours. A CPC score of 1 or 2 at 90 days was achieved in 10.2% of the 33°C and 5.7% of the 37°C (p=0.04) with NNT ~22. There was no difference in mortality.

Major criticisms:
 * High proportion of fever in normothermia arm
 * Fragility Index of 1

Goal temperature
Both the HACA trial and the Bernard et al. study clearly showed benefit of TTM to a goal of ~33°C, but were criticized because patients became febrile in the "normothermia" group. The TTM trial sought to address this, but in a sense it did not, as neither group in the TTM trial was normothermia. They really tested two different temperatures of hypothermia.

A retrospective cohort study of 453 patients who underwent TTM to either 33°C or 36°C (the hospital switched to 36°C goals after publication of the TTM trial in 2013) showed higher rates of favorable neurological status at discharge (defined as CPC 1-2) in those who underwent TTM to 33°C compared with those who underwent TTM to 36°C (40% vs. 30%, OR 1.79, 95% CI 1.09-2.93). There was no significant difference in mortality.

Method of cooling
A 2022 meta-analysis suggested that invasive cooling has the highest probability of being the most beneficial cooling method for survival and improved neurological outcome.

Duration of cooling
Some have proposed that patients should undergo TTM for longer durations if they had a longer time to ROSC. While the hypothermia/ischemic ratio (total TTM time in hours divided by ischemic time in minutes) correlates with functional outcome, it is primarily driven by the length of ischemic time. Whether longer durations will prove to be of benefit remains uncertain.