Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial

Abstract

Background Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. Methods In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4–6 on modified Rankin scale). Results A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84–1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80–1.26). Conclusions Using a hospital’s average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.

Optimal Timing of Targeted Temperature Management for Post-Cardiac Arrest Syndrome: Is Sooner Better?

“…This speculation was in line with the finding of the TTM-2 trial [ 17 ]. In the sub-group analysis of the TTM-2 trial, [ 47 ] Simpson et al divided included sites into six groups according to the speed of hypothermia, which was surrogated as the average temperature at four hours from ROSC in the hypothermia group. Of the patients enrolled in the fastest sites, whose average temperature was ≤34 °C at four hours, 49% of the patients died at six months in the hypothermia group compared with 46% in the normothermia group.…”

Temperature Control After Cardiac Arrest: A Narrative Review

“…In a post hoc study of the TTM2 trial, no association of faster time to target 33 °C was noted with outcomes, challenging the critique that achievement of hypothermia earlier in the TTM2 trial could have altered the trial results [ 59 ].…”

Targeted temperature management with hypothermia for comatose patients after cardiac arrest

“…Conversely, patients in normothermia group with the shortest time to goal temperature had lower lactate levels. With limited sample sizes, adjustment for all of these interactions may not be possible, and post hoc analyses of pediatric and adult OHCA trials do not show a clear interaction of time to cooling and hypothermia for outcomes [67,72] In summary, clinical trials in neonates demonstrate how TTM-hypothermia can improve recovery from HIBI when treatment groups have different temperatures within 6 hours and treatment continues for 72 hours, but trials of TTM-hypothermia for 48 hours in children share many implementation challenges with adult trials.…”

“…Conversely, patients in the normothermia group with the shortest time to goal temperature had lower lactate levels. With limited sample sizes, adjustment for all of these interactions may not be possible, and post hoc analyses of pediatric and adult OHCA trials do not show a clear interaction of time to cooling and hypothermia for outcomes [ 67 , 72 ].…”

“…Rapid infusions of cold intravenous fluids in the ambulance after ROSC can quickly reduce temperature [ 72 , 73 ]. A trial of postROSC cold intravenous fluids allowed patients to reach target temperature about 1 hour faster than usual care patients but did not treat patients differently after hospital arrival [ 16 ].…”