Therapeutic hypothermia after paediatric cardiac arrest: Pooled randomized controlled trials

Abstract

Background: Separate trials to evaluate therapeutic hypothermia after paediatric cardiac arrest for out-ofhospital and in-hospital settings reported no statistically significant differences in survival with favourable neurobehavioral outcome or safety compared to therapeutic normothermia. However, larger sample sizes might detect smaller clinical effects. Our aim was to pool data from identically conducted trials to approximately double the sample size of the individual trials yielding greater statistical power to compare outcomes. Methods: Combine individual patient data from two clinical trials set in forty-one paediatric intensive care units in USA, Canada and UK. Children aged at least 48 hours up to 18 years old, who remained comatose after resuscitation, were randomized within 6 hours of return of circulation to hypothermia or normothermia (target 33.0°C or 36.8°C). The primary outcome, survival 12 months post-arrest with Vineland Adaptive Behaviour Scales, Second Edition (VABS-II) score at least 70 (scored from 20-160, higher scores reflecting better function, population mean=100, SD=15), was evaluated among patients with pre-arrest scores ≥70. Results: 624 patients were randomized. Among 517 with pre-arrest VABS-II scores ≥70, the primary outcome did not significantly differ between hypothermia and normothermia groups (28% [75/271] and 26% [63/246], respectively; relative risk, 1.08; 95% confidence interval [CI], 0.81 to 1.42; p=0.61). Among 602 evaluable patients, the change in VABS-II score from baseline to 12 months did not differ significantly between groups (p=0.20), nor did, proportion of cases with declines no more than 15 points or improvement from baseline [22% (hypothermia) and 21% (normothermia)]. One-year survival did not differ significantly between hypothermia and normothermia groups (44% [138/317] and 38% [113/ 297], respectively; relative risk, 1.15; 95% CI, 0.95 to 1.38; p=0.15). Incidences of blood-product use, infection, and serious cardiac arrhythmia adverse events, and 28-day mortality, did not differ between groups. Conclusions: Analysis of combined data from two paediatric cardiac arrest targeted temperature management trials including both in-hospital and out-of-hospital cases revealed that hypothermia, as compared with normothermia, did not confer a significant benefit in survival with favourable functional outcome at one year.

Efficacy of Targeted Temperature Management after Pediatric Cardiac Arrest: A Meta-Analysis of 2002 Patients

“…The characteristics of the 10 included studies are presented in Table 1 , Tables S1 and S2 . The author, year and country of publication, study type, and the participants’ number, age, and gender are presented for the TTM and non-TTM groups [ 19 , 20 , 21 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

“…However, large studies, like the recent in-hospital Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA-IN) and a similar out-of-hospital Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA-OH) trials, showed no clear benefit [ 19 , 20 ] either separately or in the pooled data analysis. The results revealed that in children after CA, cooling did not appear as useful as in adults [ 21 ]. Consequently, it has been argued by some that the THAPCA-OH study may prove a worthwhile clinical effect that is just too small to be picked up by the conventional statistical framework [ 22 ].…”

Necessity of early and continuous monitoring for possible infectious complications in children undergoing therapeutic hypothermia

“…By inhibiting proinflammatory mechanisms such as leucocyte migration, phagocytosis and proinflammatory cytokine synthesis, TH may lead to an increased risk of infection 5 . The occurrence of infections during TH, however, does not appear to worsen patient outcomes 6‐8 . Mild to moderate TH (32‐34°C core body temperature) rather than deep TH (<30°C) not only improves neurological outcomes, but also leads to a reduction in severe side effects 6 .…”

Hypothermia: Impact on plasticity following brain injury

“…[1] Although clinical evidence of efficacy is less impressive and sometimes contradictory, there is still much interest in the potential of TH. [2][3][4] However, several problems must be resolved before that goal is fully realized. First, mechanisms of injury vary between diseases, which may necessitate different approaches and treatment parameters, such as depth, duration, and delay in order to get optimal neuroprotection.…”