THAPCA-IH
PubMed • Full text • PDF • ClinicalTrials.gov
Clinical Question
Amongst comatose children aged 2 days to 18 years with return of spontaneous circulation (ROSC) after in-hospital cardiac arrest of any cause, does mild hypothermia (32-34ºC) lead to improved neurological outcomes at 12 months as compared to normothermia?
Bottom Line
This trial was stopped early for Futility. Among comatose children 2 days to 18 years who survived in-hospital cardiac arrest from any cause, mild therapeutic hypothermia (32-34ºC), as compared with targeted temperature control at normothermia (37ºC), does not improve favorable functional outcome at 12 months.
Major Points
The Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children (THAPCA-IH) trial was designed to answer the question if mild hypothermia is neuroprotective in children with ROSC after in-hospital cardiac arrest. In the adult literature leading up to this trial it was suggested that patients may benefit from hypothermia or just fever prevention.
This trial, which was stopped early due to futility, randomized patients to either hypothermia (target temperature, 33.0°C, n=166) or normothermia (target temperature, 36.8°C, n=163). Their primary outcome was survival with a good neurobehavioral outcome at 12 months, defined as a Vineland Adaptive Behavior Scales, second edition (VABS-II) score of at least 70. Enrolling children between 48 hour and 18 years old who experience cardiac arrest within hospital walls and received at least 2 chest compressions, they found no difference in their primary outcome with 36% vs. 39% (95% CI −14.5 to 9.2, P = 0.63), as well as their secondary outcomes of all-cause mortality at 28 days (37% vs. 41%, P = 0.4) or alive at 1 year (49% vs. 46%, P = 0.56). For their safety analysis, there was no statistical difference for utilization of blood products, arrhythmias, and culture proven infections within 7 days of randomization.
This is not without critique, stopping early may have occurred prior to statistical significance was achieved, it took a long time to reach target temperature (median 6 hours), and patient received longer duration of CPR than in comparative trials. The findings of this trial are consistent with the THAPCA-OH Trial, the out-of-hospital sibling to this trial.
Guidelines
Pediatric Post-Cardiac Arrest Care: A Scientific Statement From the American Heart Association 2019, adapted [1]
- Post–cardiac arrest pyrexia is common
- Persistent hyperthermia is associated with unfavorable neurological outcomes in children.
- Fever (≥38°C) should be aggressively managed
- 2015 AHA PALS guidelines update recommended either:
- maintain continuous normothermia (Target Temperature Management (TTM) 36°C–37.5°C) for 5 days, or
- maintain 2 days continuous hypothermia (TTM 32C°–34°C) then 3 days continuous normothermia (TTM 36°C–37.5°C)
Design
- Multicenter, randomized, controlled trial
- N=257
- hypothermia [target temperature, 33.0°C] (n=166)
- normothermia [target temperature, 36.8°C] (n=163)
- Setting: 37 centres in Canada, the United Kingdom, and the United States of America
- Enrollment: 1 September 2009 and 27 February 2015
- Mean follow-up: 12 months
- Analysis: Intention-to-treat
- Primary outcome: Survival with a good neurobehavioral outcome at 12 months (VABS-II score ≥70)
Population
Inclusion Criteria
- older than 48 hours, younger than 18 years
- resuscitated after cardiac arrest inside hospital walls
- received chest compressions for minimum 2 minutes
- remained dependent to mechanical ventilation following ROSC
Exclusion Criteria
- GCS motor response scale 5 or 6
- unable to undergo randomization within 6 hours of ROSC
- Active/refractory severe bleeding
- pre-existing illness with life expectancy less than 12 months and decision to withhold aggressive treatment.
Baseline Characteristics
Hypothermia Group displayed
- Demographics: median age 1.4 years
- Arrest type: 8% asystole, 57% bradycardia, 20% PEA, 10% Ventricular fibrillation / tachycardia, 4% unknown
- Arrest information: 93% occurring at trial hospital, median time to CPR 0 minutes, median duration CPR 23 minutes, median epinephrine doses 4
Interventions
- Targeted temperature management actively maintained for 120 hours.
- hypothermia [target temperature, 33.0°C]
- pharmacologically paralyzed and sedated, mechanically cooled to maintain core temperature (range, 32.0 to 34.0) for 48 hours, then rewarmed over 16 hours or longer to 36.8°C and maintained through rest of 120 hours.
- normothermia [target temperature, 36.8°C]
- same therapy as hypothermic group but temperature (range, 36.0 to 37.5) maintained for entire 120 hours.
Outcomes
Comparisons are Hypothermia group vs. Normothermia group.
Primary Outcomes
- Alive with VABS-II score ≥70 at 1 year
- 36% vs. 39% (risk difference −2.6 (95% CI −14.5 to 9.2) P = 0.63
Secondary Outcomes
- All-cause mortality at 28 days
- 37% vs. 41%, P = 0.4
- Alive at 1 year
- 49% vs. 46% (risk difference 2.8 (95% CI −8.0 to 13.7) P = 0.56
Safety Outcomes
No statistical difference for utilization of blood products, arrhythmias, and culture proven infections within 7 days of randomization
Criticisms
- stopped early due to futility, may have stopped before finding statistical difference
- long time (median 6 hours) to achieve temperature targets, faster cooling may have led to greater outcomes
- patients had a long duration of CPR, which may affect external validity
Funding
- National Heart, Lung, and Blood Institute