PLS 4210.03 Temperature control after cardiac arrest in children: Temperature target and duration: TF SR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest:

The following intellectual conflicts of interest have been declared. B Scholefield, A Guerguerian and A Topjian were co-investigator on the THAPCA-IH trial. A Topjian, H Krishnan, and A-M Guerguerian are co-investigators/site PIs in the P-ICECAP study. B Scholefield, A Topjian, H Krishan and A-M Guerguerian were excluded from study selection, data abstraction and risk of bias assessment. No members of the writing group have any financial conflicts of interest.

CoSTR Citation

Barnaby R Scholefield, Thomas Main, Idan Yoel, Anne-Marie Guerguerian, Jason Acworth, Olugbenga Akinkugbe, Arun Bansal, James Gray, Hari Krishnan Kanthimathinathan, Maria Frazier, Jennifer Murphy, Andrea Christoff, Jessie Cunningham, Laurie J. Morrison on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Temperature control after pediatric cardiac arrest: Temperature target and duration, Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Pediatric Life Support Task Force, 2026 XXX.  Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of Temperature Target and Duration After Paediatric Cardiac Arrest (Prospero: CRD420251084345) conducted by the Pediatric Life Support Task Force. Evidence was sought and considered by the Task Force groups. These data were taken into account when formulating the Treatment Recommendations.

Systematic Review

Idan Yoel, Thomas Main, Anne-Marie Guerguerian, Olugbenga Akinkugbe, Arun Bansal, James Gray, Hari Krishnan Kanthimathinathan, Maria Frazier, Jennifer Murphy, Andrea Christoff, Jessie Cunningham, Laurie J. Morrison, Jason Acworth, Barnaby R Scholefield, on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Temperature control after pediatric cardiac arrest: Systematic Review of Temperature target and duration (in press).

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe) 

Population: Children (>24 hours to 18 years of age) with a sustained return of circulation after an in-hospital or out of hospital cardiac arrest treated with a targeted temperature management protocol* (except where marked).

Question 1:

Intervention 1: A temperature target with active control* (e.g. 36.5C)

Comparators 1:  A different temperature target with active control* (e.g. 33C)

Question 2:

Intervention 2: A temperature target with active control*.

Comparators 2: No active control* of temperature target

Question 3:

Intervention 3: A temperature target with active control* for a specific duration (e.g. 24 hours)

Comparators 3: A temperature target with active control* for a different duration (e.g 72 hours).

*Active temperature management (ATM) involves intentionally controlling a patient's body temperature to a specific temperature target range using a standardized management protocol. This includes all cooling/warming methods, temperature maintenance duration, pharmaco-therapy and monitoring strategies to achieve and sustain the desired target temperature.

Outcomes: Any clinical outcome (e.g. Survival or survival with favorable neurological outcome as defined by the Pediatric Core Outcome Set for Cardiac Arrest)(1)

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) are excluded. All relevant publications in any language are included as long as there is an English abstract

Timeframe:  Published data from 1966 to date of search. Literature search updated to April 22, 2025.

PROSPERO Registration CRD420251084345

Consensus on Science

Question 1: ATM at 32-34°C vs ATM at 36-37.5°C

• Favorable Neurological Outcome:

For the critical outcome of long-term good neurobehavioral survival (1 year), the evidence of very low certainty (downgraded for inconsistency and imprecision) from 2 RCTs(2, 3) (1 OHCA and 1 IHCA study) with 517 children who achieved return of circulation but remained comatose with a Glasgow Coma Scale Motor Score <5, showed no significant benefit or harm of ATM 32-34°C compared to ATM 36-37.5°C (RR=1.05, 95% CI 0.80-1.39; absolute risk reduction [ARR]=1.3%, or 13 more patients/1000 had good neurobehavioral survival with the intervention, 95% CI 51 fewer patients/1000 to 100 more patients/1000).

For the critical outcome of intermediate-term good neurobehavioral survival (6 months), the evidence of very low certainty (downgraded for risk of bias, inconsistency, indirectness, and imprecision) from 1 adjusted observational cohort study(5) with 79 children who achieved ROSC after OHCA or IHCA, showed no statistical benefit or harm of ATM <35°C compared to ATM 36-37.5°C or no ATM (aOR=0.50, 95% CI 0.11-2.22; ARR= -17.2%, or 172 fewer patients/1000, 95% CI 448 fewer to 174 more patients/1000).

• Survival:

For the critical outcome of long-term survival (1 year), the evidence of very low certainty (downgraded for inconsistency and imprecision) from 2 RCTs(2, 3) (1 OHCA and 1 IHCA study) with 614 children who achieved return of circulation but remained comatose with a Glasgow Coma Scale Motor Score <5, showed no statistical benefit or harm of ATM 32-34°C compared to ATM 36-37.5°C (RR=1.14, 95% CI 0.94-1.37; ARR=5.3%, or 53 more patients/1000, 95% CI 25 fewer to 141 more patients/1000).

For the critical outcome of intermediate-term survival (6 months), the evidence of very low certainty (downgraded for risk of bias, inconsistency, indirectness, and imprecision) from 1 adjusted observational cohort study(5) with 79 children who achieved ROSC after OHCA or IHCA showed no statistical benefit or harm of ATM <35°C compared to ATM 36-37.5°C or no ATM (aOR=0.50, 95% CI 0.11-2.22; ARR= -17.2%, or 171 fewer patients/1000, 95% CI 468 fewer to 164 more patients/1000).

For the critical outcome of short-term survival (30 days or hospital discharge), the evidence of very low certainty (downgraded for risk of bias, inconsistency, and imprecision) from 3 non-randomized observational cohort studies(5-7) with 388 children who achieved ROSC after OHCA or IHCA showed no statistical benefit or harm of ATM 32-36°C compared to ATM 36-37.5°C or no ATM. Due to significant clinical heterogeneity, these studies could not be pooled.

• Health-Related Quality of Life:

For the important outcome of health-related quality of life (HRQoL), the evidence of very low certainty (downgraded for risk of bias and imprecision) from 1 observational cohort study(7) with 128 children after IH or OHCA showed improved adjusted HRQoL physical differences and psychosocial scores in the ATM 33°C group compared to the ATM 35.4°C group, measured at a mean follow up of 3.8 years (MD=11.2 HRQoL score higher, 95% CI 3.1 higher to 19.3 higher).

• Table: PLS_4210.03_TTMSR_ATM 32-34°C vs. ATM 36-37.5°C EtD v5_SAC approved

Question 2: ATM (Any Temperature) vs No Active Temperature Management

• Favorable Neurological Outcome:

For the critical outcome of short-term good neurobehavioral survival (at hospital discharge), the evidence of very low certainty (downgraded for risk of bias, inconsistency, and imprecision) from 2 observational cohort studies(8, 9), that adjusted for confounding using propensity score methods, with 877 children who achieved ROSC after OHCA showed statistical benefit of ATM (any temperature) compared to no active temperature management (OR=1.21, 95% CI 1.05-1.40; ARR=3.0%, or 30 more patients/1000, 95% CI 7 more to 56 more patients/1000).

• Survival:

For the critical outcome of short-term survival (30 days or hospital discharge), the evidence of very low certainty (downgraded for risk of bias and imprecision) from 2 observational cohort studies(8, 10), that adjusted for confounding using propensity score methods, with 830 children who achieved ROSC after OHCA showed no statistical benefit or harm of ATM (any temperature) compared to no active temperature management (OR=1.06, 95% CI 0.67-1.68; ARR=1.4%, or 14 more patients/1000, 95% CI 92 fewer to 129 more patients/1000).

• Table: PLS_4210.03_TTMSR_ATM (any temperature) vs. no ATM EtD v5_SAC approved

Question 3: Duration of ATM (24 Hours vs 72 Hours)

• Favorable Neurological Outcome:

For the critical outcome of short-term good neurobehavioral survival (at hospital discharge), the evidence of very low certainty (downgraded for risk of bias, inconsistency, and extremely serious imprecision) from 1 RCT(11) with 34 children after OHCA or IHCA showed no statistical benefit or harm of 24 hours ATM 33°C compared to 72 hours ATM 33°C (RR=0.86, 95% CI 0.36-2.02; ARR= -5.8%, or 58 fewer patients/1000, 95% CI 264 fewer to 420 more patients/1000).

• Survival:

For the critical outcome of short-term survival (at hospital discharge), the evidence of very low certainty (downgraded for risk of bias, inconsistency, and extremely serious imprecision) from 1 RCT(11) with 34 children after OHCA or IHCA showed no statistical benefit or harm of 24 hours ATM 33°C compared to 72 hours ATM 33°C (RR=0.69, 95% CI 0.41-1.16; ARR= -23.7%, or 237 fewer patients/1000, 95% CI 451 fewer to 122 more patients/1000).

• Table: PLS_4210.03_TTMSR_ATM for one duration (eg 24 hrs) vs. ATM for another duration EtD v5.0_SAC approved

Treatment Recommendations

We recommend using active temperature management* (ATM) for comatose infants and children following OHCA or IHCA. (Strong recommendation; low certainty.)

We recommend using ATM to prevent central temperatures >37.5°C. (Strong recommendation; low certainty.)

We suggest that ATM protocols follow one of the published THAPCA trial interventions:

• ATM 32–34°C for 48 hours, followed by gradual rewarming and maintenance at 36–37.5°C until a total of 120 hours, or

• ATM 36–37.5°C for 120 hours total.

as current evidence does not show superiority of either temperature target and there is insufficient evidence to recommend alternative durations. (Weak recommendation; low certainty.)

*Active temperature management (ATM) is defined as intentionally controlling a patient's body temperature to a specific temperature target range using a standardized management protocol.

Justification and Evidence to Decision Framework Highlights

• The PLS Task Force prioritized this topic based on ongoing uncertainty regarding the optimal use of active temperature management (ATM) in children after cardiac arrest, including the choice of temperature target, duration, and the value of active temperature management compared to no intervention.

• The evidence base includes two large RCTs (THAPCA-OH and THAPCA-IH)(2, 3) and several observational studies. For the comparison of hypothermia (ATM 32–34°C) versus normothermia (ATM 36–37.5°C), RCTs did not demonstrate a statistically significant difference in survival or good neurobehavioral outcome at one year.

• A Bayesian re-analysis of the THAPCA-OH trial(4) suggested a possible benefit for hypothermia, but with wide credible intervals and low certainty.

• For the critical outcome of long-term good neurobehavioral survival (1 year) using Bayesian reanalysis of the THAPCA-OH RCT(4) showed a posterior median absolute benefit of 6.8% for the intervention (ATM 32-34°C) (95% Credible Interval: -1.9% to 15.4%) with a probability of any benefit of 94%.

• For the critical outcome of long-term survival (1 year) using Bayesian reanalysis of the THAPCA-OH RCT(4) showed a posterior median absolute benefit of 6.8% for the intervention (ATM 32-34°C) (95% Credible Interval: -1.9% to 15.4%) with a probability of any benefit of 94%.

• The PLS TF agreed that following IHCA, there is insufficient evidence to support or refute the use of induced hypothermia (ATM 32-34°C) compared with active temperature management at normothermia (ATM 36-37.5°C) (or an alternative temperature).

• Following OHCA, there is some evidence supporting the use of induced hypothermia (ATM 32-34°C for 48 hours) compared with active temperature management at normothermia (ATM 36-37.5°C) in comatose patients. However, the body of evidence remains insufficient to provide a separate treatment recommendation.

• A single observational study of both OHCA and IHCA patients suggests long term health related quality of life outcomes are promising with lower target temperatures however more rigorous trials addressing quality of life outcomes are needed.

• No RCTs or high-quality studies support a specific duration of TTM, and available data are limited to a small pilot trial with very low certainty. There is insufficient evidence to recommend a duration of ATM different to the two ATM protocols used in the THAPCA trials (ATM 32-34°C: 48 hours at target temperature, gradual rewarming and maintenance at 36-37.5°C until 120 hours total duration of ATM, verses ATM 36-37.5°C for 120 hours total duration).

• Observational studies comparing any active temperature management to no active management suggest a moderate benefit for good neurobehavioral outcome, but no significant effect on survival. Across all comparisons, the certainty of evidence is very low due to methodological limitations, confounding, and imprecision. The intervention duration for ATM varied across these studies with durations of 12 to 24 hours.

• Both hypothermia and normothermia protocols require ICU-level care, active temperature management, invasive monitoring, and specialized equipment, resulting in significant resource requirements. Cost-effectiveness and true costs are unknown, and implementation may increase health inequities, particularly in resource-limited settings.

• There is important variability in values and preferences among families and clinicians, with survival and good neurobehavioral outcome generally prioritized, but some families value any survival while others prioritize meaningful neurological recovery.

• Given the lack of clear superiority of any approach, the balance of effects varies depending on the analytic method and outcome considered. The intervention is probably acceptable and feasible in well-resourced centers but may be challenging to implement universally. Therefore, the Task Force issues a conditional recommendation for either hypothermia or normothermia, and for active temperature management over no management, allowing for individualized decision-making based on patient context, available resources, and family values.

Knowledge Gaps

• There is a need for further high-quality randomized controlled trials comparing hypothermia (ATM 32–34°C) and normothermia (ATM 36–37.5°C) in children after cardiac arrest, focusing on long-term neurological outcomes and survival. These will required thoughtful inclusion criteria and appropriate statistical power.

• There is insufficient evidence to guide the optimal duration of active temperature management, with only a small pilot trial addressing this question; larger, adequately powered studies are needed.

• The PLS TF recognizes that there remains uncertainty about the application of temperature management in children after OHCA and IHCA (e.g. timing of starting ATM, technique to achieve and rewarming rate). Further research in these areas are needed.

• Data on health-related quality of life and functional outcomes are limited, and future studies should use standardized measures, such as those recommended by the P-COSCA initiative, to assess these outcomes.

• Rates of adverse events, including fever, arrhythmia, infection, bleeding, and accidental overcooling, are not systematically reported in current studies, and there is a need for prospective data collection on these outcomes in both intervention and control groups.

• The true cost and cost-effectiveness of hypothermia versus normothermia, and of ATM versus no ATM, are unknown, as no studies have directly addressed these outcomes; resource requirements may impact feasibility and equity.

• There is limited evidence on barriers and facilitators to implementation, especially in centers with restricted access to specialized equipment or trained personnel.

• Implementation of ATM may increase disparities in access and outcomes between high-resource and low-resource settings, and research is needed to understand and address these equity concerns.

• Effects in specific subgroups, such as patients supported on ECMO, and differences between out-of-hospital and in-hospital cardiac arrest, require further investigation.

• No studies have used risk stratification approaches to select patients for ATM, and future research should focus on developing and validating tools to guide individualized treatment decisions, particularly for children with moderate risk of hypoxic-ischemic encephalopathy (HIE).

• Participation in multicenter registries and collaborative research is needed to enhance data quality, generalizability, and benchmarking.

References

1. Topjian AA, Scholefield BR, Pinto NP, Fink EL, Buysse CMP, Haywood K, et al. P-COSCA (Pediatric Core Outcome Set for Cardiac Arrest) in Children: An Advisory Statement From the International Liaison Committee on Resuscitation. Resuscitation. 2021;162:351–64.

2. Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. N Engl J Med. 2017;376(4):318–29.

3. Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. The New England journal of medicine. 2015;372(20):1898–908.

4. Harhay MO, Blette BS, Granholm A, Moler FW, Zampieri FG, Goligher EC, et al. A Bayesian Interpretation of a Pediatric Cardiac Arrest Trial (THAPCA-OH). NEJM evidence. 2023;2(1):EVIDoa2200196.

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7. Magee A, Deschamps R, Delzoppo C, Pan KC, Butt W, Dagan M, et al. Temperature Management and Health-Related Quality of Life in Children 3 Years After Cardiac Arrest. Pediatr Crit Care Med. 2022;23(1):13–21.

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9. Namba T, Nishikimi M, Emoto R, Kikutani K, Ohshimo S, Matsui S, et al. Effect Size of Targeted Temperature Management in Pediatric Patients with Post-Cardiac Arrest Syndrome According to the Severity. Life (Basel, Switzerland). 2024;15(1).

10. Matsui S, Hirayama A, Kitamura T, Sobue T, Hayashi T, Takei H, et al. Target Temperature Management and Survival with Favorable Neurological Outcome After Out-of-Hospital Cardiac Arrest in Children: A Nationwide Multicenter Prospective Study in Japan. Therapeutic hypothermia and temperature management. 2022;12(1):16–23.

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