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: none applicable
The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: none applicable
CoSTR Citation
Kurosawa H, Ong G, Raymond T, Acworth J, Atkins D, Scholefield B on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Vasopressor use during cardiac arrest in children- Paediatric Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Paediatric Advanced Life Support Task Force, 2025 January xxxxx. 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 vasopressor use during cardiac arrest in children (Kurosawa 2024 – PROSPERO CRD42024596959), by clinical content experts of the Pediatric Life Support Task Forces of ILCOR, with assistance from Mary-Doug Wright, Information Specialist at Apex Information, Vancouver, Canada, and Hung Chew Wong, Biostatistician at Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Evidence was sought and considered by members of the Pediatric Life Support Task Force group. Additional scientific literature was published after the completion of the systematic review and identified by the Pediatric Task Force and is described before the justifications and evidence to decision highlights section of this CoSTR. These data were taken into account when formulating the Treatment Recommendations.
Systematic Review
Kurosawa H, Ong G, Raymond T, Acworth J, Atkins D, Scholefield B on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Vasopressor use during cardiac arrest in children (in preparation)
PICOST
The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)
Population: Infants and children (<18 years) in cardiac arrest who received chest compression in any setting.
Intervention: Any use of vasopressors (epinephrine, vasopressin, combination of vasopressors).
Comparators: The use of no vasopressor.
Outcomes: Short-term and long-term survival or neurological outcomes were ranked as critical outcomes. Return of spontaneous circulation (ROSC) was ranked as an important outcome.
Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) and case series with a minimum of 5 number of cases were eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) were excluded. All relevant publications in any language were included as long as there was an English abstract.
Timeframe: All years were included. The last search was performed on July 16, 2024.
PROSPERO Registration CRD42024596959
Consensus on Science
Two studies were included in the systematic review1,4. None of these provided clinical trial data. Both studies were in the out-of-hospital settings. We did not identify any clinical studies in the in-hospital settings.
The identified studies were both propensity score matched observational studies which provided very low to low certainty evidence for the comparisons with the important and critical outcomes described.
All results are presented as Risk Ratios (RR) and our assessment of statistical significance is based on the absolute risk reduction 95% confidence interval (CI 95%).
Studies comparing no epinephrine to administration of epinephrine in paediatric out-of-hospital cardiac arrest:
Favorable neurological survival at 1-month (Cerebral Performance Category)
For this critical outcome, we identified low certainty data (downgraded for serious risk of bias, and serious indirectness), from 1 cohort study which was propensity score matched for children 8 to 17 years old4 , involving 608 patients which showed no significant difference associated when epinephrine was administered compared to when no epinephrine was administered (10 more patients with favorable neurological survival at 1-month per 1,000 resuscitations; 95 CI%: 20 fewer to 40 more).
Favorable neurological survival at hospital discharge (Modified Rankin Score)
For this critical outcome, we identified low certainty data (downgraded for serious risk of bias, and serious indirectness), from 1 cohort study which was propensity score matched for children less than 18 years old1 , involving 1432 patients which showed no significant difference associated when epinephrine was administered compared to when no epinephrine was administered (20 more patient with favorable neurological survival at hospital discharge per 1,000 resuscitations; 95 CI%: 10 fewer to 40 more).
Survival at 1-month
For this critical outcome, we identified low certainty data (downgraded for serious risk of bias, and serious indirectness), from 1 cohort study which was propensity score matched for children 8 to 17 years old4 , involving 608 patients which showed no significant difference associated when epinephrine was administered compared to when no epinephrine was administered (20 more survivors per 1,000 resuscitations; 95 CI%: 20 fewer to 70 more).
Survival to hospital discharge
For this critical outcome, we identified low certainty data (downgraded serious risk of bias, and serious indirectness), from 1 cohort study which was propensity score matched for children less than 18 years old1 , involving 1432 patients which showed no significant difference associated with survival at hospital discharge when epinephrine was administered compared to when no epinephrine was administered (20 more survivor per 1000 resuscitations; 95 CI%: 0 fewer to 50 more).
Pre-hospital Return of spontaneous circulation (ROSC)
For this important outcome, we identified very low certainty data (downgraded for serious risk of bias, very serious inconsistency, and serious indirectness), from the 2 cohort studies , involving 2038 patients less than 18 years old4, which showed significant associations with ROSC when epinephrine was administered, compared to when no epinephrine was administered (60 more patients with ROSC per 1,000 resuscitations; 95 CI%: 30 more to 90 more).
Summary of findings
Acknowledging the very low to low level of certainty, the current available data suggest that the critical outcomes (favorable neurological survival, and survival to discharge or at 1-month) were not significantly better or worse when epinephrine was given in paediatric out-of-hospital cardiac arrest. However, administration of epinephrine in paediatric out-of-hospital cardiac arrest was significantly associated with ROSC.
Treatment recommendations
We suggest to use epinephrine in paediatric out-of-hospital cardiac arrest. [weak recommendation, very low-quality evidence].
There is insufficient evidence to generate a treatment recommendation for the use of epinephrine in pediatric in-hospital cardiac arrest. However, the task force considers the indirect evidence from OHCA to support the administration of epinephrine in pediatric in-hospital cardiac arrest. [Good practice statement].
Justification and Evidence to Decision Framework Highlights
While there is limited evidence that in paediatric out-of-hospital cardiac arrest, administration of epinephrine was associated with ROSC but not to other neurological and survival outcomes.
EtD table: PLS 4080 21 Et D vasopressor in CA Epi vs no Epi
The taskforce acknowledged that the included studies were from settings with advanced Emergency Medical Services. In similar settings, the administration of epinephrine as part of advanced paediatric life support for paediatric out-of-hospital cardiac arrest should be continued but also further evaluated.
However, there is paucity of studies looking at resources required to train, maintain skillsets and provide the necessary equipment for EMS systems to administer epinephrine in paediatric out-of-hospital cardiac arrests. Future studies should be undertaken to evaluate the ability of EMS systems to provide advanced care in paediatric out-of-hospital cardiac arrest, to better inform equity issues of such systems in both resource-rich healthcare but also in resource-limited countries.
The taskforce acknowledged that the ALS taskforce currently recommends the use of vasopressor in adult cardiac arrest6. However, the PLS taskforce, despite no RCTs in children, did not include indirect evidence from adults because of differences in aetiology of cardiac arrest.
Knowledge gaps
Specific undesirable effects (outside of the lack of reported neurological or survival benefits) were not reported in the studies identified. Adverse outcomes from administration of epinephrine have been reported2.
Further studies should address if specific sub-populations might potentially benefit (or not) from administration of epinephrine in the pre-hospital settings. Cost-effectiveness and feasibility of the provision of advanced paediatric life support in the pre-hospital settings to facilitate the administration of epinephrine, in paediatric out-of-hospital cardiac arrest while ensuring high-quality basic life support, should be explored in all healthcare settings, including in LMICs.
Future studies would benefit from including outcome measures consistent with the P-COSCA recommendations7.
There were no inpatient studies identified. Future studies should include evaluation of use of vasopressors in the inpatient setting, especially in the context of initial resuscitation of pediatric cardiac arrest patients prior to extracorporeal cardiopulmonary resuscitation (ECPR)3, 5.
References
1. Amoako J, Komukai S, Izawa J, Callaway CW, Okubo M. Evaluation of Use of Epinephrine and Time to First Dose and Outcomes in Pediatric Patients With Out-of-Hospital Cardiac Arrest. JAMA Netw Open. 2023;6:e235187. doi: 10.1001/jamanetworkopen.2023.5187
2. Eriksson CO, Bahr N, Meckler G, Hansen M, Walker-Stevenson G, Idris A, Aufderheide TP, Daya MR, Fink EL, Jui J, et al. Adverse Safety Events in Emergency Medical Services Care of Children With Out-of-Hospital Cardiac Arrest. JAMA Netw Open. 2024;7:e2351535. doi: 10.1001/jamanetworkopen.2023.51535
3. Lasa JJ, Jain P, Raymond TT, Minard CG, Topjian A, Nadkarni V, Gaies M, Bembea M, Checchia PA, Shekerdemian LS, Thiagarajan R. Extracorporeal Cardiopulmonary Resuscitation in the Pediatric Cardiac Population: In Search of a Standard of Care. Pediatr Crit Care Med. 2018 Feb;19(2):125-130. doi: 10.1097/PCC.0000000000001388.
4. Matsuyama T, Komukai S, Izawa J, Gibo K, Okubo M, Kiyohara K, Kiguchi T, Iwami T, Ohta B, Kitamura T. Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac Arrest. J Am Coll Cardiol. 2020;75:194-204. doi: 10.1016/j.jacc.2019.10.052
5. Ortmann LA, Reeder RW, Raymond TT, Brunetti MA, Himebauch A, Bhakta R, Kempka J, di Bari S, Lasa JJ. Epinephrine dosing strategies during pediatric extracorporeal cardiopulmonary resuscitation reveal novel impacts on survival: A multicenter study utilizing time-stamped epinephrine dosing records. Resuscitation. 2023 Jul;188:109855. doi: 10.1016/j.resuscitation.2023.109855.
6. Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379:711-721. doi: 10.1056/NEJMoa1806842
7. Topjian AA, Scholefield BR, Pinto NP, Fink EL, Buysse CMP, Haywood K, Maconochie I, Nadkarni VM, de Caen A, Escalante-Kanashiro R, 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;162:351-364. doi: 10.1016/j.resuscitation.2021.01.023