2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations

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Pediatric Life Support 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

Ian K. Maconochie, MB, BS, LMSSA, PhD; Richard Aickin, MB, ChB Mary Fran Hazinski, RN, MSN Dianne L. Atkins, MD; Robert Bingham, MRCS, MB, BS, LRCP; Thomaz Bittencourt Couto, MD, PhD; Anne-Marie Guerguerian, MD, PhD; Vinay M. Nadkarni, MD; Kee-Chong Ng, MBBS, MMed (Peds); Gabrielle A. Nuthall, MBChB Gene Y.K. Ong, MBBS, MRCPCH; Amelia G. Reis, MD, PhD Stephen M. Schexnayder, MD Barnaby R. Scholefield, MBBS, MRCPCH, PhD; Janice A. Tijssen, MD, MSc Jerry P. Nolan, MBChB Peter T. Morley, MBBS Patrick Van de Voorde, MD, PhD; Arno L. Zaritsky, MD Allan R. de Caen, MD; On behalf of the Pediatric Life Support Collaborators

DOI: 10.1542/peds.2020-038505B Journal: Pediatrics Article Type: Supplement Article

Citation: Maconochie IK, Aickin R, Hazinski MF, et al. Pediatric Life Support 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Pediatrics. 2020; doi: 10.1542/peds.2020-038505B

This is a prepublication version of an article that has undergone peer review and been accepted for publication but is not the final version of record. This paper may be cited using the DOI and date of access. This paper may contain information that has errors in facts, figures, and statements, and will be corrected in the final published version. The journal is providing an early version of this article to expedite access to this information. The American Academy of Pediatrics, the editors, and authors are not responsible for inaccurate information and data described in this version.

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ABSTRACT: This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) for pediatric life support is based on the most extensive evidence evaluation ever performed by the Pediatric Life Support Task Force. Three types of evidence evaluation were used in this review: systematic reviews, scoping reviews, and evidence updates. Per agreement with the evidence evaluation recommendations of the International Liaison Committee on Resuscitation, only systematic reviews could result in a new or revised treatment recommendation. Systematic reviews performed for this 2020 CoSTR for pediatric life support included the topics of sequencing of airway-breaths-compressions versus compressions-airway-breaths in the delivery of pediatric basic life support, the initial timing and dose intervals for epinephrine administration during resuscitation, and the targets for oxygen and carbon dioxide levels in pediatric patients after return of spontaneous circulation. The most controversial topics included the initial timing and dose intervals of epinephrine administration (new treatment recommendations were made) and the administration of fluid for infants and children with septic shock (this latter topic was evaluated by evidence update). All evidence reviews identified the paucity of pediatric data and the need for more research involving resuscitation of infants and children. Key Words: AHA Scientific Statements arrhythmia cardiopulmonary resuscitation child congenital heart ■disease ECMO◼ pediatrics ◼ ◼ © 2020 ◼American◼ Heart Association, Inc., European Resuscitation Council, and International Liaison Committee on Resuscitation Reprinted with permission of the American Heart Association, Inc. This article has been published in Circulation.

https://www.ahajournals.org/journal/circ

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CONTENTS PALS: Recognition and Treatment of Nonarrest Arrhythmias ...... S155 Abstract ...... S140 Drugs for Supraventricular Tachycardia Topics Reviewed in This 2020 PLS CoSTR ...... S143 (PLS 379: EvUp) ...... S155 PBLS: CPR and CPR Quality ...... S144 Treatment for Unstable Ventricular Sequence of Compression and Ventilation Tachycardia (PLS 409: EvUp) ...... S155 (BLS 661: Shared SysRev) ...... S144 CPR for Heart Rate of Less Than 60/min Pulse Check Accuracy (PLS 393: EvUp) ...... S145 (PLS 1535: EvUp) ...... S155 Chest Compression–Only Versus Drugs for the Treatment of Bradycardia: Conventional CPR (2017 CoSTR) ...... S145 Atropine Versus No Atropine and Atropine Pediatric Compression Depth (PLS 314: ScopRev) ...... S146 Versus Epinephrine (PLS 2 New: EvUps) ...... S156 One-Hand Versus 2-Hand Compressions Emergency Transcutaneous Pacing for for Children (PLS 375: EvUp) Combined Bradycardia (PLS New: EvUp) ...... S156 With Circumferential Compressions for Channelopathies (PLS 417: EvUp) ...... S157 Infants (PLS 416: EvUp) ...... S146 PALS: Manual Defibrillation ...... S157 PBLS: Automated External Defibrillation ...... S147 Pad Size, Type, and Placement for Pediatric Use of Automated External Defibrillators Defibrillation (PLS 378 and PLS 043: EvUp) ..... S157 for Infants With Out-of-Hospital Cardiac Energy Doses for Defibrillation Arrest (PLS 425: EvUp) ...... S147 (PLS 405: ScopRev) ...... S158 PBLS: Prevention of Cardiac Arrest...... S147 Single or Stacked Shocks for Pediatric Pediatric Early-Warning Scores Defibrillation (PLS 389: EvUp) ...... S158 (PLS 818: ScopRev) ...... S147 PALS: Airways, Oxygenation, and Ventilation ...... S159 Pediatric Medical Emergency/Rapid Ventilation Rate When a Perfusing Rhythm Response Teams (PLS 397: EvUp) ...... S148 Is Present (PLS 3103A and PLS 382: EvUp) ...... S159 PALS: Recognition and Treatment of Septic Shock ..... S148 Oxygen Concentration During Cardiac Fluid Administration for the Child With Arrest (PLS 396: ScopRev) ...... S159 Septic Shock (PLS New: EvUp) ...... S148 Ventilation During CPR With Bag and Mask Vasoactive Drugs for Septic Shock Compared With an Advanced Airway (PLS 1604: ScopRev) ...... S149 (2019 CoSTR) ...... S160 Corticosteroids for Pediatric Septic Shock Use of Cuffed or Uncuffed Tracheal Tubes (PLS 413: EvUp)...... S150 (PLS 412: EvUp) ...... S160 PALS: Recognition and Prearrest Treatments Atropine for Emergency Intubation for Shock ...... S151 (PLS 821: EvUp) ...... S161 Graded Volume Resuscitation for Traumatic/ Cricoid Pressure During Intubation Hemorrhagic Shock (PLS 400: ScopRev) ...... S151 (PLS 376: EvUp) ...... S161 Timing of Intubation for Shock Use of Devices to Verify Advanced Airway (PLS 399: EvUp) ...... S152 Placement (PLS 385: EvUp) ...... S162 Prearrest Care of the Infant or Child With Ventilation Rate With Advanced Airway Dilated Cardiomyopathy or Myocarditis During Cardiac Arrest (PLS 3103A and (PLS 819: EvUp)...... S152 PLS 382: EvUp) ...... S162 Cardiogenic Shock and Inotropes PALS: Circulatory Support During CPR ...... S163 (PLS 418: EvUp)...... S153 Extracorporeal CPR for In-Hospital Cardiac Arrest PALS: Management of Deterioration With (2019 CoSTR) ...... S163 Pulmonary Hypertension ...... S153 PALS: Physiological Monitoring During Arrest to Prevention and Management of Postoperative Guide Therapy and/or Intra-arrest Prognostication .... S163 Pulmonary Hypertensive Crises in Infants Invasive Blood Pressure Monitoring During and Children (PLS 391: EvUp) ...... S153 CPR (PLS 826: ScopRev) ...... S163 Opioids, Sedatives, and Neuromuscular Use of Near-Infrared Spectroscopy During Blocking Drugs for Pulmonary Hypertension Cardiac Arrest (PLS New: ScopRev) ...... S164 (PLS New: EvUp) ...... S154 Bedside Ultrasound to Identify Perfusing Therapy With Inhaled Nitric Oxide or Rhythm (PLS 408: ScopRev) ...... S165 Prostaglandin I for Pulmonary Hypertensive 2 End-Tidal CO2 Monitoring During CPR Crisis and Right Heart Failure (PLS New: EvUp) .... S154 (PLS 827: ScopRev) ...... S165

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PALS: Resuscitation Drug Administration and Timing .... S166 since 2010. The 3 major types of evidence evaluation Methods of Calculating Pediatric Drug supporting this 2020 publication are the SysRev, the Doses (PLS 420: EvUp) ...... S166 Scoping Review (ScopRev), and the Evidence Update Intraosseous Versus Intravenous Route of Drug (EvUp). Administration (PLS, NLS, and ALS: SysRev) ...... S167 Topics and types of reviews were prioritized by the PLS Epinephrine Time of Initial Dose and Dose Task Force over the past 12 months on the basis of task Interval During CPR (PLS 1541: SysRev) ...... S167 force consensus that the answers to the review ques- Amiodarone Versus Lidocaine for Shock- tions were critical, task force expert awareness of recent Resistant Ventricular Fibrillation or Pulseless studies on the topics that could change treatment rec- Ventricular Tachycardia (2018 CoSTR) ...... S171 ommendations, and input and requests from the ILCOR Sodium Bicarbonate Administration for member councils. SysRevs were performed on topics if Children in Cardiac Arrest (PLS 388: EvUp) ...... S171 deemed critical on the basis of the questions involved or Calcium Administration in Children if publication of studies suggested the need to consider (PLS 421: EvUp) ...... S172 new or modified treatment recommendations. ScopRevs PALS: Special Resuscitation Situations—Septic and EvUps were performed if the task force or member Shock, Congenital Heart Disease, and Trauma ...... S172 councils identified a topic as important or if it had not Resuscitation of the Child With Septic been reviewed in several years; ScopRevs and EvUps were Shock (PLS 1534: EvUp) ...... S172 intended to determine if sufficient published evidence ex- Resuscitation of the Patient With a Single isted to suggest the need for a SysRev. Ventricle (PLS 390: EvUp) ...... S172 The SysRev is a rigorous process following strict Resuscitation of the Patient With Hemi- methodology to answer a specific question, and each Fontan or Fontan Circulation (PLS 392: EvUp) .... S173 of these ultimately resulted in the generation of a task Resuscitation After Traumatic Arrest force CoSTR included in this summary. The SysRevs (PLS 498: EvUp)...... S173 were performed by a knowledge synthesis unit, an PALS: Post–Cardiac Arrest Care, Including expert systematic reviewer, or the PLS Task Force, and Postarrest Prognostication ...... S174 many resulted in separate SysRevs publications. Targeted Temperature Management To begin the SysRev, the question to be answered was (2019 CoSTR) ...... S174 phrased in terms of the PICOST (population, interven- Oxygen and Carbon Dioxide Targets in Pediatric tion, comparator, outcome, study design, time frame) Patients With Return of Spontaneous Circulation format. The methodology used to identify the evidence After Cardiac Arrest (PLS 815: SysRev) ...... S174 was based on the Preferred Reporting Items for Sys- 1 Post-ROSC Blood Pressure Control tematic Reviews and Meta-Analyses (PRISMA). The ap- (PLS 820: EvUp) ...... S176 proach used to evaluate the evidence was based on that Post-ROSC Neuroprognostication and proposed by the Grading of Recommendations, Assess- Use of Electroencephalogram ment, Development and Evaluation (GRADE) working 2 (PLS 813 and PLS 822: EvUp) ...... S177 group. Using this approach, the PLS Task Force rated Topics Not Reviewed in 2020 ...... S177 as high, moderate, low, or very low the certainty/confi- Future Tasks ...... S177 dence in the estimates of effect of an intervention or as- Acknowledgments ...... S178 sessment across a body of evidence for each of the pre- Disclosures ...... S178 defined outcomes. Randomized controlled trials (RCTs) References ...... S180 generally began the analysis as high-certainty evidence, and observational studies generally began the analysis as low-certainty evidence; examination of the evidence The 2020 International Consensus on Cardiopul- using the GRADE approach could result in downgrading monary Resuscitation (CPR) and Emergency Car- or upgrading the certainty of evidence. For additional diovascular Care (ECC) Science With Treatment information, refer to “Evidence Evaluation Process and 3,3a Recommendations (CoSTR) is the fourth in a series Management of Potential Conflicts of Interest.” of annual publications from the International Liaison When a pre-2015 CoSTR treatment recommenda- Committee on Resuscitation (ILCOR). This 2020 CoSTR tion was not updated, the language used in the recom- summary for pediatric life support (PLS) includes new mendation differed from that used in the GRADE ap- 4–6 topics addressed by Systematic Reviews (SysRevs) per- proach because GRADE was not used before 2015. formed within the past 12 months. It also includes Draft 2020 (ie, new) CoSTRs for PLS were posted on updates of the PLS CoSTR statements published from the ILCOR website7 for public comment between March 2010 through 2019 as needed, based on additional 26, 2018, and January 10, 2020. The draft CoSTR state- evidence evaluations. As a result, this 2020 CoSTR ments were viewed 31468 times with 16 comments summary for PLS is the most comprehensive update received. All comments were discussed by the PLS Task

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Force and modifications made as needed to the content TOPICS REVIEWED IN THIS 2020 PLS or to the recommendations for future search strategies. CoSTR This summary contains the final wording of the CoSTR statements as approved by the ILCOR PLS Task Force and Note: As indicated above, the PLS CoSTR evidence re- the ILCOR member councils after review and consider- views were all completed by January 10, 2020. As a re- ation of comments posted online in response to the draft sult, this document does not address the topic of poten- CoSTRs. In this publication, each topic includes the PI- tial influence of coronavirus disease 2019 (COVID-19) COST as well as the CoSTR, an expanded Justification and on resuscitation practice. In the spring of 2020, an IL- Evidence to Decision Framework Highlights section, and a COR writing group was assembled to identify and eval- list of knowledge gaps requiring future research studies. uate the published evidence regarding risks of aerosol An evidence-to-decision table is included for each CoSTR generation and infection transmission during attempted in Appendix A in the Supplemental Materials. resuscitation of adults, children, and infants. This group The second major type of evidence evaluation per- developed a consensus on science with treatment rec- formed to support this 2020 CoSTR summary for PLS is ommendations and task force insights. This statement a ScopRev. ScopRevs are designed to identify the extent, is published as a separate document.8 As new evidence range, and nature of evidence on a topic or question, emerges, the ILCOR task forces will review and update and they were performed by topic experts in consulta- this statement, so the reader is referred to the ILCOR tion with the PLS Task Force. The task force analyzed the website7 for the most up-to-date recommendations. identified evidence and determined its value and implica- Pediatric Basic Life Support (PBLS): CPR and CPR tions for resuscitation practice or research. The rationale Quality for the ScopRev, the summary of evidence, and task force • Sequence of compression and ventilation (BLS insights—all are highlighted in the body of this publica- 661: Shared SysRev) tion. Any previous treatment recommendations are reit- • Pulse check accuracy (PLS 393: EvUp) erated. The task force noted whether the ScopRev iden- • Chest compression–only versus conventional CPR tified substantive evidence that could result in a change (2017 CoSTR) in the ILCOR treatment recommendations. If sufficient • Pediatric compression depth (PLS 314: ScopRev) evidence was identified, the task force suggested consid- • 1-hand versus 2-hand compressions for children eration of a (future) SysRev to support the development (PLS 375: EvUp) combined with circumferential of an updated CoSTR. All ScopRevs are included in their compressions for infants (PLS 416: EvUp) entirety in Appendix B in the Supplemental Materials. PBLS: Automated External Defibrillation The third type of evidence evaluation supporting this • Use of automated external defibrillators (AEDs) for 2020 CoSTR for PLS is an EvUp. EvUps were generally infants with out-of-hospital cardiac arrest (OHCA) performed to identify new studies published after the (PLS 425: EvUp) most recent ILCOR evidence evaluation, typically by using search terms and methodologies from previous PBLS: Prevention of Cardiac Arrest reviews. These EvUps were performed by task force • Pediatric early-warning scores (PEWS) (PLS 818: members, collaborating experts, or members of council ScopRev) writing groups. The EvUps are cited in the body of this • Pediatric medical emergency/rapid response teams publication with a note as to whether the evidence sug- (PLS 397: EvUp) gested the need to consider a SysRev; the most recent Pediatric Advanced Life Support (PALS): Recogni- ILCOR treatment recommendation was reiterated. tion and Treatment of Septic Shock In this publication, no change in an ILCOR treatment • Fluid administration for the child with septic shock recommendation resulted from a ScopRev or an EvUp; if (PLS 1534: EvUp) substantial new evidence was identified, the task force • Vasoactive drugs for septic shock (PLS 1604: recommended consideration of a SysRev. All EvUps are ScopRev) included in Appendix C in the Supplemental Materials, • Corticosteroids for pediatric septic shock (PLS 413: as they were drafted by the reviewers. EvUp) Note: The reviews and treatment recommendations apply to infants (28 days to 12 months) and children PALS: Recognition and Prearrest Treatments for (the age definitions varied in the cited studies). Evidence Shock evaluation of studies of resuscitation of newborns (es- • Graded volume resuscitation for traumatic/hemor- pecially at birth) can be found in “Neonatal Life Sup- rhagic shock (PLS 400: ScopRev) port: 2020 International Consensus on Cardiopulmo- • Timing of intubation for shock (PLS 399: EvUp) nary Resuscitation and Emergency Cardiovascular Care • Prearrest care of the infant or child with dilated Science With Treatment Recommendations”7a,7b in this cardiomyopathy or myocarditis (PLS 819: EvUp) supplement. • Cardiogenic shock and inotropes (PLS 418: EvUp)

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PALS: Management of Deterioration With Pulmo- • End-tidal CO2 monitoring during CPR (PLS 827: nary Hypertension ScopRev) • Prevention and management of pulmonary hyper- PALS: Resuscitation Drug Administration and tensive crises in infants and children (PLS 391: EvUp) Timing • Opioids, sedatives, and neuromuscular blocking • Methods of calculating pediatric drug doses (PLS drugs for pulmonary hypertension (PLS New: EvUp) 420: EvUp) • Therapy with inhaled nitric oxide or prostaglandin • Intraosseous (IO) versus intravenous (IV) route of I for pulmonary hypertensive crisis and right heart 2 drug administration (PLS, neonatal life support failure (PLS New: EvUp) [NLS], and advanced life support [ALS]: SysRev) PALS: Recognition and Treatment of Nonarrest • Epinephrine time of initial dose and dose interval Arrhythmias during CPR (PLS 1541: SysRev) • Drugs for supraventricular tachycardia (PLS 379: EvUp) • Amiodarone versus lidocaine for shock-resistant • Treatment for unstable ventricular tachycardia (PLS ventricular fibrillation or pulseless ventricular 409: EvUp) tachycardia (2018 CoSTR) • CPR for heart rate of less than 60/min (PLS 1535: EvUp) • Sodium bicarbonate administration for children in • Drugs for the treatment of bradycardia: Atropine cardiac arrest (PLS 388: EvUp) versus no atropine and atropine versus epineph- • Calcium administration in children (PLS 421: EvUp) rine (PLS New: EvUp) PALS: Special Resuscitation Situations—Septic • Emergency transcutaneous pacing for bradycardia Shock, Congenital Heart Disease, and Trauma (PLS New: EvUp) • Resuscitation of the child with septic shock (PLS • Channelopathies (PLS 417: EvUp) 1534: EvUp) PALS: Manual Defibrillation • Resuscitation of the patient with a single ventricle • Pad size, type, and placement for pediatric defibril- (PLS 390: EvUp) lation (PLS 378 and PLS 043: EvUp) • Resuscitation of the patient with hemi-Fontan or • Energy doses for defibrillation (PLS 405: ScopRev) Fontan circulation (PLS 392: EvUp) • Single or stacked shocks for pediatric defibrillation • Resuscitation after traumatic arrest (PLS 498: EvUp) (PLS 389: EvUp) PALS: Post–Cardiac Arrest Care, Including PALS: Airways, Oxygenation, and Ventilation Postarrest Prognostication • Ventilation rate when a perfusing rhythm is pres- • Targeted temperature management (2019 CoSTR) ent (PLS 3103A and PLS 382: EvUp) • Oxygen and carbon dioxide targets in pediatric • Oxygen concentration during cardiac arrest (PLS patients with return of spontaneous circulation 396: ScopRev) (ROSC) after cardiac arrest (PLS 815: SysRev) • Ventilation during CPR with bag and mask com- • Post-ROSC blood pressure control (PLS 820: EvUp) pared with an advanced airway (2019 CoSTR) • Post-ROSC neuro-prognostication and use of elec- • Use of cuffed or uncuffed tracheal tubes (PLS 412: troencephalogram (PLS 813 and PLS 822: EvUp) EvUp) • Atropine for emergency intubation (PLS 821: EvUp) • Cricoid pressure during intubation (PLS 376: EvUp) PBLS: CPR AND CPR QUALITY • Use of devices to verify advanced airway place- The PBLS topics in this section include the optimal se- ment (PLS 385: EvUp) quence of compressions and ventilation, pulse check • Ventilation rate with advanced airway during car- accuracy, compression-only compared with convention- diac arrest (PLS 3103A and PLS 382: EvUp) al CPR, the optimal depth of chest compressions, and 1-hand versus 2-hand chest compressions for children PALS: Circulatory Support During CPR and circumferential chest compressions for infants. • Extracorporeal CPR for in-hospital cardiac arrest (2019 CoSTR) Sequence of Compression and PALS: Physiological Monitoring During Arrest to Guide Therapy and/or Intra-arrest Prognostication Ventilation (BLS 661: Shared SysRev) • Invasive blood pressure monitoring during CPR The PLS Task Force last reviewed the sequence of pedi- (PLS 826: ScopRev) atric BLS in 2015.9,10 In 2020, the BLS Task Force per- • Use of near-infrared spectroscopy (NIRS) during formed a SysRev on the topic (see the Starting CPR cardiac arrest (PLS New: ScopRev) section [BLS 661: SysRev] of the BLS publication in this • Bedside ultrasound to identify perfusing rhythm supplement). This SysRev search included adults and (PLS 408: ScopRev) children in all settings. Refer to the BLS publication

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for details of the evidence summary and task force • Outcome: Improve accuracy of diagnosis of pedi- considerations. atric cardiopulmonary arrest • Study design: RCTs and nonrandomized stud- Population, Intervention, Comparator, Outcome, ies (non-RCTs, interrupted time series, controlled Study Design, and Time Frame before-and-after studies, cohort studies) eligible • Population: Adults and children with OHCA for inclusion • Intervention: Commencing CPR beginning with • Time frame: All years and all languages were compressions first (30:2) included if there was an English abstract. Literature • Comparator: CPR beginning with ventilation first was updated in December 2019. (2:30) • Outcome: Survival with favorable neurological / Treatment Recommendations functional outcome at discharge, 30 days, 60 days, This treatment recommendation (below) is unchanged 9,10 180 days, and/or 1 year; survival only at discharge, from 2010. 30 days, 60 days, 180 days, and/or 1 year; and Palpation of a pulse (or its absence) is not reliable ROSC as the sole determinant of cardiac arrest and need for • Study design: RCTs and nonrandomized studies chest compressions. If the victim is unresponsive, and (nonrandomized controlled trials [non-RCTs], inter- not breathing normally, and there are no signs of life, rupted time series, controlled before-and-after lay rescuers should begin CPR. studies, cohort studies) eligible for inclusion In infants and children with no signs of life, health- • Time frame: All languages were included if there care providers should begin CPR unless they can defi- was an English abstract. The literature search was nitely palpate a pulse within 10 seconds. updated in September 2019. Summary of Evidence Chest Compression–Only Versus The 2020 PLS ScopRev did not identify any new human Conventional CPR (2017 CoSTR) pediatric evidence about sequencing for initiating CPR 13 14,15 11,12 In 2017, a SysRev and an ILCOR Pediatric CoSTR published after the 2015 CoSTR. were published on the topic of compression-only CPR As a result, the recommendations for sequencing compared with conventional CPR for infants and chil- of BLS steps for infants and children in cardiac arrest dren. Refer to those publications for details of the evi- remain unchanged from those published in 2015 (see dence summary and task force considerations. Treatment Recommendations), with insufficient evidence to make a recommendation. To review the entire Population, Intervention, Comparator, Outcome, SysRev for adult data, see the Starting CPR section [BLS Study Design, and Time Frame 661: SysRev] of the BLS publication in this supplement. • Population: Patients of all ages (ie, neonates, children, adults) with cardiac arrest from any cause Treatment Recommendations and across all settings (in-hospital and out-of-hos- This treatment recommendation (below) is unchanged 11,12 pital); studies that included animals not eligible from 2015. • Intervention: All manual CPR methods including The confidence in effect estimates is so low that the compression-only CPR, continuous compression panel decided that a recommendation was too CPR, and CPR with different compression-to- speculative. ventilation ratios. Compression-only CPR included continuous delivery of compressions with no venti- Pulse Check Accuracy (PLS 393: EvUp) lation; continuous chest compression CPR included compression with asynchronous ventilation or This EvUp was performed to identify studies after the minimally interrupted cardiac resuscitation. Studies review about pulse check accuracy in 2010.9,10 Studies that mentioned the use of a mechanical device dur- about the accuracy of pulse check versus assessment of ing CPR were considered only if the same device signs of life were insufficient to identify cardiac arrest, was used across all relevant intervention arms and and the task force agreed that there is no need to sug- would therefore not confound the observed effect. gest consideration of a SysRev. As a result, the 2010 • Comparator: Studies had to compare at least 2 treatment recommendation is unchanged.9,10 To review different CPR methods from the eligible interven- the EvUp, see Supplement Appendix C-1. tions; studies without a comparator were excluded Population, Intervention, Comparator, Outcome, • Outcome: The primary outcome was favorable Study Design, and Time Frame neurological outcomes, evaluated by cerebral per- • Population: Infants and children in cardiac arrest formance scale or a modified Rankin Scale score; • Intervention: Use of pulse check secondary outcomes were survival, ROSC, and • Comparator: Assessment of signs of life quality of life

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• Study design: RCTs and nonrandomized stud- • Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled ies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) eligible before-and-after studies, cohort studies) eligible for inclusion; study designs without a compara- for inclusion tor group (eg, case series, cross-sectional studies), • Time frame: All years and languages were included reviews, and pooled analyses excluded if there was an English abstract. The search was • Time frame: All years and languages were included updated to October 2019. if there was an English abstract. The literature Summary of Evidence search was updated in December 2019. No new published evidence was identified with this Treatment Recommendations ScopRev. The PLS Task Force did identify an ongoing large These treatment recommendations are unchanged prospective observational international multicenter study 14,15 from 2017. on CPR quality using dual-sensor CPR feedback devices.20 We suggest that bystanders provide CPR with ven- The results of this study, once published, may help ad- tilation for infants and children younger than 18 years dress the impact of chest compression depth on CPR out- with OHCA (weak recommendation, very low-quality comes. The task force concluded that there is no need evidence). to recommend a new SysRev at this time, and the deci- We recommend that if bystanders cannot provide sion will be reconsidered following the publication of any rescue breaths as part of CPR for infants and children relevant studies. For this 2020 CoSTR update, the 2015 younger than 18 years with OHCA, they should at least treatment recommendations11,12 are unchanged. provide chest compressions (good practice statement). Task Force Insights The PLS Task Force recognized the paucity of pediatric Pediatric Compression Depth (PLS 314: studies and substantial identified gaps in the pediatric lit- ScopRev) erature about chest compression depth (eg, the absence of data on the impact of overcompression). Previous studies Rationale for Review used feedback devices with a single displacement sensor/ The most recent (2015) PLS review11,12 about pediatric accelerometer; these are notably unreliable because the chest compression depth was based on a SysRev that compression depth they measure can be affected by the identified 2 observational pediatric studies.16,17 There is type of surface on which the compressions are performed; now greater availability of CPR feedback devices provid- overestimation of compression depth occurs if the surface ing real-time data about the specific targets for compo- on which the patient rests (eg, bed or trolley mattress) en- nents of CPR, including depth of compression; studies ables movement even if a CPR board is used. Chest com- in adults18,19 demonstrated that overcompression can pression depth studies using feedback devices with dual cause harm. The ScopRev was undertaken to determine displacement sensors/accelerometers may improve the ac- the extent of current available evidence about the ef- curacy of measurement of compression depth. fectiveness of various compression depths used during resuscitation of infants and children. For details of the Treatment Recommendations ScopRev, see Supplement Appendix B-1. These treatment recommendations are unchanged 11,12 from 2015. Population, Intervention, Comparator, Outcome, We suggest that rescuers compress an infant’s chest Study Design, and Time Frame by at least one third the anteroposterior dimension, or • Population: Infants and children who had received approximately 1½ inches (4 cm). We suggest that res- chest compressions after out-of-hospital or in-hos- cuers compress a child’s chest by at least one third the pital cardiac arrest (excluding newborn children) anteroposterior dimension, or approximately 2 inches (5 • Intervention: Any specific chest compression depth cm) (weak recommendation, very low-quality evidence). • Comparator: Depth specified in 2017 CoSTR 14,15 publication – At least one third the AP [anteroposterior] chest One-Hand Versus 2-Hand Compressions depth for Children (PLS 375: EvUp) Combined – Approximately 1½ inches (4 cm) in infants, 2 With Circumferential Compressions for inches (5 cm) in children • Outcome: Infants (PLS 416: EvUp) – Short-term survival and neurological outcomes An EvUp was performed to identify the available evi- (eg, ROSC, hospital discharge, 28 days, 30 days, dence about different techniques for chest compres- and 1 month) sions for infants and children. The previous review – Long-term survival and neurological outcomes was published in 2010.9,10 The EvUp did identify sev- (eg, 3 months, 6 months, and 1 year) eral studies published after 2010, and the task force

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agreed that these studies suggest the need to consider • Study design: RCTs and nonrandomized stud- requesting a SysRev. Until a new SysRev is completed ies (non-RCTs, interrupted time series, controlled and analyzed by the PLS Task Force, the 2010 treatment before-and-after studies, cohort studies) eligible recommendation remains in effect. To review the EvUp, for inclusion see Supplement Appendix C-2. • Time frame: All years and languages were included if there was an English abstract. Literature was Population, Intervention, Comparator, Outcome, Study Design, and Time Frame searched to December 2019. • Population: Infants and children in cardiac arrest Treatment Recommendations in any setting This treatment recommendation (below) is unchanged 9,10 • Intervention: 2 hands, 1 hand, circumferential, 2 from 2010. fingers, a specific other method, a specific location For treatment of out-of-hospital ventricular fibrilla- • Comparator: Another method or location tion (VF)/pulseless ventricular tachycardia (pVT) in in- • Outcome: Any fants, the recommended method of shock delivery by • Study design: RCTs and nonrandomized studies (non- device is listed in order of preference below. If there RCTs, interrupted time series, controlled before-and- is any delay in the availability of the preferred device, after studies, cohort studies) eligible for inclusion the device that is available should be used. The AED al- • Time frame: All years and languages were included gorithm should have demonstrated high specificity and if there was an English abstract. Literature was sensitivity for detecting shockable rhythms in infants. searched to December 2019. The order of preference is as follows: Treatment Recommendation 1. Manual defibrillator This treatment recommendation (below) is unchanged 2. AED with dose attenuator 9,10 from 2010. 3. AED without dose attenuator Either a 1-hand or a 2-hand technique can be used for performing chest compressions on children. There are insufficient data to make a recommendation PBLS: PREVENTION OF CARDIAC for or against the need for a circumferential squeeze of ARREST the chest when performing the 2 thumb–encircling hands Pediatric Early-Warning Scores (PLS 818: technique of external chest compression for infants. ScopRev) Rationale for Review PBLS: AUTOMATED EXTERNAL The topic was selected for review because the task force DEFIBRILLATION was aware of several recent relevant publications, including SysRevs, a ScopRev, and a large-scale RCT published 11,12 Use of Automated External Defibrillators after the most recent (2015) CoSTR on the topic. for Infants With Out-of-Hospital Cardiac PEWS are tools that evaluate clinical presentation Arrest (PLS 425: EvUp) risk of clinical deterioration. An EvUp was performed to determine if there were See Supplement Appendix B-2. any published studies about the use of AEDs for infants Population, Intervention, Comparator, Outcome, with OHCA. The EvUp identified insufficient evidence Study Design, and Time Frame to justify a SysRev or suggest the need for a change to • Population: Infants and children in a hospital the 2010 treatment recommendation; as a result, the setting 9,10 2010 treatment recommendation is unchanged. To • Intervention: PEWS with or without rapid response review the EvUp, see Supplement Appendix C-3. teams/medical emergency teams Population, Intervention, Comparator, Outcome, • Comparator: No PEWS with or without rapid Study Design, and Time Frame response teams or medical emergency teams • Population: Infants and children in cardiac arrest • Outcome: In-hospital deterioration, including in any setting mortality • Intervention: Use of an automated external defi- • Study design: RCTs and nonrandomized stud- brillators at a certain moment in the algorithm ies (non-RCTs, interrupted time series, controlled • Comparator: At another moment in the algorithm before-and-after studies, cohort studies) eligible or not using an automated external defibrillator or for inclusion using an automated external defibrillator with a • Time frame: All years and languages were included dose attenuator if there was an English abstract; unpublished stud- • Outcome: Any ies (eg, conference abstracts, trial protocols) were

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excluded. The literature search was updated to additional important outcome in determining sample September 15, 2019. sizes for such studies. The PLS Task Force agreed that there is a need to Summary of Evidence 21–23 24 request a SysRev. Until completion of the SysRev, the We identified 3 SysRevs and 1 ScopRev published 11,12 2015 treatment recommendations remain in effect. after 2015; all noted the limited evidence for the usefulness of PEWS for preventing physiological deteriora- Treatment Recommendations tion and improving clinical outcomes. This treatment recommendation (below) is unchanged 11,12 The Evaluating Processes of Care and the Outcomes from 2015. of Children in Hospital (EPOCH) study was published in The confidence in the estimate of predictive value is 2018. This was an international cluster RCT of 21 hos- so low that the panel decided that a recommendation pitals enrolling patients from birth (gestational age 37 is too speculative. weeks or more) up to 18 years of age.25 This study included all-cause mortality as a primary outcome and as a secondary outcome a composite outcome reflecting Pediatric Medical Emergency/Rapid late critical care admission. Ten hospitals implemented a Response Teams (PLS 397: EvUp) bedside PEWS system compared with usual care (ie, did Rapid response teams (RRTs) are hospital teams that not use a severity early-warning score) in 11 hospitals. are activated to evaluate and respond to patients at This was one of the largest studies of its kind, involving risk for clinical deterioration. The topic of medical 144 539 patient discharges with 559 443 patient days emergency teams (METs)/RRTs was last reviewed in and 144 539 patients in total completing the trial. 2015.11,12 This EvUp was requested to identify relevant There was no significant reduction in all-cause mor- evidence on the topic published after that date. Two tality when the use of bedside PEWS was compared preintervention/postintervention studies demonstrat- with standard care (1.93 per 1000 patient discharges ed a decrease in the number of resuscitation events, compared with 1.56 per 1000 patient discharges; ad- although there was no clear decrease in mortality. One justed odds ratio [OR], 1.01; 95% CI, 0.61–1.69). The observational registry study demonstrated no change prevalence of significant clinical deterioration events in the mortality rate beyond that which was already was lower (0.5 per 1000 patient days compared with expected from the preimplementation trends. This 0.84 per 1000 patient days) at hospitals using bedside finding is not significantly different from the 2015 re- PEWS compared with usual care hospitals (adjusted view. To review the EvUp, see Supplement Appendix C- rate ratio 0.77 [95% CI, 0.61–0.97]). 4. There is no indication to change the 2015 CoSTR The EPOCH authors concluded that their findings did 25 recommendation. not support the use of PEWS to reduce mortality. The PLS draft ScopRev was posted on the ILCOR web- Treatment Recommendation site and was viewed 345 times without any comments This treatment recommendation (below) is unchanged 11,12 that addressed the need for a SysRev on this topic. To from 2015. review the ScopRev, see Supplement Appendix B-2. We suggest the use of pediatric MET/RRT systems Task Force Insights in hospitals that care for children (weak recommenda- The PLS Task Force concluded that the implementation tion, very low-quality evidence). In making this recom- of PEWS should be part of an overall clinical response mendation, we place a higher value on the potential to system, with the task force placing a higher value on recognize and intervene for patients with deteriorating improving healthcare provider ability to recognize and illness over the expense incurred by a healthcare system intervene for patients with deteriorating illness over the committing significant resources to implement a MET/ expense incurred by a healthcare system committing RRT system. We recognize that the decision to use a significant resources to implement PEWS. The task force MET/RRT system should be balanced by the existing re- also noted that the complex process of optimizing pa- sources and capabilities of the institution. tient care is likely to include both the implementation of PEWS and ongoing healthcare provider education. The PLS Task Force agreed that the decision to use PEWS PALS: RECOGNITION AND TREATMENT should be balanced between use of existing resources OF SEPTIC SHOCK and capabilities of the healthcare setting to adapt to its use and the consequences of its use. Fluid Administration for the Child With In the PEWS studies, mortality is a common out- Septic Shock (PLS 1534: EvUp) come marker. However, the incidence of cardiac arrest Note: This topic was prioritized for review because the is low (especially outside the critical care setting), so approach to the management of fluid resuscitation in the incidence of significant clinical deterioration is an infants and children with septic shock is changing as

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a result of recent published evidence. The summary of Population, Intervention, Comparator, Outcome, this EvUp is more detailed than for other EvUps ow- Study Design, and Time Frame ing to the critical nature of these new findings and • Population: Infants and children who are in septic in acknowledgment of the 2020 publication of new shock in any setting guidelines for the management of infants and children • Intervention 1: Use of restrictive volume of resusci- 26 with septic shock. tation fluid (less than 20 mL/kg) This topic was last reviewed in 2015,11,12 when the • Comparator 1: Nonrestrictive volume (20 mL/kg or evidence evaluation included fluid administration for greater) or the use of noncrystalloid fluids shock associated with dengue fever and malaria. This • Intervention 2: Use of noncrystalloid fluids EvUp looked specifically at the impact of different fluid • Comparator 2: Use of crystalloid fluids regimens in infants and children with septic shock but • Intervention 3: Use of balanced crystalloid solution excluded studies of shock associated with dengue or (eg, Ringer’s lactate) malaria because the pathophysiology of shock with • Comparator 3: Use of unbalanced isotonic crystal- those conditions is atypical when compared with septic loid solution (normal saline) shock associated with other causes. The role of fluid ad- • Outcome: Survival to hospital discharge, need for ministration in shock associated with dengue or malaria mechanical ventilation, need for vasopressor sup- will be considered in future reviews. port, complications, time to resolution of shock, This draft EvUp can be viewed in Supplement Ap- hospital length of stay, ventilator-free days, or total pendix C-5 because it is only outlined here in the main IV fluids administered body of text. Among the 12 studies in the final evi- • Study design: RCTs and nonrandomized stud- dence review were 3 RCTs27–29 and 3 SysRevs.30–32 In ad- ies (non-RCTs, interrupted time series, controlled dition, the EvUp identified 1 RCT33 that did not directly before-and-after studies, cohort studies) eligible address the PICO (population, intervention, compara- for inclusion tor, outcome) question but provided information about • Time frame: All years and all languages were the effect of a fluid bolus on pediatric cardiac index. included if there was an English abstract. The litera- The EvUp also analyzed the results of 4 nonrandomized ture search was from January 2015 to January 2020. 34–37 38 studies and 1 study protocol. Treatment Recommendations The Society of Critical Care Medicine’s Surviving These treatment recommendations are unchanged Sepsis Campaign International Guidelines for the 11,12 from 2015. Management of Septic Shock and Sepsis-Associated We suggest using an initial fluid bolus of 20 mL/kg Organ Dysfunction in Children was published in Feb- for infants and children with shock, with subsequent ruary 2020,26 immediately before the submission of patient reassessment, for patients with the following this publication. In these 2020 surviving sepsis guide- disease states: lines, recommendations for fluid administration differ • Severe sepsis (weak recommendation, low-quality based on the availability of intensive care within the evidence) system caring for the infant or child. For systems with • Severe malaria (weak recommendation, low-qual- the availability of intensive care, the authors suggest ity evidence)* the administration of 10 to 20 mL/kg boluses, up to a • Dengue shock syndrome (weak recommendation, total of 40 to 60 mL/kg in the first hour, to be titrated low-quality evidence)* to the patient’s response and to be discontinued if the We suggest against the routine use of bolus intrave- signs of fluid overload develop. If hypotension is nous fluids (crystalloids or colloids) for infants and chil- present in systems without the availability of inten- dren with a “severe febrile illness” who are not in shock sive care, the authors suggest the administration of 10 (weak recommendation, low-quality evidence).* to 20 mL/kg boluses, up to a total of 40 mL/kg in the first hour (also titrated to response and discontinued Reassessment, regardless of therapy administered, if signs of fluid overload develop). If the infant or child should be emphasized so that deterioration is detected is not hypotensive and is in a system without the at an early stage. availability of intensive care, the authors recommend against bolus fluid administration but to start Vasoactive Drugs for Septic Shock (PLS 26 maintenance fluids. 1604: ScopRev) The PLS Task Force agreed that a new SysRev is needed to reevaluate the evidence and modify the Rationale for Review 2015 PLS treatment recommendations as needed. Un- Although pediatric septic shock is associated with sig- til the SysRev is completed and analyzed by the task nificant mortality/morbidity, substantial progress has force, the 2015 treatment recommendations remain in 11,12 effect. *These populations were included in the 2015 CoSTR but not the 2020 EvUp.

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been made in improving the recognition of septic shock compared with dopamine based on very-low-quality and the development of bundles of care aimed at bet- evidence. The authors state that they could not make a tering patient outcomes. The most recent review of va- recommendation for a first-line vasoactive infusion for soactive drugs (labeled “inotropes and vasopressors”) septic shock, noting that in their practices they use epi- for septic shock was published in 2010.9,10 That CoSTR nephrine or norepinephrine. considered all forms of distributive shock, whereas this ScopRev looked specifically at the use of vasoactive Task Force Insights drugs in pediatric septic shock, excluding other forms The studies identified by the ScopRev did not evaluate of distributive shock. This ScopRev looked at compara- vasoactive agents other than dopamine and epinephrine tive studies of 1 vasoactive drug with another. To review and did not include other drugs such as norepinephrine the ScopRev, see Supplement Appendix B-3. that are commonly used to treat fluid-resistant septic shock. The 2 RCTs were single-center studies in low- and Population, Intervention, Comparator, Outcome, middle-income healthcare systems, so questions about Study Design, and Time Frame their generalizability to other healthcare settings arose. • Population: Infants and children with septic shock, The task force agreed that the adult findings could not with and without myocardial dysfunction be extrapolated to the pediatric population because in- • Intervention: Use of any specific vasoactive drug fants and children have different physiological responses • Comparator: Standard care to vasoactive drugs (varying according to age even with- • Outcome: Improved patient outcomes (hemody- in the age range of infants and children), particularly namics, survival) when compared with adult physiological responses. • Study design: RCTs and nonrandomized stud- The task force agreed that the current evidence does ies (non-RCTs, interrupted time series, controlled not support the need for a SysRev and the 2010 treat- before-and-after studies, cohort studies) eligible 9,10 ment recommendations remain in effect. for inclusion • Time frame: All years and languages were included Treatment Recommendations if there was an English abstract. The literature This treatment recommendation (below) is unchanged 9,10 search was from 1946 to November 2019. from 2010. Summary of Evidence There is insufficient evidence to recommend a spe- The ScopRev identified 2 relevant RCTs. The first39 in- cific inotrope or vasopressor to improve mortality in pe- cluded 60 children with septic shock in emergency de- diatric distributive shock. The selection of an inotrope partments or critical care units and compared the effects or vasopressor to improve hemodynamics should be tai- of dopamine with those of epinephrine. The primary lored to each patient’s physiology and adjusted to the outcome was resolution of shock in the first hour, which individual’s clinical responses. was more likely to occur among those receiving epinephrine rather than dopamine (OR, 4.8; 95% CI, 1.3– Corticosteroids for Pediatric Septic Shock 17.2; P=0.019). On day 3, there were lower sequential organ failure assessment scores (ie, less derangement) in (PLS 413: EvUp) the epinephrine group (8 versus 12, P=0.05). There was The PLS Task Force sought an EvUp on this topic be- no difference in the adverse event rate (16.1% versus cause it was last reviewed in 2010.9,10 The evidence for 13.8%, P=0.8) and no difference in mortality, although or against the use of corticosteroids in pediatric septic this study was not powered for mortality. shock is of very low certainty. There is limited evidence The second study40 was a double-blind RCT that eval- that a specific subpopulation may benefit from the ad- uated 120 children with refractory septic shock (despite ministration of corticosteroids, but these patients are not the administration of 40 mL/kg of fluid). Randomiza- easily identifiable at the bedside. As a result, the current tion was to either dopamine or epinephrine, with the (2010) treatment recommendation continues unmodi- primary outcome of 28-day mortality and the second- fied. To review the EvUp, see Supplement Appendix C-6. ary outcome of healthcare-associated infection. Dopa- mine administration was linked with an increased risk of Population, Intervention, Comparator, Outcome, death and healthcare-associated infection in compari- Study Design, and Time Frame son with epinephrine administration. The PLS Task Force • Population: Infants and children being treated for members were concerned that the doses of epinephrine septic shock and circulatory failure in any setting, would have produced a disproportionately greater phys- during the first hours of treatment iological effect than the matched doses of dopamine. • Intervention: Early administration of corticosteroids To review the ScopRev, see Supplement Appendix B-3. • Comparator: No corticosteroid or postponed Of note, the 2020 surviving sepsis guidelines26 administration suggest the use of epinephrine or norepinephrine • Outcome: All

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• Study design: RCTs and nonrandomized stud- with traumatic injuries in the prehospital setting.41 Four ies (non-RCTs, interrupted time series, controlled studies compared the total crystalloid volume given in before-and-after studies, cohort studies) eligible 24 hours,42,44–46 and 1 study assessed the volume of for inclusion crystalloid given to patients needing transfusion.43 The • Time frame: All years and languages were included study that reported the critical outcome of survival to if there was an English abstract. The literature 24 hours41 found no benefit to survival associated with search was conducted to December 2019. graded/“limited” volume compared with standard care for trauma resuscitation. None reported on survival at Treatment Recommendations 30 days with good neurological outcome. For the criti- This treatment recommendation (below) is unchanged 9,10 cal outcome of survival to discharge, 4 studies found from 2010. no benefit associated with graded/limited volume ad- There is insufficient evidence to support or refute the ministration compared with standard care.41,44,46,47 One routine use of stress-dose or low-dose hydrocortisone study reported lower survival to hospital discharge as- and/or other corticosteroids in infants and children with sociated with high-volume crystalloid administration septic shock. Stress-dose corticosteroids may be considered in children with septic shock unresponsive to fluids (greater than 60 mL/kg per 24 hours) compared with and requiring vasoactive support. low- and moderate-volume crystalloid administration (ie, 0–40 mL/kg per 24 hours or 40–60 mL/kg per 24 hours),42 and 1 reported lower survival rates associ- PALS: RECOGNITION AND PREARREST ated with higher administered crystalloid volumes (ie, TREATMENTS FOR SHOCK greater than 150 mL/kg per 24 hours compared with 150 mL/kg or less per 24 hours) among those receiv- Graded Volume Resuscitation for Traumatic/ ing massive transfusions.43 Five studies reported an in- Hemorrhagic Shock (PLS 400: ScopRev) creased hospital or intensive care length of stay associated with higher crystalloid volume administration in Rationale for Review the first 24 hours.42–44,46,47 All studies were retrospective, The PLS Task Force reevaluated this topic because the and they reported different interventions on differing previous review was published in 2010.9,10 This 2020 patient populations and differing associated outcomes. ScopRev sought to identify available evidence about the Although it is difficult to compare results, there is a sug- effectiveness of graded volume resuscitation compared gestion of a possible advantage of using limited volume with standard care for traumatic hemorrhagic shock. resuscitation. To review the ScopRev, see Supplement To review the ScopRev, see Supplement Appendix B-3. Appendix B-4. The term graded volume resuscitation includes restrictive volume resuscitation and permissive hypoten- Task Force Insights sion, with volume administered to resuscitate a hypo- The task force discussed the term graded resuscitation volemic trauma victim with relatively small volumes, used in the 2010 CoSTR evidence evaluation; this term repeated to restore perfusion to a specific target. was infrequently found in the trauma literature published in the past decade. The task force discussed the Population, Intervention, Comparator, Outcome, definition of hypotensive resuscitation in children and Study Design, and Time Frame infants with trauma (because it was agreed that this is • Population: Infants and children in hemorrhagic unclear in the literature), as well as other terms used shock following trauma in any setting in trauma resuscitation, such as restrictive resuscitation • Intervention: Graded volume resuscitation (now and delayed versus early resuscitation. restrictive volume resuscitation) Adult data favor restrictive volume resuscitation, and • Comparator: Standard care the recommendations for this population have been to • Outcome: Any clinical outcome promote damage control resuscitation. The National • Study design: RCTs and nonrandomized stud- Institute for Health and Care Excellence trauma guide- ies (non-RCTs, interrupted time series, controlled lines48 and the American College of Surgeons Advanced before-and-after studies, cohort studies) eligible Trauma Life Support guidelines49 follow these principles for inclusion for adult practice because both suggest restrictive vol- • Time frame: All years and languages were included ume resuscitation with early use of blood components if there was an English abstract. The literature in hemorrhagic shock. search was from March 2009 to November 2019. The task force discussed the ILCOR mandate and Summary of Evidence whether it includes the review and analysis of trauma Seven retrospective pediatric studies were identified.41– resuscitation topics. Because trauma remains a major 47 All were derived from trauma registries. Only 1 cause of death in children worldwide and there is still study assessed the volume of fluid given to children a lack of evidence-based guidelines, most task force

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members agreed that this is an important issue for IL- • Study design: RCTs and nonrandomized stud- COR to address. ies (non-RCTs, interrupted time series, controlled RCTs or, in their absence, studies from large trauma before-and-after studies, cohort studies) eligible registries are required to address the effects of different for inclusion volume resuscitation strategies on mortality and mor- • Time frame: All years and languages were included bidity outcomes. Optimal timing for the administration if there was an English abstract. The literature of fluid resuscitation in pediatric trauma was not ad- search was updated to December 2019. dressed in this review but will be considered for a future Treatment Recommendation SysRev. This treatment recommendation (below) is unchanged The task force agreed that more data are needed, 9,10 from 2010. but this ScopRev did not identify sufficient new evi- There is insufficient evidence to support or refute the dence to prompt a new SysRev, so the 2010 treatment recommendation (noting insufficient evidence to make use of endotracheal intubation of infants and children in a recommendation) remains in place. shock before the onset of respiratory failure.

Treatment Recommendations This treatment recommendation (below) is unchanged Prearrest Care of the Infant or Child With 9,10 from 2010. Dilated Cardiomyopathy or Myocarditis There is insufficient evidence about the best timing (PLS 819: EvUp) or quantity for volume resuscitation in infants and chil- This EvUp was performed because the most recent PLS dren with hemorrhagic shock following trauma. CoSTR on the topic of prearrest care for a child with dilated cardiomyopathy or myocarditis was in 2015.11,12 Timing of Intubation for Shock (PLS 399: The management of these patients has continued to EvUp) evolve since then, noting that the EvUp identified an additional 5 studies not captured in the 2015 CoSTR. The evidence to support specific timing of intuba- The task force agreed to consider a request for a tion for infants and children in shock (ie, all types SysRev to assess those studies and any others identified 9,10 of shock) was most recently evaluated in 2010. pertaining to the prearrest care of an infant or child At that time, the PLS Task Force noted the paucity with myocarditis. Until a new SysRev is completed and of published evidence. This EvUp was undertaken to analyzed by the PLS Task Force, the 2015 treatment identify any relevant evidence published thereafter. recommendation (noting insufficient evidence to make Once again, insufficient evidence was found to war- a recommendation) remains in effect. To review the rant the suggestion of a pediatric SysRev. Only 5 ani- EvUp, see Supplement Appendix C-8. mal studies, one 1 adult study and the 2020 Society of Critical Care Medicine Surviving Sepsis Campaign Population, Intervention, Comparator, Outcome, International Guidelines for the Management of Sep- Study Design, and Time Frame tic Shock and Sepsis-Associated Organ Dysfunction • Population: Infants and children with myocarditis or in Children26 were identified. The 2020 surviving dilated cardiomyopathy and impending cardiac arrest sepsis guidelines authors noted they were “unable • Intervention: A specific approach to make a recommendation about whether to intu- • Comparator: The usual management of shock or bate children with fluid-refractory-catecholamine- cardiac arrest resistant septic shock. However, in our practice, we • Outcome: Survival with favorable neurological/ commonly intubate children [with] fluid-refractory- functional outcome at discharge, 30 days, 60 days, catecholamine-resistant septic shock without respira- 180 days, and/or 1 year; survival to hospital dis- tory failure.”26 To review the EvUp, see Supplement charge; cardiac arrest frequency; ROSC Appendix C-7. • Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled Population, Intervention, Comparator, Outcome, before-and-after studies, cohort studies) eligible Study Design, and Time Frame for inclusion • Population: Infants and children in shock • Time frame: All years and languages were included • Intervention: Early intubation and assisted if there was an English abstract. The literature ventilation search was completed in September 2019. • Comparator: The use of these interventions only for respiratory failure Treatment Recommendation • Outcome: Improved patient outcomes (hemody- This treatment recommendation (below) is unchanged 11,12 namics, survival) from 2015.

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The confidence in effect estimates is so low that the crises in the infant or child. All were evaluated by EvUps panel decided that a specific recommendation was too to identify the availability of evidence published after speculative. the most recent review of the management of infants and children with pulmonary hypertension (appeared in 9,10 the literature in 2010). Cardiogenic Shock and Inotropes (PLS 418: EvUp) This EvUp was undertaken because the most recent Prevention and Management of CoSTR on the topic was published in 2010,9,10 and the Postoperative Pulmonary Hypertensive task force sought to identify any studies published after Crises in Infants and Children (PLS 391: that review. The task force agreed that there is insuf- EvUp) ficient evidence identified in the EvUp to consider a re- Although the general topic of pulmonary hypertension quest for a SysRev. As a result, the 2010 treatment rec- was reviewed in the 2010 CoSTR,9,10 the focus was on 9,10 ommendations remain in place. To review the EvUp, treatment of cardiac arrest in patients with pulmonary see Supplement Appendix C-9. hypertension. This EvUp was performed to identify any Population, Intervention, Comparator, Outcome, evidence about the postoperative care of infants and Study Design, and Time Frame children with pulmonary hypertension at high risk of • Population: Infants and children who are being pulmonary hypertensive crisis. The EvUp identified sev- treated for cardiogenic shock in any setting, dur- eral RCTs. In addition, the PLS Task Force is aware of 3 ing the first hours of treatment scientific publications—2 from the American Heart As- • Intervention: The early addition of certain vasoac- sociation (AHA)50,51 and 1 from the European Pediatric tive drugs Pulmonary Vascular Disease Network51a—each group • Comparator: Postponed administration and/or a having completed a SysRev in 2015. The task force specific vasoactive drug versus another agreed that the EvUp identified sufficient published evi- • Outcome: All dence to indicate the need to consider a SysRev. Until • Study design: RCTs and nonrandomized stud- such time as a new SysRev is completed and analyzed ies (non-RCTs, interrupted time series, controlled by the PLS Task Force, the 2010 treatment recommen- before-and-after studies, cohort studies) eligible dation remains in effect for treatment of children with for inclusion pulmonary hypertension and cardiac arrest. To review • Time frame: All years and languages were included the EvUp, see Supplement Appendix C-10. if there was an English abstract. The literature Population, Intervention, Comparator, Outcome, search was updated to December 2019. Study Design, and Time Frame Treatment Recommendations • Population: Infants and children with pulmonary This treatment recommendation (below) is unchanged hypertension at high risk of postoperative pulmo- 9,10 from 2010. nary hypertensive crises The catecholamine dose for inotropic support in • Intervention: Postoperative care such as careful cardiogenic shock must be titrated for each individual respiratory management and monitoring to avoid because there is wide variability in the clinical response hypoxia and acidosis to vasoactive drugs. It is reasonable to use epineph- • Comparator: Standard postoperative care rine, levosimendan, dopamine, or dobutamine for ino- • Outcome: All tropic support in infants and children with cardiogenic • Study design: RCTs and nonrandomized stud- shock. Milrinone may be beneficial for the prevention ies (non-RCTs, interrupted time series, controlled and treatment of low cardiac output following cardiac before-and-after studies, cohort studies) eligible surgery. There are insufficient data to support or re- for inclusion fute the use of norepinephrine in pediatric cardiogenic • Time frame: All years and languages were included shock. if there was an English abstract. The literature search was updated to November 2019. PALS: MANAGEMENT OF Treatment Recommendations DETERIORATION WITH PULMONARY This treatment recommendation for the care of children with pulmonary hypertension and cardiac arrest 9,10 HYPERTENSION (below) is unchanged from 2010. This section includes 3 topics about the management Rescuers should provide conventional PALS, includ- and prevention of critical pulmonary hypertension ing oxygenation and ventilation, for cardiac arrest

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associated with pulmonary hypertension. It may be Therapy With Inhaled Nitric Oxide beneficial to attempt to correct hypercarbia. If the ad- or Prostaglandin I2 for Pulmonary ministration of medications (IV or inhaled) to decrease Hypertensive Crisis and Right Heart pulmonary artery pressure has been interrupted, it may Failure (PLS New: EvUp) be advisable to reinstitute it. Inhaled nitric oxide or aerosolized prostacyclin or an- Although the general topic of pulmonary hypertension 9,10 alogues to reduce pulmonary vascular resistance should was reviewed in the 2010 CoSTR, the focus was on the treatment of cardiac arrest; this 2020 EvUp fo- be considered. If these are unavailable, an IV bolus of cused on the evidence supporting inhaled nitric oxide prostacyclin may be considered. or prostaglandin I to manage pulmonary hypertensive Note: A SysRev will be needed to generate treatment 2 crises and right heart failure in infants and children postoperative recommendations for care of children with or without cardiac arrest. This EvUp identified 3 with pulmonary hypertension at risk for pulmonary hy- scientific publications—2 from the AHA50,51 and 1 from pertensive crisis. the European Pediatric Pulmonary Vascular Disease Network51a—each group having completed a SysRev Opioids, Sedatives, and Neuromuscular in 2015. In addition, a previous EvUp (see Supplement Appendix C-12) identified a SysRev52 that reported the Blocking Drugs for Pulmonary results of an RCT on inhaled nitric oxide for the post- 53 Hypertension (PLS New: EvUp) operative treatment of pulmonary hypertension. Although the general topic of pulmonary hyperten- The EvUp and the PLS Task Force member group sion was reviewed in the 2010 CoSTR,9,10 the focus identified sufficient published data about the use was on treatment during cardiac arrest; there were of inhaled nitric oxide and prostaglandin I2 to con- no specific PICOST questions and no treatment rec- sider recommending a SysRev to evaluate the avail- ommendations about the use of opioids, sedatives, able evidence and, if required, make new treatment recommendations. Until a new SysRev is completed and neuromuscular blocking drugs for an infant or and analyzed, the 2010 treatment recommendations a child with pulmonary hypertension who is not in remain in effect for the general management of pul- cardiac arrest. The PLS Task Force is aware of 3 sci- 50,51 monary hypertension and not specifically to address entific publications—2 from the AHA and 1 from this PICOST because that will require further analysis the European Pediatric Pulmonary Vascular Disease of the literature. Network51a—each group having completed a SysRev in 2015. To review the EvUp, see Supplement Appen- Population, Intervention, Comparator, Outcome, dix C-11. The PLS Task Force agreed to consider the Study Design, and Time Frame need for a SysRev to evaluate the available evidence • Population: Infants and children at high risk of pul- and see if treatment recommendations were required monary hypertensive crises • Intervention: Provision of pulmonary vasodilators after review of the literature.

such as inhaled nitric oxide or prostaglandin I2 Population, Intervention, Comparator, Outcome, • Comparator: Standard therapy with no provision Study Design, and Time Frame of therapy such as inhaled nitric oxide or prosta-

• Population: Infants and children at high risk of pul- glandin I2 monary hypertensive crises • Outcome: Alter the outcome of pulmonary hyper- • Intervention: Provision of adequate opiates, seda- tensive crises or acute right heart failure tives, and neuromuscular blocking drugs • Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled • Comparator: Standard care without opiates before-and-after studies, cohort studies) eligible • Outcome: All, especially pulmonary hypertensive for inclusion crises • Time frame: All years and languages were included • Study design: RCTs and nonrandomized stud- if there was an English abstract. The literature ies (non-RCTs, interrupted time series, controlled search was updated to November 2019. before-and-after studies, cohort studies) eligible for inclusion Treatment Recommendations • Time frame: All years and languages were included The broad treatment recommendations published in 9,10 if there was an English abstract. The literature 2010, regarding inhaled nitric oxide, remain in effect. search was updated to November 2019. Rescuers should provide conventional PALS, including oxygenation and ventilation for cardiac arrests associ- Treatment Recommendations ated with pulmonary hypertension. It may be beneficial There are no previous treatment recommendations. to attempt to correct hypercarbia. If the administration

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of medications (IV or inhaled) to decrease pulmonary Note: The 2020 PLS Task Force wishes to add the artery pressure has been interrupted, it may be advis- caveat that expert consultation is encouraged before able to reinstitute it. the use of procainamide or amiodarone. Inhaled nitrous oxide or aerosolized prostacyclin or analogue to reduce pulmonary vascular resistance should be considered. If unavailable, an IV bolus of Treatment for Unstable prostacyclin may be considered. Ventricular Tachycardia (PLS 409: EvUp) The management of unstable VT was last reviewed in 2010.9,10 This 2020 EvUp was to determine if there PALS: RECOGNITION AND TREATMENT was sufficient evidence to consider a SysRev. The task OF NONARREST ARRHYTHMIAS force concluded that there was insufficient published evidence of the management of unstable tachycardia Drugs for Supraventricular Tachycardia to recommend the consideration of a SysRev, so the (PLS 379: EvUp) 2010 treatment recommendations remain in effect.9,10 This topic was last reviewed in 2010.9,10 This EvUp was To review the EvUp, see Supplement Appendix C-14. to identify any evidence about the management of su- Population, Intervention, Comparator, Outcome, praventricular tachycardia in infants and children pub- Study Design, and Time Frame lished after 2010. The EvUp identified 6 studies; all were • Population: Infants and children with unstable ven- retrospective and observational, and none compared tricular tachycardia (prehospital and in-hospital) adenosine with other IV drugs for the management and • Intervention: Any drug, combination of drugs, or resolution of supraventricular tachycardia. The PLS Task intervention (eg, cardioversion) Force concluded that there was insufficient evidence to • Comparator: No drugs or intervention suggest the need for a SysRev and no need to consider • Outcome: Termination of rhythm, survival a change in the previous (2010) treatment recommen- • Study design: RCTs and nonrandomized stud- dations.9,10 To review the EvUp, see Supplement Appen- ies (non-RCTs, interrupted time series, controlled dix C-13. before-and-after studies, cohort studies) eligible Population, Intervention, Comparator, Outcome, for inclusion Study Design, and Time Frame • Time frame: All years and languages were included • Population: Infants and children with supraven- if there was an English abstract. The search was tricular tachycardia with a pulse finished in November 2019. • Intervention: Use of any drug or combination of Treatment Recommendations drugs This treatment recommendation (below) is unchanged • Comparator: Adenosine 9,10 from 2010. • Outcome: Termination of abnormal rhythm, It is reasonable to use synchronized electric car- survival dioversion as the preferred first therapy for pediatric • Study design: RCTs and nonrandomized stud- VT with hypotension or evidence of poor perfusion. ies (non-RCTs, interrupted time series, controlled If drug therapy is used to treat unstable VT, ami- before-and-after studies, cohort studies) eligible odarone may be a reasonable choice, with careful for inclusion hemodynamic monitoring performed during its slow • Time frame: All years and languages were included delivery. if there was an English abstract from ILCOR 2010 guidance. The search was performed in November 2019. CPR for Heart Rate of Less Than 60/min Treatment Recommendations (PLS 1535: EvUp) This treatment recommendation (below) is unchanged PLS council guidelines54,55 recommend that PLS pro- 9,10 from 2010. viders begin chest compressions if an infant or child For infants and children with supraventricular tachy- has a heart rate under 60 beats per minute with signs cardia with a palpable pulse, adenosine should be con- of poor perfusion despite support of the airway, ade- sidered the preferred medication. Verapamil may be quate oxygenation, and ventilation; this recommenda- considered an alternative therapy in older children, but tion represents expert consensus provided by council it should not be routinely used in infants. Procainamide guidelines rather than by an ILCOR evidence review. or amiodarone given by a slow IV infusion with care- No previous search strategy was identified for this top- ful hemodynamic monitoring may be considered for ic. As a result, a new search strategy was developed. refractory supraventricular tachycardia. The EvUp identified 2 nonrandomized studies that

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documented improved outcomes associated with CPR Population, Intervention, Comparator, Outcome, for bradycardia with pulses and poor perfusion when Study Design, and Time Frame compared with outcomes associated with pulseless • Population: Infants and children with bradycardia electric activity or asystole cardiac arrest without pre- for any reason ceding chest compressions.56,57 Lower survival was as- • Intervention: Use of atropine at a specific dose sociated with longer time intervals between the start • Comparator: Not using atropine, using another of CPR for bradycardia with pulse and poor perfusion, drug, or using it [atropine] at a different dose 56 and the loss of the pulse. • Outcome: All Although the evidence base is limited, the task force • Study design: RCTs and nonrandomized stud- agreed that the importance of the question when to ies (non-RCTs, interrupted time series, controlled initiate CPR for bradycardia suggests the need for con- before-and-after studies, cohort studies) eligible sideration of a SysRev. To review the EvUp, see Supple- for inclusion ment Appendix C-15. • Time frame: All years and languages were included if there was an English abstract. The literature Population, Intervention, Comparator, Outcome, search was conducted in November 2019. Study Design, and Time Frame • Population: Infants and children who are in cardiac Treatment Recommendations arrest This treatment recommendation (below) is unchanged 9,10 • Intervention: Starting CPR if they have a heart rate from 2010. of less than 60/min with signs of shock and with a Epinephrine may be administered to infants and palpable pulse children with bradycardia and poor perfusion that is • Comparator: Starting CPR for patients with a heart unresponsive to ventilation and oxygenation. It is rea- rate of less than 60/min and no palpable pulse sonable to administer atropine for bradycardia caused • Outcome: All by increased vagal tone or anti-cholinergic drug toxic- • Study design: RCTs and nonrandomized stud- ity. There is insufficient evidence to support or refute ies (non-RCTs, interrupted time series, controlled the routine use of atropine for pediatric cardiac arrest. before-and-after studies, cohort studies) eligible for inclusion; unpublished studies (eg, conference Emergency Transcutaneous Pacing for abstracts, trial protocols) excluded Bradycardia (PLS New: EvUp) • Time frame: All years since 2010 and all languages were included if there was an English abstract until This topic was last addressed by the Pediatric Task Force 59 December 2019. in 2000, when an international consensus on science and international guidelines were published. As a re- Treatment Recommendations sult, the PLS Task Force requested an EvUp to determine There is no ILCOR PLS treatment recommendation at if there was relevant evidence to suggest the need to this time. consider a SysRev. After review of the EvUp (see Supple- ment Appendix C-18), the task force agreed that there Drugs for the Treatment of Bradycardia: is insufficient evidence to suggest the need for a Sys- Rev. As a result, the 2000 treatment recommendation Atropine Versus No Atropine and 59 remains in effect. Atropine Versus Epinephrine (PLS New: EvUps) Population, Intervention, Comparator, Outcome, Study Design, and Time Frame The PLS Task Force reviewed this topic in 2010.9,10 Two • There was no previous PICOST for this question. EvUps were performed to determine if any studies were See Supplement Appendix C-18 for details of the published after 2010 about atropine compared with search strategy. epinephrine (see Supplement Appendix C-16) and atropine compared with no atropine (see Supplement Ap- Treatment Recommendations pendix C-17) for the treatment of bradycardia in infants This treatment recommendation (below) is unchanged 59 or children. The EvUps identified no studies published from 2000. after 2010. After completion of the reviews, however, In selected cases of bradycardia caused by complete the task force identified 1 nonrandomized (in-hospital heart block or abnormal function of the sinus node, registry) study about epinephrine for children receiving emergency transthoracic pacing may be lifesaving. Pac- CPR for bradycardia and poor perfusion.58 The PLS Task ing is not helpful in children with bradycardia secondary Force agreed that there remains insufficient evidence to a postarrest hypoxic/ischemic myocardial insult or re- for consideration of a SysRev; as a result, the 2010 spiratory failure. Pacing was not shown to be effective 9,10 treatment recommendation remains in effect. in the treatment of asystole in children.

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Channelopathies (PLS 417: EvUp) PALS: MANUAL DEFIBRILLATION The topic of channelopathies was last addressed in the This section includes several topics on the subject of 9,10 PLS 2010 CoSTR. That review as well as this 2020 pediatric manual defibrillation, including pad size and EvUp considered a channelopathy after either sudden, type and pad or paddle placement during defibrillation, unexplained death in children or after an attempted re- the use of stacked shocks, and the evidence about defi- suscitation following sudden unexplained cardiac arrest brillation energy dose in infants and children. in a previously healthy child or young adult. One issue identified in both the 2010 and this 2020 evidence evaluation is that there is a role for selective Pad Size, Type, and Placement for screening for inheritable heart disease and channelopa- Pediatric Defibrillation (PLS 378 and thy where indicated but that expert advice should be sought in this regard. To review the EvUp see Supple- PLS 043: EvUp) ment Appendix C-19. The 2010 treatment recommen- The topics of pad size and placement and adhesive pads dation remains in effect.9,10 For clarity, the task force compared with paddles were last reviewed in 2010.9,10 modified the first sentence to begin with “Following In the decade after that review, the technological ad- attempted resuscitation for” before “sudden cardiac vances were rapid, hence an EvUp was performed to arrest” to make clear that the screening is performed identify any relevant evidence published after 2010. after resuscitation efforts, not during them. The PLS Task Force agreed to combine these topics into Population, Intervention, Comparator, Outcome, a single EvUp because they expected to identify rela- Study Design, and Time Frame tively little evidence. (To review the EvUp, see Supple- The following PICOST elements were used in the 2010 ment Appendix C-20). The task force agreed that the 9,10 review. EvUp did not identify sufficient evidence to suggest the • Population: Infants and children undergoing resus- need to consider a SysRev, so the 2010 treatment rec- citation from cardiac arrest 9,10 ommendations for both topics remain in effect. • Intervention: Consideration of a channelopathy as the etiology of the cardiac arrest Population, Intervention, Comparator, Outcome, • Comparator: Standard management Study Design, and Time Frame • Outcome: ROSC, survival to discharge, survival • Population: Infants and children in cardiac arrest with favorable neurological outcome in any setting • Study design: RCTs and nonrandomized stud- • Intervention: Specific use of self-adhesive pads or ies (non-RCTs, interrupted time series, controlled any specific paddle or pad size, orientation, and before-and-after studies, cohort studies) eligible position for inclusion • Comparator: Use of paddles or any other paddle • Time frame: All years and languages were included or pad size, orientation, and position if there was an English abstract in ILCOR. The search was performed in November 2019. • Outcome: All • Study design: RCTs and nonrandomized stud- Treatment Recommendations ies (non-RCTs, interrupted time series, controlled This treatment recommendation (below) is unchanged before-and-after studies, cohort studies) eligible 9,10 from 2010. for inclusion After attempted resuscitation for sudden unexplained • Time frame: All years and languages were included cardiac arrest, providers should obtain a thorough history if there was an English abstract. The literature (including syncopal episodes, seizures, unexplained ac- cidents/ or drownings, or sudden death) and review any search was from 2010 to December 2019. available previous electrocardiograms. All infants, chil- Treatment Recommendations dren, and young adults with sudden, unexpected death These treatment recommendations (below) are un- should, if possible, have an unrestricted complete au- 9,10 changed from 2010. topsy, preferably performed by pathologists with training There is insufficient evidence to alter the current rec- and expertise in cardiovascular pathology. Consideration should be given to the reservation and genetic analysis ommendations to use the largest size paddles that fit of tissue from the index patient to determine the pres- an infant’s or child’s chest without touching each other ence or absence of a channelopathy. It is recommended or to recommend one paddle or pad position or type that families of patients who child’s cause of death is not over another. found on autopsy be referred to a healthcare provider Either self-adhesive defibrillation pads or paddles or center with expertise in cardiac rhythm disturbances. may be used in infants and children in cardiac arrest.

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Energy Doses for Defibrillation (PLS 405: department setting for such patients), hence the cal- ScopRev) culation of defibrillation doses administered in J/kg could be imprecise. In addition, the interval from car- Rationale for Review diac arrest to the delivery of first shock and the quality 11,12 In the 2015 CoSTR, the PLS Task Force recommended of CPR could each influence the outcomes for VF or an initial dose of 2 to 4 J/kg to treat shockable rhythms pVT survival after shock delivery. of cardiac arrest. There are differences in the first shock None of the studies identified in the single SysRev61 dose recommended by ILCOR member councils, how- found a significant association between the initial defi- ever, with the European Resuscitation Council recom- brillation energy dose and the rate of sustained ROSC 55 mending 4J/kg for the first and all subsequent shocks or survival. The task force agreed to prioritize this topic and the AHA recommending an initial dose of 2 to 4 J/kg for consideration of a SysRev; until it is completed and (but for ease of teaching, a dose of 2 J/kg is used in algo- reviewed, the 2015 treatment recommendation re- 11,12 rithms and training materials). For refractory VF, the AHA mains in effect. guidelines recommend increasing the defibrillation dose Note: In June 2020, task force members received a to 4 J/kg, suggesting that subsequent energy doses should PubMed automated alert about the publication of a be at least 4 J/kg and noting that higher levels may be new study of energy doses for pediatric defibrillation. 60 considered, not to exceed 10 J/kg. The task force under- The task force chair (IM) repeated the original search took this review to determine if sufficient evidence exists and verified that the study identified67 was the only to recommend consideration of a SysRev that may result study meeting the search criteria published since the in greater consistency in doses recommended for pediatric November 2019 search on the topic. The new in-hos- manual defibrillation. See Supplement Appendix B-5. pital registry study identified 422 infants and children Population, Intervention, Comparator, Outcome, 18 years of age or younger with cardiac arrest and ini- Study Design, and Time Frame tial VF/pVT. First shock energy doses other than 1.7 to • Population: Infants and children who are in VF or 2.5 J/kg were associated with lower survival to hospital pVT in any setting discharge among the 301 patients 12 years of age or • Intervention: Specific energy dose or regimen of younger with initial VF/pVT, and first shock doses more energy doses for the initial or subsequent defibril- than 2.5 J/kg were associated with lower survival rates lation attempt(s) in all patients 18 years of age or younger with initial VF.67 There was insufficient time for the task force to • Comparator: 2 to 4 J/kg • Outcome: Harm to the patient, ROSC, hospital analyze the study or its conclusions before submission discharge, long-term survival, survival with good of this PLS CoSTR, but the task force did want to ac- neurological outcome knowledge this additional new publication. Summary of Evidence Treatment Recommendations 61 This treatment recommendation (below) is unchanged The review identified a single 2019 SysRev of pediatric 11,12 human and animal studies that met the search crite- from 2015. ria. The SysRev identified no studies linking the initial We suggest the routine use of an initial dose of or cumulative energy delivered to survival to hospital 2 to 4 J/kg of monophasic or biphasic defibrillation discharge and no link between long-term survival or waveforms for infants or children in VF or pVT car- survival with good neurological outcome. Meta-analysis diac arrest (weak recommendation, very-low-quality evidence). There is insufficient evidence on which to could not be performed because the component popu- base a recommendation for second and subsequent lation groups were extremely heterogeneous. defibrillation doses. Task Force Insights Shockable rhythms are less common in infants and children with OHCA (less than 10%62,63) compared with in- Single or Stacked Shocks for Pediatric hospital cardiac arrest (IHCA) (5% to 24%64,65) and less Defibrillation (PLS 389: EvUp) common in pediatric than in adult OHCA66 and in The evaluation of the evidence in support of single IHCA.64 The task force acknowledged that the lower compared with stacked shocks for pediatric defibrilla- frequency of occurrence does affect the sample size for tion was most recently addressed in 2010.9,10 The task studies to demonstrate statistically significant improve- force undertook this EvUp to identify any new evidence ment in survival associated with different defibrillation published after 2010. The task force agreed that there energy doses. was no new evidence to suggest the need to consider It may be difficult to determine accurately the a request for a SysRev or to change the 2010 treatment precise weight of children with OHCA in the pre- recommendation. To review the EvUp, see Supplement hospital arena (as may be the case in the emergency Appendix C-21.

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Population, Intervention, Comparator, Outcome, concentration while minimizing risk of iatrogenic inju- Study Design, and Time Frame ry.”68 The recommendation was based on expert con- • Population: Infants and children in VF or pVT in sensus rather than a formal review of the evidence on any setting the subject. To review the EvUp, see Supplement Ap- • Intervention: More than 1 shock for the initial or pendix C-22. subsequent defibrillation attempt(s) The PLS Task Force has not made any previous rec- • Comparator: A single shock ommendations for specific ventilation rate for the in- • Outcome: All fant or child with respiratory arrest and a perfusing • Study design: RCTs and nonrandomized stud- rhythm. Such recommendations have been included ies (non-RCTs, interrupted time series, controlled in council guidelines rather than in the ILCOR CoSTRs. before-and-after studies, cohort studies) eligible The search conducted in December 2019 for this EvUp for inclusion did not reveal any relevant evidence, and the task force • Time frame: All years and languages were included concluded that there was no need to consider a recom- if there was an English abstract. The literature mendation for a SysRev. search was updated in December 2019. Population, Intervention, Comparator, Outcome, Treatment Recommendations Study Design, and Time Frame This treatment recommendation (below) is unchanged • Population: Infants and children with a perfusing 9,10 from 2010. rhythm but absent or inadequate respiratory effort A single-shock strategy followed by immediate • Intervention: Giving 1 breath every 3 to 5 seconds CPR (beginning with chest compressions) is recom- (12–20 breaths/min) mended for children with out-of-hospital or in-hos- • Comparator: Alternative ventilation rates pital VF or pVT. • Outcome: All • Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled PALS: AIRWAYS, OXYGENATION, AND before-and-after studies, cohort studies) eligible VENTILATION for inclusion • Time frame: All years and languages were included Central to the management of the critically ill or injured if there was an English abstract. The literature child is to ensure that the airway is patent and that ven- search was updated in February 2019. tilation and oxygenation are effective. In this section, the evidence evaluations for the fol- Treatment Recommendations lowing airway and oxygenation and ventilation top- No treatment recommendations will be made until a ics are summarized: ventilation rate when a perfusing future SysRev identifies sufficient evidence to make a rhythm is present, oxygen concentration during car- recommendation. diac arrest, ventilation during CPR with bag and mask compared with an advanced airway, use of cuffed or Oxygen Concentration During Cardiac uncuffed tracheal tubes, minute ventilation during car- Arrest (PLS 396: ScopRev) diac arrest, use of cricoid pressure during intubation, use of devices to verify advanced airway placement, Rationale for Review and ventilation rate with an advanced airway during The published evidence supporting a specific inspired cardiac arrest. oxygen concentration to use during attempted resuscitation of infants and children was last reviewed in 2010.9,10 To review the ScopRev, see Supplement Ap- Ventilation Rate When a Perfusing pendix B-6. Rhythm Is Present (PLS 3103A and PLS The evidence supporting titration of oxygen after 382: EvUp) ROSC is addressed in a separate review; see Oxygen and Carbon Dioxide Targets in Pediatric Patients With This EvUp was undertaken to determine if there was Return of Spontaneous Circulation After Cardiac Arrest. published evidence to support the recommendation to deliver 1 breath every 3 seconds or any other specific Population, Intervention, Comparator, Outcome, ventilation rate for infants and children who require Study Design, and Time Frame bag-mask ventilation but have a pulse and perfusing • Population: Infants (age 28 days to 12 months) rhythm. The 2000 CoSTR on pediatric basic life sup- and children in cardiac arrest in any setting port noted, “the goal of ventilation with a bag and • Intervention: Fraction of inspired oxygen (Fio2) mask should be to approximate normal ventilation titrated to oxygenation during cardiac arrest and achieve physiological oxygen and carbon dioxide • Comparator: Use of 100% oxygen (Fio2 1.00)

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• Outcome: Any arrest, comparing bag-mask ventilation with venti- • Study design: RCTs and nonrandomized stud- lation through an advanced airway. Refer to those ies (non-RCTs, interrupted time series, controlled publications for details of the evidence summary and before-and-after studies, cohort studies) eligible task force considerations. for inclusion Population, Intervention, Comparator, Outcome, • Time frame: All years and languages were included Study Design, and Time Frame if there was an English abstract. The literature search was updated to October 2019. • Population: Infants and children in any setting (in- hospital or out-of-hospital) who have received Summary of Evidence chest compressions or a shock and are receiving The ScopRev identified no human studies in infants (be- CPR yond the neonatal period) and children about oxygen • Intervention: Placement of an advanced airway concentration or its titration during cardiopulmonary device 69,70 resuscitation. The ScopRev identified 2 SysRevs and • Comparator: Primary—bag-mask ventilation alone 71,72 a 2019 ILCOR CoSTR summary statement about or with non–advanced airway interventions; sec- initial resuscitation of newborns, although these were ondary—another advanced airway device not relevant to this 2020 ScopRev. This is because they • Outcome: Any clinical outcome pertained to the resuscitation of newborns in the first • Study design: RCTs and nonrandomized stud- minutes of life (ie, during the transition from placental ies (non-RCTs, interrupted time series, controlled to pulmonary oxygenation). before-and-after studies, cohort studies) eligible The ScopRev identified 2 studies in immature animal for inclusion 73,74 models, a SysRev with meta-analysis of neonatal an- • Time frame: All years and languages were included 75–77 78,79 imal models, and 2 mature animal studies. From if there was an English abstract. The literature this body of work there appeared to be no difference in search was updated to January 2019. ROSC rates but greater evidence of metabolic derangement associated with the administration of 100% oxy- Treatment Recommendations gen during resuscitation of the animals. This treatment recommendation (below) is unchanged from 2019, with the minor addition of “or insertion of” Task Force Insights 71,72 before “a supraglottic airway.” There were no human studies in infants or children We suggest the use of bag-mask ventilation rather that addressed the topic, and the indirectness of results than tracheal intubation or insertion of a supraglottic from animal models were considered insufficient to al- airway in the management of children with cardiac ar- ter the existing 20109,10 treatment recommendation. rest in the out-of-hospital setting (weak recommenda- Also see Oxygen and Carbon Dioxide Targets in Pedi- tion, very-low–certainty evidence). atric Patients With Return of Spontaneous Circulation There is insufficient evidence to support any rec- After Cardiac Arrest below. ommendation about the use of tracheal intubation or Treatment Recommendations insertion of a supraglottic airway in the management This treatment recommendation (below) is unchanged of children with cardiac arrest in the in-hospital set- from 2010. Note that the task force deleted a second ting. recommendation that was included in the 2010 treatment recommendations regarding Fio2 after ROSC because it is addressed in a separate 2020 treatment rec- Use of Cuffed or Uncuffed Tracheal Tubes 9,10 ommendation. (PLS 412: EvUp) There is insufficient information to recommend a The PLS Task Force last reviewed the evidence specific inspired oxygen concentration for ventilation comparing cuffed with uncuffed tracheal tubes in during attempted resuscitation after cardiac arrest in 2010.9,10 This 2020 EvUp was to identify any evi- infants and children. dence on the topic published after 2010. The EvUp identified 3 SysRevs, 2 RCTs, and 3 observational Ventilation During CPR With Bag and studies published since the previous evidence review. To review the EvUp, see Supplement Appendix C-23. Mask Compared With an Advanced The task force agreed that the evidence identified by Airway (2019 CoSTR) the 2020 EvUp supports the consideration of a Sys- A 2019 SysRev80 and an ILCOR Pediatric CoSTR Rev about the use of cuffed versus uncuffed tubes statement were published as part of the 2019 in cardiopulmonary resuscitation to ascertain if the CoSTR summary.71,72 The publications addressed treatment recommendation requires modification. advanced airway interventions for pediatric cardiac Until the completion and analysis of a new SysRev,

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the 2010 treatment recommendation remains in ef- • Time frame: All years and languages were included 9,10 fect. if there was an English abstract. The literature Population, Intervention, Comparator, Outcome, search was updated to September 2019. Study Design, and Time Frame Treatment Recommendations • Population: Infants and children with respiratory This treatment recommendation (below) is unchanged 11,12 failure who undergo endotracheal intubation in from 2015. any setting The confidence in effect estimates is so low that the • Intervention: Use of cuffed tracheal tubes panel decided that a recommendation was too • Comparator: Use of uncuffed tracheal tubes speculative. • Outcome: Any • Study design: RCTs and nonrandomized stud- Cricoid Pressure During Intubation (PLS ies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) eligible 376: EvUp) for inclusion The PLS Task Force last reviewed the evidence about • Time frame: All years and languages were included the use of cricoid pressure during tracheal intubation 9,10 if there was an English abstract. The literature in 2010. search was updated to December 2019. The EvUp identified 2 observational studies suggest- Treatment Recommendations ing an association between external laryngeal manipu- This treatment recommendation (below) is unchanged lation, such as cricoid pressure, and increased difficulty 9,10 from 2010. during tracheal intubation of children in the emergency Both cuffed and uncuffed tracheal tubes are accept- setting. To review the EvUp, see Supplement Appendix able for infants and children undergoing emergency C-25. The PLS Task Force concluded that they should intubation. If tracheal tubes are used, avoid excessive consider the need for a comprehensive SysRev to de- cuff pressures. termine if the 2020 treatment recommendation should be amended. Until a new SysRev is completed and ana- Atropine for Emergency Intubation (PLS lyzed by the PLS Task Force, the 2010 treatment recommendation remains in effect. 821: EvUp) The PLS Task Force reviewed the evidence about the Population, Intervention, Comparator, Outcome, routine use of atropine as a premedication before Study Design, and Time Frame emergency intubation in 2015.11,12 An EvUp was un- • Population: Infants and children treated for acute dertaken but found insufficient literature for consid- illness or injury in any setting, during first hour of eration of a SysRev. To review the EvUp, see Supple- treatment ment Appendix C-24. The 2015 CoSTR remains in • Intervention: Use of cricoid pressure or laryngeal 11,12 effect. manipulation during endotracheal intubation Population, Intervention, Comparator, Outcome, • Comparator: Any other type of or no laryngeal Study Design, and Time Frame manipulation • Population: Infants and children requiring emer- • Outcome: All gency tracheal intubation • Study design: RCTs and nonrandomized stud- • Intervention: Use of atropine as a premedication ies (non-RCTs, interrupted time series, controlled before intubation before-and-after studies, cohort studies) eligible • Comparator: No use of atropine for inclusion • Outcome: Survival with favorable neurological • Time frame: All years and languages were included outcome at 180 days, survival to hospital dis- if there was an English abstract. The literature charge, survival with favorable neurological out- search was updated to December 2019. come at 30 days follow-up, survival with favorable neurological outcome at discharge, likelihood of Treatment Recommendations cardiac arrest, likelihood of shock, incidence of This treatment recommendation (below) is unchanged 9,10 arrhythmias from 2010. • Study design: RCTs and nonrandomized stud- If cricoid pressure is used during emergency intuba- ies (non-RCTs, interrupted time series, controlled tion in infants and children, it should be discontinued before-and-after studies, cohort studies) eligible if it impedes ventilation or interferes with the speed or for inclusion ease of intubation.

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Use of Devices to Verify Advanced Ventilation Rate With Advanced Airway Airway Placement (PLS 385: EvUp) During Cardiac Arrest (PLS 3103A and PLS This 2020 EvUp was undertaken to determine if there 382: EvUp) was new evidence to support the use of devices to con- The 2010 CoSTR was the most recent review of the firm advanced airway placement published after the evidence about optimal minute ventilation (product of most recent review of the topic in 2005.81,81a The EvUp tidal volume and respiratory rate/min) after the place- identified 1 SysRev,82 relevant output from national sur- ment of an advanced airway during CPR in infants or 83 84,85 children. The minute ventilation recommended in the veys, and 2 RCTs. Although these studies chiefly 9,10 2010 CoSTR was based on expert consensus. involved adults or preterm infants rather than infants This 2020 EvUp was to identify any evidence pub- beyond 28 days of age or children, the PLS Task Force lished after 2010 that might indicate the need for a agreed that there is sufficient new evidence to sug- new SysRev and for possible modification of the cur- gest the need to consider a SysRev. Until a new SysRev rent treatment recommendations. This EvUp was pri- is completed and analyzed by the PLS Task Force, the oritized for inclusion in this 2020 CoSTR because the 2005 treatment recommendation remains in effect. To task force identified the differences in recommended review the EvUp, see Supplement Appendix C-26. or proposed minute ventilation and respiratory rates across resuscitation councils and sought to identify Population, Intervention, Comparator, Outcome, any evidence that could assist in the development of a Study Design, and Time Frame consistent recommended ventilation rate. • Population: Infants and children who are in respi- The EvUp identified a small single-center obser- ratory failure who undergo endotracheal intuba- vational paper that reported an association of ven- tion in any setting tilation rates during cardiac arrest higher than 12 to 86 • Intervention: The use of devices (eg, CO2 detec- 20/min with improved outcomes. Ongoing studies are anticipated to conclude later in 2020 that may tion device, CO2 analyzer, or esophageal detector device) provide further data. As a result, the PLS Task Force • Comparator: Not using such a device will await the publication of more evidence to con- • Outcome: All sider the need for a SysRev and possible revision of the treatment recommendation. To review the • Study design: RCTs and nonrandomized stud- EvUp, see Supplement Appendix C-27. ies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) eligible Population, Intervention, Comparator, Outcome, for inclusion Study Design, and Time Frame • Time frame: All years and languages were included • Population: Infants and children with cardiac arrest if there was an English abstract. The literature and an advanced airway search was updated to November 2019. • Intervention: The use of a higher ventilation rate • Comparator: The current recommendation of 8 to Treatment Recommendations 10 breaths/min This treatment recommendation (below) is unchanged • Outcome: ROSC, survival to discharge, survival from 2005.81 The task force agreed to remove the with favorable neurological status weight minimum of 20 Kg or greater for capnography. Treatment Recommendations In addition, the task force noted that continuous moni- The treatment recommendations (below) are un- toring of waveform capnography has now become rou- changed from 2010 except for a minor edit to clarify tine in many settings. types of arrest as asphyxial or arrhythmic (rather than 9,10 Confirmation of tracheal tube position using exhaled VF) in origin.

CO2 detection (colorimetric detector or capnography) After placement of a secure airway, avoid hyperven- should be used for intubated infants and children with tilation of infants and children during resuscitation from a perfusing cardiac rhythm in all settings (eg, out-of- cardiac arrest, whether asphyxial or arrhythmic in origin. hospital, emergency department, intensive care unit, A reduction in minute ventilation to less than baseline for age is reasonable to provide sufficient ventila- inpatient, operating room). In infants and children with tion to maintain adequate ventilation-to-perfusion ratio a perfusing rhythm, it may be beneficial to monitor during CPR while avoiding the harmful effects of hyper- continuous capnography or frequent intermittent de- ventilation. tection of exhaled CO2 during out-of-hospital and in- There are insufficient data to identify the optimal trahospital or interhospital transport. tidal volume or respiratory rate.

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PALS: CIRCULATORY SUPPORT DURING may also allow for “individualized CPR” tailored to the CPR patients’ needs and their responses to resuscitation interventions. This section highlights the reviews about the Extracorporeal CPR for In-Hospital use of invasive blood pressure monitoring, bedside ultra- Cardiac Arrest (2019 CoSTR) sound, near-infrared spectroscopy, and end-tidal carbon dioxide (ETCO ) to assist with the optimal delivery of CPR. A SysRev about extracorporeal CPR (ECPR) for pediatric 2 IHCA was performed in 201887 and an ILCOR Pediatric CoSTR was published as part of the 2019 CoSTR sum- Invasive Blood Pressure Monitoring 71,72 mary. The summary of the consensus on science can During CPR (PLS 826: ScopRev) be found in that 2019 CoSTR. Refer to those publications for details of the evidence summary and task force Rationale for Review considerations. Maintenance of adequate arterial systolic (compression) and diastolic (relaxation) or mean pressure during Population, Intervention, Comparator, Outcome, CPR is crucial to maintain coronary and cerebral perfu- Study Design, and Time Frame sion. Maintaining a sufficient minimum threshold blood • Population: Adults (age 18 years or older) and pressure should be associated with improved clinical children (age younger than 18 years) with cardiac outcomes. It is unknown if CPR directed to meet indi- arrest in any setting (out-of-hospital or in-hospital) vidualized rather than uniform standard blood pressure • Intervention: Extracorporeal CPR (ECPR) including targets will improve outcomes from cardiac arrest. This extracorporeal membrane oxygenator therapy or topic was most recently reviewed in 2015,11,12 and the cardiopulmonary bypass during cardiac arrest 2020 ScopRev was performed to identify any evidence • Comparator: Manual or mechanical CPR on this topic published after 2015. • Outcome: Clinical outcomes, including short-term survival and neurological outcomes (eg, hospital Population, Intervention, Comparator, Outcome, discharge, 28 days, 30 days, and 1 month) and Study Design, and Time Frame long-term survival and neurological outcomes (eg, • Population: Infants and children undergoing CPR at 3 months, 6 months, and 1 year) • Intervention: Use of invasive hemodynamic moni- • Study design: RCTs and nonrandomized studies (non- toring to titrate to a specific systolic and diastolic RCTs, interrupted time series, controlled before-and- blood pressure after studies, cohort studies) eligible for inclusion • Comparator: No use of invasive monitoring to a • Time frame: All years and languages were included specific systolic and diastolic blood pressure if there was an English abstract. The literature • Outcome: Change in survival to 180 days with search was updated to January 2019. good neurological outcome, survival to 60 days with good neurological outcome, survival to hos- Treatment Recommendations pital discharge with good neurological outcome, These treatment recommendations (below) are un- the likelihood of survival to discharge or ROSC 71,72 changed from 2019. • Study design: RCTs and nonrandomized stud- We suggest that ECPR may be considered as an in- ies (non-RCTs, interrupted time series, controlled tervention for selected infants and children (eg, pediat- before-and-after studies, cohort studies) eligible ric cardiac populations) with IHCA refractory to conven- for inclusion tional CPR in settings where resuscitation systems allow • Time frame: All years and languages were included ECPR to be well performed and implemented (weak if there was an English abstract. The literature recommendation, very low-quality evidence). search was updated to November 2019. There is insufficient evidence in pediatric OHCA to for- mulate a treatment recommendation for the use of ECPR. Summary of Evidence There was no association between blood pressures measured during CPR and neurological outcomes in PALS: PHYSIOLOGICAL MONITORING an observational study of survivors of pediatric critical 88 DURING ARREST TO GUIDE care (including cardiac critical care). In an observational study of a highly selected pediatric critical care THERAPY AND/OR INTRA-ARREST population with arterial pressure monitoring in place PROGNOSTICATION when cardiac arrest developed, there was a significant Physiological monitoring and feedback during CPR can association between the mean diastolic blood pressure facilitate the adjustment of CPR delivery during resuscita- of 25 mm Hg or greater in infants and 30 mm Hg or tion and, as a result, may improve the quality of resuscita- greater in children within the first 10 minutes postarrest tion and even resuscitation outcomes. Such monitoring and their survival as well as with survival with favorable

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neurological function.89 To review the ScopRev, see Population, Intervention, Comparator, Outcome, Supplement Appendix B-7. Study Design, and Time Frame • Population: Infants and children in any setting (in- Task Force Insights hospital or out-of-hospital) with cardiac arrest The information identified in this ScopRev applies only • Intervention: The presence of variables—images, to pediatric patients with intra-arterial access along with cut-off values, or trends—during CPR (intra-arrest) continuous monitoring of blood pressure at the time that can provide physiological feedback to guide they develop cardiac arrest. The work by Berg and col- 89 resuscitation efforts, namely NIRS and cerebral leagues identified an association between the mean oxygen saturation monitoring diastolic blood pressure associated with neurologically • Comparator: The absence of such factors— intact survival and the blood pressure thresholds below images, cut-off values, or trends which no child survived. The evidence was too limit- • Outcome: Any clinical outcome ed, however, to consider the diastolic blood pressure • Study design: RCTs and nonrandomized stud- threshold by itself sufficient to identify CPR futility. ies (non-RCTs, interrupted time series, controlled The PLS Task Force considered that, for children with before-and-after studies, cohort studies) eligible IHCA and an arterial line already in place, hemodynam- for inclusion ic-directed CPR might be considered. The task force • Time frame: All years and languages were included agreed, however, that more evidence is required and if there was an English abstract. The literature that there is insufficient evidence currently available to search was updated to October 2019. consider a request for a SysRev. The 2015 treatment 11,12 recommendation remains in effect. Summary of Evidence The ScopRev identified no pediatric RCTs but did iden- Treatment Recommendations tify 1 ongoing adult RCT that compared the outcomes This treatment recommendation (below) is unchanged of NIRS-guided CPR with current standard CPR prac- 11,12 from 2015. tice (this study is anticipated to conclude in 2021) The confidence in effect estimates is so low that (NCT03911908) and 2 adult SysRevs. Both adult Sys- the panel decided that a recommendation was too Revs concluded that higher rSco2 was associated with speculative. higher likelihood of ROSC and survival, whereas lower o 90,91 rSc 2 was associated with an increased mortality. Use of Near-Infrared Spectroscopy During There was no consensus on the predictive threshold value of rSco for any outcomes.92–94 A trend of ris- Cardiac Arrest (PLS New: ScopRev) 2 ing rSco2 (between 7% and 15% from baseline mea- Rationale for Review surement) may be a more reliable predictive factor for ROSC.90,95,96 NIRS is a noninvasive mode of estimating regional ce- The ScopRev also identified 2 observational studies rebral and renal/mesenteric oxygen saturation (rSco ) 2 of NIRS in children during CPR. One found that cerebral and can detect these signals in no blood flow situa- physiological changes were associated with changed tions as in cardiopulmonary arrest. Cerebral NIRS val- NIRS measurements during cardiac arrest, increased ues can reflect cerebral physiological changes (ie, intracranial pressure reduction, arrest resolution, and intracranial tissue oxygenation that can be affected 97 after ROSC. by arterial blood flow, tissue perfusion, and venous The second small study found an association be- drainage) during cardiac arrest, during changes in in- 98 tween higher minimum rSco2 during CPR and ROSC, tracranial pressure, during arrest resolution, and af- but overall survival was too low to detect changes in ter ROSC. NIRS uses adhesive sensors placed on the survival. An adult observational study found ETCO2 to forehead (to evaluate regional cerebral oxygen satu- 99 be a more accurate predictor of ROSC in OHCA. ration of hemoglobin rSco2 and over the abdomen. Each sensor contains a light source and 2 fiberoptic Task Force Insights bundles that can detect the light absorption and re- Survival after cardiac arrest may increase when resusci- flection at different tissue depths. tation is tailored to the cause of the arrest and to the This ScopRev addresses the use of NIRS as an intra- patient’s responses to treatment. The level of certainty arrest variable that may assist in tailoring CPR technique about the use of NIRS is very low, however, and the to improve blood flow and oxygen delivery. The PLS absence of consensus thresholds reduces its usefulness. o Task Force has not previously considered use of NIRS The value of monitoring trends in the rSc 2 during pe- in this manner, hence there are no current treatment diatric resuscitation still requires validation. The PLS Task recommendations. To review the ScopRev, see Supple- Force agreed that given the limited evidence available, ment Appendix B-8. there was currently insufficient evidence to warrant

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consideration of a SysRev. As a result, there will con- to hospital discharge.105 Complete cardiac standstill as tinue to be no treatment recommendation. determined sonographically is unlikely to be used as a sign of futility during pediatric resuscitation in light of Treatment Recommendations case reports demonstrating that use of ECPR resulted No treatment recommendation has been made. in viable cardiac function after cardiac standstill.106 Fi- nally, significant cost is associated with the purchase of Bedside Ultrasound to Identify Perfusing equipment and training of users, which may limit its use Rhythm (PLS 408: ScopRev) in resource-limited settings. Rationale for Review Task Force Insights This topic was most recently reviewed in the 2010 The PLS Task Force agreed that they would not accept CoSTR document.9,10 The PLS Task Force agreed that the direct extrapolation from adult studies of bedside ultra- increased use of this technology warranted a ScopRev sonography because there are substantial differences be- to determine any evidence published after 2010. To re- tween adult and pediatric cardiac arrest in terms of causes, view the ScopRev, see Supplement Appendix B-9. anatomy, and technical matters—challenges that could affect the usefulness and accuracy of the ultrasound. Al- Population, Intervention, Comparator, Outcome, though the technology is widely used within the pediatric Study Design, and Time Frame critical care, emergency, and resuscitation communities, • Population: Infants and children in any setting (in- more data detailing its advantages, pitfalls, and character- hospital or out-of-hospital) with cardiac arrest istics of performance are needed so that its usefulness and • Intervention: Point-of-care ultrasound (echocar- limitations in pediatric cardiac arrest can be fully defined. diography during cardiac arrest) In addition, there is inadequate pediatric evidence • Comparator: Absence of point-of-care ultrasound about its intra-arrest prognostic utility, and the task (echocardiography) force urges great caution until more literature is avail- • Outcome: Any clinical outcome able. See Supplement Appendix B-9. • Study design: RCTs and nonrandomized stud- Treatment Recommendations ies (non-RCTs, interrupted time series, controlled This treatment recommendation (below) is unchanged before-and-after studies, cohort studies) eligible 9,10 from 2010. for inclusion There is insufficient evidence to recommend for • Time frame: All years and all languages were or against the routine use of bedside ultrasound and included if there was an English abstract. This lit- echocardiography during a pediatric arrest. Ultrasonog- erature search was updated to May 2019. raphy may be considered to identify potentially treat- Summary of Evidence able causes of an arrest when appropriately skilled per- The PLS Task Force posed 3 questions for this ScopRev: sonnel are available, but the benefits must be carefully 1. Can diagnostic images be reliably obtained by weighed against the known deleterious consequences noncardiology sonographers? of interrupting chest compressions. 2. Can reversible causes of death be identified with high sensitivity and specificity? 3. Can the procedure be used to predict outcome? End-Tidal CO2 Monitoring During CPR Echocardiography typically requires pauses in chest (PLS 827: ScopRev) compressions,100–103 although the use of a protocol can Rationale for Review 103,104 reduce the duration of these pauses. Practical dif- The PLS Task Force initially recommended ETCO2 moni- ficulties in the use of ultrasound in infants and children toring to confirm tracheal tube placement in 2000.59

(that do not occur in adults) include small patient size ETCO2 monitoring can also offer an indirect indication that may limit access to some views, particularly if other of cardiac output and pulmonary blood flow (noting monitoring pads are on the chest. In addition, abnor- caveats in relation to pulmonary blood flow and ven- mal cardiac anatomy requires advanced training if non- tilation: perfusion ratio or with, for example, rapid cardiac sonographers are to derive helpful information changes caused by deterioration or response to effec- in this setting. tive treatment). As a result, ETCO2 has been proposed There is very limited pediatric evidence documenting as a method to evaluate the effectiveness of CPR and the use of ultrasonography to identify reversible causes to identify possible ROSC. A rapid increase in ETCO2 of arrest, for prognostication, or to determine cardiac may be associated with improved CPR (or ROSC), and a futility. One small series of high-risk children with ultra- sustained decline or persistently low ETCO2 may be ob- sound diagnosis of pulmonary emboli resulted in suc- served in the absence of ROSC. This 2020 ScopRev was cessful thrombolytic therapy for all, with 80% survival performed to identify the evidence available to support

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the use of ETCO2 to provide feedback to guide resusci- PALS: RESUSCITATION DRUG tation efforts. ADMINISTRATION AND TIMING Population, Intervention, Comparator, Outcome, Drugs are used in resuscitation to support cardiovascu- Study Design, and Time Frame lar physiology and organ perfusion and to ameliorate • Population: Infants and children in any setting (in- underlying pathophysiologic processes to reduce mor- hospital or out-of-hospital) with cardiac arrest bidity and mortality. The medication topics that were • Intervention: Presence of variables—images, cut- evaluated for 2020 included the optimal ways to calcu- off values, or trends—during CPR (intra-arrest) late body weight for prescribing medications dosed by that can provide physiological feedback to guide weight, amiodarone versus lidocaine for shock-resistant VF or pVT, and the role of sodium bicarbonate and of resuscitation efforts, namely ETCO 2 calcium in the management of cardiopulmonary arrest. • Comparator: The absence of such factors— images, cut-off values, or trends • Outcome: Any clinical outcomes Methods of Calculating Pediatric Drug • Time frame: All years and languages were included Doses (PLS 420: EvUp) if there was an English abstract. This literature The PLS Task Force last considered this topic in 2010.9,10 search was updated to January 2020. The search performed for this EvUp identified multiple publications relating to pediatric weight estimation, Summary of Evidence considering many different methods of weight estima- The ScopRev identified only 2 pediatric observational tion. In light of the volume of pediatric publications studies,107,108 so the search was extended to include identified, the PLS Task Force agrees that there is suf- adult and animal literature. The latter evidence is indi- ficient evidence to consider a request for a SysRev. Until rect, meaning that caution is needed in extrapolating the SysRev is completed and analyzed, the 2010 treat- their findings to children. To review the ScopRev, see ment recommendation remains in effect. To review the Supplement Appendix B-10. EvUp, see Supplement Appendix C-28. Task Force Insights Population, Intervention, Comparator, Outcome, The PLS Task Force agreed that it is important to identify Study Design, and Time Frame measures to improve the quality of CPR. Accurate mon- • Population: Pediatric patients with cardiac arrest itoring of ETCO during resuscitation, however, requires (prehospital [OHCA] or in-hospital [IHCA]) 2 • Intervention: The use of any specific alternative the insertion of an advanced airway; advanced airway method for calculating drug dosages insertion may produce undesirable effects (see Ventila- • Comparator: Standard weight-based dosing tion During CPR With Bag and Mask Compared With • Outcome: Achieving expected drug effect, ROSC, an Advanced Airway). The 2 pediatric observational survival, avoidance of toxicity studies identified by the ScopRev included a subset of • Study design: RCTs and nonrandomized stud- children in cardiac arrest, namely those who were in- ies (non-RCTs, interrupted time series, controlled tubated in the intensive care unit at the time of arrest. before-and-after studies, cohort studies) eligible This is a very different population from infants and chil- for inclusion dren with OHCA or those who arrest in less specialized • Time frame: All years and languages were included settings such as a less well-resourced general pediatric if there was an English abstract. The literature hospital setting or clinic. search was updated to October 2019. The PLS Task Force agreed that the evidence for or Treatment Recommendations against the use of ETCO to guide resuscitation efforts 2 These treatment recommendations (below) are un- 9,10 and improve pediatric cardiac arrest outcomes is insuf- changed from 2010. ficient to recommend consideration of a SysRev. As a To calculate the dose of resuscitation medications, result, the 2015 treatment recommendation remains in use the child’s weight if known. If the child’s weight 11,12 effect. is unknown, it is reasonable to use a body length tape with precalculated doses. Treatment Recommendations In nonobese pediatric patients, initial resuscitation This treatment recommendation (below) is unchanged drug doses should be based on actual body weight 11,12 from the 2015. (which closely approximates ideal body weight). If nec- The confidence in effect estimates is so low that essary, body weight can be estimated from body length. the panel decided that a recommendation was too In obese patients, the initial doses of resuscitation speculative. drugs should be based on ideal body weight that can

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be estimated from length. Administration of drug doses The PLS Task Force agreed that, in the absence of based on actual body weight in obese patients may re- new evidence, the previous (2010) treatment recom- 9,10 sult in drug toxicity. mendation should remain in effect. Subsequent doses of resuscitation drugs in both Treatment Recommendations nonobese and obese patients should take into account This treatment recommendation (below) is unchanged the observed clinical effects and toxicities. It is reason- 9,10 from 2010. able to titrate the dose to the desired therapeutic ef- Intraosseous cannulation is an acceptable route of vas- fect, but it should not exceed the adult dose. cular access in infants and children with cardiac arrest. It should be considered early in the care of critically ill chil- Intraosseous Versus Intravenous Route of dren whenever venous access is not readily available. Drug Administration (PLS, NLS, and ALS: SysRev) Epinephrine Time of Initial Dose and Rationale for Review Dose Interval During CPR (PLS 1541: This topic was last reviewed in 2010.9,10 A SysRev was SysRev) requested to identify evidence comparing effects of in- Rationale for Review traosseous with intravenous drug administration during Epinephrine administration for cardiac arrest was previ- pediatric cardiac arrest. The PLS Task Force joined with the ously reviewed in the 2015 CoSTR.11,12 The task force ALS and NLS Task Forces in requesting the SysRev. reported receiving many questions about the effective- Refer to the ALS and NLS publications in this supple- ness and timing of epinephrine administration, so they ment for details of the evidence summary. requested a SysRev to identify any evidence published Population, Intervention, Comparator, Outcome, after 2015 that could enable the formulation of a new Study Design, and Time Frame treatment recommendation. To review the SysRev Ev- • Population: Pediatric patients in any setting (in- idence-to-Decision Table, see Supplement Appendix A- hospital or out-of-hospital) with cardiac arrest 2. • Intervention: Placement of an intraosseous (IO) Population, Intervention, Comparator, Outcome, cannula and drug administration through this IO Study Design, and Time Frame during cardiac arrest • Population: Infants and children in cardiac arrest • Comparator: Placement of an intravenous (IV) can- (in- or out-of-hospital) (excluding resuscitation at nula and drug administration through this IV dur- birth) ing cardiac arrest • Intervention: (1) Administration of the initial dose • Outcome: Return of spontaneous circulation, sur- of epinephrine earlier or later than current guide- vival to hospital discharge, and survival to hospital line recommendations. (2) Administration of epi- discharge with a favorable neurological outcome nephrine more or less frequently than every 3 to 5 • Study design: Randomized trials, non-RCTs, and minutes following the initial dose observational studies (cohort studies and case- • Comparator: Timing of administration of epineph- control studies) comparing IO with IV administra- rine in line with current guideline recommendations tion of drugs included; randomized trials assessing • Outcome: Clinical outcomes, including short-term the effect of specific drugs (eg, epinephrine, amio- survival and neurological outcomes (eg, hospital darone/lidocaine) in subgroups related to IO versus discharge, 28 days, 30 days, and 1 month), and IV administration also included long-term survival and neurological outcomes (eg, • Time frame: All years and languages were included 3 months, 6 months, and 1 year) if there was an English abstract; unpublished stud- • Study design: RCTs and nonrandomized studies (eg, conference abstracts, trial protocols) were ies (non-RCTs, interrupted time series, controlled excluded. The literature search was updated to before-and-after studies, cohort studies) eligible September 2019. for inclusion; unpublished studies (eg, conference Consensus on Science abstracts, trial protocols) excluded The SysRev identified no papers involving infants and • Time frame: All years and languages were included children in cardiac arrest. To review the adult evidence if there was an English abstract. The literature identified by the SysRev, see the ALS publication in this search was updated to July 2019. supplement (ALS 2046: SysRev). To review the neonatal • International Prospective Register of Systematic evidence identified by the SysRev, see the intraosseous Reviews (PROSPERO) Registration: Registered versus umbilical vein for emergency access discussion in November 21, 2019. Final registration number the NLS publication of this supplement (NLS 616: SysRev). 146531.

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Consensus on Science CI, 1.09–2.28; 178 more per 1000; 95% CI, from 28 We identified no pediatric RCTs on this topic. We did, more to 394 more). however, identify 1 observational study of pediatric For the critical outcome of ROSC, we found the IHCA109 and 4 observational studies110-113 of OHCA same study of 1558 pediatric patients with IHCA.109 In comparing the administration of the initial dose of epi- multivariable analysis, this study provided very low-cer- nephrine earlier or later than current guideline recom- tainty evidence (downgraded for risk of bias) of benefit mendations; we also identified 2 observational stud- associated with time to first epinephrine dose of less ies114,115 of pediatric IHCA on the topic of administration than 10 minutes compared with 10 minutes or more of epinephrine more or less frequently than every 3 to 5 after cardiac arrest (RR, 1.56; 95% CI, 1.16–2.08; 233 minutes after the initial dose. We identified no observa- more per 1000; 95% CI, from 66 more to 449 more). tional studies of pediatric OHCA addressing the interval Time to First Epinephrine Less Than 5 Minutes between epinephrine doses. Compared With 5 Minutes or More After Pediatric Time to First Epinephrine Less Than 15 Minutes IHCA Compared With 15 Minutes or More After Pediatric For the critical outcome of survival with good neuro- IHCA logical outcome, we identified the same observational For the critical outcomes of survival with good neuro- study reporting on outcomes of 1395 children young- 109 logical outcome, survival to discharge, or ROSC, we er than 18 years with IHCA. In multivariable anal- identified 1 observational in-hospital registry study of ysis, this study provided very low-certainty evidence 1558 children younger than 18 years with cardiac ar- (downgraded for risk of bias) of benefit of time to first rest.109 In multivariable analysis, this study provided very epinephrine dose less than 5 minutes compared with low-certainty evidence (downgraded for risk of bias and 5 minutes or more after cardiac arrest (RR, 1.74; 95% CI, 1.13–2.66; 71 more per 1000; 95% CI, from 12 imprecision) of no benefit associated with first epinephrine dose less than 15 minutes compared with adminis- more to 159 more). For the critical outcome of survival to discharge, we tration 15 minutes or more after cardiac arrest. identified the same observational study of reporting on Time to First Epinephrine Less Than 10 Minutes 1558 pediatric patients with IHCA.109 In multivariable Compared With 10 Minutes or More After Pediatric analysis, this study provided very low-certainty evidence IHCA (downgraded for risk of bias) of benefit associated with For the critical outcome of survival with good neuro- time to first epinephrine dose less than 5 minutes com- logical outcome, we found an observational study from pared with 5 minutes or more after cardiac arrest (RR, the same database that identified 1395 pediatric pa- 1.57; 95% CI, 1.21–2.04; 120 more per 1000; 95% CI, tients younger than 18 years of age with IHCA.109 In from 44 more to 219 more). multivariable analysis, the study provided very low-cer- For the critical outcome of 24-hour survival, we tainty evidence (downgraded for risk of bias) of benefit identified the same observational study reporting on 109 associated with time to first epinephrine dose of less outcomes of 1558 children with IHCA. In multivari- than 10 minutes compared with 10 minutes or more able analysis, this study provided very low-certainty after cardiac arrest (RR, 3.37; 95% CI, 1.11–10.25; 113 evidence (downgraded for risk of bias) of benefit as- more per 1000; 95% CI, from 5 more to 440 more). sociated with time to first epinephrine dose less than 5 For the critical outcome of survival to discharge, minutes compared with 5 minutes or more (RR, 1.44; we identified the same observational study report- 95% CI, 1.20–1.73; 153 more per 1000; 95% CI, ing outcomes of 1558 children with IHCA.109 After from 70 more to 254 more). multivariable analysis, this study provided very low- For the critical outcome of ROSC, we identified the certainty evidence (downgraded for risk of bias) of same observational study reporting on outcomes of 109 a benefit associated with time to first epinephrine 1558 pediatric patients with IHCA. In multivariable dose of less than 10 minutes compared with 10 min- analysis, this study provided very low-certainty evi- utes or more after cardiac arrest (RR, 2.61; 95% CI, dence (downgraded for risk of bias) of benefit associated with time to first epinephrine dose less than 5 1.36–5.01; 198 more per 1000; 95% CI, from 44 minutes compared with 5 minutes or more (RR, 1.29; more to 494 more). 95% CI, 1.13–1.47; 149 more per 1000; 95% CI; For the critical outcome of 24-hour survival, we from 67 more to 242 more). found the same observational study of 1558 children with IHCA.109 In multivariable analysis, the study pro- Time to First Epinephrine Less Than 3 Minutes vided very low-certainty evidence (downgraded for Compared With 3 Minutes or More After Pediatric risk of bias) of benefit associated with time to first epi- IHCA nephrine dose less than 10 minutes compared with 10 For the critical outcome of survival with good neuro- minutes or more after cardiac arrest (RR, 1.58; 95% logical outcome, we identified 1 observational study of

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1395 pediatric patients with IHCA.109 In multivariable considerations of large effect) of benefit associated analysis, this study provided very low-certainty evidence with time to first epinephrine dose less than 15 min- (downgraded for risk of bias) of benefit from time to utes compared with 15 minutes or more (RR, 2.49; first epinephrine dose less than 3 minutes compared 95% CI, 1.30–4.77; 28 more per 1000; 95% CI, from with 3 minutes or more (RR, 1.38; 95% CI, 1.05–1.81; 6 more to 70 more). 48 more per 1000; 95% CI, from 6 more to 101 more). For the critical outcome of 30-day survival, we iden- For the critical outcome of survival to discharge, we tified 1 observational registry study of 225 children be- identified the same observational study of 1558 pedi- tween 1 and 17 years with OHCA.113 This study pro- atric patients with IHCA.109 In multivariable analysis, vided very-low-certainty evidence (downgraded for risk this study provided very low-certainty evidence (down- of bias, imprecision, and other considerations of very graded for risk of bias) of benefit associated with time large effect) of benefit associated with time to first epi- to first epinephrine dose less than 3 minutes compared nephrine dose less than 15 minutes compared with 15 with 3 minutes or more (RR, 1.38; 95% CI, 1.17–1.63; minutes or more (RR, 5.78; 95% CI, 2.82–11.86; 348 95 more per 1000; 95% CI, from 43 more to 158 more). more per 1000; 95% CI, from 133 more to 791 more). For the critical outcome of 24-hour survival, we For the critical outcome of survival to intensive care identified the same observational study of 1558 pe- unit admission, we identified 1 observational study of 109 diatric patients with IHCA. In multivariable analy- 225 children 19 years or younger with nontraumatic, sis, this study provided very-low-certainty evidence nonshockable OHCA.111 This study provided very-low- (downgraded for risk of bias) of benefit associated certainty evidence (downgraded for risk of bias and with time to first epinephrine dose less than 3 minutes imprecision) of benefit associated with time to first epi- compared with 3 minutes or more (RR, 1.27; 95% nephrine dose less than 15 minutes compared with 15 CI, 1.13–1.43; 110 more per 1000; 95% CI, from 53 minutes or more (RR, 1.96; 95% CI, 1.37–2.81; 274 more to 175 more). more per 1000; 95% CI, from 106 more to 517 more). For the critical outcome of ROSC, we identified the For the critical outcome of ROSC, we identified 2 same observational study of 1558 pediatric patients observational studies of 725 pediatric patients with with IHCA.109 In multivariable analysis, this study pro- traumatic110 and nontraumatic, nonshockable111 OHCA. vided very-low-certainty evidence (downgraded for risk These studies provided very-low-certainty evidence of bias) of benefit associated with time to first epineph- (downgraded for risk of bias and imprecision) of benefit rine dose less than 3 minutes compared with 3 minutes associated with time to first epinephrine dose less than or more (RR, 1.24; 95% CI, 1.13–1.35; 133 more per 15 minutes compared with 15 minutes or more (RR, 1000; 95% CI, from 72 more to 195 more). 1.61; 95% CI, 1.37–1.90; 226 more per 1000; 95% CI, Time to First Epinephrine Less Than 15 Minutes from 137 more to 334 more). Compared With 15 Minutes or More After Pediatric Time to First Epinephrine Less Than 10 Minutes OHCA Compared With 10 Minutes or More After Pediatric For the critical outcome of survival with good neuro- OHCA logical outcome, we identified 2 observational studies of 725 pediatric patients 19 years or younger with trau- For the critical outcome of 30-day survival, we identi- matic (509 children)110 and nontraumatic, nonshock- fied 1 observational study of 225 children between 1 113 able (216 children)111 OHCA. These studies provided and 17 years with OHCA. This study provided very- very-low-certainty evidence (downgraded for risk of low-certainty evidence (downgraded for risk of bias, bias, inconsistency, and imprecision), finding no benefit imprecision, and other considerations of very large ef- associated with a first dose of epinephrine less than 15 fect) of benefit associated with time to first epinephrine minutes compared with 15 minutes or more (RR, 3.94; dose less than 10 minutes compared with 10 minutes 95% CI, 0.99–15.64; 80 more per 1000; 95% CI, from or more (RR, 5.07; 95% CI, 1.20–21.42; 402 more per 0 fewer to 397 more). 1000; 95% CI, from 20 more to 1000 more). For the critical outcome of survival to discharge, For the critical outcome of survival to discharge, we we identified 3 observational studies enrolling 27 480 identified 1 observational study of 26 755 emergency children. These included emergency medical services– medical service–treated children younger than 18 years treated children younger than 18 years with non- with nonshockable OHCA arrest who did not experi- shockable arrest who did not experience ROSC within ence ROSC within 10 minutes.112 This study provided very- 10 minutes (26 755 children)112 and children 19 years low-certainty evidence (downgraded for risk of bias) of or younger with traumatic (509 children)110 and non- benefit with time to first epinephrine dose less than 10 traumatic, nonshockable (216 children)111 OHCA. minutes compared with 10 minutes or more (RR, 1.55; These studies provided very-low-certainty evidence 95% CI, 1.31–1.83; 9 more per 1000; 95% (downgraded for risk of bias, inconsistency, and other CI, from 5 more to 14 more).

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Time to First Epinephrine Less Than 5 Minutes 8-minute dose intervals (adjusted OR [AOR], 1.81; 95% Compared With 5 Minutes or More After Pediatric CI, 1.26–2.59) and 8 to less than 10-minute OHCA intervals (AOR, 2.64; 95% CI, 1.53–4.55) compared For the critical outcome of survival to discharge, we with dose intervals of 1 to 5 minutes. identified 1 observational study of 26 755 emergen- For the critical outcome of ROSC (survival of the cy medical services–treated children younger than 18 IHCA event), we identified the same observational years with nonshockable OHCA arrest who did not ex- study of 1630 children with IHCA.115 This study pro- perience ROSC within 10 minutes.112 This study provid- vided very-low-certainty evidence (downgraded for risk ed very-low-certainty evidence (downgraded for risk of of bias, imprecision, and plausible confounding sug- bias) of benefit associated with time to first epinephrine gesting spurious effect) of benefit associated with more dose less than 5 minutes compared with 5 minutes or than 5 to less than 8 minute dose intervals (AOR, 1.71; more (RR, 1.81; 95% CI, 1.43–2.30; 16 more per 1000; 95% CI, 1.27–2.31) and 8 to less than 10-minute in- 95% CI, from 9 more to 26 more). tervals (AOR, 1.93; 95% CI, 1.23–3.03) compared with dose intervals of 1 to 5 minutes. Time to First Epinephrine Less Than 3 Minutes The same observational study of 1630 pediatric pa- Compared With 3 Minutes or More After Pediatric tients with IHCA included a subset analysis of 1183 OHCA children who were not receiving vasoactive infusions at For the critical outcome of survival to discharge, we the time of arrest.115 We identified very-low-certainty identified 1 observational study of 26 755 emergen- evidence (downgraded for risk of bias, imprecision, and cy medical services–treated children younger than 18 plausible confounding suggesting spurious effect) of years with nonshockable OHCA arrest who did not ex- benefit associated with more than 5 to less than 8 perience ROSC within 10 minutes.112 This study provid- minute dose intervals (AOR, 1.99; 95% CI, 1.29–3.06) ed very-low-certainty evidence (downgraded for risk of and 8 to less than 10-minute dose intervals (AOR, 2.67; bias) of benefit associated with time to first epinephrine 95% CI, 1.41–5.04) compared with dose intervals of 1 dose less than 3 minutes compared with 3 minutes or to 5 minutes. more (RR, 1.74; 95% CI, 1.14–2.67; 16 more per 1000; The same observational study of 1630 pediatric 95% CI, from 3 more to 35 more). patients with IHCA included a subset analysis of 447 Epinephrine Dose Interval of Less Than 5 Minutes children who were receiving vasoactive infusions at Compared With 5 Minutes or More for Pediatric IHCA the time of arrest.115 We identified very-low-certainty For the critical outcome of 12-month survival, we iden- evidence (downgraded for risk of bias, imprecision, and tified 1 observational study of 235 pediatric patients plausible confounding suggesting spurious effect) of with IHCA who received 2 minutes or more of chest benefit associated with more than 5 to less than 8 114 compressions. minute dose intervals (AOR, 1.52; 95% CI, 0.77–3.02) This study represented a subset of all patients with and 8 to less than 10-minute intervals (AOR, 2.62; 95% IHCA because it enrolled only patients who were eli- CI, 0.85–8.07) compared with dose intervals of 1 to 5 gible for the Therapeutic Hypothermia After Pediatric minutes. Cardiac Arrest in-hospital (THAPCA-IH) trial; the en- Epinephrine Dose Interval of Less Than 3 Minutes rollees were all comatose and mechanically ventilated Compared With 3 Minutes or More for Pediatric IHCA after cardiac arrest, and the parents consented to en- For the critical outcome of 12-month survival, we roll the children in the trial. This study provided very identified 1 observational study of 161 pediatric pa- low-certainty evidence (downgraded for risk of bias, tients with IHCA who were enrolled in the THAPCA- imprecision, and plausible confounding reducing dem- IH trial.114 This study provided very-low-certainty evi- onstrated effect) of lower 12-month survival associated dence (downgraded for risk of bias, imprecision, and with an epinephrine dose interval of less than 3 min- plausible confounding reducing demonstrated effect) utes (adjusted OR 0.50; 95% CI, 0.24–1.06), 5 to less of harm associated with a dose interval of less than than 8 minutes (adjusted OR 0.42; 95% CI, 0.20–0.89), 3 minutes (AOR, 0.50; 95% CI, 0.24–1.06) as well as or more than 8 minutes (adjusted OR 0.35; 95% CI, 5 to less than 8 minutes (AOR, 0.42; 95% CI, 0.20– 0.16–0.75) compared with a 3 to less than 5-minute 0.89) as well as 8 minutes or more (AOR, 0.5; 95% dose interval. CI, 0.16–0.75) compared with a dose interval of 3 to For the critical outcome of survival to discharge, we less than 5 minutes. identified 1 observational in-hospital registry study of 1630 children with cardiac arrest.115 This study Treatment Recommendations provided very-low-certainty evidence (downgraded We suggest that the initial dose of epinephrine in pe- for risk of bias, imprecision, and plausible confounding diatric patients with nonshockable IHCA and OHCA be suggesting spurious effect) of benefit associated with administered as early in the resuscitation as possible more than 5-minute to less than (weak recommendation, very low-certainty evidence).

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We cannot make a recommendation for the timing • There is a need to minimize the effects of resusci- of the initial epinephrine dose in shockable pediatric tation time bias in resuscitation clinical trials. cardiac arrest. The confidence of the effect estimates is so low that we cannot make a recommendation about the optimal Amiodarone Versus Lidocaine for Shock- interval for subsequent epinephrine doses in pediatric Resistant Ventricular Fibrillation or patients with IHCA or OHCA. Pulseless Ventricular Tachycardia (2018 Justification and Evidence to Decision Framework CoSTR) Highlights The topic of amiodarone versus lidocaine for shock-resistant VF or pVT was evaluated by the PLS Task Force in Time to the Initial Dose of Epinephrine the 2018 CoSTR Update.115b,115c Refer to those publica- In general, observational studies can be associated with tions for details of the evidence summary and task force many potential biases. Resuscitation time bias often oc- considerations. curs in intracardiac arrest studies such as epinephrine ad- The task force agreed that a multicenter trial com- ministration studies because the longer the duration of paring different anti-arrhythmic agents would be help- the resuscitation, the lower the rate of survival. As a re- ful. Until further data are available, the 2018 treatment sult, patients who received the epinephrine earlier rather 115b,115c recommendation remains in effect. than later may have a lower mortality for reasons other than the time of the epinephrine administration.115a This Population, Intervention, Comparator, Outcome, bias can contribute to a trend toward appearance of a Study Design, and Time Frame harmful effect of later initial epinephrine doses. There- • Population: Patients of all ages (neonates, chil- fore, when interpreting studies of time to the initial dose dren, adolescents younger than 18 years) in any of epinephrine, the task force considered the role of po- setting with cardiac arrest and a shockable rhythm tential resuscitation time bias. at any time during CPR or immediately after ROSC Epinephrine Interval • Intervention: Administration (IV or IO) of an anti- Hoyme et al115 demonstrated that an increased epineph- arrhythmic drug rine interval was associated with a decreased probability • Comparator: Another anti-arrhythmic or placebo of survival, with an unadjusted odds ratio for survival of • Outcome: Survival to hospital discharge with good 0.60 for 5 to 8 minutes between epinephrine doses and neurological outcome, survival to hospital dis- 0.62 for 8 to 10 minutes between epinephrine doses charge, ROSC, and rearrest after ROSC compared with 1 to 5 minutes between epinephrine • Study design: RCTs and nonrandomized stud- dose. However, in the adjusted statistical model, con- ies (non-RCTs, interrupted time series, controlled versely, an increased epinephrine interval was associ- before-and-after studies, cohort studies) eligible ated with an increased probability of survival. The task for inclusion force considered the fact that in the current meta-anal- • Time frame: All years and languages were included ysis, the unadjusted results, rather than the adjusted if there was an English abstract. The literature results, were incorporated. In addition, both Hoyme et search was updated to August 2017. 115 114 al and Meert et al calculated the average interval Treatment Recommendations of epinephrine doses by averaging all doses within the This treatment recommendation (below) is unchanged total arrest time; this differs from the actual interval be- from 2018.115b,115c tween any 2 doses. For these reasons, the task force felt We suggest that amiodarone or lidocaine may be that confidence in the estimates of effect was too low used for the treatment of pediatric shock-resistant VF to support a treatment recommendation regarding epi- or pVT (weak recommendation, very low-quality evi- nephrine dose interval. For further information, please dence). refer to Supplement Appendix A-2.

Knowledge Gaps Sodium Bicarbonate Administration for Current knowledge gaps include but are not limited to • There is clinical equipoise and the need for pediat- Children in Cardiac Arrest (PLS 388: EvUp) ric randomized trials addressing the optimal timing The most recent PLS Task Force review of the evidence of initial epinephrine dose and the optimal interval about sodium bicarbonate administration during cardi- of epinephrine doses. ac arrest was in 2010.9,10 An EvUp was performed and • Researchers must establish a consistent method found insufficient evidence to consider a SysRev of this to accurately calculate/report the interval between topic, so the recommendations of 2010 remain in effect. epinephrine doses. To review the EvUp, see Supplement Appendix C-29.

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Population, Intervention, Comparator, Outcome, PALS: SPECIAL RESUSCITATION Study Design, and Time Frame SITUATIONS—SEPTIC SHOCK, • Population: Infants and children who are in cardiac arrest in any setting CONGENITAL HEART DISEASE, AND • Intervention: Buffering agent administration TRAUMA • Comparator: No use of buffering agents This section summarizes the evidence reviews about • Outcome: All resuscitation of children with cardiac arrest and septic • Study design: RCTs and nonrandomized stud- shock, congenital heart disease such as single-ventricle ies (non-RCTs, interrupted time series, controlled physiology, or Fontan circulation. The PLS Task Force before-and-after studies, cohort studies) eligible also reviewed the evidence about unique aspects of re- for inclusion suscitation after traumatic arrest. • Time frame: All years and languages were included if there was an English abstract. The literature search was updated to November 2019. Resuscitation of the Child With Septic Shock (PLS 1534: EvUp) Treatment Recommendations The management of children with septic shock–asso- This treatment recommendation (below) is unchanged 9,10 ciated cardiac arrest has not been previously reviewed from 2010. by the PLS Task Force. This EvUp was requested to de- Routine administration of sodium bicarbonate is not termine the available evidence about this topic. The recommended in the management of pediatric cardiac EvUp identified several studies involving prevention of arrest. cardiac arrest, but there was insufficient evidence of unique management approaches to the children with Calcium Administration in Children (PLS septic shock–associated cardiac arrest. As a result, the 421: EvUp) task force agreed that there was no indication of a need to consider a SysRev, and no treatment recommenda- This EvUp was performed to identify any evidence pub- tion could be made at this time. To review the EvUp, see lished after the most recent PLS Task Force review of 9,10 Supplement Appendix C-31. this topic in 2010. The PLS Task Force agreed that there is insufficient evi- Population, Intervention, Comparator, Outcome, dence to suggest the need for a SysRev or alter the 2010 Study Design, and Time Frame treatment recommendation, which remains in effect. To • Population: Infants and children with sepsis in car- review the EvUp, see Supplement Appendix C-30. diac arrest • Intervention: Specific alteration in treatment Population, Intervention, Comparator, Outcome, algorithm Study Design, and Time Frame • Comparator: Standard care (according to 2010 • Population: Infants and children who are in cardiac treatment algorithm) arrest in any setting • Outcome: All • Intervention: Calcium administration • Comparator: No calcium administration Treatment Recommendation • Outcome: All clinical outcomes There is no treatment recommendation at this time. • Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled Resuscitation of the Patient With a Single before-and-after studies, cohort studies) eligible Ventricle (PLS 390: EvUp) for inclusion • Time frame: All years and languages were included This EvUp was performed to identify any evidence if there was an English abstract. The literature published after the most recent PLS Task Force re- 9,10 search was updated to November 2019. view in 2010. The EvUp identified nonrandomized studies reporting the impact of modification to stan- Treatment Recommendations dard cardiac arrest care on outcomes in postsurgical This treatment recommendation (below) is unchanged infants. The PLS Task Force agreed that this and ad- 9,10 from 2010. ditional evidence50,115d may warrant consideration for a Routine use of calcium for infants and children with SysRev. Until a new SysRev is performed and ana- cardiopulmonary arrest is not recommended in the ab- lyzed by the PLS Task Force, the 2010 treatment rec- sence of hypocalcemia, calcium channel blocker over- ommendations remain in effect. To review the EvUp, dose, hypermagnesemia, or hyperkalemia. see Supplement Appendix C-32.

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Population, Intervention, Comparator, Outcome, • Comparator: Standard resuscitation practice Study Design, and Time Frame • Outcome: All • Population: Infants and children with single-ventri- • Study design: RCTs and nonrandomized stud- cle, status/post–stage I repair who require resusci- ies (non-RCTs, interrupted time series, controlled tation from cardiac arrest or prearrest states before-and-after studies, cohort studies) eligible • Intervention: Any specific modification to standard for inclusion practice • Time frame: All years and languages were included • Comparator: Standard resuscitation practice if there was an English abstract. The literature • Outcome: ROSC, survival to discharge, survival search was from January 2013 to September 2019. with good neurological outcome Treatment Recommendations • Study design: Included only observational stud- This treatment recommendation (below) is unchanged ies and RCTs from the time of the previous search from 2010 with the exception of limiting the recom- review mendation to children with hemi-Fontan9,10 or bidirec- • Time frame: All years and languages were included tional Glenn physiology who are in a prearrest state; if there was an English abstract. The literature hypercarbia achieved by hypoventilation may be benefi- search was from January 2008 to October 2019. cial to increase oxygenation and cardiac output. Treatment Recommendations Negative-pressure ventilation, if available, may be These treatment recommendations are unchanged beneficial for children with either hemi-Fontan or bi- 9,10 from 2010. directional Glenn or Fontan physiology by increasing Standard resuscitation (prearrest and arrest) proce- cardiac output. dures should be followed for infants and children with During cardiopulmonary arrest, it is reasonable to single-ventricle anatomy after stage I repair. Neonates consider ECPR for patients with Fontan physiology. with a single ventricle before stage I repair who demon- There is insufficient evidence to support or refute the strate shock caused by elevated pulmonary to systemic use of ECPR in patients with hemi-Fontan or bidirec- flow ratio might benefit from inducing mild hypercar- tional Glenn physiology. bia (Paco 50–60 mm Hg); this can be achieved during 2 mechanical ventilation by reducing minute ventilation, Resuscitation After Traumatic Arrest (PLS adding CO2 to inspired air, or administering opioids with or without chemical paralysis. 498: EvUp) An EvUp was performed to identify any relevant studies published in the decade after the 2010 PLS Task Force Resuscitation of the Patient With Hemi- 9,10 Fontan or Fontan Circulation (PLS 392: review of the topic. The PLS Task Force agreed that the evidence warrants consideration of a SysRev, pref- EvUp) erably one including not only adults but also infants This EvUp was performed to identify any evidence and children in the study population, to determine the about this topic published after the PLS Task Force’s evidence to support specific recommendations about most recent review in 2010.9,10 The EvUp identified 1 resuscitation for traumatic cardiac arrest. To review the registry-based study that reported outcomes of infants EvUp, see Supplement Appendix C-34. and children with Fontan/ or bidirectional Glenn who Population, Intervention, Comparator, Outcome, had circulatory support initiated during a peri-arrest Study Design, and Time Frame phase.115d The PLS Task Force agreed that there is insuf- • Population: Infants and children with major (blunt ficient evidence50,115d to recommend a new SysRev, and or penetrating) injury in cardiac arrest in any setting the 2010 treatment recommendation remains in ef- • Intervention: Any specific alteration in treatment fect,9,10 with the addition of a brief explanatory phrase algorithm within brackets. To review the EvUp, see Supplement • Comparator: Standard care (according to 2010 Appendix C-33. treatment algorithm) Population, Intervention, Comparator, Outcome, • Outcome: All Study Design, and Time Frame • Study design: RCTs and nonrandomized stud- • Population: Infants and children with Fontan or ies (non-RCTs, interrupted time series, controlled hemi-Fontan or bidirectional Glenn circulation before-and-after studies, cohort studies) eligible who require resuscitation from cardiac arrest or for inclusion prearrest states (prehospital or in-hospital) • Time frame: All years and languages included if • Intervention: Specific modification to standard there was an English abstract; literature search was resuscitation practice updated to December 2019.

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Treatment Recommendations before-and-after studies, cohort studies) eligible This treatment recommendation (below) is unchanged for inclusion 9,10 from 2010. • Time frame: All years and languages included if There is insufficient evidence to make a recommen- there was an English abstract; literature search was dation for modification of standard resuscitation for updated to December 2018. infants and children experiencing cardiac arrest due to Treatment Recommendations major trauma, although consideration should be given This treatment recommendation (below) is unchanged to selectively performing a resuscitative thoracotomy in children with penetrating injuries who arrive at the hos- from 2019 (with the exception of the addition of text to pital with a perfusing rhythm. clarify that recommendations apply to children who remain comatose after OHCA or IHCA and to clarify that the temperature should be maintained 37.5°C or less). PALS: POST–CARDIAC ARREST We suggest that for infants and children who remain CARE, INCLUDING POSTARREST comatose following ROSC from OHCA and IHCA, TTM be used to maintain a central temperature of 37.5°C or PROGNOSTICATION less (weak recommendation, moderate-certainty evi- Targeted Temperature Management dence). (2019 CoSTR) On the basis of 2 randomized trials and 8 retrospective observational cohort studies that provided compar- A SysRev addressing targeted temperature manage- ative data on favorable neurological outcome, survival, 116 ment (TTM) was published in 2019, and an ILCOR Pe- and in-hospital adverse events, there is inconclusive diatric CoSTR was published as part of the 2019 CoSTR evidence to support or refute the use of TTM 32°C to 71,72 summary. Refer to those publications for details of 34°C compared with TTM 36°C to 37.5°C (or an alter- the evidence summary and task force considerations. native temperature) for children who achieve ROSC but Population, Intervention, Comparator, Outcome, remain comatose after OHCA or IHCA. Study Design, and Time Frame • Population: Pediatric patients (more than 24 hours Oxygen and Carbon Dioxide Targets to 18 years of age) who achieved ROSC after OHCA or IHCA in Pediatric Patients With Return of • Intervention: TTM with a target temperature of Spontaneous Circulation After Cardiac 32°C to 36°C Arrest (PLS 815: SysRev) • Comparator: No TTM or TTM at an alternative tar- A SysRev of arterial oxygen and carbon dioxide targets get temperature range in adults and children with ROSC after cardiac arrest,116a • Outcome: was conducted with involvement of clinical content ex- – Primary outcome: Good neurobehavioral sur- perts from the ALS and PLS Task Forces. Evidence from vival long term adult and pediatric literature was sought and consid- – Secondary outcomes: ered by the ALS and PLS Task Forces, respectively. This Good neurobehavioral survival short term and CoSTR focuses on evidence derived from infants and intermediate term ○ children. See Supplement Appendix A-3 for more de- Survival short term, intermediate term, and tails. long term ○ Neurobehavioral score changes from prear- Population, Intervention, Comparator, Outcome, rest, intermediate term, and long term Study Design, and Time Frame ○ Health-related quality of life score intermedi- • Population: Unresponsive children with sustained ate term and long term return of spontaneous circulation (ROSC) after car- ○ Health-related quality of life score change diac arrest in any setting from prearrest, intermediate term, and long • Intervention: A ventilation strategy targeting spe- ○ term cific Spo2 [oxygen saturation], Pao2 [partial pressure

– Additional in-hospital adverse outcomes: of oxygen], and/or Paco2 [partial pressure of car- Infection (culture proven) bon dioxide] targets Recurrent cardiac arrest (not leading to death) • Comparator: Treatment without specific targets or ○ Serious bleeding (red blood cell transfusion) with an alternate target to the intervention ○ Arrhythmias (any) • Outcome: Clinical outcome including survival/ ○ • Study design: RCTs and nonrandomized stud- survival with a favorable neurological outcome at ○ ies (non-RCTs, interrupted time series, controlled hospital discharge/30 days, and survival/survival

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with a favorable neurological outcome after hos- than the others, it was deemed at critical risk of bias as a pital discharge/30 days (eg, 90 days, 180 days, 1 result of lack of adjustment for cardiac arrest characteris- year) tics (increasing the risk of confounding) and the exclusion • Study design: Randomized trials, non-RCTs, and of the 31% of all eligible patients who lacked an arterial observational studies (cohort studies and case- blood gas analysis within 1 hour of ROSC. The task force control studies) with a control group (ie, patients thought that this exclusion increased risk of selection bias

treated with no specific Spo2, Pao2, and/or Paco2 because patients who did not have an arterial blood gas targets or an alternative target to the intervention) analysis within 1 hour of ROSC are likely disproportionally included normoxemic or hyperoxemic rather than hypoxemic. • Time frame: All years and languages included; literature search was updated to August 2019. Carbon Dioxide Targets We identified no pediatric RCTs on this topic. Two ob- Consensus on Science servational studies were identified,118,119 1 of which118 Oxygen Targets was published in the interval after the search was com- We identified no pediatric RCTs on this topic but did pleted for the 2015 CoSTR. Only adjusted results from identify 2 observational studies published in the 5 these studies were reported. One study119 including 223 years after the previous (201511,12) review.117,118 One patients provided very-low-certainty evidence (down- of these118 was deemed at critical risk of bias for lack graded for risk of bias and indirectness) of an increase of adjustment for cardiac arrest characteristics; for this in hospital mortality associated with both hypocapnia reason, interpretation of these results is severely lim- (OR, 2.71; 95% CI, 1.04–7.05; 242 more per 1000; ited. Within these limitations, this study included 253 95% CI, from 9 more to 446 more) and hypercapnia patients and found no association between hyperoxe- after ROSC (OR, 3.27; 95% CI, 1.62–6.61; 286 more mia and clinical outcomes in adjusted analyses (numeric per 1000; 95% CI, from 114 more to 423 more). The 1 adjusted results not reported). Of all studies identified study published after the 2015 review118 was deemed at (including those reviewed in 201511,12), only 3 pediatric critical risk of bias for lack of adjustment for cardiac ar- studies,117,119,120 including a total of 618 patients, were rest characteristics. Within these limitations, this study deemed to have only serious risk of bias, and in all of included 253 patients and found an increase in hospital these studies only adjusted results were reported. mortality associated with both hypocapnia compared For the critical outcome of survival to hospital dis- with normocapnia (OR, 2.62; 95% CI, 1.08–6.4; 233 charge with good neurological outcome, we identified more per 1000; 95% CI, from 17 more to 429 more) 1 observational study of 153 pediatric patients with and hypercapnia compared with normocapnia (OR, 2.0; 120 ROSC after cardiac arrest. This study provided very- 95% CI, 1.01–3.97; 166 more per 1000; 95% CI, from low-certainty evidence (downgraded for indirectness, 2 more to 332 more) 1 hour after ROSC. imprecision, and risk of bias), finding no benefit of hy- The available evidence on the effect of hypercapnia peroxemia compared with no hyperoxemia (OR, 1.02; or hypocapnia in adults is inconsistent, with the ran- 95% CI, 0.46–2.27; 5 more per 1000; 95% CI, from domized trials done to date showing no effect. 170 fewer to 202 more). For the critical outcome of survival to hospital dis- Treatment Recommendations o charge, we identified 1 observational study of 164 pe- We suggest that rescuers measure Pa 2 after ROSC and diatric patients with ROSC after IHCA119 providing very target a value appropriate to the specific patient condi- low-certainty evidence (downgraded for indirectness, tion. In the absence of specific patient data, we suggest imprecision, and very serious risk of bias) comparing rescuers target normoxemia after ROSC (weak recom- hyperoxemia with normoxemia and finding no benefit mendation, very low-quality evidence).* to hyperoxemia, although numeric results of adjusted Given the availability of continuous pulse oximetry, analyses were not reported. We identified a second targeting an oxygen saturation of 94% to 99% may be study of 200 pediatric patients with ROSC after car- a reasonable alternative to measuring Pao2 for titrating diac arrest117 that provided very low-certainty evidence oxygen when feasible to achieve normoxia (based on (downgraded for indirectness, imprecision, and serious expert opinion). risk of bias) and that showed no association of post- We suggest that rescuers measure Paco2 after ROSC

ROSC Pao2 greater than 200 mm Hg with outcome (OR and target normocapnia (weak recommendation, very 0.81; 95% CI, 0.41–1.59; absolute risk difference not low-certainty evidence). calculable because the number of survivors in the normoxemia group was not reported). *Note: This treatment recommendation applies to infants 28 days to 12 One large registry-based study121 found that hyperoxe- months and children in cardiac arrest. For recommendations applying to newborns resuscitated at birth, refer to “Neonatal Life Support: mia was associated with higher mortality when compared 2020 International Consensus on CPR and ECC Science With Treatment with normoxemia. Although this study was much larger Recommendations”7a,7b in this supplement.

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Consider adjustments to the target Paco2 for specific published evidence on this topic, see the evidence-to- patient populations where normocapnia may not be desir- decision table in Supplement Appendix A-3. able (eg, chronic lung disease with chronic hypercapnia, Knowledge Gaps congenital heart disease with single-ventricle physiology, increased intracranial pressure with impending herniation). The PLS Task Force identified the following knowledge gaps: Justification and Evidence to Decision Framework • There are no pediatric randomized trials compar- Highlights ing oxygen or carbon dioxide management strate- o co Measurement of the arterial Pa 2 and Pa 2 is much gies in post–cardiac arrest care. easier to perform in the hospital than in the out-of- • We found no published evidence to determine hospital setting. Yet without such monitoring in the how Paco2 targets should be adjusted in infants out-of-hospital setting, it will be difficult for providers and children with chronic CO2 retention. to judge within tolerable ranges the balance between • We found no published evidence to determine hypoxemia and hyperoxemia and between overventila- whether adjusting arterial blood gas analysis tion and underventilation. These ranges of appropriate to 37°C or to a patient’s current temperature is Pao and Paco will also differ for some patients, such as 2 2 beneficial. those with cyanotic congenital heart disease. In steady state situations (eg, steady temperature,

Paco2, and pH), providers may be able to correlate the Post-ROSC Blood Pressure Control (PLS co Pa 2 with the ETCO2 to determine trends that may 820: EvUp) provide information about ongoing ventilatory respons- 11,12 es to support ventilation. This topic was most recently reviewed in 2015. The PLS Task Force recognized the paucity of data This EvUp was performed to identify new evidence available to make recommendations about target values published in the most recent 5 years. The EvUp identified evidence to suggest that post–cardiac arrest hypo- for Pao2 and Paco2 in infants and children after ROSC. tension below the fifth percentile for age is associated Oxygen Targets with poorer outcomes when compared with post–car- Accurate targeting of post-ROSC normoxemia might be diac arrest normotension, and those patients requiring achievable and acceptable being guided by pulse oxim- higher inotropic drug support have lower rates of sur- etry in the hospital setting, but the use of pulse oximetry vival to hospital discharge. The task force agreed that to titrate oxygen administration to target normoxemia in the EvUp identified sufficient new evidence to suggest the out-of-hospital setting has not been studied and is the need for a SysRev. Until such time as a SysRev is not without risk of inadvertent patient hypoxemia. Given completed and evaluated, the 2015 treatment recom- the known risks of hypoxemia and the uncertain risks mendations remain in effect.11,12 To review the EvUps, of hyperoxia, any titration of oxygen delivery to children see Supplement Appendix C-35 and Supplement Ap- after ROSC must be balanced against the risk of inadver- pendix C-36. tent hypoxemia stemming from overzealous weaning of

Fio2. Further challenges include identifying the appropri- Population, Intervention, Comparator, Outcome, ate targets for specific pediatric patient subpopulations Study Design, and Time Frame (eg, infants and children with cyanotic heart disease). • Population: Infants and children after ROSC Carbon Dioxide Targets • Intervention: Use of parenteral fluids and inotro- Accurate targeting of post-ROSC normocapnia might pes and/or vasopressors to maintain targeted mea- be achievable and acceptable in the in-hospital critical sures of perfusion such as blood pressure care setting. Serial assessment of ventilation through • Comparator: No use of these interventions arterial blood gas analysis is facilitated by arterial cath- • Outcome: Patient satisfaction; survival with favor- erization, which may also be beneficial for targeting able neurological and functional outcome at dis- post-ROSC blood pressure targets. Correlation of Paco2 charge, 30 days, 60 days, 180 days, and/or 1 year; survival with favorable neurological and functional and ETCO2 may allow ongoing monitoring of ventilation when continuous capnography is available. Fur- outcome at discharge, 30 days, 60 days, 180 days, ther challenges include identifying any modified Paco2 and/or 1 year; survival to hospital discharge; harm targets needed for specific pediatric patient subpop- to patient ulations (eg, infants and children with suspected in- • Study design: RCTs and nonrandomized stud- creased intracranial pressure). ies (non-RCTs, interrupted time series, controlled For further information about task force devel- before-and-after studies, cohort studies) eligible opment of treatment recommendations from the for inclusion

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• Time frame: All years and languages included if • Study design: RCTs and nonrandomized stud- there was an English abstract; literature search was ies (non-RCTs, interrupted time series, controlled updated to September 2019. before-and-after studies, cohort studies) eligible for inclusion Treatment Recommendations • Time frame: All years and languages included if This treatment recommendation (below) is unchanged 11,12 there was an English abstract; literature search from 2015. from January 2013 to August 2019 We recommend that for infants and children after ROSC, parenteral fluids and/or inotropes or vaso- Treatment Recommendations pressors should be used to maintain a systolic blood This treatment recommendation (below) is unchanged 11,12 pressure of at least greater than the fifth percentile for from 2015. age (strong recommendation, very low-quality We suggest that practitioners use multiple variables evidence). when attempting to predict outcomes for infants and children after cardiac arrest (weak recommendation, very low-quality evidence). Post-ROSC Neuroprognostication and Use of Electroencephalogram (PLS 813 and PLS 822: EvUp) TOPICS NOT REVIEWED IN 2020 The most recent PLS Task Force review of post-ROSC • Etomidate and pediatric septic shock (PLS 402) predictive factors was published in the 2015 CoSTR but • Compression-only CPR for intubated neonates was focused only on the use of electroencephalogra- outside delivery room (PLS 380) phy.11,12 This EvUp was performed to determine if suf- • Formulas for peds endotracheal tube size (PLS 401) ficient evidence exists to suggest the need for a SysRev. • Endotracheal tube versus IV drugs (PLS 403) The EvUp identified 8 studies reporting associations of several factors in addition to electroencephalography with outcomes after cardiac arrest. FUTURE TASKS The PLS Task Force agreed that this topic is of such The following PICOSTs were prioritized by the task interest that they support the suggestion of a SysRev, force for performing a SysRev. The PLS Task Force will with a broader search strategy to include studies of determine the time-tabling for this body of work. additional potential prognostic indicators beyond the Fluid administration for septic shock (PLS New) electroencephalography. Until the SysRev is complet- Fluid administration in shock associated with dengue ed, the 2015 treatment recommendation remains in Fluid administration in malaria with shock effect.11,12 To review the EvUp, see Supplement Ap- Optimal timing for the administration of fluid resus- pendix C-37. citation in pediatric trauma Population, Intervention, Comparator, Outcome, Prearrest care of the infant or child with dilated car- Study Design, and Time Frame diomyopathy or myocarditis (PLS 819: EvUp) • Population: Infants and children who have had Prevention and management of pulmonary hyper- cardiac arrests in the hospital or out-of-hospital tensive crisis in infants and children (PLS 391: EvUp) setting Opioids, sedatives, and muscle relaxants for pulmo- • Intervention: Use of neuro-electrophysiology infor- nary hypertension (PLS 056: EvUp)

mation (electroencephalography). Note: the PLS Therapy with inhaled nitric oxide or prostaglandin I2 Task Force agreed that the list of possible interven- for pulmonary hypertensive crisis and right heart failure tions or diagnostic tools must expand for the next (2020 New EvUp) search. CPR for heart rate of less than 60/min (PLS 1535: • Comparator: None EvUp) • Outcome: Survival to 1 year with good neuro- Energy doses for defibrillation (PLS 405: ScopRev) logical outcome, survival to 180 days with good Advanced airways: Cuffed versus uncuffed tubes neurological outcome, survival to 60 days with (PLS 412: EvUp) good neurological outcome, survival to 6 months, Resuscitation of the patient with a single ventricle survival to 30 days with good neurological out- (PLS 390: EvUp) come, survival to 30 days with good neurological Resuscitation after traumatic arrest (PLS 498: EvUp) outcome, survival to hospital discharge with good Post-ROSC blood pressure control (PLS 820: EvUp) neurological outcome, survival with favorable neu- Further work will be undertaken to look at diagnostic rological outcome, survival to hospital discharge tests (PLS 411)

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Effect of identification and preventive management This article has been copublished in Resuscitation. Published by Elsevier Ire- of genetically related family members of those with land Ltd. All rights reserved. This article has been reprinted in Pediatrics. channelopathies on incidence of cardiac arrest (PLS 417) Acknowledgments The authors thank the following individuals (the Pediatric Life Support Collabo- rators) for their contributions: Alex Moylan, MB, BS, MRCPCH; Alexis Topjian, ARTICLE INFORMATION MD, MSCE; Kevin Nation, RN; Shinchiro Ohshimo, MD, PhD; Ronald A. Bronicki, The American Heart Association requests that this document be cited as fol- MD; Kelly D. Kadlec, MD, MEd; Lynda J. Knight, MSN, RN; Taylor N. McCormick, lows: Maconochie IK, Aickin R, Hazinski MF, Atkins DL, Bingham R, Couto TB, MD, MSc; Ryan W. Morgan, MD, MTR; Joan S. Roberts, MD; Sarah Tabbutt, Guerguerian A-M, Nadkarni VM, Ng K-C, Nuthall GA, Ong GYK, Reis AG, MD, PhD; Ravi Thiagarajan, MBBS, MPH; Brian Walsh, PhD, RRT, RRT-NPS; Tia Schexnayder SM, Scholefield BR, Tijssen JA, Nolan JP, Morley PT, Van de Voorde Raymond, MD; Melissa Chan, MD; Jonathan P. Duff, MD, MEd; Benny L. Joyner P, Zaritsky AL, de Caen AR; on behalf of the Pediatric Life Support Collabora- Jr, MD, MPH; Javier J. Lasa, MD; Arielle Levy, MD, MEd; Kathryn E. Roberts, MSN, tors. Pediatric life support: 2020 International Consensus on Cardiopulmonary RN; Robert M. Sutton, MD, MSCE; Nieves de Lucas, MD, PhD; Florian Hoffmann, Resuscitation and Emergency Cardiovascular Care Science With Treatment MD; Nigel Turner, MB, ChB, PhD, MMEd, EDICM; Dominique Biarent, MD, PhD; Recommendations. Circulation. 2020;142(suppl 1):S140–S184. doi: 10.1161/ Torsten Lauritsen, MD; Olivier Brissaud, MD; Groa Johannesdottir, MD; Jana Dja- CIR.0000000000000894 kow, MD; Abel Martinez Mejias, MD; and Garth Meckler, MD, MSHS. Supplemental materials are available with this article at https://www. The authors also wish to acknowledge the work of Matt Buchanan, MD, ahajournals.org/doi/suppl/10.1161/CIR.0000000000000894 and Laurie J. Morrison, MD, MSc.

Disclosures

Writing Group Disclosures

Writing Other Speakers’ Consultant/ Group Research Bureau/ Expert Ownership Advisory Member Employment Research Grant Support Honoraria Witness Interest Board Other Ian K. Imperial College None None None None None None None Maconochie Healthcare Trust (United Kingdom)

Richard Aickin Starship Children’s None None None None None None None Hospital (New Zealand) Dianne L. University of Iowa None None None None None None None Atkins Robert Great Ormond Street None None None None None None None Bingham Hospital NHS Foundation Trust (United Kingdom) Thomaz Hospital Israelita Albert None None None None None None None Bittencourt Einstein, Universidade de Couto São Paulo (Brazil) Allan R. de University of Alberta None None None None None None None Caen (Canada) Anne-Marie The Hospital for Sick None None None None None None None Guerguerian Children Mary Fran Vanderbilt University None None None None None American None Hazinski Heart Association† Peter T. Morley University of Melbourne, None None None None None None None Royal Melbourne Hospital (Australia) Vinay M. Children’s Hospital NIH (Unrestricted None None Consultant: None None None Nadkarni Philadelphia Research Grant to my Expert Institution)*; AHRQ Opinion for (Unrestricted Research Pediatric Grant to my Institution)*; CPR* Zoll Medical (Unrestricted Research Grant to my Institution)*; Nihon- Kohden (Unrestricted Research Grant to my Institution)*; AHA-RQIP (Unrestricted Research Grant to my Institution)* Kee-Chong Ng KK Hospital (Singapore) None None None None None None None Jerry P. Nolan Warwick Medical School, None None None None None None None University of Warwick Gabrielle A. Starship Children’s None None None None None None None Nuthall Hospital (New Zealand) (Continued ) Downloaded from www.aappublications.org/news by guest on September 25, 2021 S178

Writing Group Disclosures. Continued

Writing Other Speakers’ Consultant/ Group Research Bureau/ Expert Ownership Advisory Member Employment Research Grant Support Honoraria Witness Interest Board Other Gene Y.K. Ong KK Women’s and None None None None None None None Children’s Hospital (Singapore) Amelia G. Reis Inter-American Heart None None None None None None None Foundation (Brazil) Stephen M. Univ. of Arkansas/ None None None None None None None Schexnayder Arkansas Children’s Hospital Barnaby R. University of Birmingham National Institute for None None None None None Salary–NIHR Scholefield (United Kingdom) Health Research (NIHR) UK Fellowship (UK Clinician Scientist Funding Fellowship program (Clinician for research into Scientist) neuroprognostication (academic, after paediatric cardiac noncommercial)† arrest)† Janice A. London Health Sciences MedEvac Foundation None None None None None None Tijssen Center (Canada) Grant (Transport study)*; Heart and Stroke Foundation of Canada (Grant-in-Aid)* Patrick Van de Ghent University None None None None None None None Voorde Hospital; Federal Dpt of Health, Belgium Arno L. Children’s Hospital of The NHLBI (On DSMB for ICU- None None None None None None Zaritsky King’s Daughters RESUS study evaluating effect of CPR training on outcome)†

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. *Modest. †Significant.

Reviewer Disclosures

Other Speakers’ Research Research Bureau/ Expert Ownership Consultant/ Reviewer Employment Grant Support Honoraria Witness Interest Advisory Board Other Nandini Saint Louis University None None None None None None None Calamur Leon Connecticut Children’s None None None None None None None Chameides Medical Center Todd P. Chang Children’s Hospital Los None None None None None None None Angeles & Keck School of Medicine, University of Southern California Ericka L. Fink Children’s Hospital of NIH† None None None None None None Pittsburgh of UPMC Monica E. Children’s Hospital None None None None None International None Kleinman Boston Liaison Committee on Resuscitation* Ola Didrik University of Oslo None None None None None None None Saugstad (Norway)

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. *Modest.

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Note: These tables contain draft treatment recommendations that underwent further discussion by the PLS Task Force. Please refer to the 2020 PLS CoSTR for final wording of all treatment recommendations.

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QUESTION Should IHCA_Epinephrine Interval <3min or >5min vs. 3-5min be used for Pediatric cardiopulmonary arrest?

POPULATION: Pediatric cardiopulmonary arrest

INTERVENTION: Intervention: 1) Administration of the initial dose of epinephrine earlier or later than current guideline recommendations. 2) Administration of epinephrine more or less frequently than

every 3-5 minutes following the initial dose.

COMPARISON: Comparators: Timing of administration of epinephrine in line with current guideline recommendations.

MAIN OUTCOMES: ROSC; Survival to hospital discharge; 12-month survival;

SETTING:

PERSPECTIVE:

BACKGROUND:

CONFLICT OF INTERESTS:

ASSESSMENT Problem Is the problem a priority?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ No As the main pharmacological treatment of cardiopulmonary arrest, epinephrine use, dosing ○ Probably no and interval have high potential to affect outcomes of pediatric CPR. The current ○ Probably yes recommendation is based on moderate quality non randomized studies. ● Yes ○ Varies ○ Don't know Desirable Effects How substantial are the desirable anticipated effects?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

Downloaded from www.aappublications.org/news by guest on September 25, 2021 ○ Trivial Desirable effects are reduced mortality and improved neurological prognosis ○ Small ○ Moderate ● Large ○ Varies ○ Don't know Undesirable Effects How substantial are the undesirable anticipated effects?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

● Large Undesirable effects are higher mortality and worse neurological prognosis ○ Moderate ○ Small ○ Trivial ○ Varies ○ Don't know

Certainty of evidence What is the overall certainty of the evidence of effects?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

● Very low There are no pediatric randomized controlled trials in this issue. Evidence from observational ○ Low studies has very serious risk of bias. The epinephrine interval studied was a mean, calculated as ○ Moderate the duration of the resuscitation divided by the number of doses. The actual dose interval was ○ High not measured ○ No included studies

Values Is there important uncertainty about or variability in how much people value the main outcomes?

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○ Important uncertainty or variability As outcomes are survival and survival with good neurological outcome there is probably low ○ Possibly important uncertainty or variability variability. ● Probably no important uncertainty or variability ○ No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Favors the comparison Too few studies to give a confident answer. Adjusted data seems to favor longer intervals, ○ Probably favors the comparison whereas unadjusted data favors the comparator ● Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ○ Don't know

Resources required How large are the resource requirements (costs)?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Large costs Epinephrine is a cheap drug, easily available even in remote settings. ○ Moderate costs ● Negligible costs and savings ○ Moderate savings ○ Large savings ○ Varies ○ Don't know

Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

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○ Very low No studies on cost included, but most likely low cost. ○ Low ○ Moderate ○ High ● No included studies

Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Favors the comparison Longer intervals would mean less doses of epinephrine, so it favors intervention. ○ Probably favors the comparison Overall cost is low either way. ○ Does not favor either the intervention or the comparison ● Probably favors the intervention ○ Favors the intervention ○ Varies ○ No included studies

Equity What would be the impact on health equity?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Reduced Drug already used in most settings, and not very expensive. ○ Probably reduced ● Probably no impact ○ Probably increased ○ Increased

Downloaded from www.aappublications.org/news by guest on September 25, 2021 ○ Varies ○ Don't know Acceptability Is the intervention acceptable to key stakeholders?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ No As epinephrine is already used and current recommendations are similar to previous ones, ○ Probably no acceptability will probably be high ● Probably yes ○ Yes ○ Varies ○ Don't know Feasibility Is the intervention feasible to implement?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ No Very easy to implement as it would mean less interventions during CPR ○ Probably no ○ Probably yes ● Yes ○ Varies ○ Don't know

SUMMARY OF JUDGEMENTS JUDGEMENT

PROBLEM No Probably no Probably yes Yes Varies Don't know

DESIRABLE EFFECTS Trivial Small Moderate Large Varies Don't know

UNDESIRABLE EFFECTS Large Moderate Small Trivial Varies Don't know

CERTAINTY OF EVIDENCE Very low Low Moderate High No included studies

Possibly important Probably no important No important Important uncertainty uncertainty or uncertainty or uncertainty or VALUES or variability variability variability variability

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Does not favor either Probably favors the Probably favors the Favors the comparison the intervention or the Favors the intervention Varies Don't know BALANCE OF EFFECTS comparison intervention comparison

Negligible costs and Large costs Moderate costs Moderate savings Large savings Varies Don't know RESOURCES REQUIRED savings

CERTAINTY OF EVIDENCE OF Very low Low Moderate High No included studies REQUIRED RESOURCES

Does not favor either Probably favors the Probably favors the Favors the comparison the intervention or the Favors the intervention Varies No included studies COST EFFECTIVENESS comparison intervention comparison

EQUITY Reduced Probably reduced Probably no impact Probably increased Increased Varies Don't know

ACCEPTABILITY No Probably no Probably yes Yes Varies Don't know

FEASIBILITY No Probably no Probably yes Yes Varies Don't know

TYPE OF RECOMMENDATION Strong recommendation against the Conditional recommendation against the Conditional recommendation for either Conditional recommendation for the Strong recommendation for the intervention intervention the intervention or the comparison intervention intervention ○ ● ○ ○ ○

CONCLUSIONS Recommendation

Maintain current interval of 3-5min

Justification

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Subgroup considerations

Implementation considerations

Monitoring and evaluation

Research priorities

An RCT into longer epinephrine dosing intervals would be justifiable ethically as there is equipoise between the current interval and longer dose intervals

Downloaded from www.aappublications.org/news by guest on September 25, 2021 APPENDIX A-2: OXYGEN (A) AND CARBON DIOXIDE (B) TARGETS IN PEDIATRIC PATIENTS WITH RETURN OF SPONTANEOUS CIRCULATION AFTER CARDIAC ARREST (PLS 815: 2020 COSTR)

ASSESSMENT QUESTION Should IHCA_Epinephrine Interval <3min or >5min vs. 3-5min be used for Pediatric cardiopulmonary arrest?

POPULATION: Pediatric cardiopulmonary arrest

INTERVENTION: Intervention: 1) Administration of the initial dose of epinephrine earlier or later than current guideline recommendations. 2) Administration of epinephrine more or less frequently than

every 3-5 minutes following the initial dose.

COMPARISON: Comparators: Timing of administration of epinephrine in line with current guideline recommendations.

MAIN OUTCOMES: ROSC; Survival to hospital discharge; 12-month survival;

SETTING:

PERSPECTIVE:

BACKGROUND:

CONFLICT OF INTERESTS: QUESTION (A) Oxygenation strategy after return of spontaneous circulation (ROSC) in children with cardiac arrest POPULATION: Children with cardiac arrest in any setting who have attained ROSC INTERVENTION: A specific oxygenation strategy COMPARISON: An alternative oxygenation strategy or no specific oxygenation strategy MAIN Survival to hospital discharge, 3 months or longer; survival to hospital discharge, 3 months or longer with favorable neurologic outcome. OUTCOMES: SETTING: Pre-hospital or in the hospital setting

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ASSESSMENT Problem Is the problem a priority?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ No Cardiac arrest in children is a high morbidity and mortality event, and neurologic injury is common in those who do survive. Both ○ Probably no hypoxemia and hyperoxia have been thought to possibly be associated with worse outcome in post-arrest patients previously. ○ Probably yes Hypoxemia may worsen ischemic brain injury and injury to other organs, while hyperoxia may lead to increased oxidative stress ● Yes and organ damage after reperfusion. Several new adult studies, both observational and randomized trials, have been published ○ Varies since this topic was last updated in 2015. There have been no pediatric studies investigating this question since 2015. ○ Don't know Desirable Effects How substantial are the desirable anticipated effects?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Trivial The three pediatric studies {Del Castillo 2012, Bennet 2013, Van Zellem 2015} deemed to have only serious risk of bias all found ○ Small no significant association between hyperoxia and outcomes. Only one of these {Del Castillo 2012} looked at hypoxia, and also ○ Moderate found no association with outcome. One larger registry-based study {Ferguson 2012} did find that hyperoxia was associated with ○ Large higher mortality, but although this study was much larger than the others it was deemed at critical risk of bias. This was due to ○ Varies high concern for both residual confounding due to the lack of adjustment for cardiac arrest characteristics, and selection bias. ● Don't know There is therefore no convincing evidence from clinical studies demonstrating harm from hyperoxia in children. The evidence on the effect of hyperoxia on survival and neurologic outcome in adults is very mixed, with many inconsistencies in methodology and results across studies. Randomized trials done in adults to date are very small and the observational studies are all at serious or critical risk of bias. Within these limitations studies have reported a mix of positive and negative results, leaving true uncertainty. Randomized trials and observational studies have generally found either no effect or a possible benefit from normoxia compared to hyperoxia. The recent adult RCT that included a subgroup of post-arrest patients (larger than any of the RCTs done previously) found a benefit in the conservative (lower) oxygen group. GRADE TABLES FOR LOWER OXYGEN STRATEGY COMPARED TO HIGHER OXYGEN STRATEGY IN THE ICU (all studies are in adults, downgraded additionally for indirectness for pediatrics)

Downloaded from www.aappublications.org/news by guest on September 25, 2021 lower % higher % Relative Absolute № of studies Study design Certainty Importance oxygen oxygen (95% CI) (95% CI)

Survival to discharge-Young

1 randomised trials 4/8 (50.0%) 4/9 (44.4%) RR 1.13 58 more per CRITICAL (0.41 to 1,000 ◯◯◯ 3.08) (from 262 fewer VERY LOW to 924 more) ⨁

Survival to discharge-Jakkula

1 randomised trials 43/61 (70.5%) 39/59 RR 1.07 46 more per CRITICAL (66.1%) (0.84 to 1,000 ◯◯ 1.36) (from 106 fewer LOW to 238 more) ⨁⨁

3 month survival-ICU-ROX

1 randomised trials 49/86 (57.0%) 32/78 RR 1.39 160 more per CRITICAL (41.0%) (1.01 to 1,000 ◯◯◯ 1.92) (from 4 more to VERY LOW 377 more) ⨁

Discharge to home-Young

1 randomised trials 2/8 (25.0%) 4/9 (44.4%) RR 0.56 196 fewer per CRITICAL (0.14 to 1,000 ◯◯◯ 2.29) (from 382 fewer VERY LOW to 573 more) ⨁

CPC 1-2 at 6 months-Jakkula

1 randomised trials 42/61 (68.9%) 36/59 RR 1.13 79 more per CRITICAL (61.0%) (0.87 to 1,000 ◯◯ 1.47) (from 79 fewer to LOW 287 more) ⨁⨁

Favorable GOSE at 6 months-ICU-ROX

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1 randomised trials 35/78 (44.9%) 23/72 RR 1.40 128 more per CRITICAL (31.9%) (0.93 to 1,000 ◯◯◯ 2.13) (from 22 fewer to VERY LOW 361 more) ⨁

Undesirable Effects How substantial are the undesirable anticipated effects?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Large Although the evidence is of low certainty, it is likely that the undesirable effects of hypoxia are significant. The undesirable effects ○ Moderate on neurologic outcome of hyperoxia are very uncertain based on inconsistency of study results. ○ Small ○ Trivial ● Varies ○ Don't know Certainty of evidence What is the overall certainty of the evidence of effects?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

● Very low The certainty of evidence varies across the included studies from very low to low (see tables and summary of observational data ○ Low above). ○ Moderate ○ High ○ No included studies

Values Is there important uncertainty about or variability in how much people value the main outcomes?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Important uncertainty or variability Survival with favorable neurologic outcome and survival are generally accepted as critical outcomes. ○ Possibly important uncertainty or variability ● Probably no important uncertainty or variability ○ No important uncertainty or variability Balance of effects Does the balance between desirable and undesirable effects favor the intervention or the comparison?

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○ Favors the comparison For hyperoxia, pediatric and adult studies generally show either association with harm or no association, but do not generally ○Probably favors the comparison show association with benefit. The balance of evidence therefore slightly favors avoiding hyperoxia, although it should be noted ○ Does not favor either the intervention or that the only pediatric studies finding association with harm were deemed at critical risk of bias. For hypoxemia, limited evidence the comparison favors avoiding hypoxemia in adults, although this is not supported by data in pediatrics. ○ Probably favors the intervention ○ Favors the intervention ○ Varies ● Don't know

Resources required How large are the resource requirements (costs)?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Large costs We did not identify any studies evaluating the cost of an oxygen strategy targeting a specific/lower oxygen saturation. However, ○ Moderate costs as it is the current standard of care to measure an oxygen saturation continuously in post-arrest, critically-ill patients, and since a ○ Negligible costs and savings titrated oxygen approach would lead the same or decreased oxygen use, it is likely that an intervention to avoid hyperoxia would ○ Moderate savings not incur significant cost. For EMS systems, many are not equipped to titrate oxygen, so providing titratable systems would incur ○ Large savings additional resource costs. ○ Varies ● Don't know

Certainty of evidence of required resources What is the certainty of the evidence of resource requirements (costs)?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

Downloaded from www.aappublications.org/news by guest on September 25, 2021 ○ Very low We did not identify any studies specifically comparing resources including costs between the two interventions. ○ Low ○ Moderate ○ High ● No included studies

Cost effectiveness Does the cost-effectiveness of the intervention favor the intervention or the comparison?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Favors the comparison We did not identify any studies addressing cost-effectiveness. ○ Probably favors the comparison ○ Does not favor either the intervention or the comparison ○ Probably favors the intervention ○ Favors the intervention ○ Varies ● No included studies Equity What would be the impact on health equity?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ Reduced We did not identify any studies addressing health equity regarding this topic. ○ Probably reduced ○ Probably no impact ○ Probably increased ○ Increased ○ Varies ● Don't know Acceptability Is the intervention acceptable to key stakeholders?

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○ No We have not identified any research that assessed acceptability, but these TRs do not include any substantial changes compared Although we did not identify any ○ Probably no to 2015. studies addressing acceptability, it ● Probably yes is common practice to decrease ○ Yes FiO2 for other critically ill patients ○ Varies and would likely be acceptable to ○ Don't know those treating post-arrest patients. The TR for carbon dioxide targets is also in line with current clinical practice for other critically ill patients. Feasibility Is the intervention feasible to implement?

JUDGEMENT RESEARCH EVIDENCE ADDITIONAL CONSIDERATIONS

○ No Feasibility was not specifically addressed by this review. However, avoiding hyperoxia should be feasible in most ICU settings ○ Probably no where patients are continually monitored. Decreasing FiO2 in the pre-hospital setting or in the immediate post-arrest period may ● Probably yes be less feasible as oxygen saturations may be hard to obtain reliably. ○ Yes ○ Varies ○ Don't know