2025+AHA心肺复苏与心血管急救指南-第10部分：成人和儿童复苏的特殊情况

PREAMBLE

The chain of survival is a series of steps in the process of cardiac arrest management that begins with prevention and concludes with survivorship. Throughout, coordinated efforts are required of laypeople and health care profes-sionals in a variety of disciplines across the health care system. These guidelines contain recommendations for basic life support(BLS) and advanced life support(ALS) for adults and children in special circumstances resulting in cardiac arrest and are based on the best available re-suscitation science. For these recommendations, children are defined as those without signs of puberty in the BLS setting and those who are<18 years of age in the ALS setting. Depending on the clinical data immediately avail-able, there are numerous special circumstances in which additional interventions or modifications to BLS and ALS in adults and children may be required, spanning each link in the chain of survival. Management of patients in cardiac arrest from these special circumstances often differs from standard resuscitation. For example, patients may develop hypotension fromβ-adrenergic receptor antagonist(eg,β-blocker) or calcium channel antagonist(eg, CCB) poisoning that does not respond to atropine,standard vasopressors, or cardiac pacing but is ame-nable to targeted therapies, such as high-dose insulin In addition, specific recommendations about the training of resuscitation professionals are provided in“Part 12:Resuscitation Education Science" and recommendations about systems of care are provided in“Part 4: Systems of Care."

INTRODUCTION

# Scope of the Guidelines

These guidelines are designed primarily for North Ameri-can health care professionals treating adults and chil-dren in cardiac arrest or a life-threatening state from a special circumstance requiring modification of BLS and ALS. Life-threatening conditions include a range of medical emergencies that pose an immediate risk to sur-vival(eg, respiratory arrest, refractory hypotension, criti-cal metabolic acidosis), while a cardiac arrest refers to the cessation of cardiac output and, with that, cessation of oxygen delivery throughout the body. Depending on the data available, recommendations are made for the management of patients in cardiac arrest or for patients with life-threatening conditions inclusive of cardiac ar-rest. Additionally, for certain topics, the relevant literature regarding the management of cardiac arrest in these settings may be limited to patients in a life-threatening condition. The same therapies are recommended for life-threatening conditions and cardiac arrest unless other-wise stated.

These guidelines contain recommendations for BLS and ALS for both adults and children. Unless otherwise

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specified, the interventions recommended here are intended for use in addition to standard BLS, pediat-ric BLS, ALS, and pediatric ALS, prediat-ric BLS, ALS, and pediatric ALS(PALS) resuscitation.Although many of these treatments are impractical outside of the hospital setting, several can be initiated by emergency medical services and some(eg, giving breaths to drowning victims) may be relevant to lay res-cuers. These guidelines are intended to be used in con-junction with topic-specific references and advice from local and regional experts.

The special circumstances guidelines have historically been developed from predominantly adult data. As is common in pediatric medicine, these recommendations were often applied to the resuscitation of children in similar contexts. For the 2025 recommendations, the lit-erature searches performed included all age groups, and for which pediatric data are available, recommendations were made in line with those data. For those where there are sparse to no pediatric data, the recommendations will be absent or extrapolated from adult data.

Throughout these guidelines, recommendations may include therapies including procedures that all centers are not sufficiently resourced to offer, such as ECLS,hyperbaric oxygen therapy, and mechanical thrombec-tomy. These therapies may, however, be available for select centers and in those settings should be imple-mented or considered depending on the strength of the evidence and the clinical context. It is important for health care professionals to follow their institutional guidelines as well as the available literature.

Organization of the Writing Group

The writing group included a diverse group of experts with backgrounds in emergency medicine, pediatric emergen-cy medicine, adult and pediatric critical care, anesthesi-ology, adult and pediatric cardiology, electrophysiology,obstretrics and gynecology, maternal fetal medicine, hy-perbaric medicine, medical toxicology, pharmacy, trauma care, education, and research. Group members were ap-pointed by the American Heart Association (AHA) Emer-gency Cardiovascular Care Science Subcommittee. Each recommendation was developed and formally approved by the writing group and subsequently reviewed and ap-proved by the AHA Emergency Cardiovascular Care Sci-ence Subcommittee.

The AHA has rigorous conflict-of-interest policies and procedures to minimize the risk of bias or improper influence during the development of guidelines. Before appointment, writing group members disclosed all rel-evant commercial relationships and other potential(including intellectual) conflicts. These procedures are described more fully in“Part 2: Evidence Evaluation and Guidelines Development" in the 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. The Writing Group

Disclosures table at the end of this document lists the writing group members' relevant relationships with indus-try(Appendix 1).

METHODOLOGY AND EVIDENCE REVIEW

The writing group members first created and approved a list of special circumstances topics, drawing on the scope of prior guidelines and new topics that have gained prominence since the 2020 publication. A population, in-tervention, comparison, outcome, study design, and time frame (PICOST) question was created for each topic.Guided by the writing group chairs and with assistance from a professional medical librarian as needed, the writ-ing group performed a structured evidence evaluation for each topic, which was internally peer reviewed. These searches were executed in Medline and the Excerpta Medica Database (Embase) using the Ovid search inter-face, and the Cochrane Central Register of Controlled Trials. International Liaison Committee on Resuscitation(ILCOR) evidence reviews published since 2020 were reviewed, and the dates of updated searches were har-monized with these reviews to avoid search overlap. Fi-nal complete searches were executed in July 2024 with single database searches in November through Decem-ber 2024. Structured searches were supplemented by bibliography review and ad hoc searches when needed.Search results were imported into Covidence (Covidence systematic review software, Veritas Health Innovation,Melbourne, Australia). At least 2 writing group members performed dual screening of the titles and abstracts of all articles identified from each search and identified articles for full-text review. Screening conflicts were re-solved between the 2 writing group members and writ-ing group leadership before full-text review. Two writing group members reviewed the full text of all selected ar-ticles and applied the information contained to develop treatment recommendations appropriate for each clinical question. Each draft recommendation was created by a group of 2 writing group members and then reviewed and refined by all writing group members during regular virtual meetings and 2 in-person meetings. Completed draft recommendations were reviewed by organizational leaders in the AHA with recommendations incorporated as draft revisions. Final draft recommendations were then externally peer reviewed. A more comprehensive description of these methods is provided in "Part 2: Evi-dence Evaluation and Guidelines Development."

Class of Recommendation and Level of Evidence

Each recommendation was assigned a Class of Recom-mendation(COR) based on the strength and consistency of the evidence, alternative treatment options, and impact

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<BeginOfPara>on patients and society (Table 1). Recommendation wording flows in a structured manner based on the COR determination. The Level of Evidence (LOE) is based on

<EndOfPara>the quality, quantity, relevance, and consistency of the available evidence. For each recommendation, the writing group discussed and approved specific recommendation

Table 1. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care(updated December 2024)*

CLASS(STRENGTH) OF RECOMMENDATION

Class 1(STRONG)

Benefit >>> Risk

Suggested phrases for writing recommendations:

• Is recommended

● Is indicated/useful/effective/beneficial

• Should be performed/administered/other

• Comparative-Effectiveness Phrases+</

- Treatment/strategy A is recommended/indicated in preference to treatment B

- Treatment A should be chosen over treatment B

Class 2a (MODERATE)

Benefit >> Risk

Suggested phrases for writing recommendations:

• Is reasonable

• Can be useful/effective/beneficial

• Comparative-Effectiveness Phrases $\dagger$

- Treatment/strategy A is probably recommended/indicated in preference to treatment B

- It is reasonable to choose treatment A over treatment B

Class 2b (WEAK)

Benefit ≥ Risk

Suggested phrases for writing recommendations:

● May/might be reasonable

• May/might be considered

• Usefulness/effectiveness is unknown/unclear/uncertain or not well-established

Class 3: No Benefit(MODERATE) (Generally, LOE A or B use only)

Benefit = Risk

Suggested phrases for writing recommendations:

● Is not recommended

● Is not indicated/useful/effective/beneficial

● Should not be performed/administered/other

Class 3: HARM(STRONG)

Risk> Benefit

Suggested phrases for writing recommendations:

• Potentially harmful

· Causes harm

● Associated with excess morbidity/mortality

$\_$ Should not be performed/administered/other

LEVEL(QUALITY) OF EVIDENCE±

Level A

• High-quality evidence\# from more than 1 RCT

• Meta-analyses of high-quality RCTs

•One or more RCTs corroborated by high-quality registry studies

Level B-R

(Randomized)

• Moderate-quality evidence $\pm$ from 1 or more RCTs

• Meta-analyses of moderate-quality RCTs

Level B-NR

(Nonrandomized)

• Moderate-quality evidence $\pm$ from 1 or more well-designed, well-executed nonrandomized studies,observational studies, or registry studies

• Meta-analyses of such studies

(Limited Data)

• Randomized or nonrandomized observational or registry studies with limitations of design or execution

• Meta-analyses of such studies

•Physiological or mechanistic studies in human subjects

Level C-EO

(Expert Opinion)

• Consensus of expert opinion based on clinical experience

COR and LOE are determined independently (any COR may be paired with any LOE).

A recommendation with LOE C does not imply that the recommendation is weak. Many important clinical questions addressed in guidelines do not lend themselves to clinical trials. Although RCTs are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.

*The outcome or result of the intervention should be specified (an improved clinical outcome or increased diagnostic accuracy or incremental prognostic information).

+ For comparative-effectiveness recommendations (COR 1 and 2a; LOE A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.

$\ddagger$ The method of assessing quality is evolving, including the application of standardized, widely-used, and preferably validated evidence grading tools; and for systematic reviews, the incorporation of an Evidence Review Committee.

COR indicates Class of Recommendation; E0, expert opinion;LD, limited data; LOE, Level of Evidence; NR, nonrandomized;R,randomized; and RCT, randomized controlled trial.

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wording and the COR and LOE assignments. In deter-mining the COR, the writing group considered the LOE and other factors, including systems issues, economic factors, and ethical factors, such as equity, acceptability,feasibility, and risk of harm. These evidence review meth-ods, including specific criteria used to determine COR and LOE, are described more fully in "Part 2: Evidence Evaluation and Guidelines Development" of the 2025 Guidelines.

Despite improvements in the design and funding sup-port for emergency care research, the overall quality of the evidence for special circumstances science is very low. Only 2 of the 235 recommendations in these guide-lines are supported by Level A evidence (high-quality evidence from more than 1 randomized controlled trial[RCT] or 1 or more RCTs corroborated by high-quality registry studies). Nine recommendations are supported by Level B randomized evidence (moderate evidence from 1 or more RCTs) and 32 by Level B nonrandomized evidence. The majority of recommendations are based on Level C evidence, including those based on limited data (67 recommendations) and expert opinion (125 recommendations). Accordingly, the strength of recom-mendations is weaker than optimal; 66 Class 1 (strong)recommendations, 84 Class 2a (moderate) recommen-dations, and 58 Class 2b (weak) recommendations are included in these guidelines. In addition, 21 recommen-dations are designated Class 3: No Benefit and 6 recom-mendations are Class 3: Harm. Clinical trials, thoughtfully designed intervention studies with real-world applicabil-ity, and well-controlled observational studies in special circumstances science are needed.

Guideline Structure

These guidelines are organized into modular knowledge chunks grouped into discrete modules of information on specific topics or management issues. Each modular knowledge chunk includes a table of recommendations that uses standard AHA nomenclature of COR and LOE.A brief introduction is provided for topics with multiple sets of recommendations, and a synopsis may also be written to put the recommendations into context with important background information and overarching management or treatment concepts. Recommendation-specific support-tive clarifies the rationale and key study data support-ing the recommendations. When appropriate, figures, flow diagrams, and additional tables are included.

Document Review and Approval

All guidelines were reviewed and approved for publica-tion by the AHA Emergency Cardiovascular Care Sci-ence Advisory Committee, the AHA Scientific Advisory and Coordinating Committee, and the AHA Executive Committee. These guidelines were also submitted for

blinded peer review to subject matter experts nominated by the AHA. Before appointment, all peer reviewers were required to disclose relationships with industry and any other conflicts of interest, and all disclosures were re-viewed by AHA journal staff. Comprehensive disclosure information for peer reviewers is listed in the Reviewer Disclosure Table (Appendix 2).

These recommendations supersede the last full set of AHA special circumstances guidelines, published in 2020, and recommendations from the focused updates on toxicology and drowning. ${ }^{1-3}$

To maintain consistency across the different chapters of the guidelines, the LOE for some recommendations that were previously assigned LOE B-NR(nonrandom-ized) or C-LD(limited data) based on uncontrolled obser-vational studies, case reports, and nonhuman studies were modified to C-EO(expert opinion). Supporting data are provided in the recommendation-specific supportive text.

REFERENCES

1. Dezfulian C, McCallin TE, Bierens J, Dunne CL, Idris AH, Kiragu A, Mahgoub M, Shenoi RP, Szpilman D, Terry M, et al. 2024 American Heart Associa-tion and American Academy of Pediatrics Focused Update on Special Circumstances: Resuscitation Following Drowning: An Update to the Ameri-can Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Resuscitation and Emergency Cardiovascular Resuscitation.

2. Lavonas EJ,Akponunov PD,Arens AM,Babu KM,Cao D,Hoffman RS,Hoyte CO, Mazer-Amirshahi ME,Stolbach A,St-Ongre M,et al;American Heart As-sociation.2023 American Heart Association Focused Update on the Man-agement of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circu-lation.2023;148:e149-e184.doi:10.1161/CIR.00000000000001161

3. Panchal AR, Bartos JA, Cabanas JG, Donnino MW, Drennan IR, Hirsch KG,Kudenchuk PJ, Kurz MC, Lavonas EJ, Morley PT, et al; on behalf of the Adult Basic and Advanced Life Support: Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circu-lation.2020;142:S366-S468. doi: 10.1161/CIR.0000000000000916

MAJOR CONCEPTS

Overview

Survival and recovery from cardiac arrest depend on a complex system working together to achieve the best outcomes. The main focus of treatment of adults and chil-dren in cardiac arrest includes rapid recognition, prompt provision of CPR, defibrillation of malignant shockable rhythms, adequate ventilation, post-return of spontane-ous circulation(ROSC) supportive care, and treatment of underlying causes. This approach recognizes that cardiac arrest is due to either primary cardiac causes, such as myocardial infarction and electric disturbances, or with-out a primary cardiac origin, such as respiratory failure or toxic ingestion. In such cases, treatment for revers-ible underlying causes is important for the rescuer to consider. For any cardiac arrest, rescuers are instructed

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to call for help, perform CPR with breaths, and apply an automated external defibrillator(AED) to directly treat ventricular fibrillation(VF) or ventricular tachycardia(VT),if present. Although the majority of resuscitation success is achieved by the provision of high-quality CPR and de-fibrillation, other specific treatments for likely underlying causes may be helpful in some cases.

These guidelines, focusing on the special circum-stances as etiologies of cardiac arrest, provide and evaluate specific treatment options meant to be admin-istered in addition to, and alongside, traditional resus-citation care. Unless otherwise specified, all patients should receive standard airway management, support of breathing, and treatment of hypotension, arrhythmias,and cardiac arrest consistent with local protocols and the resources available at the site of treatment.

ALTERNATIVE CPR TECHNIQUES

Introduction

In addition to defibrillation, several alternative and pseudoelectrical therapies have been explored as pos-sible treatment options during cardiac arrest. Precordial thump is a single, sharp, high-velocity impact(or“punch”)to the middle of the sternum delivered by the ulnar as-pect of a tightly clenched fist. A precordial thump can generate an electric impulse, theoretically interrupting a life-threatening tachyarrhythmia or“kick-starting” the heart in asystole.' However, if a precordial thump is ad-ministered during the electrically vulnerable portion of an organized rhythm(T wave), like an unsynchronized shock or commotio cordis, there is a risk of deterioration of cardiac rhythm. Percussion(fist) pacing is the delivery of serial, rhythmic, relatively low-velocity impacts to the sternum by the ulnar aspect of a closed fist. This is ad-ministered to stimulate an electric impulse sufficient to cause myocardial depolarization and electrically pace the heart in cases of asystole or a life-threatening bradyar-rhythmia.1 Cough CPR involves a deep breath followed immediately by a cough, repeated every few seconds,to provide transient hemodynamic support at the onset of a hemodynamically significant arrhythmia in a patient who is both conscious and cooperative. Interposed ab-dominal compression CPR is a 3-rescue technique that involves conventional chest compressions combined with alternating abdominal compressions. The dedicat-ed rescuer who provides manual abdominal compres-sions will compress the abdomen midway between the xiphoid and the umbilicus during the relaxation phase of chest compression. Alternative techniques for perform-ing interposed abdominal compression involve use of compression devices. One such device consists of pres-sure application handles, a compression plate, and a display panel showing compression force, and a second device uses a seesaw-like function, causing abdominal

decompression during sternal compression and vice ver-sa.2,3 These devices are not currently available in North America and are therefore outside the scope of these recommendations.

Recommendations for precordial thump, precordial pacing, and interposed abdominal compression in adults and children inform the management of adults and chil-dren in cardiac arrest. Recommendations for cough CPR inform the management of adults and children who have life-threatening arrhythmias but are conscious and able to follow commands.

Recordial Thump

|Recommendations for Precordial Thump in Adults and Children in Cardiac Arrest||| |---|---|---| |COR|LOE|Recommendations| |3: No Benefit|B-NR|1. A precordial thump should not be performed on adults in cardiac arrest.| |3: No Benefit|C-EO|2. A precordial thump should not be performed on children in cardiac arrest.|

Recommendation-Specific Supportive Text

1. The use of a precordial thump during routine car-diac arrest care in the out-of-hospital setting did not improve survival to hospital discharge com-pared with standard CPR in adults in 2 nonran-dominated studies.4,5 Defibrillation, as a first-line intervention, is significantly more likely to result in ROSC.4 In adults, precordial thump resulted in immediate ROSC in some cases of in-hospital cardiac arrest(IHCA) and out-of-hospital cardiac arrest(OHCA) but also led to rhythm degenera-tion, such as from VT to VF or asystole.4,6-9 The majority of reports of successful use of precordial thump are for ventricular arrhythmias in adults with IHCA with success more likely in cases with VT than VF.79-15 There are also cases of a precordial thump successfully causing ROSC in adults with asystole.5,6 There are reports of successful use of a precordial thump for restoration of cardiac out-put in adult cases of induced ventricular tachyar-rhythmias in the inpatient cardiology setting, but the majority of cases failed to respond.16-19 Across studies, there is a lack of standardization in the technique of precordial thump, the number of times it was used, pharmacological therapy administered before or after its delivery, and-in some cases-its timing related to the onset of the arrhythmia.

2.There are no studies on the use of precordial thump during cardiac arrest in children. Extrapolating from data for adults, it can be stated that precordial thump does not improve outcomes compared with standard ALS in OHCA, and there are no compara-tive studies for IHCA. There are case reports of

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serious complications due to the use of precordial thumb in children. 4,5,20

Percussion Pacing

|Recommendations for Percussion Pacing in Adults and Children in Cardiac Arrest|||| |---|---|---|---| |COR|LOE|Recommendations|| |2b|C-EO|1. Percussion(fist) pacing may be considered in adults as a temporizing measure in the witnessed, monitored, in-hospital (eg, cardiac intervention laboratory or intensive care unit (ICU)), onset of asystole or a nonperfusing bradyarrhythmia before loss of consciousness and if performed without delaying definitive therapy.|| |3:No Benefit|C-EO|2. Percussion pacing should not be performed routinely in adults in cardiac arrest.|| |3:No Benefit|C-EO|3. Percussion pacing should not be performed in children in cardiac arrest.||

Recommendation-Specific Supportive Text

1. Limited evidence from adult descriptive studies demonstrates effective use of percussion pac-ing during witnessed inpatient astolic or life-threatening bradycardic events with favorable outcomes of survival to hospital discharge, ROSC,or restoration of cardiac output.21-25

2.No controlled or comparative studies show that the use of percussion pacing improves outcomes com-pared with standard therapy in adults. It would not be appropriate to prioritize percussion pacing over other measures with proven efficacy.25

3.No controlled or comparative studies show that the use of percussion pacing improves outcomes com-pared with standard therapy in children. Two pedi-pared with standard therapy in children. Two pedi-patic cases show successful generation of a QRS complex and pulse with percussion pacing.25,26 It would not be appropriate to prioritize percussion pacing over other measures with proven efficacy.

Cough CPR

|Recommendations for Cough CPR in Adults and Children With Life-Threatening Arrhythmias|||| |---|---|---|---| |COR|LOE|Recommendations|| |2b|C-LD|1. Cough CPR may be reasonable as a temporizing measure in the witnessed, monitored, in-hospital(eg, cardiac intervention laboratory or ICU), onset of a hemodynamically significant tachyarrhythmia or bradyarhythmia before loss of consciousness and if performed without delaying definitive thera-py in adults.|| |3: No Benefit|C-EO|2. Cough CPR should not be performed routinely by adults with life-threatening arrhythmias.|| |3: No Benefit|C-EO|3. Cough CPR should not be performed by children with life-threatening arrhythmias.||

Recommendation-Specific Supportive Text

1.Some evidence suggests that cough CPR increases aortic and left ventricular pressures. ${}^{27,28}$Observational studies describe the use of cough CPR in conscious adults at the witnessed onset of several arrhythmias (VT, VF, high-degree atrioven-tricular [AV] blocks, severe bradycardia, and asys-tole) with successful termination and prevention of loss of consciousness. ${}^{6,27-29}$ In 1 study of 115 adults with Morgagni-Adams-Stokes syndrome and frequent fainting episodes during arrhythmias,patients were trained in cough CPR. On follow-up,66 patients applied cough CPR in a total of 365 events, 80\% of which were reported as effective,but these occurred in an unmonitored setting so the cardiac rhythm at the time of symptoms is unknown. ${}^{28}$ Importantly, while cough CPR may be reasonable in specific circumstances, it may divert time, effort, and attention from clinicians perform-ing high-quality CPR or patients seeking medical attention.

2.No controlled or comparative studies show that use of cough CPR improves outcomes compared with standard therapy in adult patients. The risks are (1) that it delays effective treatment (early call for help, early CPR and defibrillation if the patient loses consciousness and stops breath-ing normally) and (2) that members of the pub-lic who confuse cardiac arrest with heart attack delay seeking help when suffering chest pain or other symptoms indicating a possible ischemic cardiac event. An untrained adult is unlikely to be able to reliably identify a cardiac arrest rhythm in time to initiate coughing to maintain a cardiac output. It would not be appropriate to prioritize cough CPR over other measures with proven efficacy.

3.There are no studies of cough CPR in children.There is risk of delaying effective treatment, and younger children are unlikely to understand or cor-rectly perform the technique. It would not be appro-priate to prioritize the cough CPR over other measures with proven efficacy.

Interposed Abdominal Compression

|Recommendations for Interposed Abdominal Compression in Adults and Children in Cardiac Arrest|||| |---|---|---|---| |COR|LOE|Recommendations|| |2b|B-R|1. The effectiveness of interposed abdominal compression CPR is uncertain in adults.|| |2b|C-EO|2. The effectiveness of interposed abdominal compression CPR is uncertain in children.||

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Recommendation-Specific Supportive Text

1. Two early, relatively small, unblinded adult RCTs of interposed abdominal compression CPR com-pared with standard CPR for IHCA done at a single institution during different time periods showed improved ROSC, short-term survival, and survival to hospital discharge.30,31 Two recent, relatively small,unblinded adult RCTs of interposed abdominal compression CPR in IHCA showed no difference in ROSC.32,33 Two RCTs of adult OHCA did not show any increase in ROSC.34,35.49 More evaluation is needed to define the optimal clinical scenario for this technique.

2. There are no studies on the use of interposed abdominal compression CPR in children. More evaluation is needed to define the optimal clinical scenario for this technique.

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2. Antriz HR, Arawigh R, Richter H, Schmidt S, Rechelet T, Menges M,Burbach H, Schroder J, Schultheis HP. Phased chest and abdominal compression-decompression versus conventional cardiopulmonary resuscit-tation in out-of-hospital cardiac arrest. Circulation. 2001;104:768-772. doi:10.1161/hc3101.093905

3. Li M, Song W, Ouyang YH, Wu DH, Zhang J, Wang LX, Li J. Clini-cal evaluation of active abdominal lifting and compression CPR in pa-tients with cardiac arrest. Am J Emerg Med. 2017;35:1892-1894. doi:10.1016/j.jemar.201706.031

4. Nehme Z, Andrew E, Bernard SA, Smith K. Treatment of monitored out-of-hospital ventricular fibrillation and pulseless ventricular tachycardia utilising the precordial thump. Resuscitation. 2013;84:1691-1696. doi:10.1016/j.resuscitation.2013.08.011

5. Pellis T, Kette F, Lovis D, Franceschino E, Magagin L, Mercante WP: Kohl P. Utility of pre-cordal thump treatment of out of hospital car-diac arrest: a prospective study. Resuscitation. 2009;80:17-23. doi:10.1016/j.resuscitation.2008;10.018

6. Caldwell, G. Millar G, Quinn E, Vincent R, Chamberlain DA. Simple me-chanical methods for cardioversion: defence of the precordial thump and cough version. Br Med J(Clin Res Ed). 1985;291:627-630. doi:10.1136/bmj.291.6946.627

7. Gersch M, Hottinger S, Hess T. Serial chest tumps for the treatment of ventricular tachycardia in patients with coronary artery disease. Clin Cardiol.1992;15:181-188. doi:10.1002/cl.4960150309

8. Miller J, Tresch D, Horwitz L, Thompson BM. Aprahamian C, Darwin JC. The precordial thumb. Annerg Med. 1984;13:791-794. doi:10.1016/s0196-0644(84)80439-4.

9. Rajagopalan RS, Appu KS, Sultan SK, Jagannahan TG, Nityanandan K, Sethrinawans S. Precordial thump in ventricular tachycardia. J Assoc Physi-cans India 197:197:25-729.

10. Befeler B. Mechanical Mechanism of the heart: the therapeutic value in tachyarrhythmias. Chest 1978;73:8323-88. doi:10.1378/chest73.6832

11.Morgera T, Baid N], Schernavari D, Meduggo C, Meariere F. Chest thump and ventricular tachycardia. Pacing Clin Electrophysiol. 1979:269-75. doi:10.1111/j.1540-8159.1979.tb05178.x

12.Nejima J. Clinical features and treatment of ventricular tachycardia as-sociated with acute myocardial infarction). Nihon Ika Daigaku Zasshi.1991;58:40-49. doi:10.1272/jmsn19235.4810

13. Pennington J, Taylor J, Lown B. Chest thump for reverning ven-tricular tachycardia. N Engl J Med. 1970;283:1192-1195. doi:10.1056/NEJ.19701126832204

14. Rahner E, Zeh E.[Regulation of ventricular tachycardia with precordial fist blow]. Med 1978;29:1659-1663.

15. Volkmann H, Klumbies A, Kuhnert H, Paliege R, Dannberg G, Siegert K.[Terminating ventricular tachycardias by mechanical heart stimulation with precordial thumps]. Z.Karadol. 1990;79:717-724.

16. Amir O, Schliamser JE, Nemer S, Arie M. Ineffectiveness of precordial thump for cardioversion of malignant ventricular tacharyrhythmias. Pacing Clin Elec-trophysiol.2007;30:153-156. doi:10.1111/j.1540-8159.2007.00643.x

17. Cotol S, Moldovan D, Carasca E. Precordial thump in the treatment of cardiac arrhythmias(electrophysiologic considerations). Physiologie 1980;17:285-288.

18. Haman L, Parizek P, Vojacek J. Precordal thump efficacy in termination of induced ventricular arrhythmias. Resuscitation. 2009;80:14-16. doi:10.1016/j.resuscitation.2008.07.022

19. Miller J, Addas A, Akhtar M. Electrophysiology studies: precordial thumping patients paced into ventricular tachycardia. J Emerg Med. 1985;3:175-179. doi: 10.1016/0736-4679(85)90069-1

20. Muller GI, Ulmer HE, Bauer JA. Complications of chest thump for termina-tion of supraventricular tachycardia in children. Eur J Pediatr. 1992;151:12-14. doi: 10.1007/BF02073881

21. Iseri LT, Allen BJ, Baron BK, Brodsky MA. Fist pacing, a forgotten procedure in bradyastolic cardiac arrest. Am Heart J. 1987;113:1545-1550. doi:10.1016/0002-8703(87)90697-1

22. Klumbies A, Paliege R, Volkmann H, Volkmann H.[Mechanical emergency stimulation in astysole and extreme bradycardia]. Z Gesamte Inn Med. 1988;43:348-352.

23. Paliege R, Volkmann H, Kumbles A. The first as pace maker. Investigations about mechanical emergency pacing of the heart. Deut Gesundheitswes.1982;37:1094-1100.

24. Scherf D, Bornemann C. Thumping of the precordium in ventricular stand-still. Am J Cardiol. 1960;5:30-40. doi: 10.1016/0002-9149(60)90006-0

25. Eich C, Bleckmann A, Schwarz SK. Percussion pacing-an almost forgotten procedure for haemrodynamically unstable bradycardias? A report of three case studies and review of the literature. Br J Anaesth. 2007;98:4293-433.

26.Ben-Menachem E, Gargy Y, Berkenstadt H, Keidan I, Sidi A, Wignanaski T. Percussion pacing as management of nonresponsive asystole dur-ing pediatric strabismus surgery. J Clin Anesth. 2014;26:332-334. doi:10.1016/j.jclinane.2014.01.011

27.Niemann JT,Rosborough J, Hausknecht M, Brown D, Criley JM. Cough-CPR: documentation of systemic perfusion in man and in an experimental model: a"window" to the mechanism of blood flow in external CPR. Crit Care Med.1980;8:141-146.doi:10.1097/00003246-198003000-00011

20.Betreani 锡三,Shinf J.,Chibelyk J,Czyz Z,Flak Z,Fuotiowski L,Zaorski K,Petenzel T, Zeman S. Self-administered cough cardiopulmonary resuscita-tion(c-CPR) in patients threatened by MAS events of cardiovascular origin.Wad Lek 1998;51:326-336.

29. Marzanski L, Albared JL, Sizatary LJ, Life-threatening arrhythmias stopped by cough. Cor Vasa. 1990;32:401-408.

30. Sack JB, Kesselbrner MR, Bregman D. Survival from in-hospital cardiac arrest with interposed abdominal counterpulsation dur-ing cardiopulmonary resuscitation. JAMA 1992;267:379-385. doi:10.1001/jama.1992.0340035007307

31. Sack JB,Kesselner MB, Jarrad A.Interposed abdominal compression-cardiopulmonary resuscitation and resuscitation outcome during asystole and electromechanical dissociation. Circulation. 1992;86:1692-1700. doi:10.1161/01/cir.86:66.1692

32. Ghanbari Khanghah A, Moghadamnia MT, Panahi L, Pouy S,Aghajani Nardiasi M, Kazemnezhadley Liy E. Effect of Interposed Ab-dominal Compression on Cardiopulmonary Resuscitation Outcomes;a Randomized Clinical Trial. Arch Acad Emerg Med.2022;10:e57. doi:10.22037/aaem.1011.1678

33.Movahedi A. Mihafte SR, Behnam-Voshani H, Reihani H, Kavosi A, Ferns GA, Malekzadeh J. A. Comparison of the Effect of Interposed Abdominal Compression Cardiopulmonary Resuscitation and Standard Cardiopulmo-nary Resuscitation Methods on End-tidal CO_{2} and the Return of Spontane-ous Circulation Following Cardiac Arrest: A Clinical Trial. Acad Emerg Med.2016;23:448-454. doi: 10.1111/acem.12903

34. Materi J, Suveen HA, Thompson BM, Aprahamian C, Darin JC.Pre-hospital IAC-CPR versus standard CPR: paramedic ruscita-tion of cardiac arrests. Am J Emerg Med. 1985;3:143-146. doi:10.1016/0735-6757(85)990038-5

35. Ward KR, Sullivan RJ, Zelenak RR, Summer WR. A comparison of in-terperposed abdominal compression CPR and standard CPR by moni-toring end-tidal PCO2. Ann Emerg Med. 1989;18:831-837. doi: 10.1016/s0196-0644(8)80206-9

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ANAPHYLAXIS

|Recommendations for Adults and Children in Cardiac Arrest From Anaphylaxis|||| |---|---|---|---| |COR|LOE|Recommendations|| |2a|C-EO|1. It is reasonable to fluid resuscitate adults and children in cardiac arrest from anaphylaxis with isotonic IV fluids.|1. It is reasonable to fluid resuscitate adults and children in cardiac arrest from anaphylaxis with isotonic IV fluids.| |2a|C-EO|2. It is reasonable to use extracorporeal CPR (ECPR) for adults and children in cardiac arrest from anaphylaxis refractory to pharmacological interventions.|1. It is reasonable to fluid results, in 3. It may be reasonable to administer glucagon to adults and children who are in cardiac arrest from anaphylaxis with suspected or confirmed concurrent β-blocker use and who are refractory to standard ALS or PALS medications.| |2b|C-EO|4. For adults and children in cardiac arrest from rouronium-induced anaphylaxis, the effectiveness of sugammadex is uncertain.|4. For adults and children in cardiac arrest from rouronium-induced anaphylaxis, the effectiveness of sugammadex is uncertain.| |2b|C-EO|5. For adults and children in cardiac arrest from anaphylaxis, the effectiveness of sugammadex is uncertain.|4. For adults and children in cardiac arrest from rouronium-induced anaphylaxis, the effectiveness of sugammadex is uncertain.|

Synopsis

Anaphylaxis represents a severe multisystem immune mod-ulated reaction to a substance that can occur across all age groups. Common triggers include insects, foods, and medi-cations, such as anesthetics,antibiotics, blood products, and chemotherapeutics. Perioperative anaphylaxis can be chal-lenging to diagnose and has resulted in delayed treatment.1.Anaphylaxis after neuromuscular blockade resulting in car-diac arrest has been associated with high mortality (34.7%)even when ALS guidelines are followed. ${}^{2}$ Acute coronary syndrome resulting from a rare allergic reaction, also known as Kounis syndrome, with patient-specific complexities is beyond the scope of this review. ${}^{3}$

Immune activation can manifest systemically, most commonly affecting the skin, gastrointestinal, pulmonary and cardiovascular systems. The rapidity of onset and progression to airway occlusion with potential cardio-vascular collapse make timely diagnosis and treatment essential for positive outcomes.

Options for treatment of anaphylaxis in the peri-arrest setting include epinephrine(IM or IV), antihistamines,bronchodilators, corticosteroids, glucagon, and discon-tinuation or removal of the trigger.

Our review did not identify any interventional studies for cardiac arrest from anaphylaxis. All reviewed studies were observational studies of anaphylaxis, which included subgroups with cardiac arrest. These recommendations inform the management of adults and children in cardiac arrest from anaphylaxis.

Recommendation-Specific Supportive Text

1. Intravascular volume depletion secondary to fluid extravasation is a reversible cause of cardiac

arrest. The use of isotonic fluid resuscitation for cardiac arrest from anaphylaxis is supported only by case studies. In 1 adult case report, 73% of administered fluid had been reported to extrava-sate to the extravascular space via third spacing and increased vascular permeability during ana-phylaxis.4 In a non-cardiac arrest clinical trial of adult patients with anaphylaxis, patients had more rapid improvement in symptoms with IV fluids.5 There is no data specific to children.

2.Evidence for CPR in the setting of anaphylaxis is limited to case reports. In 1 case series of 6 patients(5 adults and 1 adolescent), only 1 of the 4 adults in cardiac arrest received ECPR.6 The patient survived and had a favorable neurological outcome.In a case series of 6 adults with cardiac arrest from anaphylaxis following succinylcholine exposure,only 1 received ECPR but died after 12 days.

3.Indirect evidence from anaphylaxis-induced hypo-tension in adult case reports supports the admin-istration of glucagon(1-5 mg IV in adults, 20-30 mcg/kg IV push up to 1 mg in children) in the treat-ment of refractory anaphylaxis in patients with con-currentβ-blocker use or suspected exposure.8-10 Administration should not preclude standard ALS or PALS protocols. There is no data specific to children.

4. In an adult observational study of severe anaphy-laxis after exposure to neuromuscular blocking agents, a history of cardiovascular disease other than hypertension was identified as a risk factor for death from cardiac arrest.2 The survival from cardiac arrest in this study was 156/199(78%).Case reports exist suggesting sugammadex as a potential treatment for anaphylaxis associated with rocururonium. However, a case series in adults did not show improvement in outcomes of anaphylaxis without cardiac arrest.11 A second study in adults found decreased vasopressor requirements in 4 of 7 patients who received sugammadex.1 There are no data specific to children.

5. Extrapolation of findings from studies in adults and children indicates that the bioavailability and time to peak blood concentration for equal-dose(eg,mg/kg) IM epinephrine is inferior to IV and intraos-seous(IO) routes of administration. When com-paring pharmacokinetics across different studies,anaphylaxis dose IM epinephrine had lower and delayed peak epinephrine concentrations as com-pared to IV epinephrine in cardiac arrest.12-16 There is limited high-quality data directly comparing IV or IO epinephrine with IM epinephrine, including no data for cardiac arrest secondary to anaphylaxis.In a before-and-after implementation study of an early, first-dose IM epinephrine(5 mg) for 1405 adults with OHCA compared with usual care, IM

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epinephrine was associated with improved survival to hospital admission(adjusted ratio d328 ratio[aOR],1.37;95% CI,1.06-1.77), hospital survival(aOR,1.73;95% CI,1.10-2.71), and favorable neuro-logic status at hospital discharge(aOR, 1.72;95% CI,1.07-2.76).17 Notably, the dose of epinephrine administered by the IM route was much higher than standard ALS or PALS IV or IO dosing and standard dosing for anaphylaxis management.18 In cardiac arrest from anaphylaxis, standard anaphy-laxis IM epinephrine dose may be insufficient.

REFERENCES

1. Harper NJN, Cook TM, Garcez T, Lucas DN, Thomas M, Kemp H, Kong Mar, Linhoar S, Karaman S, Ferguson K, et al. Anaesthesia, surgery and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project(NAP6). Br J Anaesth. 2018;121:172-188. doi: 10.1016/j.jba.2018.04.015

2. Reitter M, Pettipain N, Latarche C, Cottin J, Massy N, Demoly P,Gillet P,Mertes PM; on behalf of the French Network of Regional Pharmacovigilance Centres.Fatal anaphylaxis with neuromuscular blocking agents: a risk factor and man-agement analysis. Allergy.2014;69:954-959. doi:10.1111/all.12426

3.Dai B,Cavaye,J Udd M,Beut J,Weishar A,Hungathan U.Perivative Presentations of Kouni Syndrome: A Systematic Literature Review. J Cardio-ardio thorac Vasc Anesth.2022;36:2070-2076. doi:10.1053/j.jvca.2022.01.042

4. Clarke R, Sadleir P, Van Niekerk AW P, Platt P Q. Quantification of volume loss and haemodynamic changes of Gelofusine-induced anaphylaxis during cardiopulmonary bypass. Anaesth Intensive Care.2011;39:492-495. doi:10.1177/0310057X1103900324

5. Shamir Q, Bartra J, Alvarez O, Lakhani A, Patel S, Tang A, Sim M,Shamji MH, Skypala I, Mills ENC, et al. Cardiovascular changes during peanut-induced allergic reactions in subjects, J Allergi C. Imaging 2021;147:633-642. doi:10.1016/j.jaci.2020.06.033

6. Park H, Kim SM. Kim WY. Cardiac Arrest caused by Anaphylaxis Re-fractory to Prompt Management. Am J Emerg Med. 2022;61:74-80. doi: 10.1016/j.ajem.2022.08.035

7. Le Dorze M, Plaud B, Bembaaa A. A case series of life-threatening succinylcholine-induced anaphyls. Eur J Anaesthesiol. 2017;34:563-566. doi: 10.1097/EJA.00000000000000561

8. Murakami Y, Kaneko S, Yokoyama H, Ishizaki H, Sekino M, Murata H, Hara T. Successful treatment of severe adrenaline-resistant anaphylactic shock with glucagon in a patient taking a beta-blocker: a case report, JA Clin Repa 2021;7:86. doi: 10.1186/s4081-021-00490-40

9. Thomas M, Crawford I. Best evidence topic report. Glacugon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med.J 2005;22:272-273. doi:10.1136/jem.2005.23:0507

10. Lieberman P,Nicklas RA,Randolph C, Oppenheimer J,Bernstein D,Bernstein J,Ellis A, Golden DB, Greenberger P,Kemp et S, an Alnaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol. 2015;11:351-348. doi: 10.1016/jan.2015.07.019

11.PBtr, PLr Care, RC Johnson, GH, Sadier PH. Efficacy of sugmaxen in roccuronium-induced or antibiotic-induced anaphylaxis. A case-control study.

128.Dreborg S H. Kim H. The pharmacokinetics of epinephrine/adrena-line autoinjectors. Allergy Asthma Clinm. 2021;17:25. doi:10.1186/s13223-021-00511-y

13.Duuchavelle T, Robert P, Donazzolo Y, Loyau S, Orlandini B, Lehert P,Lecomte JM, Schwartz JC. Bioavailability and cardiovascular effects of adrenaline administered by Anenap 500 mu8 autoinjector in healthy volu-teers. Br J Clin Pharmacol 2023;89:1012-1019. doi:10.1111/bcp.15545

14.Heradstev BE, Sunde GA, Asjbornsen V, Alhavik R. Wentzel-Larsen T, Heltke J. Pharmacokokinetics of Epinephrine During Car-diac Arrest: A Pilot Study. Resuscitation. 2023;193:110025. doi:10.1016/j.resuscitation.2023.110025

15. Simones FR,Abdova R, LMB, Elo B, Malung R, Ydellon R, BDK, Ren Sanchez-Borges M, Senna GE, Sheikh A, Thong BY; World Allergy Or-ganization. World allergy organization guidelines for the assessment and management of anaphylaxis. World allergy Organ J. 2011;4:13-37. doi:10.1097/WOX0.013e318211496c

16. Turner PJ, Muraro A, Roberts G. Pharmacokinetics of adrenaline autoinjec-tors. Clin Exp Allergy.2022;52:18-28. doi: 10.1111/cea.14055

17. Palatinus HN, Johnson MA, Wang HE, Hoareau GL, Youngquist ST. Early intramuscular adrenaline administration is associated with improved survival from out-of-hospital cardiac arrest. Resuscitation. 2024;201:110266. doi: 10.1016/j.resuscitation.2024.110266

18.Pugh AE,Stoebedin HH,Tonna JE,Hoareau GL,Johnson MA,Youngquist ST.Intramuscular adrenaline for out-of-hospital cardiac arrest is associated with faster drug delivery: A feasibility study. Resuscus Plus.2021;7:100142.doi:10.1016/j.respu.2021.100142

ASTMA

|Recommendations for Adults and Children With Life-Threatening Asthma||| |---|---|---| |COR|LOE|Recommendations| |COR|1.CL|1. In adults and children with life-threatening asthma, sudden elevation in peak inspiratory pressures or difficulty ventilating should prompt evaluation for tension pneumothorax.| |2a|C-LD|2. It may be reasonable to use ECLS for adults and children with life-threatening asthma, children with life-threatening asthma refractory to standard therapies.| |2a|C-LD|2. It may be reasonable to use ECLS for adults and children with life-threatening asthma, children with life-threatening asthma refractory to standard therapies.| |2a|C-LD|3. A ventilation strategy of low respiratory rate and tidal volume is reasonable in adults with life-threatening asthma.| |2a|C-EO|4. A ventilation strategy of low respiratory rate and tidal volume is reasonable in children with life-threatening asthma.| |2b|C-LD|3. Treatment with volatile anesthetics for adults and children with life-threatening asthma refractory to standard therapies may be considered.| |2b|C-EO|6. Active exhalation maneuvers in adults and children with life-threatening asthma refractory to standard therapies may be considered.|

Synopsis

Asthma can lead to cardiac arrest primarily from in-creased lower airway obstruction leading to hypoxemia,hypercarria, respiratory acidosis, and increased intra-thoracic pressure leading to decreased cardiac output.'Care of the patient in the setting of an acute asthma exacerbation includes bronchodilators, steroids, and noninvasive ventilation and in cardiac arrest standard re-suscitation.2 There are insufficient data to comment on the use of magnesium or ketamine in patients with life-threatening asthma

These recommendations inform the management of adults and children with life-threatening asthma exacer-bation, including cardiac arrest.

Recommendation-Specific Supportive Text

1. Tension pneumothorax is a rare life-threatening complication of asthma and a potentially revers-ible cause of cardiac arrest. Although tension pneumothorax usually occurs in mechanically ventilated patients, cases are also reported in spontaneously breathing adults and children.3-5

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High peak airway pressures resulting from positive-pressure ventilation can lead to pneu-mothorax. While difficulty ventilating an adult or child with asthma in extremis is more likely due to hyperinflation and high intrathoracic pressure, evaluation for tension pneumothorax remains important.3-5

2. Multiple observational studies in adults and children have demonstrated the use of ECLS in the context of respiratory failure from asthma refractory to standard care.6-13 Survival rates in these studies are 83.5% to 100%. Most patients in these studies were supported with venovenous ECMO; however, patients with hemodynamic instability in addition to persis-tent hypoxia, hypercarbia, or barotra may require VA-ECMO support.

3 and 4. Acute respiratory failure can precipitate car-diac arrest in adults and children with asthma,which is characterized by severe obstruction leading to air trapping. Because of the limita-tion in exalation air flow, delivery of large tidal volumes at a higher respiratory rate can lead to progressive worsening of air trapping and a decrease in effective ventilation. An approach described in adult asthma patients using lower tidal volumes, lower respiratory rate, and increased expiratory time may minimize the risk of intrinsic positive end-expiratory pressure and barotrauma.14,15 This approach may be extrapo-lated to children with life-threatening asthma.

5.Several observational studies in adults and children have demonstrated the use of volatile anesthetics in the context of respiratory fail-ure from asthma refractory to bronchodilators,steroids, intubation, mechanical ventilation,sedation, and neuromuscular blockade.7,10,16-20 Survival ranged from 87% to 100% in these studies. Two of these studies compared ECLS versus volatile anesthetics.7,10 These studies did not show a significant difference in mortal-ity but had mixed results in other clinical end-points, such as length of stay, complication rate,and occurrence of patient procedures.

6. Adults and children with severe asthma have limited ability to exhale and have a phenome-non known as breath stacking. This, in turn, can lead to an increase in intrathoracic pressure,decrease in venous return, decrease in blood pressure, decrease in coronary perfusion pres-sure, and, ultimately, cardiac arrest. Adults and children manifest with difficulty ventilating, high airway pressure during ventilation, or a sudden decrease in blood pressure. Brief disconnec-tion from the ventilator or a pause in bag-mask ventilation and compression of the thorax to

aid exhalation may relieve hyperinflation. This practice is informed by several case series with mixed conclusions. In 3 case series, adults and children received active exhalation maneuvers via external compression to relieve air trap-ping with improvement in clinical status.21-23 However,1 case series of 4 adults showed no improvement with external compression during exhalation.24

REFERENCES

1. de Latorre FJ. Management of acute severe asthma. Resuscitation.2000;47:335-338. doi:10.1016/s0300-9572(00)00324-5

2. Gayen S, Dachert S, Lashari BH, Gordon M, Desai P, Criner GJ, Cardet JC,Shenoy K. Critical Care Management of Severe Asthma Exacerbations.J Clin Med 2024;13:859. doi:10.3390/jcm13030859

3. Karakaya Z, Demir S, Sagay SS, Karakaya O, Ozdinc S. Bilateral spon-taneous pneumothorax, pneumomediastinum, and subcutaneous em-physema: rare and fatal complications of asthma. Case Rep Emerg Med.2012;2012:242579. doi: 10.1155/2012/242579

4. Leigh-Smith S, Christey G. Tension pneumothorax in asthma. Resuscitation.2006;69:525-527. doi: 10.1016/j.resuscitation.2005.10.011

5. Metry AA. Acute severe asthma complicated with tension pneumotho-rax and hemopheumothorax. Int J Crit Iln Inj Sci 2019;9:91-95. doi: 10.4103/JCICIISJCIIS_83_18

6. Bromberger BJ, Agerstrand C, Abrams D, Serra A, Apsel D, Tipograf Y,Ginsburg ME,Ebright MI,Stanifer BP,Oommen R,et al.Extracorporeal Car-bon Dioxide Removal in the Treatment of Status Asthmaticus. Crit Care Med.2020;48:e1226-e1231.doi:10.1097/CCM.00000000004645

7. Custer CM,O'Neil ER, Paskaradevan J, Rissmiller BJ, Gazzaneo MC. Chil-dren with Near-Fatal Asthma: The Use of Inhaled Volatile Anesthetics and Extracoreporal Membrane Oxygenation. Pediatr Allergy Immunol Pulmonol.2022;35:170-173. doi: 10.10897/ped.2022.0126

8. Ibarra CD, Sangiovanni S, Bautista DF, Calderon-Miranda CA, Cruz GA,Fernandez-Trujillo L. Use of venovenous(VV) extracorporeal membrane oxygenation(ECMO) in near-fatal asthma: a case series. Multidiscip Respir Med.2024;19:943. doi:10.5826/mrm.2024.943

9.Medar SS,Derespina KR,Jakobleff WA, Ushay MH, Peek GJ. A winter to remember! Extracorporeal membrane oxygenation for life-threatening asthma in children: A case series and review of literature. Pediatr Pulmonary 2020;55:E1-E4. doi: 10.1002/ppu.24616

10. Pineda EY, Sallam M, Brueer RK, Perez GF, Wrotnak B, Swayampakula AK, Asthma Cases Treated With Inhaled Anesthetics or Extracorpo-real Membrane Oxygenation: A Virtual Pediatric Systems Database Study of Outcomes. Pediatr Crit Care Med. 2023;24:e937-e402. doi:10.1097/PCC.00000000000000000000000000000

11. Setlur A, Meyer M, Nelson JS, Liedel JL, Kahana M, Maul TM. Pediatric extracorporeal life support for refractory status asthmicus: ELSO Reg-istry trends from the past decade. Artif Organs.2023;47:1632-1640. doi:10.1111/aor.14595

12.Warren A, Chiu YD, Villar SS, Fowles JA, Symes N, Barker J, Camporota L, Harvey C, Ledot S, Scott I, et al; on behalf of the NHS England-commissioned National ECMO Service. Outcomes of the NHS England National Extracorporeal Membrane Oxygenation Service for adults with respiratory failure: a multicentre observational cohort study. Br J Anaethst 2020;125:259-266. doi: 10.1016/j.bja.2020.05.065

13.Yeo HJ, Kim D, Jeon D, Kim YS, Rycus P, Cho WH. Extracorporeal mem-brane oxygenation for life-threatening asthma refractory to mechanical ven-tilation: analysis of the Extracorporeal Life Support Organization registry. Crit Care.2017;21:297. doi: 10.1186/s13054-017-1886-8

14.Leatherman J. Mechanical ventilation for severe asthma. Chest 2015;147:1671-1680.doi:10.1378/chest.14-1733

15.Leatherman JW, McArthur C, Shapiro RS. Effect of prolongation of ex-piratory time on dynamic hyperinflation in mechanically ventilated pa-tients with severe asthma. Crit Care Med. 2004;32:1542-1545. doi: 10.1097/01.ccm.0000130993.43076.20

16.Adi O,Papo FN,Fong CP,Ahmad AH,Roslan NL,Khan FA,Fathil S.In-haled volatiseal membrane gas for severe bronchospasm in the emer-gency department. Am J Emerg Med. 2023;68:213.e5-213.e9. doi:10.1016/j.ajem.2023.04.032

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17. Carrie S, Anderson TA. Volatile anstheetics for status asthmaticus in pedi-atric patients: a comprehensive review and case series. Paediatr Anaesth.2015;25:460-467. doi:10.1111/pan.12577

18.Keenan LM, Hoffman TL, Refractory Status Asthmaticus: Treatment With Sevoflurane.Fed Pract.2019;36:476-479.

19.Kolli S, Opolka C, Westbrook A, Gillespie S, Mason C, Truitt B, Kamat P,Fitzpatrick A, Grunwell JR. Outcomes of children with life-threatening status asthmatics requiring isofluane therapy and extracorporeal life support.J Asthma.2023;60:1926-1934. doi:10.1080/02770903.2023.2191715

20. Lew A,Morrison JM,Amankwah EK,Elliott RA,Sochet AA, Volisale anesthetic agents for life-threatening pediatric asthma: A multicenter retrospective co-hort study and narrative review. Paedat Anaesth. 2021;31:1340-1349.doi:10.111/14.114925

21. Chan EY,Chan PH,Yeung GM,Ng D.Ksynchronized abdominal compres-sion as a novel treatment of life-threatening preschool asthma. J Asthma 2020;57:765-768. doi: 10.1080/02770903.2019.1606234

22. Harrison R. Chest compression first aid for respiratory arrest are due to acute asphystatic asthma. Emerg Med J. 2010;27:59-61. doi: 10.1136/emj;2007056119

23. Myles P, Maddar H, Morgan EB. Intraoperative cardiac arrest after un-recognized dynamic hyperinflation. Br J Aneuth. 1995;74:340-342. doi:10.1093/bja/74.3.340

24. Van der Touw T, Mudaliar Y, Nayyar V. Cardiosrpiratory effects of manu-ally compressing the rib cage during tidal expiration in mechanically ven-tilated patients recovering from acute severe asthma. Crit Care Med.1998;26:1361-1367. doi:10.1097/00003246-19808000-00021

CARDIAC INTERVENTION LABORATORY

|Recommendations for Adults in Cardiac Arrest in the Cardiac Intervention Laboratory||| |---|---|---| |COR|LOE|Recommendations| |2a|C-LD|1. It is reasonable to use mechanical CPR devices to provide chest compressions to adults in cardiac arrest in the cardiac intervention laboratory.| |2a|C-LD|2. It is reasonable to use ECLS in adults in cardiac arrest in the cardiac intervention laboratory when initial therapy is failing.| |2b|C-LD|3. It may be reasonable to use intracoronary epinephrine for adults in cardiac arrest in the cardiac intervention laboratory during percutaneous coronary intervention(PCI).|

Synopsis

Diagnostic and therapeutic cardiovascular procedures-such as coronary angiography, PCI, transtheter valvu-lar intervention, and catheter ablation-are performed in the cardiac intervention laboratory. Potential procedural risks include coronary or myocardial injury associated with coronary ischemia, pericardial effusion or cardiac tamponade, severe valvular dysfunction, or malignant ar-rhythmia, all of which can lead to cardiac arrest. Severe cardiovascular comorbidities are common in these pa-tients, increasing the risk of cardiovascular complications.

Cardiac arrest during PCI has better survival than in other settings, including in-hospital units, likely because of vigilant monitoring, immediate defibrillator availability,established intravascular access, and rapid intervention to treat the cause of cardiac arrest.1-10

Many patients with cardiac arrest in the cardiac inter-vention laboratory will respond to standard advanced cardiovascular life support (ACLS). In some cases,

high-quality CPR may interfere with corrective interven-tions(eg, pericardiocentesis) or vice versa.

These recommendations inform the management of adults in cardiac arrest and do not pertain to adults who are in cardiogenic shock without cardiac arrest or those who are in cardiac arrest prior to arrival in the cardiac interventional laboratory.

These recommendations are specific to adults because studies specific to children were not included in the literature review.

Recommendation-Specific Supportive Text

1. Observational studies in adults have demonstrated the feasibility of using mechanical CPR devices for administering chest compressions to adults in cardiac arrest in the cardiac intervention labo-ratory.11-17 This allows performance of potentially lifesaving interventions, such as PCI or placement of mechanical circulatory support, while avoiding gaps in the performance of CPR. Most studies utilized a mechanical piston device, and 1 used a load-distributing band.11,13-17 Two studies on mechanical CPR in adults in cardiac arrest that specifically occurred in the cardiac intervention laboratory showed 25% survival with good neu-rological outcome, and 1 showed improved out-comes compared with manual CPR.16,17 In another comparative study including adults in cardiac arrest prior to arrival in the cardiac intervention labora-tory, patients receiving mechanical chest compres-sions were more likely to achieve ROSC than those receiving manual chest compressions.15 However,both comparative studies were nonrandomized,had small sample sizes, and compared against a historical cohort, which coincided with major changes in resuscitation guidelines.15,16

2.There are no comparative studies on the use of ECLS versus standard therapy for adults in cardiac arrest in the cardiac intervention laboratory.The rec-ommendation for ECLS is informed by prospective observational studies. ${}^{18-24}$ However, many studies include adults receiving ECLS for cardiac arrest that occurred prior to the cardiac intervention laboratory or ECLS use for cardiogenic shock without cardiac arrest.The Extracorporeal Life Support Organization(ELSO) Registry found survival to hospital discharge was 39% in patients receiving ECLS for cardiac arrest in the cardiac intervention laboratory, with a lower risk-adjusted odds of mortality in this popu-lation than in those with cardiac arrest receiving ECLS in an ICU or in a hospital bed. ${}^{21}$ Notably, some patients in this study received mechanical circula-tory support prior to cardiac arrest, which may con-found outcome data. The largest study of adults who specifically had initial cardiac arrest in the cardiac

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intervention laboratory showed a 30-day survival of 44%.23 There are reports of successful use of standby ECMO in adults undergoing high-risk PCIs and transchate aortic valve replacements in the cardiac intervention laboratory.25,26 Standby ECMO(placement of small-bore vascular sheaths and preprimed ECMO circuits with appropriately sized cannulas ready prior to cannulation) was associated with lower low-flow time, lower rate of acute kidney injury, and improved 30-day survival compared with extemporaneous ECMO(no cannulation or prepa-ration of an ECMO circuit prior to cardiac arrest) in high-risk PCI.25

3. Two prospective cohort studies compared epi-nephrine(1 mg every 3-5 minutes) via intracoro-nary versus IV(peripheral or central) administration in 320 adults who developed cardiac arrest in the cardiac intervention laboratory.2728 Both showed improved outcomes, such as ROSC and survival with favorable neurological outcome, with intracor-onary epinephrine. However, both studies were lim-ited by potential confounding because the route of epinephrine administration was at the physician's discretion and due to some inherent differences between groups.

REFERENCES

1.Addada S, Kahn JK, Moccia F, Harjai K, Pellizon G, Ochoa A, O'Neill WW.Uxtome of ventricular fibrillation developing during percutaneous coronary interventions in 19,497 patients without cardiogenic shock. Am J Cardiovascular fibrillation at reperfusion in patients with acute S tE-velocity myocardial in-farction treated by primary percutaneous coronary intervention. Am J Car-doi 2015;1514;57-142.02:10.1016/jamcard.2014.11.025

2.Demidova MM,Carlson J,Eringe D, Platonog PG. Predictors of ventricular fibrillation at reperfusion in patients with acute S-tE-velocity myocardial in-farction treated by primary percutaneous coronary intervention. Am J Car-doi 2015;1514;57-142.02:10.1016/jamcard.2014.11.025

3.Ekaryoni A, Lopez JJ, Chan PS. Abstract 10476: Patient Characteristics and Survival Outcomes of Cardiac Arrest in the Cardiac Catheterization Laboratory. Insights from Get with the Guidelines-Resuscitation Registry.Circulation.2021;144:A10476. doi: 10.1161/c.144.suppl.2.10476

4. Giglioli C, Margheri M, Valente S. Timing, setting and incidence of cardiovas-cular complications in patients with acute myocardial infarction submitted to primary percutaneous coronary intervention. Can J Cardiol. 2006;22:1047-1052. doi:10.1016/s0828-2982(0)070302-80

5. Henriques JP, Gaeerja PJ, Ottervanger JP, de Boer MJ, Bdmrank JH,Gosselink AT, van t'Hof AW, Hoortje JC, Suryapranah J, Zifstra F. Ventricular fibrillation in acute myocardial infarction before and during primary PCI. Int J Cardiol. 2005;105:262-266. doi:10.1016/j.ijcard.2004.12404

6.Huang JL,Ting CT,Chen YT,Chen SA. Mechanisms of ventricular fibrillation during coronary angioplasty: increased incidence for the small orifice caliber of the right coronary artery. Int J Cardiol. 2002;82:221-228. doi:10.1016/s1027/6573(2001)00568-4

760. The Harhaj, Jr Kajr, Gines L, Stone G, Bourna J, Cox D, O'Neill W,Grines CL; on behalf of Primary Angioplasty in Myocardial Infarction(PAM) Investigators. Sustained ventricular tachycardia or fibrillation in the cardiac catheterization laboratory among patients receiving primary percu-taneous coronary intervention: incidence, predictors, and outcomes. J Am Coll Cardiol 2004;43:1765-1772.doi:1016/j.jacci.2003.09:0727

8.Mehta RH, Starr AZ, Lopes RD, Hochman JS, Widinsky PS, Pieper KS,Amstrong PW, Granger CB; APEX AMI Investigators. Incidence of and outcomes associated with ventricular tachycardia or fibrillation in pa-tients undergoing primary percutaneous coronary intervention. JAMA 2009;3011:1779-1789. doi:10.1001/jama.2009.600

● Sharma R, Bews H., Mahal A, Asselin C OY,Brien L, Hieber B,Ducas J, Jassal DS. In-Hospital Cardiac Inrest in the Cardiac Catheteriza-

tion Laboratory: Effective Transition from an ICU- to CCU-Led Resuscitation Team.J Interv Cardiol.2010;2019:1686350.doi:10.1155/2019/1686350

10.Sprung-J, Ritter MJ, Rihalos CS, Warner ME, Wilson GA, Williams BA, Stevens SR, Schroeder DR, Bourke DL, Warner DO. Outcomes of cardiopulmonary resuscitation and predictors of survival in patients undergoing coronary angiography including percutaneous coronary interventions. Anesth Analg.2006;102:217-224.doi:10.1123/01.ane.0000189082.54614.26

11.Chyrchel M, Halubie P, Duchnevic O, Lazarczyk A, Okarski M, Januszek R, Rzeszutko L, Bartus S, Surdacki A. Prognostic Factors in Patients with Sudden Cardiac Arrest and Acute Myocardial Infarction Undergoing Percuta-neous Interventions with the LUCAS-2 System for Mechanical Cardiopulmo-nary Resuscitation. J Clin Med.2022;11:3872. doi: 10.3390/jcm 11133872

12. Larsen Al, Hjornevik AS, Ellingsen CL, Nilsen DW. Cardiac arrest with continuous mechanical chest compression during percutaneous coro-nary intervention. A report on the use of the LUCAS device. Resuscitation.2007;75:454-459. doi:10.1016/j.resuscitation.2007.05.007

13. Madsen Hardig B, Kern KB, Wagner H. Mechanical chest compressions for cardiac arrest in the cathac-lab: when is it enough and who should go to extracorporeal cardioal pulmonary resuscitation? BMC Cardiovasc Disord 2019;19:134. doi:10.1186/s12872-019-1108-1

14. Spiro JR, White S, Quinn N, Gubran CJ, Ludman PF, Townend JN, Doshi SN. Automated cardiopulmonary resuscitation using a load-distributing bend external cardiopid support device for in-hospital cardiac arrest: a single centre experience of Autiopulse-CPR. Int J Cardiol. 2015;180:7-14. doi:10.1016/j.ijcard.2014.11.109

15.Venturini JM, Retzer E, Estrada JR, Friant J, Beiser D, Edelson D, Paul J, Blair J, Nathan S, Shah AP. Mechanical chest compressions im-prove rate of return of spontaneous circulation and allow for initiation of percutaneous circulatory support during cardiac arrest in the car-diac catheterization laboratory. Resuscitation. 2017;115:56-60. doi: 10.1016/j.resuscitation.2017:03.037

16. Wagner H, Hardig BM, Rundgren M, Zughraft D, Harnek J, Gotberg M,Olivecrone GK. Mechanical chest compressions in the coronary catheter-itation laboratory to facilitate coronary intervention and survival in patients requiring prolonged resuscitation efforts. Scand J Trauma Resusc Emerg Med.2016;24;4. doi:10.1186/s13049-016-0198-3

17. Wagner H, Terkelsen CJ, Friberg H, Harnek J, Kern K, Lassen JF,Olivecra GK. Cardiac arrest in the catheterisation laboratory: a 5-year experience of using mechanical chest compressions to facilitate PCl dur-ing prolonged resuscitation efforts. Resuscitation. 2010;81:383-387. doi:10.1016/j.resuscitation.2009.11.006

18.Gosar T, Krafie R, Radsel P, Fister M, Golikin A, Steblovnik K, Gorjup V,Noc M. Emergency percutaneous implantation of veno-arterial extracoro-real membrane oxygenation in the catheterisation laboratory. Eurolventen-don.2016:12:1465-1472. doi:10.4244/EJ-D-15-00192

19. Grambow DD, Deeb GM, Pavlides GS, Margulis A, O'Neill WW, Bates ER.Emergent percutaneous cardiopulmonary bypass in patients having car-divascular collapse in the cardiac catheterization laboratory. Am J Cardiol.1994;73:872-875. doi: 10.1016/0002-9149(94)90813-3

20.Hyniewicz K, Hart M, Ralle D, Wang Y, Mooney M, Mudy K, Eckman PM,Samara MA, Traverse J, Sun B, et al. Multidisciplinary shock team is as-sociated with improved outcomes in patients undergoing ECPR. Int J Artif Organs.2021:44:310-317. doi:10.1177/0391398820962807

21. Mazzeffi M, Zaaqoq A, Curley J, Buchner J, Wu I, Beller J, Teman N, Glance L. Survival After Extracorporeal Cardiopulmonary Resuscitation Based on In-Hospital Cardiac Arrest and Cannulation Location: An Analysis of the Extracoreporeal Life Support Organization Registry. Crit Care Med 2024. Crit Care Med.2024;42:1906-1917. doi: 10.1097/CCM.0000000000006439

22.Nagao K, Hayashi N, Arima K, Ooiwa K, Kikushima K, Anazawa T, Ohtsuki J, Kanmatuse K. Effects of combined emergency percutaneous cardio-pulmonary support and reperfusion treatment in patients with refractory ventricular fibrillation complicating acute myocardial infarction. Intern Med.1999;38:710-716. doi: 10.2169/internalMedicine.38:710

23.Parr CJ, Sharma R, Arora RC, Singal R, Hiebert B, Minhas K. Outcomes of extracorporeal membrane oxygenation support in the cardiac cath-eterization laboratory. Cathetero-Cardiovasc Interv. 2020;96:547-555. doi:10.1002/cd2849

24. Radsel P, Goslar T, Bunc M, Kelase J, Gorpuj V, Noc M. Emergency veno-arterial extracorporeal membrane oxygenation (VA ECMO)-supported percutaneous interventions in refractory cardiac arrest and profound cardiogenic shock. Resuscitation. 2021;160:150-157. doi:10.1016/j.resuscitation.2020.11.028

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26. Wang LS, Wang Y, Fu HF, Meng X, Li CL, Jiang CJ, Guo D, Xu B, Wang PC, Li Y, et al. Feasibility of standby ECMO with preset femoral vascular sheaths for high-risk transcatheter aortic valve replacement. Perfusion-Uk.2024;40:893-897. doi:10.1177/02676591241263285

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28. Tantawy M, Selim G, Saad M, Tamara M, Mosaad S. Outcomes with intra-coronary as. intrvavenous epinherine in cardiac arrest. Eur Heart J. Qual Care Clin Outcomes.2024;10:99-103. doi: 10.1093/ehjqcc/qcad013

CARDIAC SURGERY

Introduction

Cardiac arrest after cardiac surgery occurs in patients relatively infrequently, although these patients typically have better outcomes than those with other etiologies of cardiac arrest in different settings.'1 Common causes of cardiac arrest in this setting include VF(typically secondary to ischemia or pacemaker malfunction), car-diac tamopade, and severe hypovolemia from bleeding.Unique to this setting is the highly monitored nature of the postoperative ICU as well as the potential for car-diac trauma with chest compressions given the recent surgical suture lines. This population also often has the potential for temporary pacing through epicardial wires attached at the time of the operation as well as the relative ease of performing emergent resternotomy and internal cardiac massage, which provides improved out-put compared with external chest compressions.2 The 2017 Society of Thoracic Surgeons(STS) consensus statement on this topic, including recommendations for children, minimally invasive heart surgeries, LVADs,transplant patients, and sternotomy and nonsternoto-my operations, in addition to evidence review from the writing group informs these guidelines. Further, these societal guidelines are focused on the initial hospitaliza-tion from the operation itself, particularly during the ICU course.1 Refer to other relevant sections of the 2025 AHA guidelines for recommendations related to cardiac arrest during or immediately after cardiac catheteriza-tion(refer to Cardiac Intervention Laboratory) or cardiac arrest in patients with LVADs who are remote from the immediate postoperative period(refer to Left Ventricular Assist Devices).

These recommendations inform the management of adults and children in cardiac arrest after cardiac surgery.

|Recommendations for Adults in Cardiac Arrest After Cardiac Surgery||| |---|---|---| |COR|LOE|Recommendations| |1|B-NR|1. For adults in cardiac arrest after cardiac surgery, external chest compressions should be performed if emergency restermotomy is not immediately available.|

|Recommendations for Adults in Cardiac Arrest After Cardiac Surgery (Continued)|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-EO|2. For adults in VF cardiac arrest after cardiac surgery, if a trained professional witnesses the cardiac arrest, immediate 3-stacked defibrillation should be performed, and CPR should be initiated if defibrillation is not successful within 1 minute.|| |2|C-EO|3. For adults in asystole or a bradycardic arrest after cardiac surgery, if a trained professional witnesses the arrest and temporary pacing wires are already in place, immediate pacing is recommended and CPR should be initiated within 1 minute if pacing is unsuccessful.|| |2|B-NR|4. For adults in cardiac arrest early after cardiac surgery, it is reasonable to perform rapid resterotomy in an appropriately staffed and equipped ICU.|| |2a|B-NR|5. Internal cardiac massage can be useful in adults after cardiac surgery if cardiac arrest develops when the chest or abdomen is open or in the early operative period after cardiothoracic surgery when the chest can be reopened rapidly.|| |2a|C-EO|6. For adults in cardiac arrest after cardiac surgery who are refractory to standard resuscitation, ECLS can be effective.||

Recommendation-Specific Supportive Text

1. Chest compressions following cardiac surgery have the potential for cardiac trauma as demonstrated in adult case reports as well as cardiac trauma in our-ers who have not had cardiac surgery.3.4 However,adult observational studies have not reported such trauma.5.6 External chest compressions remain the primary means of providing perfusion while the chest is closed. In these cases, the benefit of perfusion using external chest compressions out-weighs the risk of potential cardiac trauma.

2. VF is a common presenting rhythm in cases of car-diac arrest after cardiac surgery often secondary to ischemia or pacemaker malfunction. Immediate defi-brillation presents distinct advantages in these adult patients, whereas the potential morbidity associated with external chest compressions or resternotomy may impact recovery. ${}^{7}$ Limited adult data are avail-able from defibrillator threshold testing with backup transthoracic defibrillation using variable waveforms and energy doses ${}^{8-10}$ First-shock success over 90% was observed in most of these studies, though pooled results from 15 studies found a defibrilla-tion success rate of 78% for the first shock, 35%for the second, and 14% for the third. ${}^{11}$ The STS Task Force on Resuscitation After Cardiac Surgery and the European Association for Cardio-thoracic Surgery recommend 3-stacked defibrillations within 1 minute, before initiation of CPR or resternotomy. ${}^{1,7}$This departure from standard ACLS is likely war-ranted in the post-cardiac surgery setting because

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of the highly monitored setting and unique risks of compressions and resternotomy.

3.Immediate pacing of adults in asystole or a bra-dycardic arrest after cardiac surgery is supported by surgical societies.1,7 Available hemodynamic monitoring modalities in conjunction with manual pulse detection provide an opportunity to confirm myocardial capture and adequate cardiac function.When pacing attempts are not successful within 1 minute,standard ACLS including CPR is indicated.

4.No RCTs of resternotomy have been published.Improved outcomes have been observed with rapid resternotomy protocols when performed by experienced health care professionals in an appro-priately equipped ICU.5,6,12-18 Other observational studies show no benefit of resternotomy compared with standard ACLS therapy.19-23 The STS recom-mends that resternotomy be a standard part of the resuscitation protocols for at least 10 days after surgery.1 Resternotomy performed outside of the ICU results in poor outcomes.16,21

5. A systematic review of external cardiac compres-sions compared with internal cardiac massage that included animal studies as well as 9 human stud-ies consistently demonstrated improved cardiac index and coronary perfusion pressure with inter-nal massage.1,2,12,21,24-29 The authors of the sys-tematic review concluded that prompt conversion from external chest compressions to internal car-diac massage improves opportunities for ROSC.2 The STS expert consensus statement and the European Resuscitation Council(ERC) guidelines recommend converting to internal cardiac mas-sage unless brief resuscitation with defibrillation,pacing, or medication is successful.27

6.Many case series in adults, collectively inclusive of over 4000 patients, have reported rescue with ECLS(eg,ECMO, ventricular assist device,cardio-pulmonary bypass[CPB]) in the setting of refrac-tory cardiac arrest or persistent cardiogenic shock after cardiac surgery with a survival range of 36%to 78%.30-34 Cannulation for cardiogenic shock and cardiac arrest postcardiotomy has been demon-strated to be feasible, although with a low survival rate(11%) in adults.35

|Recommendations for Children in Cardiac Arrest After Cardiac Surgery|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-EO|1. For children in cardiac arrest after cardiac surgery, external chest compressions should be performed if emergency resterotomy is not immediately available.|| |2a|C-LD|2. For children in cardiac arrest early after cardiac surgery, it is reasonable to perform resterotomy early in an appropriately staffed and equipped ICU.||

|Recommendations for Children in Cardiac Arrest After Cardiac Surgery (Continued)|||| |---|---|---|---| |COR|LOE|Recommendations|| |2a|C-LD|3. For children in cardiac arrest after cardiac surgery who are refractory to standard resuscitation procedures, ECLS can be effective.|| |2a|C-EO|4. Internal cardiac massage can be useful in children after cardiac surgery if cardiac arrest develops when the chest or abdomen is open or in the early postoperative period after cardiothoracic surgery when the chest can be reopened rapidly.||

Recommendation-Specific Supportive Text

1. Chest compressions following cardiac surgery have the potential for cardiac trauma as demon-strated in adult case reports as well as cardiac trauma in others who have not had cardiac sur-gery.3,4,36 However, adult observational studies have not reported such trauma and external chest com-pressions remain the primary means of providing perfusion while the chest is closed.5,6 No evidence was identified specific to the pediatric population.While there is no specific pediatric data, extrapolat-ing from adult literature to children in cardiac arrest following cardiac surgery, the benefit of perfusion using external chest compressions outweighs the risk of potential cardiac trauma.

2.No RCTs of resterotomy have been published.Outcomes for resterotomy in the pediatric population are extrapolated from mixed positive and neutral studies in adults with rapid rester-notomy protocols in an appropriately equipped ICU.5,6,12-20,22,23,37 One observational study including adults and children showed proportionally greater survival in children with resternotomy and open chest cardiac compression.21 The STS recom-mends that resternotomy be a standard part of the resuscitation protocols for at least 10 days after surgery.1 Resternotomy performed outside of the ICU results in poor outcomes.16,21

3.One study compared children receiving external chest compressions and those receiving ECPR for cardiac arrest post-cardiac surgery.38 Those who received ECPR had an odds ratio for survival of 2.2. Additionally, many case series in children have reported rescue with ECLS(eg,ECMO, ventricu-lar assist device, CPB) in the setting of refractory cardiac arrest or persistent cardiogenic shock after cardiac surgery with a survival range of 36% to 78%.38-46

4. A systematic review of external cardiac compres-sions compared with internal cardiac massage that included animal studies as well as 9 human studies consistently demonstrated improved cardiac index and coronary perfusion pressure with internal

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$\text{massage.}^{1,2,12,21,25,27,28}\text{ One of the 9 human studies}$included 34 children in the analysis. $^{21}$ The authors of the systematic review concluded that prompt conversion from external chest compressions to internal cardiac massage improves opportunities for ROSC. $^{2}$ The STS expert consensus statement and the ERC guidelines recommend converting to internal cardiac massage unless brief resusci-tation with defibrillation, pacing, or medication is successful. $^{2}$

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36.Sokole PE,Shavis J.,Prepance EA.Exansung due to right ven-tricular rupture during closed-chest cardiopulmonary resuscitation. J Emerg Med 2002;23:161-164.d 10:1016/s0736-4679(02)00504-8

37. Rousou JA,Engelman RM,Flacke J,Deaton DW,Owen DG.Emerging Cardiopulmonary Bypass in the Cardiac Surgical Unit Can be a Lifesaving Measure in Postoperative Cardiac-Arrest: Circulation.1994:90:280-284.

38. Kobayashi RL, Gauvreau K, Alexander P, Teele SA, Bembea M, Thiagarajan RR. Higher survival with the use of extracorporealolipmonary resuscitation with conventional cardiopulmonary resuscitation in children undergoing cardiac surgery: Analysis of the Get With the Guidelines registry. Circulation.2021;144:A9588. doi:10.1161/circ.144.suppl.1.1988

39. Alsouf A, Bui Manhi L., Guechef A, Al-Halees Z, Al-Ahahi M, McCrindle BW, Kalloghian A. Results of rapid-response extracorporeal cardiopulmonary resuscitation in children with reetratory cardiac arrestol-lowing cardiac surgery. Eur J Cardiothorac Surg. 2014;45:268-275. doi:10.1093/ejects/etz319

40.Erek E, Aydin S, Suzan D, Yildiz O, Atin F, Kirat B, Demir IH, Demis E.Extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest in children after cardiac surgery, Anfol J Cardiol.2017;17:328-333. doi:10.14744/AnatoJICardiol2016.6658

41. Guo Z,Yang Z,Yhang W,Shen J,Jiang L,Yu X,Wang W.Extracorporeal car-dupolmonary resuscitation in children after open heart surgery, Artif Organs.2019;43:633-640. doi:10.1111/aor.13408

42. Jhang WK, Lee SC, Seo DM, Park JJ. Mechanical circulatory support to control medically intractable arrhythmias in pediatric patients after cardiac surgery. Korean Circ. J 2010;40:471-474. doi: 10.4070/kcj.2010.409.471

43. Kumar J, Agarwal S, Hegde R, Rao S, John C, Reddy C, Maheshwari S. Extracoreporal membrane oxygenation in postoperative pediatric cardiac-surgical cases. Indian Heart J.2009;61:55-57.

44. Polimenakos AC, Rizzo V, El-Zein CF, Ilwihn MN. Post-cardotomy Rescue Tracorporeal Resuscitation in Neonates with Single Ventricle After Intractable Cardiac Arresti: Attention After Hospital Dis-charge and Predictors of Outcome. Pediatr Cardiol 2017;38:314-323: doi:10.1007/s00246-016-1515-3

45.Polimenakos AC,Wojtyla P,Smith PJ,Rizzo V,Nater M,Zein CF E,Ilbawi MN.Post-cardiotomy extracorporeal cardiopulmonary resuscitation in neonates with complex single ventricle: analysis of outcomes. Eur J Cardiothorac Surg.2011;40:1396-1405.doi:10.1016/j.ejcts.2011.01.087. discussion 1405

46.Zeybek C,Avsar MK,Yildirim O,0zyuksel A, Bilal MS.Utilization of Extra-corporeal Membrane Oxygenation In Pediatric Cardiac Surgery: A Single Center Experience,34 Cases in 8 Years.Iran J Pediatr.2017;27:e14402.doi:10.5812/ijp.14402

DRONING

Introduction

Drowning the third leading cause of death from unin-tentional injury worldwide, accounting for 7% of all injury-related deaths.1 Physical trauma, such as head injuries,spinal injuries, or fractures from accidents(eg, diving and

boating accidents), can impair a person's ability to re-main conscious, swim, or stay afloat, increasing the risk of drowning. Drowning generally progresses from initial respiratory arrest due to submersion-related hypoxia to cardiac arrest; thus, it can be challenging to distinguish respiratory arrest from cardiac arrest because pulses are difficult to accurately palpate within the recommended 10-second window. Therefore, resuscitation from cardiac arrest attributable to this specific circumstance must fo-cus on restoring breathing as much as it does circulation.2 cus on restoring breathing as much as it does circulation.2

These guidelines are designed for health care pro-fessionals, trained rescuers, and untrained lay rescuers resuscitating adults and children who have drowned. We have defined trained rescuer as an individual with appro-priate training to perform the task discussed in a given recommendation. This is independent of the individual's occupation or ethical duty to respond. Lifeguards, swim-ming instructors, emergency medical technicians, para-medics, police,firefiters, other volunteers, and off-duty health care professionals, if appropriately trained for the task mentioned in the recommendation, would be considered trained rescuers and would be expected to respond in the recommended manner.3 The Drown-ing Chain of Survival (Figure 1) highlights a series of interventions that reduce drowning-associated mortality when put into action by trained rescuers or untrained lay rescuers.2,4

We acknowledge the contributions of the authors of"2024 American Heart Association and American Acad-emy of Pediatrics Focused Update on Special Circum-stances: Resuscitation Following Drowning: An Update to the American Heart Association Guidelines for Car- diopulmonary Resuscitation and Emergency Cardiovas-cular Care."2,3

In-Water Breaths

|Recommendation for In-Water Breaths for Adults and Children|| |---|---| |COR|LOE| |2b|C-LD| |other|1. It may be reasonable for appropriately trained rescuers to provide in-water breaths to an unresponsive adult or child who has drowned if it does not compromise their own safety.|

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Synopsis

Whenever an unresponsive person is found in the water,the rescuer is confronted with a difficult choice of wheth-er to initiate breaths immediately or once the drowned person has been removed from the water. The drowning process involves initial hypoxia that may progress to re-spiratory arrest followed by cardiac arrest if not promptly addressed.5-12

This recommendation informs the management of adults and children who are unresponsive after drowning and not necessarily confirmed in cardiac arrest.

Recommendation-Specific Supportive Text

1. One retrospective observational study of in-water resuscitation of nonbreathing drowned and adults and children rescued by lifeguards found higher odds of survival to hospital discharge and hospital sur-vival with favorable neurological outcome compared with similar individuals who did not receive in-water resuscitation.12 Rescuers must consider personal safety,availability of equipment, and distance to shore when determining the appropriateness of performing in-water breaths. When respiratory arrest is addressed by breaths that interrupt the drowning process, the death rate is lower (44%)than in those cases that progress to cardiac arrest and receive CPR (93%).67,9-12

REFERENCES

1. World Health Organization. Drowning. 2024. Updated December 13,2024.https://www.who.int/news-room/fact-sheets/detail/drowning. Accessed January 16,2025.

2. Dezufian C, McCallin TE, Bierens J., Dunne CL, Idris AH, Kiragu A, Mahgoub M, Shenoi RP, Szilpiman D, Terry M, et al. 2024 American Heart Associa-tion and American Academy of Pediatrics focused Update on Special Emergency Cardiovascular Care. Circulation.2024;150e51-e516. doi: 10.1161/CIR.00000000000001274

3.McCallin TE,Dezufian C,Bierens J,Dunne CL,Idris AH,Kiragu A,Mahgoub M,Shenoi RP,Spilman D,Terry M,et al.2024 American Heart Associa-tion and American Academy of Pediatrics F usedox of Special Cardiac Resuscitation: Resuscitation Following Drowning: An update to the Ameri-tion and American Academy of Pediatrics F usedox of Special Cardiac Resuscitation(Circumstances: Resuscitation Following Drowing: An update to the Ameri-tion and American Academy of Pediatrics P. Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics 2024;154:e2024068444. doi:10.1542/peds.2024-068444

4. Szplipan D, Webber J, Quan Lens, Jorizot-Leite L, Langendorfer SJ,Beerman S, Lofgren B. Creating a drowning chain of survival. Resuscitation.2014;85:1149-1152. doi:10.1016/j.resuscitation.2014.05:034

5.Abelairas-Gómez C, Tipton MJ, Gonzalez-Salvado V, Bierens J. Drowning:epidemiology, prevention, pathophysiology, resuscitation, hospital treatment.Emergancy.2019;31:270-280.

6.Barala-Furelos R, Abelarias-Gomez C, Palacios-Aguilar J, Rey E,Costas-veiga J, Lopez-Garcia S, Rodriguez-Nunez A. Can surf-lifequards perform a quality cardiopulmonary resuscitation sailing on a lifeboat?A quasi-experimental study. Emerg Med J. 2017;34:370-375. doi:10.1136/emerned-2016-205652

7. Bierens J., Abelairas-Gomez, B. Carcala Furos R, Beerman S, Claesson and Dunne C, Elsenga HE, Morgan P, Mecrow T, Pereira JC, et al. Resus-citation and emergency care in drowning: A scweep review. Resuscitation.2021;162:205-217. doi: 10.1016/j.resuscitation.2021.01.033

8.Bierens JJ, Lunetta P, Tipton M, Warner DS. Physiology of Drown-ing: A Review. Physiology(Bethesda).2016;31:147-166. doi:10.1152/physiol.00002.2015

9. Ghaphery JL. In-water resuscitation. JAMA 1981;245:821. doi: 10.1001/jama.1981.03310330011004

10.Manolios N, Mackie I. Drowning and near-drowning on Australian beach-es patrolled by life-savers: a 10-year study, 1973-1983. Med J Aust 1988;148:165:7,170.doi:10.5694/j.1326-5377.1988.tb112805.x

11. Zspilman D. Near-drowning and drowning classification: a proposal to strat-ify mortality based on the analysis of 1,831 cases. Chest 1997;112:660665. doi: 10.1378/chest.112.3.660

12.Szilpman D, Soares M. In-water resuscitation-is it worthwhile? Resuscita-tion.2004;63:25-31. doi:10.1016/j.resuscitation.2004.03.017

Oxygen Administration Following Drowning

|Recommendation for Oxygen Administration in Adults and Children in Cardiac Arrest Following Drowning||| |---|---|---| |COR|LOE|Recommendation| |1|C-EO|1.Tained rescuers should provide supplemental oxygen if available to adults and children with cardiac arrest following drowning.|

Synopsis

Hypoxia is the major sequela of drowning and when se-vere and prolonged can lead to cardiac arrest. Even with effective CPR, cardiac output, cerebral oxygenation, and blood flow range from 12% to 42% of prearrest values. ${}^{1-3}$Additionally,there is decreased diffusion capacity of the lungs from aspiration. A full discussion of the pathophysi-ology of drowning is beyond the scope of this guideline. ${}^{4}$Adult BLS and pediatric BLS guidelines support the use of maximal available oxygen concentration during CPR(refer to "Part 6: Pediatric BLS" guidelines and "Part 7:Adult BLS" guidelines). Oxygen administration has regu-latory and legal restrictions in several countries and re-quires the provision, use, and maintenance of equipment as well as an understanding of the mechanisms and risks of oxygen administration and storage. Use of oxygen may be limited in low- and middle-income countries. These recommendations inform the management of adults and children in cardiac arrest following drowning.

Recommendation-Specific Supportive Text

1.No study directly addresses the use, timing, or con-centration of oxygen delivery to drowned adults and children. The use of supplementary oxygen during and after CPR is accepted practice for trained res-cuers providing resuscitation from drowning due to the hypoxic nature of the arrest.56 Hypoxemia is associated with decreased survival to hospi-tal admission, and rapid reversal of hypoxemia through prompt bystander CPR is associated with improved survival to hospital admission and neu-rologically favorable survival from drowning.7-15 We do not make a recommendation about the use of pulse oximetry monitoring during drowning because of uncertainty regarding the effectiveness

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or the accuracy of pulse oximetry in the setting of CPR.16-19

REFERENCES

1. Duggal C, Weil MH, Gazurm RJ, Tang W S, Sun O, C'Connell F, Ali M. Regional blood flow during closed-chest cardiac resuscitation in rats. J Appl Physiol(1985) 1993;74:147-152. doi: 10.1152/jappl.199374.11.147

2. Lurie KG, Nemerugut EC, Yanopoulos D; Sweeney D. The M. Physi the Physiology of cardiopulmonary Resuscitation. Anesth Anal. 2016;122:767-783. doi:10.1213/ANE.000000000000000926

3.Silver Dl, Murphy RJ, Babsb CF, Geddes LA. Cardiac output during CPR: a comparison of two methods. Crit Care Med. 1981;9:419-420. doi: 10.1097/000300428-194600-000034

4. Bierens JJ, Lunetta P, Tipton M, Warner DS. Physiology Of Drown-ing: A Review. Physiology(Bethesda), 2016:31:147-166. doi:10.1152/physiol.00002.2015

5. Manolios N, Mackie I. Drowning and near-drowning on Australian beach etés patrolled by life-savers: a 10-year study, 1973-1983. Med J Aust 1988;148:165-7,170. doi:10.5694/j.1326-5377.1988.tb112805.

6.Orlowski JP, Szpliman D. Drowning. Rescue, resuscitation, and reanimation. Pediatr Clin North Am. 2001;48:627-646. doi:10.1016/s0031-3955(05)70331-x

7. BiermaTenl, Hindberg K, Naesheim TO, Suborov EV, Reierth E, Kirov LA, WEbinsedkki KM, Tteirt a R. Rewarming From Hypothermic Car-diac Arrest Applying Extracorporeal Life Support: A Systematic Re-view and Meta-Analysis. Front Med(Lautsana) 2021;18:1-18. doi: 10.3389/fmednet.2021.641633

8.Cantu RM,PrittCM,Samuy N,Wu CL.Predictors of emergency department discharge following pediatric drawing. Am J Emerg Med.2018;36:446-449. doi:10.1016/j.ajem.201708.057

9.Claesson A, Lindqvist J, Herlitz J. Cardiac arrest due to-drowing-changes over time and factors of importance for survival. Resuscitation.2014;85:644-648. doi:10.1016/j.resuscitation.2014.02.006

10. Cohen N, Capa T, Lahat S, Glatsin M, Sadet E, Rimon A. Predic-tors for hospital admission of asymptomatic to moderately symptomatic-atic children after drowning. Eur J Pediatr. 2019;178:1379-1384. doi:10.1007/s00431-019-03429-1

11. Gassler H, M Herm, H. Söthber, F. Bischer M. Survival Follow-ing Lay Resuscitation. Dtsch Arztebl Int. 2020;117:871-877. doi:10.3238/arztebl.2020.0871

12. Kyriacou DN, Arcinue EL, Peek C, Kraus JF. Effect of immediate resuscita-tion on children with submersion injury. Pediatrics 1994;94:137-142.

13. Shenoi RP, Allahabadi S, Rubalcava DM, Camp EA. The Pediatric Submer-sion Score Predicts Children at Low Risk for Injury Following Submersions.Acad Emerg Med.2017;24:1491-1500; doi:10.1111/acem.13278

14. Spindelboev W, Schindler O, Moser A, Hausler F, Wallner S, Strasser C, Haas J, Gemes G, Prause G. Increasing arterial oxygen partial pres-sure during cardiopulmonary resuscitation is associated with improved rates of hospital admission. Resuscitation. 2013;84:770-775. doi:10.1016/j.resuscitation.2013.01.012

15. Tobin JM, Ramos WD, Pu Y, Wernicki PG, Quan L, Rossano J.W. Bystand-er CPR is associated with improved neurologically favourable survival in cardiac arrest following drowning. Resuscitation. 2017:115:39-43. doi:10.1016/j.resuscitation.2017.04.004

16. Holmberg MJ, Nicholson T, Nolan JP, Schexneyard S, Reynolds J, Nation K,Weilford M, Morley P, Soar J, Berg KM K on behalf of the Adult Pediatric Ad-vanced Life Support Task Forces at the International Liaison Jointium on Resuscitation(ILCOR). Oxygenation and ventilation targets after cardiac ar-reast. A systematic review and meta-analysis. Resuscitation. 2020;152:107-115. doi:10.1016/j.resuscitation.2020.04.031

17. Montenji LJ, de Vies W. Schwarte L. Bierens JJ. Feasibility of pulse oximetry in the initial prehospital management of victims of drown-ing: a preliminary study. Resuscitation. 2011;82:1235-1238. doi:10.1016/j.resuscitation.2011.04.019

18.O'Driscoll BR,Howard LS,Earis J,Mak V. British Thoracic Society Guideline for oxygen use in adults in healthcare and emergency settings. BMJ Open Respir Res.2017;4:00e1700. doi:10.1136/bmjresp-2016-000170

19. Shi C, Goodall M, Dumville J, Hill J, Norman G, Hamer O, Clegg A.Watkins CL, Georgiou G, Hodkinson A, et al. The accuracy of pulse ox-imetry in the measuring oxygen saturation by levels of skin pigmentation:a systematic review and meta-analysis. BMC Med. 2022;20:267. doi:10.1186/s12916-022-04258-8

Prehospital Ventilation With or Without Equipment for Adults and Children in Cardiac or Respiratory Arrest Motivation Following Drowning

|Recommendations for Prehospital Ventilation With or Without Equipment for Adults and Children in Cardiac or Respiratory Arrest Following Drowning||| |---|---|---| |COR|LOE|Recommendations| |2a|C-EO|1. It is reasonable for trained rescuers to provide breaths or ventilations by the first means available (eg, mouth-to-mouth, pocket mask, or bag-mask ventilation) for adults and children in cardiac or respiratory arrest following drowning to avoid any delay in ventilation.| |2a|C-EO|2. It is reasonable to provide ventilations using equipment (bag-mask device or advanced airways) for adults in cardiac arrest following drowning.| |2a|C-EO|3. It is reasonable to provide ventilations using equipment (bag-mask device or advanced airways) for adults in cardiac arrest following drowning.| |2a|C-EO|4. It is reasonable to provide rescuers with a respiratory based training program with regular retraining and maintenance of equipment.|

Synopsis

Adequate ventilation is a priority during resuscitation in cardiac arrest following drowning.1,2 This can be achieved with the use of mouth-to-mouth breathing, pocket masks,or other equipment (bag-mask device, supraglottic air-way, or endotracheal intubation) according to the res-cuer's training and availability of ventilatory equipment. In 30:2 CPR following OHCA, lung inflation with bag-mask ventilation is infrequent but is associated with improved ROSC, survival to discharge, and survival with favorable neurological outcomes.3 In OHCA in general, current guidelines support the use of bag-mask ventilation or an advanced airway (supraglottic airway or endotracheal tube), depending on the situation and the skill set of the rescuer (refer to "Part 8: PALS" and "Part 9: ALS" in these guidelines).3 Three RCTs comparing different airway strategies in adult OHCA yielded similar results when the rescuers were adept at advanced airway techniques (eg,endotracheal intubation, supraglottic airway) but inferior outcomes when they were not.4-6 These studies highlight the critical importance of effective ventilation by ensur-ing secondary measures, such as monitoring chest rise and fall.

These recommendations inform the management of adults and children who are either in respiratory arrest without cardiac arrest or who are in cardiac arrest follow-ing drowning.

Recommendation-Specific Supportive Text

1. Providing deaths by the first means available is associated with improved survival to hospi-tal discharge or 30 days for adults and chil-dren in cardiac arrest following drowning.7-10

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No human drowning studies have directly compared the different methods of delivering breaths.1,2 Manikin studies enrolling lefiguards showed that mouth-to-mouth ventilation resulted in fewer chest compression interrupt-tions and more effective ventilation and tidal volume delivery than the use of a pocket mask,bag-mask device, or face shield.11,12

2 and 3. Providing ventilations with equipment has not been compared with no equipment during resuscitation following drowning.1,2 In 2 large observational studies of adults with cardiac arrest from drowning, there was no difference in survival with good neurological outcome between adults who had endotracheal intu-bation and those with surragiotic airway or bag-mask ventilation.13,14 In children with car-diac arrest from drowning, endotracheal intu-bation was associated with worse neurologic outcomes.15,16

4. CPR education research demonstrates that providing effective breaths is a difficult skill to master. Training is most effective when it incor-porates a hands-on aspect and is repeated to build retention.17-19

REFERENCES

1. Bierens J, Abelairas-Gomez C, Barcala Fureso R, Beerman S, Claesson A. Dunne C, Esenga H, Morgan P, Microw T, Pereira J, Inc. et Resus-citation and emergency care in drying: A scoping review. Resuscitation 2021;162:205-217. doi: 10.1016/j.resuscitation.2021.01.033

2. Bereens J, Bray J, Abelaras-Gomez C, Barcala-Furelos R, Beerman S,Claesson and Dunne C, Fukuda T, Jayshree M, A T, L et al. A systematic review of interventions for resuscitation following drowning. Resusc Plus 2023;141:100406. doi 10.1016/j.resuscitation.2023;100406

3.Irdis AH, Aramendi Ecnero A, Leroux B, Jaureguibetia X, Yang BY, Shaver S, Chang MP, Rea T, Kudenchuk P, Christenson J, et al.Bag-Valve-Mask Ventilation and Survival From Out-of-Hospital Car-diac Arrest: A Multicenter Study. Circulation. 2023;148:1847-1856. doi: 10.1161/CIRCULATIONAHA-132.065651

4. Benger JR. Kirby K, Black SbT, Clout M, Lazaroo M, Nolan JP, Reeves BC, Robinson M, Scott LJ, et al. Effect of a Strategy of a Supra-gloitic Airway Device vs Tracheal Intubation During OuH-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial. JAMA 2018;320:779-791. doi: 10.1001/jama.2018.11597

5. Babure P, Alopanio A, Pinero D, Duchaeau BP, Bonson SW, Audavian F, Richard O, de Longueville D, Bouleau G, Devaud ML, et al. Effect of Bag-Mask Ventilation or Endotracheal Intubation During Cardiopulmonary Resuscitation on Neurological Outcome After Out-of-Hospital Cardiorespi-ratory Arrest: A Randomized Clinical Trial. JAMA 2018,319:779-787. doi:10.1001/jama.2018.018.156

6. Wang HE, Schermick R, DAYA MR, Stephens SW, Idris AH, Carlson JN-JColla MR, Herren H, Hansen M, Richmond NJ, et al. Effect of a Strategy of Initial Lryneal Tube Insertion vs Endotracheal Intubation on 72-Hour Survival in Adults With Out-of-Hospital Cardiac Arrest: A randomized Clini-tal Trial. JAMA 2018;320:769-778. doi: 10.1001/jama.2018.7044

78. Huber J, Reuxnitler J, Cheletle B, Babylky E, Chhoury E, Tazourte K,Vilhelm C, El Hiki L, Guinhouya B, Gueynumd PY, et al. Can we identify termination of resuscitation criteria in cardiac arrest are to drawing: results from the French national out-of-hospital cardiac arrest registry. J Eval Clin Pract.2016;22:924-931. doi:10.1111/jep.12562

8.Kyriacou DN Arincue ELL Pekc K, Kraus JF, Effect of immediate resusca-tion on children with submersion injury. Pediatrics 1994,94:137-142.

9. Zspilman D, Soares M. In-water resuscitation-is it worthwhile? Resuscita-tion.2004;63:25-31.doi:10.1016/j.resuscitation.2004.03.017

10. Tobin JM, Ramos WD, Pu Y, Wernicki PG, Quan L, Rossano JW. Bystand-er CPR is associated with improved neurologically favourable survival in cardiac arrest following drowning. Resuscitation. 2017;115:39-43. doi:10.1016/j.resuscitation.2017.04.004

11. Adelborg K, Bjornshave K, Mortensen MB, Espeseth E, Wolff A, Lofgren B.A randomised crossover comparison of mouth-to-face-shield ventilation and mouth-to-pocket-mask ventilation by surf lifeguards in a manikin.An-esthesia. 2014;69:712-716. doi: 10.1111/anae.12669

12. Adelborg K, Dalgas C, Grove EL, Jorgensen C, Al-Mashadi RH, Lofgren B.Mouth-to-mouth ventilation is superior to mouth-to-pocket mask and bag-valve-mask ventilation during lifeguard CPR: a randomized study. Resuscita-tion.2011;82:618-622. doi: 10.1016/j.resuscitation.2011.01.009

13. Ryan KM, Bui MD, Dugas JN, Zvonar I, Tobin JM. Impact of prehospital air-way interventions on outcome in cardiac arrest following drawing: A study from the CARES Surveillance Group. Resuscitation. 2021;163:130-135.doi: 10.1016/j.resuscitation.2020.12.027

14. Yoshimura S, Kiguchi T, Nishioka N, Ikeda N, Takegawa M, Miyamae N, Sumida Y, Kitamura T, Iwami T. Association of pre-hospital tracheal intubation with outcomes after out-of-hospital cardiac arrest by drown-ing comparing to supraglottic airway device: A nationwide propen-sily score-matched cohort study. Resuscitation. 2024;197:110129. doi: 10.1016/j.resuscitation.2024.110129.

15. Joanknecht L, Argent A C, van Dijk M, van As AB. Childhood drowning in South Africa: local data should inform prevention strategies. Pediatr Surg Int.2015;31:123-130. doi: 10.1007/s00383-014-3637-0

16. Komori A, Iriyama H, Abe T. Relationship between cardiopul-monary resuscitation duration and outcomes in children with drowning-induced cardiac arrest. Am J Emerg Med. 2025;87:82-87. doi:10.1016/j.ajem.2024.11.004

17. Chamberlain D, Smith A, Woolhard M, Colquhoun M, Handley AJ, Leaves S,Kern KB. Trials of teaching methods in basic life support(3): comparison of simulated CPR performance after first training and at 6 months, with a note on the value of re-training. Resuscitation. 2002;53:179-187. doi:10.1016/s0300-9572(02)00025-4

18. Kim YJ, Cho Y, Cho GC, Ji HK, Han SY, Lee JH. Retention of cardiopul-monary resuscitation skills after hands-only training versus conventional training in novices: a randomized controlled trial. Clin Exp Emerg Med.2017;48:83-98. doi: 10.15441/ceem.16.175

19. Smith A, Colquhoun M, Woollard M, Handley AJ, Kern KB, Chamberlain D. Trials of teaching methods in basic life support(4): comparison of simulated CPR performance at unannounced home testing af-ter conventional or staged training. Resuscitation. 2004;61:41-47. doi:10.1016/j.resuscitation.2003.12.014

CPR for Adults and Children in Cardiac Arrest Following Drowning

|Recommendations for CPR for Adults and Children in Cardiac Arrest Following Drowning|| |---|---| |COR|LOE| |COR|1. For adults and children in cardiac arrest following drowning and after removal from the water,CPR drying and breaths and chest compressions should be divided.| |2a|B-NR| |2a|For adults in cardiac arrest following drowning, if the rescue is unwilling, untrained, or unable to provide breaths, it is reasonable to provide chest compressions only, until help arrives.| |2b|3. For children in cardiac arrest following drowning, if the rescue is unwilling, untrained, or unable to provide breaths, it may be reasonable to provide chest compressions only, until help arrives.| |2b|4. For adults and children in cardiac arrest following rivers and after removal from the water,CPR rescuers to initiate CPR with breaths first followed by chest compressions.|

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Synopsis

While these recommendations adhere to standard BLS principles, adults and children removed from the water without normal breathing or consciousness have impor-tant physiologic considerations that may modify standard algorithms. Cardiac arrest following drowning is most often due to a hypoxic mechanism, whereas sudden car-diac arrest, particularly in adults, is more likely to occur with fully oxygenated blood. An emphasis on breaths is highlighted in these recommendations.

These recommendations inform the management of adults and children in cardiac arrest following drowning.

Recommendation-Specific Supportive Text

1. Multiple large observational studies of adults and children in cardiac arrest following drown-ing show improved outcomes when CPR included breaths. ${}^{1-4}$

2 and 3. One study including primarily elderly patients in hot tubs found no difference in outcomes between conventional (eg, CPR with breaths)and compression-only CPR. However, the demographics of the individuals who drowned in this study differed from those in most other drowning studies. ${ }^{5,6}$ Most cardiac arrests from drowning are hypoxic in nature, and breaths are important. However, the etiology of the arrest may be unknown and some individu-als in cardiac arrest from drowning will have a primary cardiac etiology where compression-only CPR is reasonable. No pediatric data on compression-only CPR following drowning were identified, thus, the pediatric recommen-dation is extrapolated from the adult data.

4.There is no direct evidence evaluating the sequence of resuscitation in cardiac arrest following drowning in adults or children(eg,airway-breathing-circulation versus circulation-airway-breathing). One small observational study found improved survival and neurologi-cal outcome among nonbreathing adults and children who may have had cardiac arrest following drowning and received immediate in-water breaths compared with delayed on-land resuscitation. ${}^{7}$ A manikin study that was not specific to drowning found that the time to completion of first CPR cycle(30 compres-sions and 2 breaths) was 15 seconds shorter in a compression-first strategy compared with an airway and breathing-first strategy. ${}^{8}$ Initiating CPR with airway, breathing, and chest com-pressions by trained rescuers may be appropri-ate as long as the initiation of breaths does not delay compressions(eg, waiting for ventilation equipment).

REFERENCES

1. Hubert H, Escutnaire J, Michelet P, Babykina E, El Khoury C, Tazarourte K,Vilhelm C, El Hiki L, Guirhouya B, Gueugniaud PY; on behalf GR-RéAC.Can we identify termination of resuscitation criteria in cardiac arrest due to drowning: results from the French national out-of-hospital cardiac arrest registry,J Eval Clin Pract.2016;22:924-931. doi:10.1111/jep.12562

2.Kaneto Y, Owada H, Kamikura T, Nakashima K, Ushimoto T, Inaba H.Advantages of bystander-performed conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest presumably caused by drowning in Japan: a propensity score-matching analysis using an extended nationwide database. BMJ Open. 2024;14:e080579. doi: 10.1136/bmjopen-2023-080579

3. Kiyohara K, Sado J, Matsuyama T, Nishiyama C, Kobayashi D, Kiguchi T,Hayashida S, Kitamura Y, Sobue T, Nakata K, et al. Out-of-hospital cardiac arrests during exercise among urban inhabitants in Japan: Insights from a population-based registry of Osaka City. Resuscitation.2017;117:14-17.

4.Tobin JM, Ramos WD, Pu Y, Wernicki PG, Quan L, Rossano JW. Bystand-er CPR is associated with improved neurologically favourable survival in cardiac arrest following. Resuscitation. 2017;115:39-43. doi:10.1016/j.resuscitation.201704.004

5. Bierens J; International Drowning Researchers' Alliance(IDRA) Kuna Idaho USA. Mouth-to-mouth-ventilation-first in drowning victims. Resuscitation.2020;148:273-274. doi:10.1016/j.resuscitation.2019.12.036

6. Fukuda T, Ohashi-Fukuda N, Hayashida K, Kondo Y, Kukita l. Bystander-initiated conventional vs compression-only cardiopulmonary resuscitation and outcomes after out-of-hospital cardiac arrest due to drowning. Resuscita-tation.2019;145:166-174. doi:10.1016/j.resuscitation.2019.08.026

7. Szilpman D, Soares M. In-water resuscitation-is it worthwhile? Resuscita-tion.2004;63:25-31. doi:10.1016/j.resuscitation.2004.03.017

8. Marsch S, Tschan F, Semmer NK, Zobrist R, Hunziker PR, Hunziker S.ABC versus CAB for cardiopulmonary resuscitation: a prospective, ran-domized simulator-based trial. Swiss Med Wkdy. 2013;143:w13856. doi:10.4414/smw.2013.13856

AED First Versus CPR First in Cardiac Arrest Following Drowning

|Recommendations for the Use of AED in Adults and Children in Cardiac Arrest Following Drowning||| |---|---|---| |COR|LOE|Recommendations| |1|B-NR|1.For adults and children in cardiac arrest following drowning,CPR with breaths should be started before AED or defibrillator application.| |2a|B-NR|2.AED use is reasonable for adults and children in cardiac arrest following drowning.|

Synopsis

Cardiac arrest following drowning is most commonly from a hypoxic drowning process; however, it less com-monly may be from a primary cardiac event.1 Initial shock-able rhythms constitute a minority(2%-12%) of cardiac arrests following drowning but are associated with higher odds of survival.2-8 Shockable rhythms following drown-ing may be less common because of longer durations of submersion or longer response times. The low incidence of shockable rhythm supports the emphasis placed on high-quality CPR with breaths elsewhere in this docu-ment.2,4,6 Individuals may also present with shockable cardiac arrest due to nondrowning causes in an aquatic setting. AEDs are feasible and safe to use in cardiac ar-rest following drowning.9,10 A trend toward more frequent application of AEDs in cardiac arrest following drowning has been demonstrated.11

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These recommendations inform the management of adults and children in cardiac arrest following drowning.

Recommendation-Specific Supportive Text

1. Observational studies in adults and children of OHCA, and specifically cardiac arrest following drowning, show improved survival to hospital dis-charge or 30 days when CPR including breaths were initiated promptly.8,12-14 AED application may present delays to CPR. In a study of 919 adult and children with cardiac arrest from drowning, where only 7.4%had an initial shockable rhythm, an AED was applied before emergency medical services arrival in 32.4%and was associated with a decreased likelihood of favorable neurological outcome in the adjusted analyses (aOR,0.42;95% CI, 0.23-0.77; P<0.005),which may have been due to a delay in the initiation of high-quality CPR with breaths and compressions.8

2. It is difficult to quantify the benefit of AED use in cardiac arrest following drowning given that shock-able rhythms occur less commonly in the drown-ing process. When shockable rhythms are present,AED application is practical and a shockable rhythm confers a survival benefit in studies of adults and children with cardiac arrest after drowning.4,6,8-11,15

REFERENCES

1.Kiyohara K, Sado J, Matsuyama T, Nishiyama C, Kobayashi D, Kiguchi T,Hayashida S, Kitamura Y, Sobut Nakata K, et al. Out-of-hospital cardiac arrests during exercise among urban inhabitants in Japan: insights from a population-based registry of Osaka City. Resuscitation.2017;117:14-17.doi:10.1016/j.resuscitation.201705.025

2. Bierens J, Abelairas-Gomez B, Carala Furelos R, Beerman S, Claesson A Dunne C, Elsenga HE, Morgan P, Mecraw T, Pereira JC, et al. Resus-citation and emergency care in draining: A scoping review. Resuscitation.2021;162:205-217. doi: 10.1016/j.resuscitation.2021.01.033

3.Claesson S, Svensson L,Siversilopter, J, Heritz J. Characteristics and out-come among patients suffering out-of-hospital cardiac arrest due to dropping Resuscitation.2008;76:381-387. doi:10.1016/j.resuscitation.200709.003

4.Dyson K,Morgans A,Bray J,Matthews B,Smith K. Drowing related out-of-hospital cardiac arrest: characteristics and outcomes. Resuscitation.2013;84:1114-1118. doi:10.1016/j.resuscitation.2013.01.020

<BeginOfPara>5.Mgec S, Strad M, Podgordse K. Comparison of the characteristics and outcome among patients suffering from out-of-hospital primary cardiac ar-rest and drowning victims in cardiac arrest. Int JEmergy Med 2009:27-12.doi:10.1007/s12245-0094-008-04

6. Nitta M,Kitamura T, Iwami T,Nadkami VM,Berg RA,Topjian AA,Okamoto Y,Nishiyama C, Nishiyuchi T, Hayashi Y,et al.Oth-of-hospital cardiac arrest due to drowning among children and adults from the Uststein Osaka Project. Re-suscitation.2013;84:1568-1573. doi:10.1016/j.resuscitation.2013.06.017

7.Seesink J,Nieuwenburg SAV,van der Linden T. Bierens J.Circunstances,outcome and quality of cardiopulmonary resuscitation by lifeboat crews Re.suscitation.2019;142:104-110. doi:10.1016/j.resuscitation.2019;07.012

Bobin J, Ramos WD, Yu Wernicki PG, Quan L, Rossano JW. Bystand-er CPR is associated with improved neurologically favourable survival in cardiac arrest following drawing. Resuscitation 2017;115:39-43. doi:10.1016/j.resuscitation.2017.04/2004.

9.Bhanji F, Mancini ME, Sinz E, Rodgers DL, McNeil MA, Hoadley TA, Meeks RA, Hamilton M, Feaney PA, Hunt EHA, et al Part 16: Education, implemen-tation, and teams: 2010 American Heart Association Guidelines for Cardio- pulmonary Resuscitation and Emergency Cardiovascular Care. Circulation.2010;122:S920-S933: doi:10.1161/C/CIRCULATIONAHA.110971135

10.Hoke RS,Heinroth K,Trappe HJ,Wernd K. lsan external defibrating an electric threat for bystanders? Resuscitation 2009;80:395-401: doi:10.1016/j.resuscitation.2009.01.002

11. Buick JE, Lin S, Rac Vek, Brooks SC, Kierzek G, Morrison LJ. Drowning:an overlooked cause of out-of-hospital cardiac arrest in Canada. CJEM 2014;16:314-321. doi: 10.2310/8000.2013.131069

12.Hubert H, Escutnaire J, Michel T, Babykina E, El Khoury C, Tazarourte K,Vilhelm C, El Hiki L, Guirhoya B, Gueugniaud PY; on behalf GR-RéAC.Can we identify termination of resuscitation criteria in cardiac arrest due to drowning: results from the French national out-of-hospital cardiac arrest registry,J Eval Clin Pract.2016;22:924-931. doi:10.111/jep.12562

13.Szilpman D, Soares M. In-water resuscitation-is it worthwhile? Resuscita-tion.2004;63:25-31. doi:10.1016/j.resuscitation.2004.03.017

14.Tobin JM, Ramos WD, Greenshields J, Dickinson S, Rossano JW, Wernicki PG, Markenson D, Vellano K, McNally B; CARES Surveillance Group. Out-come of Conventional Bystander Cardiopulmonary Resuscitation in Cardiac Arrest Following Drowning. Prehosp Disaster Med.2020;35:141-147. doi: 10.1017/S1049023X20000060

15. de Vries W, Bierens JJ, Maas MW. Moderate sea states do not influence the application of an AED in rigid inflable boats. Resuscitation.2006;70:247-253. doi: 10.1016/j.resuscitation.2006.01.008

Public Access Defibrillation Programs for Drowning

|Recommendation for Public Access Defibrillation Programs for Drowning|||| |---|---|---|---| |COR|LOE|Recommendation|| |2a|C-EO|1. Implementation of public access defibrillation programs is reasonable in areas where there is a high risk of cardiac arrest, including aquatic environments.||

Synopsis

Cardiac arrest can occur in high-use public areas, such as airports, parks, beaches, pools, and other areas with high population density, with frequent utilization, where other forms of exercise are performed, or with long distances or response time to the nearest AED.Early defibrillation is as-sociated with increased odds of survival; therefore, ensur-ing public access to defibrillators is important. Public access defibrillation (PAD) programs have been associated with improved outcomes for OHCA.12 Although initial shock-able rhythms from dropping are uncommon (occurring in 2%-12% of cases of cardiac arrest following drowning),for those who do have an initial shockable rhythm, early defibrillation can be lifesaving.3-6 PAD programs have been demonstrated to be cost-effective.7 Targeted AED place-ment compared with nationwide deployment has been demonstrated to have incremental cost-effectiveness;however, cost-effectiveness data for AED placement in aquatic environments are lacking. This recommendation applies only to the programmatic placement of AEDs in aquatic environments (eg, through public policies), not to their specific use in susceptibility following drowning.

Recommendation-Specific Supportive Text

1.There is no direct evidence evaluating PAD pro-grams for cardiac arrest following drowning.Tlyent-six observational studies and 1 RCT evalu-ating PAD programs in adult OHCA and 2 observa-tional studies evaluating PAD programs in pediatric OHCA demonstrated improved outcomes.$^{1,2,9,10}$ Two

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studies of PAD programs for cardiac arrest follow-ing drawing demonstrated feasibility in lifeboat and water park environments.5,11

REFERENCES

1. Olasveengen TM, Mancini ME, Perkins GD, Avis S, Brooks S, Castren M,Chung SP, Considine J, Couper K, Escalante R, et al on behalf of the Adult Basic Life Support Collaborators. Adult Basic Life Support:2020 Interna-tional Consensus on Cardiopulmonary Resuscitation and Emergency Car-dovascular Care Science With Treatment Recommendations. Circulation,2020;142:S41-S91. doi: 10.1161/CIR.00000000000000892

2. Wyckoff MH,Greif R,Rolyt PG,NK QC,Oslevastengin SM,Singletary EM,Soros J,Cheng A, Drennan IR, Liley GH,et al; on behalf of the Collabora-tors.2022 International Consensus on cardiopulmonary Resuscitation and Emergency 4 Emergency Cardiovascular Care Science With Treatment Recommenda-tions: Summary From the Basic Life Support; Advanced Life Support; Pe-diatric Life Support; Neonatal Life Support; Education, Implementation, and Teams; and First Add Task Forces. Circulation. 2022;146:e483-e557. doi:10.1016/CIR.0000000000001095

3. Bierens J,Abelairas-Gomez C,Barcala Furelos R,Beerman S,Claesson A,Dunne C,Elsenga HE, Morgan P, Mecrow T, Pereira JC,et al. Resus-citation and emergency care in drowning: A scoping review. Resuscitation.2021;162:205-217. doi:10.1016/j.resuscitation.2021.01.039

4. Claessa von Senslin, S. Livestfermer, J. Helitz J. Characteristics and out-come among patients suffering out-of-hospital cardiac arrest due to drowning.Resuscitation.2008;76:381-387. doi:10.1016/j.resuscitation.20079.003

5.Seesink J,Nieuwenburg SAV,van der Linden T, Bierens J. Circumstances,outcome and quality of cardiopulmonary resuscitation by life boat crews. Re-suscitation.2019;142:104-110.doi:10.1016/j.resuscitation.2019.07.012

6. Tobin JM, Ramos WD, Pu Y, Wernicki PG, Quan L, Rossano JW. Bystand-er CPR is associated with improved neurologically favourable survival in cardiac arrest following drowning. Resuscitation. 2017;115:39-43. doi:10.1016/j.resuscitation.2017.014.004

7. Andersen LW, Holmberg MJ, Granfeld A, James LP, Caulley L. Cost-effectiveness of public automated external defibrillators. Resuscitation.2019;138:250-258. doi:10.1016/j.resuscitation.2019.03.029

8.Shibahashi K, Sakurai S, Kobayashi M, Ishida T, Hamabe Y. Effectiveness of public-access automated external defibrillators at Tokyo railroad stations.Resuscitation.2021;164:4-11. doi:10.1016/j.resuscitation.202104.032

9. Nakashima, Noguchi T, Tahara Y, Nishimura K, Yasuda S, Onozuka D, Diwari T, Yonemoto N, Nagao K, Nonogi H, et al; on behalf of the Japanese Circulation Society with Resuscitation Science Study Group. Public-access defibrization and neurological outcomes in patients with out-of-hospital cardiac arrest in Japan: a population-based cohort study. Lancet.2019;394:2255-2262. doi:10.1016/S0140/618736(19)32488-2

10.Wyckoff MH, Singlet EM, Soar J, Olsiveengen TM, Greif R, Iley HG,Zideman D, Bhanji F, Andersen LW, Avis SR, et al; on behalf of the COVID-19 Working Group. 2021 International Consensus on Cardiopul-monary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations: Summary From the Basic Life Support: Ad-vanced Life Support; Neonatal Life Support; Education, Implementation, and Teams: First Aid Task Forces; and the COVID-19 Working Group. Resuscita-tion 2021;169:229-311. doi: 10.1016/j.resuscitation 2021;10.040

11. Trappe HJ, Nesslinger M, Schinger OM, Wusswaer H, Becker HJ.[First responder defibrillation in the LAGO-dihe-Theme results and experi-ences]. Herzschrittmacherther Elektrophysiol. 2005;16:103-11. doi: 10.1007/s00399-005-0464-y

ELECTROCUTION

|Recommendation for Adults and Children in Cardiac Arrest From Electrocution||| |---|---|---| |COR|LOE|Recommendation| |1|C-EO|1. Adults and children in cardiac arrest due to electrical injury should receive standard resuscitation.|

Synopsis

Electricity causes various injuries depending on the voltage, duration of contact, type of current(alternat-ing or direct), and pathway of current traveling through the body. ${}^{1}$ Depending on the type of exposure, patients may experience significant burns, traumatic injuries,arrhythmias, cardiac injury, or cardiac arrest. Multiple arrhythmias are described following electrical injuries,including atrial fibrillation, VF, VT, and pulseless elec-trical activity(PEA).1,2 The care of patients with burns,cardiac dysfunction, myocardial infarction, and traumat-ic injuries from electricity is beyond the scope of this recommendation.

These recommendations inform the management of adults and children in cardiac arrest from electrocution.

Recommendation-Specific Supportive Text

1. The mainstay of care of adults and children in cardiac arrest for following electrical injury includes adherence to standard BLS and pediatric BLS as well as ALS and PALS guidelines, including rapid defibrillation and high-quality CPR as well as scene safety for responders. No clinical trials or controlled observational studies are available to inform the care of adults and children in car-diac arrest or peri-arrest following electrical injury.2019;1182;3999

REFERENCES

1. Pleicky D,Vamos M,Bogyi P,Muk B,Stauder D,Racz H,Nyolczas N,Duray GZ,Zacher G,Zima E.Risk of cardiac arrhythmias after electrical accident:a single-center study of 480 patients. Clin Res Cardiol.2019;108:901-908.doi:10.1007/s00392-019-01420-2

2.Sleihaw A, Baker J, Gowers C, Elsom DM, Rashid A. Lightning injuries in Northern Ireland. Ulster Med J. 2018;87:168-172.

3. Caglar A, Ayaz A, Guacicek A, Yildirim A, Karaarslan U, Babaygit A,Duman M. Predictive Factors for Clinical Severity and Cardiopulmonary Ar-rest in Pediatric Electrical Inyssean Turkey. Pediatr Emerg Care.2018;34:661-664. doi:10.1097/PEC.000000000000832

4. Jadhav DR, Vijaya L, Alexis J, Pandit V. Survival after prolonged cardiopul-monary resuscitation in cardiac arrest due to electric shock. J Acute Dis.2018;7:137-138. doi: 10.4103/2221-6189.236830

5. Motawane M, Al-Kenany AS, Hosny M, Aglan O, Samy M, Al-Abd M. Sur-viral without sequel after prolonged cardiopulmonary resuscitation after electric shock. Am J Emerg Med. 2016;34:679.e1-679.e2. doi:10.1016/j.ajem.2015.06.059

6. Shekhar AC,Campbell T,Mann NC,Blumen I.Etiology affects predictors of survival for out-of-hospital cardiac arrest. Am J Emerg Med. 2022;57:218-219. doi:10.1016/j.ajem.2022.02.017

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GAS EMBOLISM

Recommendations for Adults and Children With Life-Threatening Gas Embolism

|COR|LOE|Recommendations| |---|---|---| |1|C-EO|1. Adults and children with life-threatening gas embolism should receive 100% oxygen.| |2a|B-NR|2. It is reasonable to use hyperbaric oxygen for adults with life-threatening gas embolism.| |2a|C-EO|3. It is reasonable to use hyperbaric oxygen for children with life-threatening gas embolism.| |2a|C-EO|4. It is reasonable to position adults and children with life-threatening gas embolism supine or in the recovery position, on a level surface.| |2b|C-EO|5. For adults, it may be reasonable to attempt aspiration of life-threatening right ventricular gas embolism, using a needle or a catheter, when the location of gas is known and accessible.|

Synopsis

Arterial or venous gas embolism can occur due to medi-cal intervention, trauma, barotrauma, decompression sickness, and other causes. Bubble composition may comprise air, nitrogen, and carbon dioxide.1

Gas in the arterial system rises to the least dependent vascular bed. Cerebral arterial gas embolism can occlude arteries, causing ischemic stroke. Coronary artery gas embolism can cause myocardial infarction, cardiogenic shock, or cardiac arrest. Venous gas can occlude right ventricular or pulmonary arterial blood flow, causing shock and cardiac arrest. Venous gas can reach the arte-rial system (“paradoxical gas embolism”) through a patent foramen ovale or transpulmonary passage. In addition to obstructing blood vessels, gas embolism causes vascular injury, vasospasm, and thromboinflammation. ${}^{2}$

Whether the same treatment is ideal for arterial and venous gas embolism, for all types of gas, or for all mech-anisms of embolism production is unclear. No clinical tri-als have been conducted, and animal studies may not fully translate to humans. Treatment is informed by many case reports, case series, and observational comparison studies, almost all involving adults.

Nothing about the presence of gas embolism pro-vides a contraindication to standard resuscitation, and some patients recover with standard resuscitation alone.3

The use of lidocaine or other medications for neuro-protection in patients with stroke due to cerebral arterial gas embolism is outside the scope of these guidelines.

These recommendations inform the management of adults and children with life-threatening gas embolism,including cardiac arrest.

Recommendation-Specific Supportive Text

1.In addition to treating tissue hypoxia, supple-mental oxygen increases the diffusion of nitro-gen out of gas bubbles while also improving

<EndOfPara>oxygenation of adjacent ischemic tissues. ${ }^{4}$ This recommendation is supported by adult and pediatric case reports. ${ }^{5}$

2 and 3. Hyperbaric oxygen therapy for gas embolism is supported by 2 adult nonrandomized observa-tional studies, adult case series, limited pediatric case series, and animal studies.3,6-10 Hyperbaric oxygen therapy compresses gas bubbles,increases diffusion of nitrogen and other gases from the bubble, oxygenates adjacent tissue,and reduces inflammatory cascades.11 It is not feasible to provide hyperbaric oxygen therapy for patients in cardiac arrest in most settings.

4.The Undersea and Hyperbaric Medical Society recommends that people with gas embolism who have normal mental status be positioned supine and that those with altered mental status be positioned in the recovery position, which is consistent with standard first aid principles.12-14 The US Navy Diving Manual also recommends level positioning during transport to definitive therapy.15 Neither organization currently recom-mends head-down (Trendelenburg) positioning.These recommendations are not universally accepted, with some experts recommending the Durant position (left lateral decubitus, head down), at least for venous gas embolism.16,17 Studies of whether head-down positioning results in redistribution of intravascular bubbles are contradictory, and limited animal data sug-gest that head-down positioning may worsen cerebral edema.18-21 Effective CPR cannot be performed in the recovery (lateral decubitus)position, and standard resuscitation practice calls for compressions to be administered with the patient positioned supine (refer to "Part 7:Adult BLS" guidelines). Treatment recommen-dations from the Undersea and Hyperbaric Medical Society do not comment on age; sup-porting data are largely based on animal studies and adult case reports, and, thus, recommenda-tions for children are extrapolated.

5.Aspiration of gas from the right ventricle using either a needle or catheter is described in adult case reports and animal studies.22-24 The suc-cess rate of this procedure and whether it can safely be performed without ultrasound or fluo-roscopic guidance is unknown.26 No data were identified for gas aspiration in children.

REFERENCES

1.Muth CM,Shank ES.Gas embolism.NEngl JMed.2000;342:476-482.doi:10.1056/NEJM200002173420706

2. Pontier JM, Vallee N, Ignatescu M, Bourdon L. Pharmacological inter-vention against bubble-induced platelet aggregation in a rat model of decompression sickness.J Appl Physiol(1985).2011;110:724-729. doi:10.1152/jappphysiol.00230.2010

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3. Hatling D, Hogset A, Gutsmortsen AB, Muller B. Latrogenic cerebral gas embolism-A systematic review of case reports. Acta Anaesthesiol Scand 2019;63:154-160. doi:10.1111/aas.13260

4. Aririel Y, Ariel R, Max A. Hyperbaric oxygen may reduce gas bubbles in decompressed war by eliminating gas nuclei. J Appl Physiol(1985).2002;92:2596p-2599. doi: 10.1152/jappphysiol.01059.2001

5. Bisclegia M,Simeone A,Forlano R,Andriulli A,Plato A,Fatal systemic venous air embrolism during endoscopic retrograde cholangioperanatography. Adv Anat Pathol.2009;16:255-262. doi:10.1097/PAP0b013e3181aab793

6.Beevor H.Frawley,G. lanogenic cerebral gas embolism: analysis of the pre-sentation, management and outcomes of patients referred to The Alfred Hospital Hyperbaric Unit. Diving Hyperb Med 2016;46:15-21.

7. Rivera J.C. Decompression sich amounts diver: an analysis of 935 cases.1-63. Rep US Navy Exp Diving Unit: 1963;1:37. doi: 10.21236/ad0400368

8. van Hulst RA, Drenthenis, H. Jaitma, J. Lamis TW, Vesser GH, Klein J.Lachmann B. Effects of hyperbaric treatment in cerebral air embolism on intra-cranial pressure, brain oxygenation, and brain glucose metabolism in the pig.Care Med 2005;33:8341-846. doi:10.1097/01.0001.0000159529.26114.ca

9. van Hulst RA, Klein J, Lachmann B. Gas embolism: pathophysiol-ogy and treatment. Clin Physiol Funct Imaging. 2003;23:237-246. doi:10.1046/j.1475-079x.2003.00505.x

10. Weenink RP, Hollmann MW, Vrijdag XC, Van Lienden KP, De Boo DW,Stevens MF, Van Guidk KM, Van Huart, HLaric Hyperabic oxygen does not improve cerebral function when started 2 or 4 hours after cerebral arte-rial gas embolism in swine. Crit Care Med. 2013;41:1719-1727. doi:10.1097/CCM0b01e382a8e300

11. Moon B. Ruggand in the brain: what to do for arterial gas embolism? Criti Care Med 2005;33:909-910. doi:10.1097/01.cm.0000159726.47336f8

12. Hewber Emburg EK, Doum MA, Albertis K, Chartun NP, Goldman MP:Harper-Kirsey K, Hawkins SC, Hoover AV, Kule A, Leichtle S, et al; on behalf of the American Heart Association and American Red Cross. 2024 American Heart Association and American Red Cross Guidelines for First Aid.Circulation.2024;150:e519-e579.doi:10.1161/CIR.00000000000001281

13. Mitchell S1, Bennett Ml, Byos Pbert, Butler K008, DJother KM, Holr J., LaFere P. Consusensus guideline: Pre hospital management of decompres-sion illness: expert review of key principles and controversies. Undersea Hy-perb Med 2018,45:2073-286.

14. Moon RE. Hyperbaric treatment of air or gas embolism: current rec-ommendations. Undersea Hyperb Med. 2019;46:673-683. doi: 10.22462/10.2012.19.13

15. US Department of the Navy, Naval Sea Systems Command, Supervisor of Savage and Diving. US Navy Diving: Manual: Volumes 1-5. Revision 7,Change A(SS521-AG-PRO-010/0910-LP-115-1921). Washington, DC: US Department of the Navy; April 30,2018.https://www.navnavay.nmil/Portals/103/Documents/SUPAVS/Living/US/203DDING%20MANU-AL_REV_7ChangeA_6-6.18.pdf.Accessed June 12,2025.

16. Chuang DY, Sundararajan S, Sundararajan VA, Feldman DI, Xiong W. Accidental Air Emboins. Stroke.2019;50:e183-e186. doi:10.1161/STROKEVA.119.025340

17. Marsh PL,Moore EE,Moore HB,Bunch CM,Aboukhaled M,Condon SM 2nd,AI-Fadhl MD,Thomas SJ, Larson JR, Bower CW,et al.latrogenic air embo-lism: pathoanatomy, thromboinflammation, endothelopathy, and therapies.Front Immunol.2023;14:1234009.48; doi:10.3389/fmmu2023,1234009

18. Butler B, Daine GA, Leiman BC, Warters D, Kurusz M, Sutton T,Katz J. Effect of the Trendelenburg position on the distribution of ar-terial air embol in dogs. Ann Thorac Surg. 1988;45:198-202, doi:10.1016/s003-4975(10)62437-x

19. Dutka AJ, Polychronidis JE, Mink RB, Hallenseck JM. The Trendelenburg position after cerebral air embolism in dogs: effects on the somatosensory evoked potential, intracranial pressure, and blood-brain barrier. Technical Report NMR 90-116 (AD-2233 B09). Bethesda, MD: Naval Real re-search Institute; 1990.

20.Geissler HJ, Allen SJ, Mehlhorn U, Davis KL, Morris WP, Butler BD, Effect of body repositioning after venous air embolism. An echocardiographic study. Anesthesiology. 1997;86:710-717. doi:10.1097/00000542-199703000-00024

21. Mehhlom U, Burke EJ, Butler BD, Davis KL, Katz J, Melamed E, Morris WP, Allen SJ. Body position does not affect the hemodynamic response to venous air embolism in dogs. Anesth Anal. 1994;79:734-739. doi:10.1013/0000539-19941000-000020

22.Adornato DC, Gildenberg PL, Ferrario CM, Smart J, Frost EA. Pathophysiol-ogy of intravenous air embols in dogs. Anesthesiology. 1978:49:120-127.doi:10.1009/000542-05642-17808-0000013

23. Rothenberg F, Schumacher JR, Rosenthal RL. Near-fatal pulmonary air embolus from presumed inadvertent pressure placed on a partially empty

plastic intravenous infusion bag. Am J Cardiol. 1994;73:1035-1036. doi: 10.1016/0002-9149(94)90170-8

24. Stallworth JM, Martin JB, Postlethwait RW. Aspiration of the heart in air embolism. J Am Med Assoc.1950;143:1250-1251. doi:10.1010/jama.1950.82910490010008

25. Mirski MA, Lele AV, Fitzsimmons L, Toung TJ. Diagnosis and treat-ment of vascular air embolism. Anesthesiology. 2007;106:164-177. doi: 10.1097/00000542-200701000-00026

HIGH-CONSEQUENCE RESPIRATORY PATHOGENS

|Recommendations to Reduce the Risk of Transmission of High- Consequence Respiratory Pathogens During Treatment of Cardiac Arsetti Adults and Children|||| |---|---|---|---| |COR|LOE|Recommendation|| |COR|C1|1. Chest compressions, bag-mask ventilation, defibrillation, suctioning, and endotracheal tubation should be considered aerosol- generating procedures(AGPs) for adults and children with confirmed or suspected high- consequence respiratory pathogens.|| |COR|1|C-LD|2. Resuscitation team members should wear PPE when in the resuscitation environment, including respiratory protection(N-95 respirator or purifying air-powered respirator),eye protection,gloves,and protection against contamination of clothing.| |COR|1|C-LD|3. When performing endotracheal intubation of adults with confirmed or suspected high-consequence respiratory pathogens, video laryngoscopy is preferred compared with direct laryngoscopy.| |1|C-EO|4. When performing endotracheal intubation of children with confirmed or suspected high-consequence respiratory pathogens, video laryngoscopy is preferred compared with direct laryngoscopy.|| |1|C-EO|5. Whenever possible, all ventilation devices applied to adults and children with confirmed or suspected high-consequence respiratory pathogens should include a high-efficiency particle air filter to remove fugitive aerosols from ventilation device outflow.|| |1|C-EO|6. Resuscitation team leaders should minimize the number of people present in the room during resuscitation, consistent with effective resuscitation.|| |2a|C-LD|7. It is reasonable to dedicate a resuscitation team member to monitor and coach team members to adhere to PPE procedures.|| |2a|C-LD|8. It is reasonable to use mechanical CPR devices to provide compressions in adults with confirmed or suspected high-consequence respiratory such suspected high-consequence respiratory pathogens, video laryngoscopy is preferred compared with direct laryngoscopy.|| |2a|C-LD|8. It is reasonable to use mechanical CPR devices to provide compressions in adults with confirmed PCR quality while reducing the number of at-risk resuscitation team members.|| |2a|C-EO|9. It is reasonable to perform endotracheal intubation, which than other than the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the right and the||

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Recommendations to Reduce the Risk of Transmission of High-Consequence Respiratory Pathogens During Treatment of Cardiac Arrest in Adults and Children(Continued)

|COR|LOE|Recommendations| |---|---|---| |3:No Benefit|C-LD|11. The use of intubating boxes and other improvised barrier devices during intubation of adults and children with confirmed or suspected high-consequence respiratory pathogens is not recommended.|

Synopsis

Worldwide pandemics caused by high-consequence pathogens, as termed by the Centers for Disease Control,are common. Recent examples include SARS(2002-2003), influenza H1N1(2009-2010), Middle East respiratory syndrome coronavirus(MERS-CoV, approxi-mately 2012-2015), and SARS-CoV-2(or COVID-19,approximately 2019-2022).These infections are spread by direct contact with a combination of respiratory se-cretions, droplets, and aerosols.1 Effective vaccines and treatment may not be available during the early stages of a pandemic, putting resuscitation team members at risk.The AHA released interim guidance for BLS and ALS modifications for patients with suspected or confirmed SARS-CoV-2 in 2020 and 2022 to provide effective re-suscitation while minimizing risk.2.3 The recommendations in this section supersede that guidance, broaden the recommendations to encompass all high-consequence pathogens, and acknowledge the limitations of not know-ing the transmissibility of future pathogens.

Most studies in this area relate to IHCA, with less litera-ture related to emergency medical services personnel and almost no studies related to lay rescuers. Lay rescuer CPR rates decreased in some regions during the early stages of the SARS-CoV-2 pandemic, and resuscitation outcomes from OHCA were worse compared with before the pan-demic.4-8 Availability of PPE may improve laypeople's will-ingness to perform CPR.9 The most effective strategy to protect members of the general public providing CPR dur-ing a disease outbreak represents a major knowledge gap.

Ethics."

Recommendation-Specific Supportive Text

1. Systematic reviews identified CPR, bag-mask ventilation, intubation, and suctioning as AGPs. ${}^{10-}$ ${}^{16}$ Other studies were less conclusive about CPR, intubation, and suctioning as AGPs. ${}^{10,17-20}$A human and animal study that evaluated aero-sol particle concentration during cardiac arrest found that compressions, bag-mask ventilation,and defibrillation all generate aerosols. ${}^{21}$

2. The use of PPE, including respiratory protec-tion, eye protection, gloves, and barrier gowns

reduces the risk of infection to health care personnel.10,13-15,17 In an observational study of over 1500 health care professionals wearing PPE for approximately 180 SARS-CoV-2-positive patients requiring AGPs, only 1 health care professional became positive in the 2 weeks after the encounter.22,23 For prehospital professionals wearing PPE, only 1% became SARS-CoV-2 positive following care for approximately 190 patients with SARS-CoV-2 receiving AGP.24 Simulation studies show a delay in CPR ini-tiation of 30 to 60 seconds to don PPE.11,25-27 Simulation studies about the effect of PPE on CPR quality are mixed.15,28-45 An IHCA study of 800 adult resuscitations before and after implementation of a resuscitation PPE policy showed a delay to initiation of compressions by 20 seconds, 2 minutes for rhythm analysis, no difference to first shock, 1 minute for epineph-rine, and 1 minute 40 seconds for intubation.46 A prospective observational study found simi-lar first-pass intubation success when intuba-tion(98% adults) was performed by a health care professional wearing full PPE.47 No differ-ence in survival was found in this study or in 2 other studies of adult OHCA and emergency department resuscitation.48,49 In a prospective observational study of 3435 adult emergency department intubations, rates of peri-intubation adverse events were not increased when full barrier PPE was used.22

(98% adults) was performed by a health care professional wearing full PPE.47 No differ-ence in survival was found in this study or in 2 other studies of adult OHCA and emergency department resuscitation.48,49 In a prospective observational study of 3435 adult emergency department intubations, rates of peri-intubation adverse events were not increased when full barrier PPE was used.22

3 and 4. Simulation studies and adult observational studies of intubations with PPE use suggest that operators wearing PPE could perform video laryngoscopy faster than direct laryngos-copy with similar intubation success rates and that video laryngoscopy could be performed with the intubator's face farther from the source of aerosols. ${}^{50-53}$ One adult observational study showed increased time to intubation with video laryngoscopy compared with direct laryngoscopy. ${}^{50}$ A large RCT of adult intubation conducted near the end of the SARS-CoV-2 pandemic(March to November 2022) found better first-attempt intubation success with video laryngoscopy than direct laryngoscopy. ${}^{54}$The type of PPE used was not reported in this study. No pediatric data on the use of video ver-sus direct laryngoscopy with PPE were identi-fied, thus, the recommendation for children is extrapolated from the adult data.

5. High-efficiency particle air and high-efficiency bacterial-viral filters remove more than 99.9%of transmissible viruses and other infectious aerosols from prefiltered air. Placing a filter

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with high viral filtration efficacy on the exhaust limb of ventilation devices, such as bag-mask ventilation devices or bag devices attached to a tracheal tube or supraglottic airway, reduces fugitive aerosol emissions in the treatment environment and is, therefore, recommended by anesthesiology safety groups and other organizations.55-62

6.Decreasing the number of people in the room during resuscitation reduces the number of people at risk of disease transmission. A simu-lated study showed that although quality of CPR metrics did not change with less person-nel in the room, there was a delay in resuscita-tion task completion with less personnel in the room. ${}^{25}$ An audio link to team members outside the room enables tasks, such as contempora-neous clinical documentation and drug prepa-ration, to be performed by personnel outside the high-risk environment.

7.Resuscitation team adherence to proper PPE procedures is often incomplete, and proper mask fit during compressions can be compro-mised.11,22,26,63,64 Just as assigning a team mem-ber to monitor and provide real-time feedback about CPR improves CPR quality, dedicating a team member to supervise PPE use may improve PPE adherence and, therefore, team member safety.Ideally,this would be done with-out exposing an additional person to the infec-tious resuscitation environment. It is standard in cases of suspected viral hemorrhagic fever to have a“trained observer” who is dedicated to providing real-time feedback to team members about their PPE use.65,66 This concept has been tested in simulated SARS-CoV-2 resuscitation and using remote video monitoring. 26,67-69

8.$$\begin{array}{l}\text{ Performing\,chest\,compressions\,while\,wear-}\\ \text{ing\,PPE\,increases\,rescerue\,fatigue,}\,and\,sev-}\\ \text{eral\,simulation\,studies\,show\,that\,wewin-}\\ \text{PPE\,also\,negatively\,mpassions\,compression}\\ \text{depth\,and\,resuscitation\,timing}.\,15,29,30,36,41,45-70,73\\ \text{Mechanical CPR devices\,can\,maintain\,high-}\\ \text{quality\,chest\,compressions\,while\,reducing}\\ \text{number\,people\,required\,perform\,study\,found\,that\,v$$

<EndOfPara>9 and 10. A case report of a healthy adult volunteer who had an awake intubation showed that the risk of exposure to aerosol particles is increased for personnel within 3 meters of the patient. ${}^{76}$ However, a study of 3 adults undergoing intu-bation showed that the mean particle con-centrations were 200 to 300 times baseline during bag-mask ventilation, compared with 30 to 50 times baseline during endotracheal tube insertion. ${}^{77}$ While no longer emphasized in standard resuscitation, endotracheal intu-bation redirects a patient's exhaled gas, respi-ratory droplets, and respiratory aerosols away from personnel in the room and contains them. ${ }^{76,77}$ No pediatric data on endotracheal intubation to contain respiratory droplets and aerosol particles recommended for children is extrapolated from the adult data. No studies were identi-fied on the use of supraglottic airways to con-tain respiratory droptery� and aerosol particles.

11.Intubation boxes,also known as aerosol boxes,were evaluated in a systematic review that included 20 simulation studies and showed a reduction in droplets but not aerosols and an increased time to endotracheal tube place-ment.78 This was further supported by more recent simulation studies with the same con-clusions, although interpretation of the data could be limited by box design heterogene-ity between studies. ${}^{79-83}$ Minimizing gaps and using negative pressure devices may improve the box's performance. Patient draping has also been investigated with similar issues. ${}^{28,407,83,84}$

Table 2 summarizes the key steps to reduce transmis-sion of these pathogens.

Table 2. Transmission Reduction in High-Consequence Respiratory Pathogens in Cardiac Arrest

|Key steps to take to reduce the risk of transmission of high-consequence respiratory pathogens during treatment of cardiac arrest in adults and children| |---| |Resuscitation team members should wear PPE| |N95 respirator or PAPR, eye protection, gloves, gown| |Consider designating a PPE monitor or coach| |Minimize the number of people in the room| |It is reasonable to use a mechanical CPR device| |Monitor for team member fatigue| |Consider intubating early in resuscitation| |Video laryngoscopy is preferred| |Use a HEPA filter to reduce fugitive aerosols from bag-mask ventilation device or ventilator| |Intubating boxes and other improvised barrier devices are not recommended|

CPR indicates cardiopulmonary resuscitation; HEPA, high-efficiency particle air;PAPR, powered air-purifying respirator; and PPE, personal protective equipment.

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50. Aditianingsh D, Pyrambood P, Antonius Wibowo J, Nissi Leonard E,Annabelle C. Comparison of Three Tracheal Intubation Procedures Us-ing Personal Protective Equipment, Direct and Video Laryngoscopes:An Open, Randomized, Parallel Clinical Trial. Anesthesiol Pain Med 2024;14:e1482008. doi:10.5812/aapm-148208

51. Ervin T, Dabkowski M, Pruc M, Hernik J, Wieczorek W, Chabowski L,Wecozker P, Chniewski J, Feduniw S, Szarpak L. ETVseti SL versus Ma-cintosh Drectary Laryngospe for Endotracheal Intubation Amid Simulated COVID-19 Cardiac Arrest: A Randomized Crossover Study. J Clin Med.2023;12:5074; doi:10.3390/907/cm12155074

52. Guru S, Singh N, Sahood S, Hansda U, Mohanty C. Comparison of en-dotracheal intubation with Macintosh versus King Vision video laryn-goscope using coronavirus disease 2019 barrier box on manikins: A randomized crossover study. Turk J Emerg Med.2022;22:149-155. doi:10.4103/2459-2473.348436

53. Puthenetill E, Rahman S, Sujayraghavan S, Suresh S, Kadapamannil D,Paul J. Comparison of aerosol box intubation with C-MAC video laryngo-scope and direct laryngoscopy-A randomised controlled trial. Indian J An-aesth.2021:65:133-138. doi:10.4103/ijaJA.1218.20

54. Prekerk ME, Driver BE, Trent SA, Resnick-Ault D, Seitz KP, Russell DW,Gaillard JP, Lairit, Al, Ghamande SA, Gibbs KW, et al; on behalf of the DEVICE Investigators and the Pragmatic Critical Care Research Group. Vid-eo versus Direct Laryngoscopy for Tracheal Intubation of Critically III Adults.NEng J Med.2023;389:418-429. doi:10.1056/NEJMoa2301601

55.Ari A,Fink JB,Pilbeam S. Secondhand aerosol exposure during mechanical ventilation with and without expiratory filters: An in-vitro study. Ind J Resr Care.2016;5:677-682.

56. FAQ on Anesthesia Machine Use, Protection, and Decontamination During the COVID-19 Pandematic 2023. Updated July 27,2023. Accessed January 16,2025. https://wwwapsf.org/faq-on-anshestesia-machine-use-protec-tion-and-decontamination-during-the-covid-19-pandemic

57.Ai A. Practical strategies for a safe and effective delivery of aerosolized medications to patients with COVID-19. Respir Med.2020;167:105987 doi:10.1016/j.mimed.2020.105987

58. Fink JB, Ehrmann S, Li Dailey P, McKiernan P, Darquenne C, Martin AR,Rothen-Rutishauser B, Kuehl RJ, Hausermann S, et al. Reducing Aerosol-Related Risk of Transmission in the Era of COVID-19: An Interim Guidance Ordesider by the International Society of Aerosols in Medicine. J. Aerosol Med Pulm Drug Deliv. 2020;33:300-304. doi: 10.1089/jamp.2020.1615

59.Kumar R,Yadav SR,Kumar A, Ish P,Gupta N,Chakrabarti S.The "masks for the ventilator" in the COVID-19 era. Adv Respir Med.2020;88:630-632.doi:10.5603/ARMa2020.0124

60.Mac Gialo Eain M, Joyezner M, O'Sullivan A, McGrath JA, Mac Loughlin R. An in vitro investigation into the release of fugitive medical aerosols into the environment during manual ventilation. J. Hosp Infect 2021;108:135-141.doi:10.1016/j.jehinom.2020:292-298.

61.$O'Toole C, Joyce M, McGrath JA, O'Sullivan A, Byrne MA, MacLoughlin R.Fugitive aerosols in the intensive care unit: a narrative review. Ann Transl Med.2021;9:592. doi:10.1016/j.2021037/atm-20-2280

62.92. Shalish W, Lakshminusma S, Manzoni P, Keszler M, SantAnna GM.COVIDr and Neonatal Respiratory Care:CurrentEvidence and Practical Ap-proach.Am J Perinatol.2020;37:780-791. doi:10.1055/s-0040-1710522

63.Curtis K, Jansen P Mains M, O'Hare A,Scotcher B, Alcorn D,Nahidi S, Harris B, Jrouillard D, Morton S,et al. Rapid development and implementation of a behaviour change strategy to improve COVID-19 personal protective equip-ment use in a regional Australian emergency department. Australas Emerg Care.2022;25:273-282. doi:10.1016/j.auec.2022.01.004

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64. Hwang SY,Yoon H,Yoon A,Kim T,Lee G,Jung KY, Park JH,Shin TG,Cha WC, Sim S, et al. N95 filtering facepeciriers respirors do not reliably af-ford respiratory protection during chest compression: A simulation study.Am J Emeged Med 2020;38:12-18: doi:10.1016/j.ajem.2019.03.041

65.Guidance for Personal Protective Equipment(PPE).2024. Updated May 2,2024.Accessed January 16,2025.https://www.cdc.gov/viral-hemorrhag-icfe-hersucd/guidance/index.html

66. Phan LT, Maita D, Mortiz DC, Weber R, Fritzen-Pedicini C, Bleasale SC,Jones RM; on behalf of the CDC Prevention epicenters Program. Personal protective equipment drifting practices of healthcare workers. J. Occup En-viron Hyg.2019;16:575-581. doi: 10.1080/15459624.2019.1628350

67. Lazar MS, Ganesh V, Naik BN, Singh A, Puri G, KD, Kaur S. Efficacy of re-mote audio-visual system versus standard onsite body tuning to monitor the difforing of personal protective equipment during COVID-19 pandemic:An observational study. Int J Health Platform Manage 2024:29530-540. doi: 10.1002/hpm.3754

68. Naik BN, Singh A, Lazar MS, Ganesh V, Soni SL, Biswal M, Das K, Kaur S, Puri G, Performance of Health Care Workers in Doffing of Personal Protec-tive Equipment Using Real-Time Remote Audio-Visual Doffing Surveillance System: Its Implications for Bio-Safety Amid COVID-19 pandemic. Curexus 2021;13:e8017. doi:10.7759/cureus.18071

69. Somri M, Hochman O, Somri-Gannam L, Gaitini L, Paz A, Burmard T, Gomez-Rios MA. Removal of Contaminated Personal Protec-tive Equipment With and Without Supervision. A Randomized Cross-over Simulation-Based Study. Simul Health. 2024;19:137-143. doi: 10.1097/SH000000000000726

76. Choy J,Kang C,Jeong W, Park JS,You Y,Hhn J,Min JH,Hwang T, Kwon O, Kim SW. Efficacy of cardiopulmonary resuscitation perfor-mance while wearing a powered air-purifying respiratory. Am J Emerg Med 2022;51:22-25. doi:10.1016/j.ajem.2021.09.060

71. Chung SP, Nezhov J, Zohnson N1, Lagina A, Bray J, International Liaon Committee on Resuscitation ILCOR Basic Life Support Task Force. Effects of personal protective equipment on cardiopulmonary resculitation qual-ity and outcomes: A systematic review. Resuscue Plus:2024:103988. doi:10.1016/j.resplu.2023.100398

72. Kou M, Donoghue AJ, Stacks H, Kochman A, Semiao M, Nash M, Siegel D, Ku L, Debsis J, Chen JY, et al; on behalf of the Best Pharmaceuticals for Children Act- Pediatric Trials Network. Impact of Personal Protective Equipment on the Performance of Emergency Pediatric Procedures by Pre-spatial Hospital Prodisers. Disease Public Health Comp. Report. 2022:66-86.9: doi: 10.1017/dmp.2020.128

37. Mathew M, Kundra P, Vinayagam S. Chest compression quality comparing 1-min 2-min of rotation reserves wearing N95 masks. Am J Emerg Med 2024;76:75-81. doi:10.1016/j.ajem.2023.11.025

74. Kim M S, Sarcevic A, Soppel K, McCarthy K, Wood EA, Riley C, Mun AH,O'Connell KJ, LaPuma PT, Burd RS. Factors associated with correction of personal protective equipment nonadherence in a multidisciplinary erener-gency department setting: A retrospective video review. Am J Infect Control 2025;53:53-30. doi: 10.1016/j.ajic.2024.08.001

75. Malysz, Mabrowski, Mottberg BW, Smerekris K, Kulak K, Szarpak A,Juszagusski M, Filipaki K, Judkar R, Zuetler K, et al. Resuscitation of the patient with suspected/confirmed COVID-19 when wearing personal protective equipment: A randomized multicenter crossover simulation trial Cardiol.J.2020;27:497-506. doi:10.5603/CJa2020.0068

76.Eain MMG,Nolan K,Murphy B,McCau L,McGau L.Rexhaled Ph R.exhated patient derived aerosol dispersion during awake tracalithation with concurrent high flow nasal therapy. J Clin Monit Comput. 2023;37:1265-1273. doi:10.1007/s10877-023-0990-x

77. Dhillon RS, Rowin WA, Humphries RS, Kevin K, Ward JD, Phan TD,Nguyen LV, Wynne DD, Scott DA; on behalf of the Clinical Aerosolisa-tion Study. Gaerosolisation during traceline intubation and exub-tion in an operating theatre setting. Anaesthesia. 2021;76:182-188. doi:10.111/anae.15301

78. Mahmudino T,Singhalal S,Mohammad AA,Fallic-Rojas V.Ecatalan Opucemia MJ,Haro AS,Salam Karim Y,Quorbon N, Kamal Abdelbasset W,Mahdi AB,et al.The impact of aerosol box on tracheal intubation during the COVID-19 pandemic: a systematic review. Expert Rev Med Devices: 2022:1979-789.doi:10.1080/17434440.2022213149

79.Ben-Yakov M, Price C, Dharams A, Tawadrous D, Choi JM. Intubator Per-formance and Contamination with the Use of Barrier Enclosure Devices:Results from a Simulated COVID-19 Resuscitation. Ann. Work Expo. Health.2021:65:737-737:10. doi:10.639/annew/waa144.

80 Burtri, CRiVette L, Bridrier A, Abie Leun, Brénm, Amaiwayapp AK,Vanoli E, Crawford C, Duchaine J, Couvet P. Effectiveness of Splash Guard

Caregiver prototype in reducing the risk of aerosol transmission in inten-sive care unit rooms of SARS-CoV-2 patients: a prospective and simulation study.J.Hospital Infect 2024;144:75-84. doi: 10.1016/j.jhin.2023.11.007

81. Fong S, Li E, Volato E, Reid A, Gu Y. Impact of aerosol box on intubation during COVID-19: a simulation study of normal and difficult airways. Can J Anaenaeth 2021:68:496-504. doi: 10.1007/s12630-020-01825-y

82. Isa R, Urbanoviz R, Richebe P, Blain J, Ferreira Benevides A, Tanoubi I. VACuum Intubation(VACClN) box restricts the exhaled air dispersion generated by simulated cough: description and simulation-based tests of an innovative aerosolization protective prototype. J Clin Monit Comput 2022;36:1289-1295.doi: 10.1007/s10877-021-00759-0

83. Oman SP, Sanghai DK, Helgeson SA, Lowman PE, Crook JE, Ball CT,Kuhlmann JL, ReK AK, Franco PM. Simulation Method for Testing Aerosol Mitigation Strategies: An Observational Study. Simul Health. 2023;18:8-15. doi: 10.1097/SH0000000000000625

84. Ibrahim M, Khan E, Babatazade R, Simon M, Vadhera R. Comparison of the Effectiveness of Different Barrier Enclosure Techniques in Protection of Healthcare Workers During Tracheal Intubation and Extubation. A A Pract 2020;14:e01252. doi:10.1213/XAA.0000000000001252

HYPERKALEMIA

|Recommendations for Adults and Children in Cardiac Arrest From Suzus-specuehkaerikalcm|| |---|---| |COR|LOE| |2b|1. The effectiveness of IV calcium administration for adults and children in cardiac arrest from suspected hyperkalemia is not well established.| |2.8|2.0| |2b|1.2| |3:0|2.8| |4.0|Inhaled $\beta_{2}$ -agonists for adults and children in cardiac arrest from suspected hyperkalemia is not well established.| |3: No Benefit|4. Inhaled $\beta_{2}$ -agonists for adults and children in cardiac arrest from cardiac arrest from suspected hyperkalemia is not recommended.|

Synopsis

Hyperkalemia, defined as serum potassium concen-tration greater than 5.5 mEq/L in children, can lead to life-threatening cardiac arrhythmias and cardiac arrest.1,2 While the prevalence of hyperkalemia in the adult population is estimated at 2% to 3%, hospitalized adults face a great-er incidence of severe hyperkalemia(>6.5 mEq/L),ranging from 1% to 10%.3-6 Risk factors contributing to the development of hyperkalemia in both adults and children include impaired kidney function, potassium supplements, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs), risk hemolysis, and crush injuries.Acidemia during cardiac arrest can also temporar-ly cause potassium to shift extracellularly, resulting in elevated serum potassium concentrations, which may conflate the etiology of cardiac arrest.7 Laboratory con-firmation is not required for initial treatment, although patient history and electrocardiogram changes can sup-port suspicion of hyperkalemia as an underlying etiol-ogy. Characteristic electrocardiogram abnormalities of

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hyperkalemia may include peaked T waves, flattened P wave,PR interval lengthening, QRS complex prolonga-tion, and ST segment depression followed by merging of S and T waves(sine wave), though the sensitivity and specificity of these findings are low.8

These recommendations are only applicable to the management of adults and children in cardiac arrest from hyperkalemia and do not discuss the treatment of life-threatening hyperkalemia with therapies such as loop diuretics and potassium binders.

Recommendation-Specific Supportive Text

1. The benefits of IV calcium administration for myo-cardial protection during hyperkalemia in the set-ting of cardiac arrest are based on an 1883 in vitro study, a 1939 dog study, and a series of 5 adult cases in 1964.9-11 Calcium administration alone in a randomized controlled porcine model of hyperka-lemic cardiac arrest did not increase ROSC(OR,1.2;95% CI,0.4-4.0;P=0.76) or time to ROSC(HR,1.5;95% CI,0.8-2.9;P=0.23) when com-pared with placebo.12 There are no high-quality human observational studies or clinical trials evalu-ating IV calcium to treat patients with hyperkale-mic cardiac arrest. One human adult retrospective observational study on the effectiveness of calcium and sodium bicarbonate is limited by small sample size, retrospective design, and multiple conflict-ing regression analyses, leading to low certainty of results.13 The study did not inform this recom-mendation. Furthermore, no significant benefit of IV calcium was observed in a subanalysis of adult out-of-hospital PEA arrests in which hyperkalemia was suspected as defined by electrocardiogram abnormalities rather than prearrest potassium concentrations.14 Limited data in children seem to demonstrate findings consistent with adults. In a separate subgroup analysis of observational data in pediatric hospitals, 8 children receiving calcium during in-hospital hyperkalemia-induced cardiac arrest showed no significant differences or trends in survival to hospital discharge or favorable neuro-logical outcome.15

2.Sodium bicarbonate shifts potassium intracel-ularly and is theoretically beneficial when severe

hyperkalemia exists with cardiac arrest. In a ran-domized controlled pig model of hyperkalemic cardiac arrest, sodium bicarbonate significantly increased ROSC(24/26[92%] versus 13/26[50%]; OR, 12.0; 95% CI, 2.3-61.5; P=0.003) and reduced time to ROSC(HR,3.6; 95% CI,1.8-7.5;P<0.001).12 One human adult retrospective obser-vational study on the effectiveness of calcium and sodium bicarbonate is limited by small sample size, retrospective design, and multiple conflict-ing regression analyses, leading to low certainty of results.13 The study did not inform this recommen-dation. There is a paucity of published literature of sodium bicarbonate in children, and, thus, recom-mendations are extrapolated from available adult data.

3. Insulin and glucose shift potassium intracellu-larly. Treatment with IV insulin in the setting of hyperkalemic cardiac arrest has produced vari-able results and is limited to case reports and case series. Notably, standard IV insulin therapy was ineffective in a reported case series of 11 adults and 5 children.16 However, a recent case report of 2 adults indicated a potential benefit of high-dose insulin(1 U/kg IV) on ROSC in the presence of hyperkalemia. ${}^{17}$ The ILCOR 2024 International Consensus on CPR and Emergency Cardiovascular Care Science With Treatment Recommendations recommends the combina-tion of insulin and glucose for adults and children with cardiac arrest from suspected hyperkalemia based on indirect non-cardiac arrest evidence demonstrating the lowering of serum potassium concentrations. ${}^{18,19}$ The use of insulin and glu-cose risks hypoglycemia and has the opportu-nity cost of forgoing other potentially efficacious interventions. Doses for insulin and glucose for cardiac arrest from suspected hyperkalemia are listed in Table 3.

4. Stimulation of the $\beta_{2}$ -adrenergic receptors pro-motes intracellular movement of potassium by activation of the Na-K ATPase pump. There are no data demonstrating additional benefit using addi-tional $\beta_{2}$ -adrenergic agonists over basic resuscita-tion in either adults or children with cardiac arrest from suspected hyperkalemia. Epinephrine is far

Table 3. Insulin-Glucose Dosing for Cardiac Arrest From Suspected Hyperkalemia

|Population|Glucose|Insulin|Administration notes| |---|---|---|---| |Adults|Adults|Adults|Adults| |Standard dose|D50W or glucose 50%:50 g IV bolus|10 Units regular insulin|Administer insulin IV over 15-30 min| |Children|Children|Children|Children| |Standard dose|D10W or Glucose 10%:5 mL/kg IV bolus|0.1 Units/kg regular insulin|Administer insulin IV over 15-30 minutes max 10 U for severe hyperkalemia|

D_{50}W indicates 50% dextrose in water; D_{10}W,10% dextrose in water; and IV, intravenous.

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more effective at $\beta$ -adrenergic activation than $\beta_{2}$-specific agonists(eg, albuterol or saltutamol). ${ }^{20}$Furthermore, differential effects on serum potas-sium concentrations may occur over the course of therapy. ${ }^{21}$ Excessive $\beta_{2}$ -agonist-induced periph-eral vasodilation and the potential for interruptions or ineffective CPR to deliver inhaled therapy could negatively impact patient outcomes.

REFERENCES

1. Alfonzo A. Survival after in-hospital pikalaryemic cardiac arrest-Does in-travenous calcium or sodium bicarbonate influence outcome? Resuscitation.2016;98:A1-A2. doi:10.1016/j.resuscitation.2015;11.001

2. Masilami K, van der Voort J. The management of acute hyperkaleae-mia in neonates and children. Arch Dis Child. 2012;97:376-380. doi: 10.1136/archisch-2011-300623

3. Acker CG,Johnson JP,Palevsky PM,Greenberg A. Hyperkalemia in hospi-talized patients: causes,adequacy of treatment, and results of an attempt to improve physician compliance with published therapy guidelines. Arch Intern Med.1998;158:917-924. doi:10.1001/archite.158.8,917

4. Khanagavi J,Gupta,Tronaw WS,Shath T,Garg J,Ahn C,Sule S,Peterson S. Hyperkalemia along hospitalized patients and association between du-ration of hyperkalemia and outcomes. Arch Med Sci 2014;10:251-257. doi:10.5114/s.2014.42577

5. Kovesp CD. Management of hyperkaleemia in chronic kidney disease. Nat Rev Nephrol.2014;10:653-662. doi: 10.1038/nneph.2014.168

6. Kovesp CD. Epideriotic of hyperkaleemia: an update. Kidney Int Suppl(2017).2016;6:3-6. doi: 10.1016/j.kisu.2016.01.002

7. Graber M. A model of the hyperkalemia produced by metabolic acidosis. Am J Kidney Dis. 1993;22:436-444. doi: 10.1016/s0272-6386(12)70148-8

8. Wrenn KD, Slovis CM, Slovis BS. The ability of physicians to predict hy-perkalemia from the ECG. Am Emerg Med 1991;201:1229-1232. doi:1016/1018/s0196-0644/058)1476-3

9. Chamberlain MJ. Emergency Treatment of Hyperkalemia. Lancet 1954;1644-467. doi:10.1016/s0140-6736(64)90797-4

10. Ringer S. A further Contribution regarding the influence of the differ-ent Constituents of the Blood on the Contraction of the Heart. J Physiol.1883;42-42.3. doi: 10.1113/jphysiol.1883sp.000120

11. Winkler AW, Hoff HE, Smith PK. Factors Affecting the Toxicity of Patrism. Am J Physiol Legacy Content: 1939;127:430-436. doi: 10.1152/ajplegacy.1939.1273.430.

12. Eggertsen MA, Munch Johannsen C, Kovacevic A, Fink Vallentin M, Mork Vmann L, Andersen LW, Granfeld A. Sodium Bicarbonate and Cal-Cium Chloride for the Treatment of Hyperkalemia-induced Cardiac Arrest: A Randomized, Blinded, Placebo- Controlled Animal Study. Crit Care Med.2024;52:e67-e78. doi:10.1097/CM.00000000000000899

13. Wang CH, Huang CH, Chang WT, Tsai MS, Yu PH, Wu YW, Hung KY, Chen WJU. The effects of calcium and sodium bicarbonate on severe hyperka-mela during cardioprolusidary retransisation: A rescutteri cohort study of adult in-hospital cardiac arrest. Resuscitation. 2016;98:105-111. doi:10.1016/j.resuscitation.2015.09.384

14. Vallinert MF, Povlosen AL, Granfeld T, Terkelsen CJ, Andersen LW.Loeffering of calcium in patients with pulseless electrical activity and elec-trocardiographic characteristics potentially associated with hyper-kalemia and ischemia-sub-study of the Calcium for Out-of-hospital Cardiac Arrest(COCA) trial. Resuscitation. 2022;181:150-157. doi:10.1016/j.resuscitation.2022.11:006

15. Cashen K, Sutton RM, Reeder RW, Ahmed T, Bell MJ, Berg RA, Burns C,Carcillo JA, Carpenter TC, Michael Dean J, et al; benefit of the Eunice Kennedy Shriver National Institute of Child Health and Human Develop-ment Collaborative Pediatric Critical Care Research Network (CPCRCN)and National Heart Lung and Blood Institute ICU-RESUSCitation Project Investigators. Calcium use during paediatric in-hospital cardiac arrest is associated with worse outcomes. Resuscitation. 2023;185:109673. doi:10.1016/j.resuscitation.2022.109673

16.Smith FM, Harrow SJ, Ackerman JD, Brussj RD. Sprung J. Cardiac ar-rests associated with hyperkalemia during red blood cell transfusion: a case series. Anesth Analg. 2008;106:1062-1069, table of contents. doi:10.1213/ane.0b013e318164f03d

17. Shikhouno MA, Abdulahdi LA, Yafes WM, Saleh MR, Consentino SA,Partin EJ. High-Dose Insulin for Hyperkalemic Cardiac Arrest. Am J Ther.2023;30:e426-e432. doi: 10.1097/MTJ.000000000000001571

18. Djakow J, Ng KC, Raymond T, Atkins D, Acworth J, Schofield B; on behalf of the International Liaois Committee on Resuscitation Pediatric Life Sup-port Task Force. Pharmacological Interventions for the Treatment of Hyper-kalemia in Paediatric Patients with Cardiac arrest- Paediatric Consensus on Science and Treatment Recommendations Internet[Internet]. 2024. Updated November 23, 2024. Accessed January 16, 2025.https://costr.ilcor.org/document/pharmacological-interventions-for-the-treatment-of-hyperkala-mia-in-paediatric-patients-with-cardiac-arrest-pls-4160-17-tfsr

19. Granfeld A, Holmberg M, Andersen L, Ng K, Djakow J; on behalf of the Advanced Life Support and Pediatric Life Support Task Forces. Pharmacological Interventions for the Acute Treatment of Hyperkalemia: a systematic review.2024. Updated November 05, 2024. https://costr.ilcor.org/docu-ment/pharmacological-in-interventions-for-the-acute-treatment-of-hyperka-lemmais-303-4tf-sr. Increased January 16, 2025.

20. Hanania NA, Sharafethane, A, Barber R, Dickey BF. Beta-agonist intrinsic efficacy: measurement and clinical significance. Am J Respir Crit Care Med.2002;165:1353-1358.doi:10.1164/rccm.2109060

21. Mandelberg, A Krupnik Z, Houri S, Smetana S, Gilad E, Matas Z,Priel IE. Salbutatol metered-dose inhaler with spacer for hyper-kalemia: how fast? How safe? Chest. 1999;115:617-622. doi: 10.1378/chest.115.3.617

HYPERHERMIA

Introduction

Life-threatening hyperthermia(defined as a core temper-ature≥40℃[104°F]) is a preventable cause of cardiac arrest that has multiple etiologies, including exertional heatstroke, environmental exposure, and medication or drug overdose. Animal data suggests that temperature and duration are critical determinants of survival.1-3 Pro-longed temperature elevation leads to multiorgan failure that resembles septic shock.1

Children are a higher risk of hyperthermia compared to adults for several reasons. Children are at higher risk for heat gain because they have larger ratios of body surface area to body mass, increased metabolic heat production, and ineffective passive sweat glands to dissipate heat. Young children also are unable to recognize or self-extricate from hyperthermic environments.4,5

No RCT on cooling patients with hyperthermic car-diac arrest has been performed. As a result, recommen-dations are made from data derived from adults with life-threatening hyperthermia and experimental mod-els of hyperthermia in human volunteers. The following recommendations only apply to adults and children with exertional heatstroke, environmental exposure, and med-ication or drug overdose. The treatment of patients with malignant hyperthermia and sepsis is outside the scope of these recommendations.

Specific discussion of the management of adults and children with life-threatening cocaine and sympathomi-metics poisoning can be found elsewhere(refer to the Toxicology: Cocaine and Toxicology: Sympathomimetics sections). These recommendations inform the manage-ment of adults and children with life-threatening hyper-thermia, including cardiac arrest.

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Recommendations for Adults With Life-Threatening Hyperthermia(Core Temperature>40°C(104°F)

|COR|LOE|Recommendations| |---|---|---| |1|C-EO|1. Active cooling is recommended to be initiated concurrently with standard resuscitation for adults with life-threatening hyperthermia.| |2a|B-R|2. It is reasonable to choose immersion in ice water(1-5℃(33.8-41°F)) over other cooling methods in adults with life-threatening hyperthermia.| |2a|B-R|3. If ice water immersion is not available, it is reasonable to choose immersion in tepid water(8-17°C(46.4-62.6°F)) or tarp-assisted ice water cooling over other cooling methods in adults with life-threatening hyperthermia.| |2a|C-LD|4. It is reasonable to cool adults with life- threatening hyperthermia as rapidly as possible with a decrease of at least 0.15°C/min (0.27°F/min).| |2a|C-LD|5. It is reasonable to stop active cooling for life-threatening hyperthermia when the core temperature of the adult patient reaches 38.6°C (101.5°F).| |3: No Benefit|B-R|6. Danrolene is not useful to treat adults with life- threatening hyperthermia from causes other than malignant hyperthermia.|

Recommendation-Specific Supportive Text

1. Standard resuscitation enhances circulation, which helps dissipate excess heat through vascular dis-tribution of blood from the core to the extremities. ${}^{6}$ Rapid body cooling addresses hyperthermia while preventing further rises in temperature. ${}^{6}$

2. A systematic review of cooling rates that included 63 studies of primarily adults(25 randomized clinical trials, 12 nonrandomized clinical trials, 2 cohort studies, and 24 case series) concluded that ice water immersion provided faster cooling rates than numerous other techniques(Figure 2). 7 The superiority of ice water(1-5°C[33.8-41°F])immersion is supported by 1 adult volunteer RCT.8 This recommendation is consistent with the 2025 Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke.9

3.When ice water immersion is not available, full body immersion in tepid water(8-17℃[46.4-62.6°F]) still often achieves adequate cooling rates in multiple systematic reviews of primarily adult populations.7,10 When immersion is not feasible,tarp-assisted ice water cooling produces adequate cooling rates in adults(Figure 2).10,11 This recom-mendation is consistent with the 2025 Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke.9

4. A systematic review of case reports and case series identified an increase in mortality in adults cooled slower than 0.15°C/min(0.27°F/min). ${}^{12}$ This recommendation is consistent with the 2025

$\text{Society of Critical Care Medicine Guidelines for}$ the Treatment of Heat Stroke.9

5. A controlled trial of 10 healthy adult volunteers with non-life-threatening hyperthermia(core tempera-ture,39.5℃[103.1°F]) demonstrated that those who were removed from ice water immersion at a core temperature of 38.6℃(101.5°F) had lower risk of overcooling compared with those removed at 37.5℃(99.5°F).13 Overcooling to below normo-thermia could cause complications, such as coagu-lopathy and adverse hemodynamic effects.14

6. Four studies that investigated the effects of dan-trolene in life-threatening hyperthermia(from causes other than malignant hyperthermia) were included in the data review and demonstrated mixed results. An adult case series(n=20) of dan-trolene use in hyperthermia for exposure-related heat stroke was associated with more rapid cooling but no difference in neurologic outcomes.15 An RCT(n=52 adults) of dantrolene(2 mg/kg IV) for envi-ronmental hyperthermia(>40.1℃[104.2°F]) did not find a reduction in cooling time.16 Data on dan-trolene for 3,4-methylenedioxymethatamine(MDMA)-induced hyperthermia is also conflicting.A meta-analysis of patients aged≥15 years identi-fied case reports and case series totaling 71 cases and found that dantrolene use was associated with improved survival.17 However, a case series of 9 adults did not find clinical differences between patients who received dantrolene versus those who did not.18 This recommendation is consistent with the 2025 Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke.9

|Recommendations for Children With Life-Threatening Hyperthermia (core temperature,>40℃(104°F)|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-EO|1. Active cooling is recommended to be initiated concurrently with standard resuscitation for children with life-threatening hyperthermia.|| |2a|C-EO|2. It is reasonable to choose immersion in ice water(1-8°C;33.8-41°F) over other cooling methods in children with life-threatening hyperthermia.|| |3a|C-EO|3. If ice water immersion is not available, it is reasonable to choose immersion in tepid water(8-17℃;46.4-62.6°F) or tarp-assisted ice water cooling over other cooling methods in children with life-threatening hyperthermia.|| |2a|C-EO|4. It is reasonable to cool children with life- threatening hyperthermia as rapidly as possible with a decrease of at least 0.15°C/min(0.27°F/ min).|| |2a|C-EO|5. It is reasonable to stop active cooling for life-threatening hyperthermia when the core temperature of a child reaches 38.6°C(101.5°F).|| |3: No Benefit|C-EO|6. Dantrolene is not useful to treat children with life- threatening hyperthermia from causes other than malignant hyperthermia.||

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 Figure 2. Weighted mean cooling rates by cooling method.?

Reproduced from Douma MJ, Aves T, Allan KS, et al. First aid cooling techniques for heat stroke and exertional hyperthermia: A systematic review and meta-analysis. Resuscitation. 2020;148:173-190. doi: 10.1016/j.resuscitation.2020.01.007

Recommendation-Specific Supportive Text

1. Standard resuscitation enhances circulation, which helps dissipate excess heat through vascular dis-tribution of blood from the core to the extremities.6 Rapid body cooling addresses hyperthermia while preventing further rises in temperature.6

2. A systematic review of cooling rates that included 63 studies of primarily adults(25 randomized clinical trials, 12 nonrandomized clinical trials, 2 cohort studies, and 24 cases series) concluded that ice water immersion provided faster cooling rates than numerous other techniques(Figure 2). ${}^{7}$ The superiority of ice water $\left(1-5^{\circ} C\right.$ [33.8-41°F]) immersion is supported by 1 adult volunteer RCT.8 No pediatric data for cooling rates with ice water immersion were identified, and, thus, the recommendation for children is extrapolated from this adult data. This recommendation is consistent with the 2025 Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke.9

3.When ice water immersion is not available, full body immersion in tepid water(8-17℃[46.4-62.6°F]) still often achieves adequate cooling rates, as shown in multiple systematic reviews of primarily adult populations.7,10 When immersion is not fea-sible, tarp-assisted ice water cooling produces

adequate cooling rates in adults (Figure 2).${ }^{10,11}$ No pediatric data for cooling rates with tepid water immersion or tarp-assisted ice water cooling pro-cedures were identified, and, thus, the recommen-dation for children is extrapolated from this adult data. This recommendation is consistent with the 2025 Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke. ${ }^{9}$

4. A systematic review of case reports and case series identified an increase in mortality in adults cooled slower than 0.15°C/min(0.27°F/min).12 No pedi-atric data for cooling rates were identified, and,thus, the recommendation for children is extrapo-lated from this adult data. This recommendation is consistent with the 2025 Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke.9

5. A controlled trial of 10 healthy adult volunteers with non-life-threatening hyperthermia(core tempera-ture,39.5℃[103.1°F]) demonstrated that those who were removed from ice water immersion at a core temperature of 38.6℃(101.5°F) had lower risk of overcooling compared with those removed at 37.5℃(99.5°F).13 Overcooling to below normo-thermia could cause complications, such as coagu-lopathy and adverse hemodynamic effects.14 No pediatric data for the optimal temperature at which

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to terminate cooling were identified, and, thus, the recommendation for children is extrapolated from this adult data.

6.Four studies that investigated the effects of dan-trolene in life-threatening hyperthermia(from causes other than malignant hyperthermia) were included in the data review and demonstrated mixed results. An adult case series(n=20) of dantrolene use in hyper-thermia for exposure-related heat stroke was asso-ciated with more rapid cooling but no difference in neurologic outcomes. ${ }^{15}$ An RCT (n=52 adults) of dan-trolene (2 mg/kg IV) for environmental hyperthermia(>40.1°C[104.2°F]) did not find a reduction in cool-ing time. ${ }^{16}$ Data on dantrolene for MDMA-induced hyperthermia are also conflicting. A meta-analysis of patients aged≥15 years identified case reports and case series totaling 71 cases and found that dan-trolene use was associated with improved survival. ${ }^{17}$ Both pediatric patients (a 16- and a 17-year-old patient) included in the study died ${ }^{17}$ Furthermore, a case series in adults did not find clinical differences between patients who received dantrolene versus those who did not ${ }^{18}$ Limited pediatric data on the use of dantrolene to treat life-effect-threatening hyperther-mia were identified; thus, the recommendation for children is extrapolated primarily from the adult data.This recommendation is consistent with the 2025 Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke. ${ }^{9}$

REFERENCES

1. Bouchama A, Knochel JP. Heat stroke. N Engl J Med. 2002;346:1978-1988. doi: 10.1056/NEJMra011089

2. Shapiro Y, Rosenthal T, Sohar E. Experimental heatstroke. A model in dogs.Arch Intern Med.1973;131:688-692. doi:10.1001/archite.131.51.688

3. Shij CJ, Lin MT, Tsai SH. Experimental study on the pathogen-esis of heat stroke. J Neurosurg. 1984;60:1246-1252. doi:10.3171/jns.1984.60.6.1246.

4.Bytomski JR, Squire DL. Heat illness in children. Curr Sports Med Rep.2003;2:320-324. doi: 10.1249/00149619-200312000-00007

5. Naughton GA, Carlson. R. Reducing the risk of heat-related decrements to physical activity in young people. J Sci Med Sport 2008;11:58-65. doi:10.1016/j.jsams.2006.07.009

6. Pittman RN. The circulatory system and oxygen transport: In: Regulation of Tissue Oxygen. San Rafael, CA: Morgan\& Claypool Life Sciences;2011.

7. Douma MJ, Aves T, Allan KS, Bendall JC, Berry DC, Chang CD, Stewart JM, Hood N, Singletary EM, Zideman D, et al; on behalf of the First Aid Task Force of the International Liaison Committee on Resuscitation. First aid cooling techniques for heat stroke and exertional hyperthermia: A sys-tematic review and meta-analysis. Resuscitation. 2020;148:173-190. doi:10.1016/j.resuscitation:202001.007

8Poulx. Crude MH, Banky MN. Effect of water temperature on cooling efficiency during hyperthermia in humans. J Appl Physiol(1985)2003/94:1317-1323. doi: 10.1152/japplysiol00541.2002

9. Barletta J F, Palmerini TL, Toomey SA, Alshamsi F, Stearns RL, Patanwala AE,Siparsky NF, Badjatia N, Schultz, Breghner CM, et al. Society of Critical Care Medicine Guidelines for the Treatment of Heat Stroke,Cit Care Med 2025;53:e490.e500. doi: 10.1097/CMC.000000000006551

10. Parker KC, Shelton R, Lopez RM. Do alternative Cooling Methods Have Effective Cooling Rates for Hyperthermia Compared With Previously es-fablished CWI Cooling Rates? J Sport Rehabil. 2020;29:367-372. doi:10.1123/jsr.2019-0098

11. Luhring KE, Butts CL, Smith CR, Bonacci JA, Ylanan RC, Ganio MS,McDermott BP Cooling Effectiveness of a Modified Cold-Water Immersion Method After Exercise-Induced Hyperthermia. J Athri train. 2016;51:946-951. doi: 10.4085/1062-6050-51.12.07

12. Filep EM, Murata Y, Endres BD, Kim G, Stearns RL, Casa DJ. Exertional Heat Stroke, Modality Cooling Rate, and Survival Outcomes: A Systematic Re-view. Medicina(Kaunas).2020;56:589. doi:10.3390/medicina56110589

13. Gagnon D, Lemire BB, Casa DJ, Kenny GP. Cold-water immersion and the treatment of hyperthermia: using 38.6 degrees C as a safe rectal temperature: cooling limit. J Athl Train. 2010;45:439-444. doi: 10.4085/1062-6050-45.5.439

14. Van Poucke S, Stevens K, Marcus AE, Lance M. Hypothermia: ef-fects on platelet function and hemostasis. Thromb J. 2014;12:31. doi:10.1186/s12959-014-0031-z

15. Channa AB, Seraj MA, Saddique AA, Kadiwal GH, Shaikh MH, Samarkandi AH. Is dantrolene effective in heat stroke patients? Crit Care Med.1990;18:290-292. doi:10.1097/00003246-199003000-00009

16. Bouchama A, Cafe A, Devol EB, Labdi O,el-Assil K, Seraj M. Ineffective-ness of dantrolene sodium in the treatment of heatstroke. Crit Care Med.1991;19:176-180. doi:10.1097/00003246-199102000-00011

17. Grunau BE, Wiens MO, Brubacher JR. Dantrolene in the treatment of MDMA-related hyperpyrexia: a systematic review. CJEM. 2010;12:435-442. doi: 10.1017/s1481803500012598

18. Nikoomanesh K, Phan AT, Choi J, Arabian S, Neeki MM. Dantrolene Admin-istration in the Management of the Prehospital Patient with Methylenedioxy-methamphetamine Overdose: A Case Series and Literature Review. Case Rep Crit Care. 2022;2022:5346792. doi: 10.1155/2022/5346792

HYPOTHERMIA

Introduction

Severe environmental hypothermia(core body tempera-ture,<30℃[86°F]) can cause cardiac arrest as well as findings that mimic death. Pulse and respiratory rates may be slow or difficult to detect, and the electrocardio-gram may show asystole. Apparent rigor mortis or fixed dilated pupils may not be reliable signs of death in this setting.2-4 Hypothermia decreases the body's metabolic rate and oxygen consumption, improving the chance of survival and neurological recovery even after prolonged cardiac arrest.5-7

Hypothermic cardiac arrest often occurs in danger-ous environmental conditions, and verification of scene safety prior to implementing resuscitative measures is important. Following removal from environmental expo-sure and removal of wet clothing, passive rewarming may include techniques such as providing a blanket, and active rewarming may include providing a warm forced-air blanket, administration of warmed IV or IO fluids, warm humidified oxygen, warm water lavage of the thoracic and peritoneal cavities, blood rewarming using a kidney replacement therapy circuit, or use of endovascular tem-perature control catheters.8-13 Warming through ECLS is possible at some centers and also provides circulatory support.

Children are at higher risk of hypothermia compared with adults due to a larger ratio of body surface area to body mass and decreased insulation by fat. Infants cannot produce heat through shivering, and both infants and children have limited glycogen stores required to produce heat and are unable to self-extricate from hypo-thermic environments. ${}^{14}$

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In the absence of human evidence, these guidelines do not make a recommendation about the use of antiar-rhythmic medications for patients in cardiac arrest from environmental hypothermia. These recommendations are specific to hypothermia management. Other specific treatment recommendations related to the setting of drowning can be found elsewhere(refer to Drowning).15 Treatment recommendations related to avalanche are outside of the scope of these guidelines.

These recommendations inform the management of adults and children with life-threatening environmen-tal hypothermia, including cardiac arrest. Other spe-cific treatment recommendations related to adults and children with hypothermia that is not immediately life-threatening can be found in the AHA and American Red Cross 2024 Guidelines for First Aid. ${}^{16}$

|Recommendations for Adults With Life-Threatening Environmental Hypothermia (Core Temperature <30°C[86°F])|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-LD|1. For adults with life-threatening environmental hypothermia with no obvious lethal injury, full resuscitative measures should be performed immediately and continued concurrently with rewarming.|| |2a|B-NR|2. It is reasonable to rearm adults in hypothermic cardiac arrest using ECLS.|| |2a|B-NR|3. It is reasonable to use prognostication scores to guide the decision for initiating ECLS for adults in hypothermic cardiac arrest.|| |2b|C-LD|4. It may be reasonable to rearm adults with envi- ronmental hypothermia (core temperature <28°C [82.4°F]) and not in cardiac arrest using ECLS.|| |2b|C-LD|5. For adults in hypothermic cardiac arrest, it may be reasonable to defibrillate once and if unsuc- cessful, defer further defibrillation until the core temperature is ≥30°C(86°F).|| |2b|C-LD|6. It may be reasonable to rearm adults with life-threatening environmental hypothermia with ECLS at a rate of 1.5-5°C/hour(2.7-9°F/hour).|| |2b|C-EO|7. It may be reasonable to defer administration of epinephrine until the core temperature is≥30°C (86°F) for adults in hypothermic cardiac arrest.|| |2b|C-EO|8. If standard CPR is not possible due to envi- ronmental conditions, it may be reasonable to perform delayed or intermittent CPR during the resuscitation of adults in hypothermic cardiac arrest to facilitate rapid extraction.|| |2b|C-EO|9. It may be reasonable to transport adults in hy- pothermic cardiac arrest to a center with ECLS capability if it can be reached within 6 hours.|| |3: No Benefit|B-NR|10. It is not recommended to use end-tidal carbon dioxide(ETCO) to predict outcomes for adults in hypothermic cardiac arrest.||

Recommendation-Specific Supportive Text

1. Obvious lethal injury(eg, decapitation, truncal transection, whole body incineration, or frozen solid) are suggested conditions to withhold or

terminate CPR.17 Absent these signs, numerous case reports and the International Hypothermia Registry describe ROSC prior to or concurrently with rewarming in adults.18-20

2. A multicenter prospective observational study of 242 adults with severe environmental hypothermia showed improved survival and favorable neuro-logic outcome for adults in cardiac arrest treated with ECMO compared with conventional warm-ing.21 Multiple retrospective observational studies of adults in hypothermic cardiac arrest rewarmed with ECLS have demonstrated a survival benefit and improved neurological outcome over conven-tional CPR.22-24 The use of ECMO is preferable over CPB; a meta-analysis including 464 adults and children in cardiac arrest due to hypothermia showed a 41% greater probability of survival with ECMO.25

3. The Hypothermia Outcome Prediction After ECLS(HOPE) probability score includes age sex, asphyxia, CPR duration, serum potassium concentration, and temperature.26 A HOPE score<0.1 has been validated for predicting mortality of adults in hypothermic cardiac arrest placed on ECLS for rewarming.27,28 The HOPE score is supe-rior to serum potassium threshold of≥12 mmol/L alone in adults and children.26 The International Accidental Hypothermia ECLS(ICE) survival score includes sex, asphyxia, and serum potas-sium concentration, and a score>12 has also been validated in predicting survival after hypo-thermic cardiac arrest in adults and children.29 Other prognostic factors in isolation have been associated with higher mortality in adults and chil-dren with hypothermic cardiac arrest, including high serum potassium concentration, high serum lactate, low pH, asphyxia, unwitnessed cardiac arrest, male sex, older age, higher or lower initial body temperature, and longer resuscitation dura-tion.19,20,25,27,30-33 These prognostic factors are less well-validated than the HOPE or ICE scores. The ELSO eligibility criteria for ECLS in normothermic OHCA may miss adults in hypothermic cardiac arrest or who would benefit from ECLS.11

4. Retrospective observational studies in adults with core temperature<28℃(82.4°F) who are not in cardiac arrest have shown successful and even faster rewarming with ECLS compared with conventional methods.22,24,34,35 A multicenter pro-spective observational study showed improved survival and neurological outcomes with the use of ECMO for adults in hypothermic cardiac arrest.However, adults with hemodynamic instability(eg,not in cardiac arrest) from hypothermia who were placed on ECMO had decreased event-free days(ICU, ventilator, and catecholamine administration)

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and increased hemorrhagic complications without the benefit of improved survival or neurological outcome.21

5. Defibrillation before rewarming can be successful in adults, but the hypothermic heart may be less responsive to defibrillation.18,20,32,36,37 The tempera-ture at which defibrillation should first be tried and the number of defibrillation attempts that should be made are not well-studied in humans. If VT or VF persists, excessive defibrillation attempts may lead to myocardial injury. In a large retro-spective observational study, while a shockable initial rhythm in adults in hypothermic OHCA was associated with better survival and neurologically favorable survival, prehospital defibrillation and increasing the number of defibrillation attempts were not.38 However, only a small number of adults with shockable rhythms were not defibrillated, so the study may have been underpowered to detect a difference in outcomes in this population. The Wilderness Medical Society guideline recom-mends defibrillating once initially and deferring additional defibrillation attempts until core temper-ature reaches 30 $^{\circ}C(86^{\circ}F)$ when defibrillations are more likely to be successful.39,40 ERC guide-lines allow up to 3 defibrillation attempts before rewarming to 30°C(86°F).41

<BeginOfPara>6. The optimal rate for rewarming hypothermic adults with ECLS is unknown. Slow rewarming may delay the return of organ perfusion, and rapid rewarming may cause relative cerebral hyperthermia, poten-tially worsening neurological outcomes. A sec-ondary review of a meta-analysis of observational studies and case reports of 658 adults and chil-dren rewarded with ECLS evaluated the optimal threshold rewarming rate. Rewarming rates less than 5 C/hour(9°F/hour) had a 2.41 greater odds(95% CI, 1.75-3.31) of neurologically intact survival over rewarming rates greater than 5 C/hour(9°F/hour).42 Neurologically intact survival decreased by 1.9% for each 1 C/hour(1.8°F/hour) increase in rewarming rate.42 Another meta-analysis of case reports and case series showed a lower relative hazard of death in adults who were rewarded at rates between 1.5°C(2.7°F) and 4°C/hour(7.2°F), though the former study had a substantially higher mean rewarming rate than the latter.30

<BeginOfPara>7.The temperature at which epinephrine should first be administered and the optimal dosing interval in the severely hypothermic adult has not been well-studied. Some adult and adolescent cases of hypothermic cardiac arrest have normal responses to epinephrine before rewarming.18 However, hypo-thermic hearts may be less responsive to cardio-vascular drugs, and slowed metabolism due to

hypothermia raises concerns for epinephrine accu-mulation and toxicity.41,43,44

8.In cases of prolonged CPR or dangerous environ-mental conditions, it may be suboptimal or impos-sible to perform continuous high-quality CPR.Delayed or interrupted CPR may facilitate rapid extraction or transportation and allow for opti-mal CPR as soon as feasible or safe. Successful resuscitation has been documented in adult cases with delayed or intermittent CPR.45 The acceptable frequency and duration of CPR interruptions and which adults can best tolerate this are unknown.

9. Rapid hospital transport is important to allow for aggressive rewarming with both noninvasive and invasive techniques. Two studies utilizing the same database conflicted on the association of low-flow time(time from cardiac arrest to the establishment of ECMO) with outcomes for adults in cardiac arrest due to hypothermia.46,47 An observational study showed that transportation to centers with ECLS capability improved neurologically favorable outcomes and 1-month survival in adults.38 Adults have been resuscitated using ECLS after hypo-thermic cardiac arrest lasting over 6 hours, so the ERC supports transporting to an ECLS-capable center if within 6 hours.41,48,49

10. ETCO ${}^{2}$ measurement by waveform capnography is utilized for confirmation of correct endotracheal tube placement and monitoring ventilation during endotracheal intubation. For adults in nonhypother-mic cardiac arrest,ETCO ${}_{2}$ is often used to monitor and optimize CPR quality, and an abrupt increase in ETCO ${}_{2}$ can indicate ROSC. In an observational study comparing adults with and without hypo-thermic cardiac arrest assessed for ECLS, those in hypothermic cardiac arrest had significantly lower ETCO ${}_{2}$ and temperature was positively cor-related with ETCO ${}_{2}{}^{27}$ Also, 45% of adult survivors had ETCO ${}_{2}$ $\leq 10$ mm Hg at hospital admission and ETCO ${}_{2}$ value did not predict survival. ${ }^{27}$

|Recommendations for Children With Life-Threatening Environmental Hypothermia(Core Temperature <30°C[86°F)|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-EO|1. For children with life-threatening environmental hypothermia with no obvious lethal injury, full resuscitative measures should be performed immediately and continued concurrently with rewarming.|| |2a|C-LD|2. It is reasonable to reward children in hypothermic cardiac arrest using ECLS.|| |2a|C-LD|3. It is reasonable to use prognostication scores to guide the decision for initiating ECLS rewarming for children in hypothermic cardiac arrest.|| |2b|C-LD|4. It may be reasonable to rewarm children with life- threatening environmental hypothermia with ECLS at a rate <5°C/hour(9°F/hour).||

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|Recommendations for Children With Life-Threatening Environmental Hypothermia (Core Temperature <30°C [86°F])(Continued)|||| |---|---|---|---| |COR|LOE|Recommendations|| |2b|C-EO|5. It may be reasonable to rewarm children with environmental hypothermia (core temperature <28°C [82.4°F]) and not in cardiac arrest using ECLS.|| |2b|C-EO|6. For children with hypothermic cardiac arrest, it may be reasonable to defibrillate once and if unsuccessful, defer further defibrillation until the core temperature is≥30°C(86°F).|| |2b|C-EO|7. It may be reasonable to defer administration of epinephrine until core temperature is≥30°C(86°F)|86°C(F) for children in hypothermic cardiac arrest.| |2b|C-EO|8. If standard CPR is not possible due to environmental conditions, it may be reasonable to perform delayed or intermittent CPR during the resuscitation of children in hypothermic cardiac arrest to facilitate rapid extraction.|| |2b|C-EO|9. It may be reasonable to transport children in hypothermic cardiac arrest to a center with ECLS capability if it can be reached within 6 hours.|| |3: No Benefit|B-NR|10. It is not recommended to use ETCO2 to predict outcomes for children in hypothermic cardiac arrest.||

|2b|C-EO|8. If standard CPR is not possible due to environmental conditions, it may be reasonable to perform delayed or intermittent CPR during the resuscitation of children in hypothermic cardiac arrest or facilitate rapid extraction.| |---|---|---| |2b|C-EO|9. It may be reasonable to transport children in hypothermic cardiac arrest to a center with ECLS capability if it can be reached within 6 hours.| |3: No Benefit|B-NR|10. It is not recommended to use ETCO, to predict outcomes for children in hypothermic cardiac arrest.|

Recommendation-Specific Supportive Text

1. Obvious lethal injury(eg, decapitation, truncal transection, whole body incineration, or frozen solid) are suggested conditions to withhold or terminate CPR.17 Absent these signs, numerous case reports and the International Hypothermia Registry describe ROSC prior to or concurrently with rewarming in adults.18-20 Data for chest compressions for children in cardiac arrest from environmental hypothermia is lacking, and the rec-ommendation is extrapolated from adult data.

2. A multicenter prospective observational study and multiple retrospective observational studies in adults have shown a survival benefit and favor-able neurological outcomes with ECLS over con-ventional CPR for adults in cardiac arrest due to severe environmental hypothermia over conven-tional CPR.21-24 In a case series of children with hypothermic drowning, survival was better with conventional rewarming compared with ECMO.50 However, due to clear clinical differences in illness severity with the ECMO group having lower pH,higher serum potassium, and longer submersion time, this case series does not change the recom-mendation for use of ECLS in children. ECMO is preferable over CPB; a meta-analysis including 464 adults and children in cardiac arrest due to hypothermia showed a 41% greater probability of survival with ECMO.25

3. The HOPE probability score includes age,sex, asphyxia, CPR duration, serum potassium

concentration, and temperature and has been vali-dated in a cohort of adults and children for predict-ing mortality and ineffective use of extracorporeal rewarming.27,28 In adults, a threshold HOPE score of<0.1 has been validated, but there are cases of children surviving with lower HOPE scores.28,51 The HOPE score may be useful in prognostica-tion for children with a more conservative lower cutoff of 0.05.51 The ICE survival score includes sex, asphyxia, and serum potassium concentra-tion, and a score>12 has also been validated in predicting survival after hypothermic cardiac arrest in a mixed cohort of adults and children.29 Other prognostic factors in isolation have been associ-ated with higher mortality in combined cohorts of adults and children in hypothermic cardiac arrest,including high serum potassium concentration,high serum lactate, low pH, asphyxia, unwitnessed cardiac arrest, male sex, older age, greater initial body temperature, and longer resuscitation dura-tion.19,26,27,33 These prognostic factors are less well-validated than the HOPE or ICE scores. The HOPE score is superior to serum potassium threshold of≥12 mmol/L alone in predicting survival in a cohort of adults and children.26

4.The optimal rate for rewarming hypothermic chil-dren with ECLS is unknown. Slow rewarming may delay the return of organ perfusion, and rapid rewarming may cause relative cerebral hyper-thermia, potentially worsening neurological out-comes. An analysis of case report data from 658 adults and children aggregated in the International Accidental Hypothermia Extracorporeal Life Support dataset evaluated the optimal threshold rewarming rate. Rewarming rates less than 5°C/hour(9°F/hour) had a 2.41 greater odds(95%CI,1.75-3.31) of neurologically intact survival over rewarming rates greater than 5°C/hour(9°F/hour).42 Neurologically intact survival decreased by 1.9% for each 1°C/hour(1.8°F/hour) increase in rewarming rate.42

5.There are no studies on rewarming with ECLS in children with severe environmental hypother-mia and not in cardiac arrest, so this recom-mendation is extrapolated from studies in adults.Retrospective observational studies have shown successful rewarming as well as faster rewarming for adults who are not in cardiac arrest with core temperature<28℃(82.4°F) with ECLS compared with conventional methods.22,24,35 A mul-ticenter prospective observational study showed improved outcomes with use of ECMO for adults in hypothermic cardiac arrest; however, patients with hemodynamic instability without cardiac arrest who received ECMO had decreased event-free days(ICU, ventilator, and catecholamine administration)

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and increased hemorrhagic complications without improving survival or neurological outcomes.21

6. Defibrillation before rewarming can be successful in adults and adolescents.18,20,36,37 The hypother-mic heart may be less responsive to defibrillation,and the temperature at which defibrillation should first be tried in the severely hypothermic child and the number of defibrillation attempts that should be made are not well studied. If VT or VF persists,excessive defibrillation attempts may lead to myo-cardial injury. In a large retrospective observational study, while a shockable initial rhythm in adult patients with hypothermic OHCA was associated with better survival and neurologically favorable survival, prehospital defibrillation and increasing the number of defibrillation attempts were not38 However, only a small number of adults with shock-able rhythms were not defibrillated, so the study may have been underpowered to detect a differ-ence in outcomes in this population.The Wilderness to Medical Society guideline recommends defibrillat-ing once initially and deferring additional defibrilla-tion attempts until core temperature reaches 30°C(86°F) because these are more likely to be suc-cessful,39,40 ERC guidelines allow up to 3 defibrilla-tion attempts before rewarming to 30°C(86°F).41 There are no relevant societal guidelines specific to children, and, thus, recommendations are extrap-olated from adult data.

7. The temperature at which epinephrine should first be administered and the optimal dosing interval in the severely hypothermic child has not been well-studied. Some adult and adolescent cases of hypo-thermic cardiac arrest have normal responses to epinephrine before rewarming.18 However, hypo-thermic hearts may be less responsive to cardio-vascular drugs and slowed metabolism due to hypothermic raises concerns for epinephrine accu-mulation and toxicity.41,43,44 There are no relevant societal guidelines specific to children, and, thus,recommendations are extrapolated from adult data.

8. In cases of prolonged CPR or dangerous environ-mental conditions, it may be suboptimal or impos-sible to perform continuous high-quality CPR.Delayed or interrupted CPR may facilitate rapid extraction or transportation and allow for optimal CPR as soon as feasible or safe. Adult cases with delayed or intermittent CPR have led to successful resuscitations, but there are no reported cases in children.45 The acceptable frequency and duration of CPR interruptions and which children can best tolerate this are unknown.

9.Rapid hospital transport is important to allow for aggressive rewarming with both noninvasive and invasive techniques. Two studies utilizing the same database conflicted on the association of low-flow

time (time from cardiac arrest to the establishment of ECMO) with outcomes for adults in cardiac arrest due to hypothermia, but there are no such studies in children.46,47 Adults have been resuscitated using ECLS after hypothermic cardiac arrest lasting over 6 hours, so the ERC supports transporting to an ECLS-capable center if within 6 hours.41,48,49 An observational study showed that transportation to centers with ECLS capability improved neurologi-cally favorable outcomes and 1-month survival in adults.38 There is no data in children, and, thus, the recommendation is extrapolated from adult data.

10. ETCO2 measurement by waveform capnography is utilized for confirmation of correct endotracheal tube placement and monitoring ventilation during endotracheal intubation. For children in nonhy-pothermic cardiac arrest, ETCO2 is often used to monitor and optimize CPR quality and an abrupt increase in CO2 can indicate ROSC. In an obser-vational study comparing adults with hypothermic with nonhypothermic cardiac arrest assessed for ECLS, those in hypothermic cardiac arrest had significantly lower ETCO2 and temperature was positively correlated with ETCO2.27 Also, 45% of adult survivors had ETCO2≤10 mm Hg at hospital admission, and the value of ETCO2 did not predict survival.27 There are no studies available in children,and, thus, recommendations are extrapolated from adult data.

REFERENCES

1.Frei C,Darocha T,Debaty G,Dami F,Blancher M,Carron PN,Oddo M,Pasquier M. Clinical characteristics and outcomes of witnessed hypother-mic cardiac arrest: A systematic review on rescue collapse. Resuscitation 2019;137:41-48. doi:10.1016/j.resuscitation.2019.02.001

2. Bunya N, Sawamoto K, Kakizaki R, Wada K, Katayama Y, Mizuno H, Inoue H, Uemura S, Harada K, Narimatsu E. Successful resuscitation for cardiac arrest due to severe accidental hypothermia accompanied by mandibular rigidity: a case of cold stiffening mimicking rigorous. Int J Emerg Med.2018;11:46.doi:10.1186/s12245-018-0205-8

3.Ko CS,Alex J,Jeffries S, Parmar JM.Dead? Or just cold: profoundly hypo-thimeric patient with no signs of life. Emerg Med.J 2002;19:478-479. doi:10.1136/emj.19.5.478

4. Mocrozk T, Gladki M, Skalski J. Successful resuscitation from ac-cidental hypothermia of 11.8℃: where is the lower bound for hu-man beings? Eur J Cardiothorac Surg. 2020;58:1091-1092. doi:10.1093/eijects/zaes159

5.Forti A, Brugnoar P, Rauch S, Cruciti M, Brugger H, Cipollotti G, Strapazon G. Hypothermic Cardiac Arrest With Full Neurologic Recovery After Ap-proximately Nine Hours of Cardiopulmonary Resuscitation: Manage-ment and Possible Complications. Ann Emerg Med.2019;73:52-57. doi:10.1016/j.annemergmed.2018.09.018

6.Gilbert M, Busund R, Sagketh A, Nilsen PA, Solbo JP. Resuscitation from accidental hypothermia of 13.7℃ with circulatory arrest. Lancet 2000;355:375-376. doi:10.1016/S0140-6736(00)01021-7

7. Tiruvoipati R, Balasubramanian SK, Khoshbin E, Hadjinikolaou L, Sosnowski AW,Firmin RK.Successful use of venovenous extracorporeal membrane ox-xygenation in accidental hypothermic cardiac arrest. ASAIO/J.2005;51:474-476. doi: 10.1097/01.mat:0000169124.32865.d6

8.Arai H, Yokoi H, Cho K, Hirata M, Yanagita M. Resuscitation from severe accidental hypothermia by active core rewarming via an indwelling peri-toneal dialysis catheter. Am J Emerg Med. 2022;55:226.e3-226.e6. doi:10.1016/j.ajem.2021.12054

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9. Kangas E, Niemela H, Kojo N. Treatment of hypothermic circulatory arrest with thoracotomy and pleural lavage. Ann Chir Gynaec. 1994;83:258-260.

10. Klein LR,Huelster J,Adil R,Schramil,BrunetDEk,Dempainen RR,Prekerk ME. Endovascular rewarming in the emergency department for moderate to severe accidental hypothermia. Am J Emerg Med.2017;35:1624-1629.doi:10.1016/j.jaem.201705.001

11. Mendranka, Karo D, Pluta M, Witllmakhr A, Ykmakra S, Nowak E,Rzamik T, Barteczo-Kgrajek B, Dabrowski W, Kosinski S, et al; on behalf of the Hypothermia Study Group. Outcomes of extracoreal life support in hypothermia: cardiac arrest: Revisiting ELSO guidelines. Resuscitation 2024;205:110424. doi: 10.1016/j.resuscitation.2024.110424

12. Plaier BR. Thoracactive l in accidental hypothermia with cardiac arrest-report of a case and review of the literature. Resuscitation. 2005;66:99-104. doi: 10.1016/j.resuscitation.2004.12.024

1. Usman S, Daloya J, Khan M, Huseaséb, Patel H, Mustafa S, Panti D. Intermittent hemodialysis as a rewarming strategy for severe hypotheremia in patients without renal failure: a case report. BMC Enthesialol. 2024;24:284.doi:10.1186/s12871-024:20664-w

14. Corneli HM. Accidental hypothesis 1. Pediatr. 1992;120:671-679. doi:10.1016/s0022-34765(05)80226-4

15. Pasquier S, Strapazzon G, Kottman A, Paal P, Zafnich K, Ortoni C, Van Tilburg C, Sheets A, Ellerton J, et al. On-site treatment of avalanche victims: Scoping review and 2023 recommendations of the international commission for mountain emergency medicine (ICAR Med.Com). Resuscita-tion.2023;184:109708. doi: 10.1016/j.resuscitation.2023.109708

16. Hewber tumberg EK, Douma MIA, Alberts K, Charton NP, Goldman MP.Harper-Kirkeyk, Kawins SC, Hoover AV, Kule A, Leichleet S, et al; on behalf of the American Heart Association and American Red Cross. 2024 Ameri-can Heart Association and American Red Cross Guidelines for First A. Di Cr-culation.2024;150:e519-e579.doi:10.1161/CIR.00000000000001281

17. Paal P, Milani M, Brown D, Boyd J, Ellert J. Termination of cardiopulo-nary resuscitation in mountain rescue. High Alt Med Biol. 2012;13:200-208. doi: 10.1089/ham.2011.1096

18. Cools E, Mayer, Courvoier D. Walpoth B. Successful Pre-Rewarming Resuscitation after Cardiac Arrest in Severe Hypotheremia: A Retrospective Cohort Study from the International Hypothermia Registry. Int J. Environ Res Public Health:2022;19:4059.doi:10.3390/10794059

19. Podsiadlo P, Darocha T, Svendens OS, Kosinski S, Sifstav L, Thacher M.,Sawamoto K, Pasquier M. Outcomes of patients suffering unweighted hy-perbolic cardiac arrest, reemuted over extracorplare life support: A sys-tematic review. Artif Organs.2021;45:222-229. doi:10.1111/a188138

10.Walphot BH, Maeder MB, Courvoisel S. Meyer, M. Cools E, Dorachi D,Blancher M,Champl F,Mantovani L,Lovis C,et al.Hypothermic Cardiac Ar-rest-Retrospective cohort study from the International Hyptheremia Registry. Res. Custonucvallation:2021:167:58-65. doi:10.1016/j.resuscitation.2021.08.016

21. Takauji S,Hayakawa M,Yamada D,Tian T,Minowa K,Inoue A,Fujimoto Y,Isokawa S,Mura N,Endo T,etal Outcome of extracorporeal membrane oxygenation use in severe accidental hyperhombia with cardiac arrest and circulatory instability.A multicentre, prospective, observational study in Japan(ICE-CRASH study).Resuscitation 2023;182:109663. doi:10.1016/j.resuscitation:20212001

24. Morisea K, Sijuchi Y, Nagamji T, Iizuka Y, Samanoyra R, Oki H, Okada M.Efficacy of portable and percutaneous cardiopulmonary bypass re-warming versus that of conventional internal rewarming for patients with accidental deep hyperhormic. Crit Med 2011;39:1064-1068. doi:10.1097/CCM.0b013e31820edd04

23. Ohbe H, logal S, Jo T, Matsui H, Fushimi K, Yasunaga H, Extraco-pol.88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88,88

24. Preker ME, Rischall M, Carlson M, Driver BE, Touroutoutidis M, Boland J,Hu M.Heather, B.Simpson NS, Extracorporeal membrane oxygen ver-conventional rewarming for severe hypotheremia in an urban emergency department. Acad Emerg Med.2023;30:65-15. doi:10.111/acm.115855

25. Berhinaes Li, Hindberg K, Shaensheim TO, Subovert E, Revi E, Kriov MY,Bedelinskii KM, TeVita T. Rewarming From Hypothermic Cardiac Arrest Ap-plying Extracorporeal Life Support: A Systematic Review and Meta-Analysis Front Med(LedusAausan) 2021:6461633. doi:10.10389/med2021.641633.

26. Pasquier M., Hugli O, Paal P, Darocha T, Blancher M, Husby P, Silvast T,Caron PN. Vousson V. Hypotherma outcome prediction after extracorpol-real life support for hyperthemic cardiac arrest patients: The HOPE score Resuscitation.2018:126:58-64. doi:10.1016/j.resuscitation.2018:02.026

27. Carloa T. Debaty G. Ageron FX. Podsiadlo P. Hutn A. Hymczak, Blancher M.Kosinski S, Mendra K, Carlon P. Yanthemia is associated with a low ETCO(2) and low ph-stat PaCO in refractory cardiac arrest. Resuscitation:2022:174:83-9. doi:10.1016/j.resuscitation.202201022

28. Pasquier M, Rousson V, Darocha T, Bouzat P, Kosinski S, Sawamoto K,Champigneulle B, Wberg S, Wanscher MCJ, Brodmann Maeder M, et al.Hypothermia outcome prediction after extracorporeal life support for hypo-thermic cardiac arrest patients: An external validation of the HOPE score.Re-suscitation.2019;139:321-328. doi:10.1016/j.resuscitation.2019.03.017

29. Saczkowski RS, Brown DJA, Abu-Laban RB, Fradet G, Schulze CJ, Kuzak ND.Prediction and risk stratification of survival in accidental hypothermia re-quiring extracorporeal support: an individual patient data meta-analysis.Resuscitation.2018,127:51-57.doi:10.1016/j.resuscitation.2018.03.028

30. Austin A.Nayes EL O.Malley TJ, Mazur P,Darocha T, Entwistle JW,Guy TS, Massey HT, Morris RJ, Tchanthaleishvili V. Outcomes of Extracorporeal Life Support Use in Accidental Hypothermia: A Systematic Review. Ann Tho-rac Surg.2020;110:1926-1932. doi:10.1016/j.athorocrasur.2020.04.076

31. Okada Y, Kiguchi T, Irisawa T, Yoshiya K, Yamada T, Hayakawa K, Noguchi K,Nishimura T, Ishbe T, Yagi Y, et al. Predictive accuracy of biomarkers for survival among cardiac arrest patients with hypothermia: a prospective observational cohort study in Japan. Scand J Trauma Resusc Emerg Med.2020/2875, doi:10.1186/s13049-020-00765-2

2. Podsiadlo P. Mendralka R. Hymczak H, Nowak E, Witt-Malchrzak A, Dabrowski W,Miazgowski B,Dudek M,Darocha T.Hypothermic cardiac arrest: prognos-tic factors for successful resuscitation before rewarming. Scand J Traum Resuscans Emerg Med Resusc l and Rerim.

33. Sevensden OS, Grong K, Andersen KS, Husby P. Outcome After Rewarming From Accidental Hypothermia by Use of Extracorporeal Circulation. Ann Thorac Surg.2017;103:920-925. doi:10.1016/j.athoracsur.2016.06.093

34. Jarosz A, Kosinski S, Darocha T, Darocha T, Sanak T, Podsiadlo P, Galakowski R.[Early complications of extracorporeal rewarming]. Wad Lek.2017;70:415-420.

35. Kosinski S, Docha T, Jarosz A, Zelias A, Zietkiewicz M, Podsiadlo P,Sanak T, Salapa K, Piatek J, Konstany-Kalandyks, J, et al. Clinical course and prognostic factors of patients in severe accidental hypothermia with circulatory instability rearmed with veno-arterial ECMO- an observational case series study. Scand J. Trauma Resuscem Emerg Med.2017;25:46. doi:10.1186/s13049-017-0388-7

36. Clift J, Munro-Davies L. Best evidence topic report. Is defibrillation effective in accidental severe hyperthermia in adults? Emerg Med.J.2007;24:50-51.doi:101136/emnlp.2006044404

37. Mair P,Gasteiger L,Mair B,Stroehle M, Walpoth B,Successful Defibrillation of Four Hypothermic Patients with Witnessed Cardiac Arrest. High Alt Med Biol.2019;2017:7-77. doi: 10.1089/ham.2018.0084

38. Ushimoto T, Murasaka K, Wato Y, Inaba H. Associations between prehos-pital defibrallation and outcomes of out-of-hospital cardiac arrests pre-summed to be caused by hypothermia: A nationwide observational study with epidemiological analysis. Medicine(Baltim). 2023;102:e33618. doi:10.1097/MD.00000000000033618

D9. Dow J,Giesbrecht GG,Danzl DF, Brugger H, Sagalyn EB, Walpoth B,Auerbach PS,McIntosh S,Enemethy M, McDevitt M,et al.Wilderness Medi-cal Society Clinical Practice Guidelines for the Out-of-Hospital Evaluation and Treatment of Accidental Hypothermia: 2019 Update. Wilderness Envi-ron Med 2019;30:547-S69. doi:10.1016/j.wem.2019.10.002

40.Nordberg I,vert D, Talmer M, Forsberg S, Hedman A. Surviving two hours of ventricular fibrillation in accidental hypothermia. Prehosp Emerg Care.2014;1846-449.doi:10.1039/10903127.2014.891066

41. Lott C, Truhlar A, Aflonov A, Barelli A, Gonzalez-Salvado V, Hinkelbein J,Nolan JP, Paal P, Perkins GD, Thies KC, et al; on behalf of ERC Special Circumstances Writing Group Collaborators. European Resuscitation Coun-cell Guidelines 2021:98. Diacic arrest in special circumstances. Resuscitation 2021;161:152-219. doi:10.1016/j.resuscitation.2021.02.011

42.Sackzowski R, Kuzak N, Grunau B, Schulze C. Extracorporeal life support rewarming rate is associated with survival with good neurological outcome in accidental hypothermia. Eur. J Cardiothorac Surg.2021;59:593-600. doi:10.1097/1003/ejcæza385

43.Meyer M,Pelurson N,Khabiri E,Siegenthaler N, Walpth BH. Sequela-free long-term survival of a 65-year-old woman after 8 hours and 40 minutes of cardiac arrest from deep accidental hypotermia. J Thorac Cardiovasc Surg.2014;147:e1-e2. doi:10.1016/j.tjcvs.2013.08.085

4.Searo J, Becker LB, Berg KM, Einav S, Ma Q, Olasveeneng TM, Paal P,Parr MJA. Cardiopulmonary resuscitation in special circumstances. Lancet 2021:398:1257-1268. doi:10.1016/S0140-6736(2011)01257-5

45 Gordon, L P aler, P lerton JA, Brugger H, Pekg J, Zafren K. Delayed and intermittent CPR for severe accidental hypothermia. Resuscitation.20150:94-49. doi:10.1016/j.resuscitation.2015.02.017

46Shoji K,Ohbe H, Matsuyama T, Inoue A, Hifumi T, Sakamoto T, Kuroda Y,Kushimoto S; SAVE-J II study group. Low-flow time and outcomes in hypo-thermic acid arrest patients treated with extracorporeal life support

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resuscitation: a secondary analysis of a multi-center retrospective cohort study.J Intensive Care.2024;12:22. doi:10.1186/s40560-00735-1

47. Tanizawa S, Kojima M, Shoko T, Inoue A, Hifumi T, Sakamoto T, Kuroda Y; SAVE J-II study group. Extracorporal cardiopulmonary resuscitation in hypothermic cardiac arrest: A secondary analysis of multicenter extracor-poreal cardiopulmonary resuscitation registry data in Japan. Resusc Plus.2024;19:100705. doi:10.1016/j.resplu.2024.100705

48. Kosinski S, Darocha T, Jarosz A, Migiel L, Zelias A, Marcinkowski W, Filip G, Galakowski R, Drwila R. The longest persisting ventricular fibrilla-tion with an excellent outcome- 6h 45min cardiac arrest. Resuscitation 2016;105:105e21-e22. doi: 10.1016/j.resuscitation.2016.05.022

49. Lexow K. Severe accidental Hypothermia: survival after 6 hours 30 minutes of cardiopulmonary resuscitation. Arctic Med Res 1991;50:112-114.

50.Andre MC, Vuille-Dib-Telle RN, Berset A, Hammer J. Rewarming Young Chil-dren After Drowning-Associated Hypothermia and Outf-Hospital Cardiac Arrest: Analysis Using the Case REport Guideline. Pediatr Crit Care Med.2023;24:e417-e424.doi: 10.1097/PCC.0000000000003254

51. Scafe JH, Hewes HA, lantano SE, Clinker CE, Fenton SJ, Skarde DE,Kastenberg SJ, Swendiman RA, Russell KW. Optimizing patient selection for ECMO after pediatric hyperthemic cardiac arrest. Injury.2025;56:111731. doi:10.1016/j.injury2024.111731

LEFT VENTRICULAR ASSIST DEVICES

|Recommendations for Unresponsive Adults and Children With Durable LVADs and Impaired Perfusion||| |---|---|---| |COR|LOE|Recommendations| |1|C-EO|1. In unresponsive adults and children with durable LVADs and impaired perfusion, chest compressions should be performed.| |2b|C-EO|2. In unresponsive adults and children with durable LVADs and impaired perfusion, it may be reasonable to start chest compressions immediately while simultaneously assessing for device-related reversible causes.| |2b|C-EO|3. In unresponsive adults and children with durable LVADs and impaired perfusion, it may be reasonable to utilize an algorithmic approach to concurrently assess and respond to impaired perfusion.|

Synopsis

LVADs deliver blood from the weakened left ventricle to the systemic circulation.1 A durable LVAD comprises an inflow from the apex of the left ventricle, an implanted electrical pump, an outflow to the ascending aorta, a per-cutaneous driveline connection, and an external control-ler powered by batteries(Figure 3). The only currently implanted durable LVAD in adults and children in the United States has a centrifugal pump(eg, HeartMate 3 LVAD[Abbott]) and is fully magnetically levitated to pre-vent mechanical wear and decrease the risk of thrombo-sis. There are patients living with older durable LVADs,such as HeartMate II(Abott) and HeartWare Ventricular Assist Device(Medtronic).

Cardiac arrest can occur in people with durable LVADs in cases of device malfunction, inadequate device flow,or low cardiac output of the unsupported right ventricle,whereas some typical causes of cardiac arrest, such as ventricular arrhythmias, may be better tolerated.2,3 Cur-rent durable LVADs have continuous rather than pulsa-tile flow, so most patients do not have a palpable pulse,making detection of cardiac arrest difficult. Additionally,automated noninvasive blood pressure and pulse oxime-try can be unreliable. Perfusion is considered adequate if any of the following is present:(1) normal skin color and temperature;(2) normal capillary refill;(3) mean arterial pressure greater than 50 mm Hg;(4) partial pressure of end-tidal carbon dioxide greater than 20 mm Hg.(Fig-ure 4). An unresponsive patient with an LVAD without adequate perfusion is likely in cardiac arrest.

Potential concerns related to performing chest com-pressions in adults and children with LVADs are device


Figure 3. Components of the Abbott HeartMate 3 LVAD.

LVAD indicates left ventricular assist device. HeartMate, HeartMate II, and HeartMate 3 are trademarks of Abbott or its related companies. Reproduced with permission of Abbott.©2025 Abbott. All rights reserved.

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 Figure 4. Adult and Pediatric Durable LVAD Algorithm.

ALS indicates advanced life support; BLS, basic life support; BP, blood pressure; ET, endotracheal; LVAD, left ventricular assist device; MAP, mean arterial pressure; PETCO, partial pressure of end-tidal carbon dioxide; and VAD, ventricular assist device.

dislodgement and ineffective or retrograde blood flow through a valveless LVAD during chest compressions.

These recommendations inform the management of adults and children with durable LVADs in cardiac arrest beyond the index placement hospitalization. Manage-ment of cardiac arrest in the peri-implantation period is discussed in the recommendations detailed in the Car-diac Surgery section.

Recommendation-Specific Supportive Text

1. There are no RCTs or high-quality observational studies comparing chest compressions versus not performing chest compressions in adults or chil-dren with an LVAD. The largest study, a retrospec-tive cohort of 578 adults with LVADs with cardiac arrest, showed patients who received chest com-pressions had higher in-hospital mortality than those who did not, and CPR was an independent

predictor of mortality. ${}^{4}$ In another retrospective cohort study including 58 adults with LVADs who had cardiac arrest, there was no difference in survival in those receiving chest compressions versus those not receiving compressions. ${}^{5}$ In a case series of 16 adults, 2 of 9(22.2%) patients who received chest compressions survived to dis-charge compared with 3 of 7(42.9%) who did not receive chest compressions. ${}^{6}$ There is high risk of bias in these retrospective studies, with potentially poorer outcomes occurring in patients receiving chest compressions due to a delay in initiation in this patient population and failure of this subset of patients to respond to other ALS interventions, such as defibrillation or epineph-rine. There is also high risk of misclassification of patients as having a cardiac arrest when not truly in cardiac arrest. There are many case reports of successful use of chest compressions in adults

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and children with an LVAD.7-14 No study reported dislodgement or other LVAD device dysfunction after chest compressions. In 1 study, 3 adults underwent autopsy to confirm the LVAD was in appropriate position, including 1 patient who underwent 2.5 hours of chest compressions.15 Despite the mechanical left ventricular support provided by an LVAD, CPR can provide tempo-rary circulatory support in cardiac arrest resulting from device malfunction or right ventricular fail-ure. CPR in the absence of LVAD saves lives, and poor outcomes may have resulted from hesitancy to start CPR in this patient population. The ben-efift of immediate initiation of CPR in unrespon-sive adults and children with LVADs and impaired perfusion outweighs the risk.

2. Multiple case series and case reports have reported delays in initiation of chest compressions in adults with an LVAD, and delays were longer for patients with an LVAD compared with controls without an LVAD.69,10,12 The most common reason for clinicians not performing chest compressions in patients with an LVAD with acutely impaired per-fusion was a belief that chest compressions were contraindicated in this population.5 Delays in chest compressions have been highlighted as a potential contributor to poor outcomes.5,9 While the British Societies recommend delaying chest compres-sions in patients with an LVAD for up to 2 minutes while attempting to restart the device, these efforts could occur in parallel to prevent delays in chest compressions per the 2024 ILCOR scoping review(Figure 4).16

3. Because of the difficulty assessing perfusion and uncertainty regarding the safety of chest com-pressions in adults and children with an LVAD,several studies and reviews have proposed algo-rithms for the resuscitation of this population(Figure 4).1,69,14,17,18 Signs and symptoms related to poor tissue perfusion, such as altered mentation or unresponsiveness, agonal breathing or apnea,cool temperature, and delayed capillary refill, are important for initial patient evaluation. The pri-mary consideration for a patient with an LVAD with acutely altered perfusion is whether the device is functioning, and this can be assessed by auscul-tating for a mechanical ventricular assist device hum over the left chest and left upper abdomen.1 Troubleshooting an LVAD includes assessment of the controller for alarms, assessment of the drive-line for disconnection or fracture and reconnect-ing if possible, and ensuring an adequate power source connection.17 Doppler with a manual cuff or an arterial line can more reliably measure blood pressure in a patient with an LVAD, and waveform capography can aid in assessment of perfusion.

There are no studies demonstrating improved out-comes with utilization of an algorithm for managing adults or children with a durable LVAD in cardiac arrest.

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2.Dogan E,Ergin F,Beyter MB,Kayan Kasikci G,Ay O,Levent RE,Engin C,Ulger Z.Evaluation of cardiac arrhythmia in pediatric patients with Left Ven-tricular Assist Device (L-VA D). Eur Rev Med Pharmacol Sci. 2024;28:2199-2206. doi: 10.26355/eurrev_202403_35724

3. Kadado AJ,Akar JG, Hummel JP. Arrhythmias after left ventricular assist device implantation: Incidence and management. Trends Cardiovasc Med.2018;28:41-50. doi:10.1016/j.tcm.2017.07.002

4. Barssoum K, Patel H, Raii D, Kumar A, Hassib M, Othman HF, Thakkar S, El Karyoni A, Idemudia O, lbrahim F, et al. Outcomes of Cardiac Arrest and Cardiopulmonary Resuscitation in Patients With Left Ventricular As-ist Device; an Insight From a National Inpatient Sample. Heart Lung Circ.2022;31:206-254. doi: 10.1016/j.jhcl.2021.05.096

5.Senman B, Pierce J, Kittipbul V, Barnes S, Whitacre M, Katz JN.Safety of Chest Compressions in Patients With a Durable Left Ven-tricular Assist Device. JACC Heart Fail. 2024;12:1928-1930. doi:10.1016/j.jchf.2024.03.004

6. Garg S, Ayers CR, Fitzsimons C, Meyer D, Peltz M, Bethea B, Cornwell W,Araj F, Imbodeau J, Dranzner MH, In-hospital cardiopulmonary arrests in patients with left ventricular assist devices. J Card Fail.2014;20:899-904.doi:10.1016/j.cardfail.2014.10.007

7. Cubillo El, Weis RA, Ramakrishna H. Emerg reconnection of a transected left ventricular assist device driveline.J.Emerg Med.2014;47:546-551.doi:10.1016/j.jemmered.2014.07.028

8.Doita T,Kawamura T,Inoue K,Kawamura A,Kashiyama N,Matsuura R,Saito T,Yoshioka D,Toda K,Miyagawa S. Sudden severe left ventricular assist de-vice inflow cannula obstruction caused by huge thrombus after closure of mechanical aortic valve: case report. J Artif Organs.2022;25:364-367. doi:10.1007/s10047-022-01332-5

9.Esangbedo ID, Yu P, Choudhury TA, Tume SC, Lasa JJ. Ventricular As-sist Device Training and Emergency Management Among Pediat-ric Cardiac Intensive Care Physicians - Multicenter Cross-Sectional Survey. World J Pediatr Congen Heart Surg. 2024;15:202-208. doi:10.1177/21501351231205804

10.Iwashita Y, Ito A, Sasaki K, Suzuki K, Fujioka M, Maruyama K, Imai H. Car-diopulmonary resuscitation of a cardiac arrest patient with left ventricular assist device in an out-of-hospital setting: A case report. Medicine (Baltim).2020;99:e18658. doi:10.1097/MD.0000000000018658

11. Ornato JP,Louka A,Grodman SW,Ferguson JD.How to determine whether to perform chest compressions on an unconscious patient with an implant-ed left ventricular assist device. Resuscitation. 2018;129:e12-e13. doi:10.1016/j.resuscitation.2018.05.024

12.Saito S, Toda K, Miyagawa S, Yoshikawa Y, Hata H, Yoshioka D, Kainuma S, Yoshida S, Sawa Y. Therapeutic hypothermia after global cerebral ischemia due to left ventricular assist device malfunction. J Artif Organs.2019;22:246-248.doi:10.1007/s10047-019-01099-2

13.Theeuwes C., Frost M., Vierecke J. Prolonged Cardiopulmonary Re-suscitation with Lucas Device in a Patient with Left Ventricular As-sist Device. J. Heart Lung Transplant. 2023;42:S356-S356. doi:10.1016/j.healun.2023.02.826

14. Yuzefolskaya M, Uriel N, Flannery M, Yip N, Mody K, Cagliostro B,Takayama H, Naka Y, Jordode UP, Goswami S, et al. Advanced cardiovascular life support algorithm for the management of the hospitalized unresponsive patient on continuous flow left ventricular assist device support outside the intensive care unit. Eur Heart J Acute Cardiovasc Care. 2016;5:522-526.doi: 10.1177/2048872615574107

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15. Shinar Z, Bellezzo J, Stahovich M, Cheskes S, Chillott S, Dembitsky W.Chest compressions may be safe in arresting patients with left ven-tricular assist devices(LVADs). Resuscitation. 2014:85:702-704. doi:10.1016/j.resuscitation.2014.01.003

16.Moskowitz A, Pocock H, Lagina A, Ng KC, Scholefield BR, Zelop CM, Bray J, Rossano J, Johnson NJ, Dunning J, et al; on behalf of the ILCOR Advanced Life Support, Basical Life Support, and Pediat-ric Life Support Task Forces. Resuscitation of patients with durable mechanical circulatory support with acutely altered perfusion or car-diac arrest: A scoping review. Resuscitation. 2024;203:110389. doi:10.1016/j.resuscitation.2024.110389

17. Akhtar KH, Khan MS, Baron SJ, Zeroth S, Estep J, Burkhoff D, Butler J, Fudim M. The spectrum of post-myocardial infarction care: from acute ischemia to heart failure. Prog Cardiovasc Dis. 2024;82:15-25. doi:10.1016/j.pcdac2024.01.017

18. Duff JP, Decaen A, Guerra GG, Lequier L, Buchholz H. Diagnosis and management of circulatory arrest in pediatric ventricular assist device pa-tients: presentation of two cases and suggested guidelines. Resuscitation 2013;84:702-705. doi: 10.1016/j.resuscitation.2012.09.032

PREGNANCY

Introduction

Cardiac arrest in pregnancy is infrequent, but the rate ap-pears to be increasing.1,2 Because of the relative rarity of the event, the exclusion of pregnant people from clinical trials, and ethical considerations, most studies addressing cardiac arrest in pregnancy are observational. Variability in the populations included in these studies further chal-lenges the interpretation of literature. The term obstet-rics encompasses pregnancy,childirth, and postpartum states, whereas the term peripartum includes late preg-nancy, intrapartum, and immediate postpartum periods.Existing recommendations center on maintaining best resuscitation practices with modifications to account for the physiologic changes of pregnancy and address underlying etiologies specific to obstetric patients.1,3,4 Reversible causes of cardiac arrest in pregnancy paral-lel those in the nonobstetric population in terms of the underlying pathophysiology(eg, hypovolemia, hypoxemia,thrombosis). A pregnancy-specific mnemonic(Figure 5)emphasizes the leading causes of death in obstetric pa-tients(eg, hemorrhage, sepsis, and hypertension) while highlighting diagnoses unique to, or commonly encoun-tered in, the peripartum period(eg, amniotic fluid em-bolism, anesthetic complications, cardiomyopathy, and medications such as magnesium infusions).

Reported rates of survival for the pregnant patient and newborn infant vary widely, reflecting differences in the causes of cardiac arrest, readiness of the clinical team,resources available, location, and gestational age at the time of the event. 1,4,5 Optimizing outcomes for both the pregnant patient and newborn infant requires advanced planning to ensure the clinical team can provide timely and effective resuscitation. ${}^{6}$

Guidelines for the resuscitation of newborn infants are provided in "Part 5: Neonatal Life Support" Ethical considerations of performing resuscitation on pregnant patients are discussed in "Part 3: Ethics."

|Recommendations for Team Preparation for Cardiac Arrest in Pregnancy|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-LD|1.Establishing a team prepared to manage cardiac arrest in a pregnant person is recommended.|| |1|C-LD|2.The resuscitation team should access resources, including health care professionals, their expertise, and the necessary equipment, to perform a resuscitative delivery at the diagnosis of cardiac arrest in a pregnant patient.|| |1|C-LD|3.Role-specific training should be provided for health care professionals with the potential to respond to cardiac arrest in a pregnant patient.||

Synopsis

The management of cardiac arrest in a pregnant patient requires modifications to account for the physiology of pregnancy, unique causes of cardiac arrest, and the po-tential need for a resuscitative delivery if ROSC cannot be achieved. Essential roles of a resuscitation team in-clude performing left lateral uterine displacement; pro-viding high-quality, minimally interrupted CPR; managing the difficult airway; and performing a resuscitative de-livery.3 If resuscitative delivery is effective in achieving ROSC, teams may be tasked with the medical and sur-gical management of life-threatening postpartum hem-orrhage. Resuscitative delivery may lead to the birth of a viable newborn infant in need of resuscitation, which will ideally be provided by a dedicated team experienced with the resuscitation of term and preterm infants. Timely access to the resources and personnel capable of co-ordinating this multidisciplinary endeavor will vary based on the local environment. The complexity of this clinical scenario underscores the need for teams to prepare and train for this situation.

These recommendations inform team preparation by facilities capable of responding to and treating pregnant patients in cardiac arrest.

Recommendation-Specific Supportive Text

1. Team composition will vary according to local resources but may include(1) a team leader skilled in the management of cardiac arrest and aware of pregnancy-specific modifications;(2) an anesthe-sologist or other operator familiar with intubating pregnant patients and supporting massive trans-fusion;(3) an obstetrician or surgeon with experi-ence performing cesarean deliveries and surgically managing hemorrhage;(4) a designated neonatal resuscitation team; and(5) nurses,pharmacists,and other professionals skilled at IV access, medica-tion selection, medication administration, and other key resuscitation tasks.3 Health care professionals capable of performing cannulation for VA-ECMO

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 Figure 5. Cardiac Arrest in Pregnancy Algorithm.

AED indicates automated external defibrillator; ALS, advanced life support; BLS, basic life support; CPR, cardiopulmonary resuscitation; IV,intravenous and ROSC, return of spontaneous circulation.

may play a role in settings where this resource is available. An analysis of 561 cases of IHCA using the Get With The Guidelines-Resuscitation registry demonstrated an association between the location of cardiac arrest within the hospital and survival.5 A cardiac arrest occurring in the ICU or postan-esthesia care unit conferred a 3 times increased adjusted odds of mortality(aOR, 3.32; 95% CI,2.00-5.52) compared with those with a cardiac arrest occurring in the labor and delivery unit. This association could reflect residual confounding based on morbidity burden, but it may also reflect lack of readiness of the team for cardiac arrest in pregnancy.

2.Despite longstanding guidelines recommending that a resuscitative delivery(historically referred to as a perimortem cesarean delivery) be initiated if ROSC is not achieved within 4 minutes of car-diac arrest, in most cases this intervention is not performed in the recommended timeframe.37-11 Institutions and organizations that may be required to manage cardiac arrest in a pregnant patient can prioritize developing, training, and implement-ing processes to perform a resuscitative deliv-ery rapidly and safely. ${}^{6}$ In cases of IHCA, this will include summoning an obstetrician or surgeon, if available, prepared to perform a resuscitative deliv-ery along with requisite tools for this procedure

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as well as the necessary equipment for neonatal resuscitation. Optimal management of OHCA dur-ing pregnancy poses significant clinical challenges and requires performing high-quality resuscitation while rapidly transporting the pregnant patient to a center capable of safely performing the procedure.A population-based study from France evaluated 55 pregnant patients with OHCA and reported that 30-day survival was 14.5% with neonatal survival rates of 10.0% when cardiac arrest occurred in the second trimester and 23.5% in the third trimester. ${}^{12}$ This underscores the potential for a good outcome for the patient and newborn infant when effective resuscitation is provided.

3.Population-based reviews of resuscitation in preg-nant patients highlight opportunities for improve-ment. A population-based surveillance study of cardiac arrest in pregnancy from the Netherlands demonstrated that less than a third of pregnant patients(4/14[29%]) received maneuvers to alleviate aortocaval compression.13 A study from the United Kingdom found similar results with only 44%(n=29/66) receiving maneuvers to relieve aortocaval compression.14 Data from the Netherlands demonstrated improved rates of appropriate resuscitation delivery before and after implementation of the Managing Obstetric Emergencies and Trauma course for health care professionals in the country(0.36/year versus 1.6/year; P=0.01), but the 15-year time period of the study limits causal inference.15 Simulation-based studies demonstrate improved knowledge of cardiac arrest in pregnancy, underscoring a need for training as a key step to improve readiness.6,16,17

|Recommendations for Pregnant Patients in Cardiac Arrest|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|B-NR|1. Resuscitative delivery is indicated for a pregnant patient in cardiac arrest when fundal height is at or above the umbilicus and ROSC is not achieved with standard resuscitation.|| |1|B-NR|2. Preparation for resuscitative delivery for a pregnant patient in cardiac arrest should begin at the recognition of cardiac arrest, with the goal to complete delivery by 5 minutes.|| |1|C-LD|3. Resuscitative delivery for a pregnant patient with IHCA should be performed at the location of the arrest, without attempts to move the pregnant patient to the operating room.|| |1|C-LD|4. Manual left lateral uterine displacement should be provided in conjunction with chest compressions for a pregnant patient in cardiac arrest when the fundal height is at or above the umbilicus.|| |1|C-LD|5. Airway management should be prioritized during the resuscitation of a pregnant patient in cardiac arrest.||

|Recommendations for Pregnant Patients in Cardiac Arrest(Continued)|||| |---|---|---|---| |COR|LOE|Recommendations|| |2a|B-NR|6. It is reasonable to use extracorporeal cardiopulmonary resuscitation in pregnant or peripartum patients in cardiac arrest not responsive to standard resuscitation.|| |2a|C-EO|Placing IV or IO access in the upper extremities as opposed to the lower extremities is reasonable for a pregnant patient in cardiac arrest.|| |2a|C-EO|8. Administration of calcium to a pregnant patient who develops cardiac arrest while receiving IV magnesium sulfate is reasonable.|| |3: No Benefit|C-EO|9. Fetal monitors should be removed, and fetal monitoring should not be performed for a pregnant patient in cardiac arrest.||

Synopsis

Modifications to resuscitation in the pregnant patient with cardiac arrest are based on the anatomic and physi-ologic changes of pregnancy.3 The growing uterus can cause position-dependent aortocaval compression when the pregnant person is supine. Compression of the in-ferior vena cava leads to a decrease in preload, stroke volume, and cardiac output, which must be overcome to enable adequate blood flow.18

The increased oxygen consumption in the pregnant person underscores the importance of ensuring adequate oxygenation and ventilation as a part of resuscitation.Pregnancy is characterized as a compensated respira-tory alkalosis driven by an increased tidal volume with metabolic compensation. The increased tidal volume with the enlarging uterus results in a lower functional residual capacity. The decrease in functional residual capacity along with increased oxygen demand leads to a greater risk of hypoxemia during advanced airway placement.3

If interventions to enhance oxygen delivery and reverse underlying causes do not achieve ROSC, atten-tion is then focused on increasing forward blood flow and decreasing oxygen demand by delivering the fetus.The primary purpose of delivery is for resuscitation of the pregnant patient by relieving a toocaval compres-sion and by returning blood sequestered in the uterus to systemic circulation.19 Improving neonatal prognosis by limiting intrauterine hypoxemia and its consequences is the secondary benefit of this intervention, noting that fetal survival is dependent on either maternal survival or resuscitative delivery.8

These recommendations inform the management of pregnant patients in cardiac arrest.

Recommendation-Specific Supportive Text

1. The term resuscitative delivery has replaced the historical term perimortem cesarean delivery to reflect its central role in the resuscitation of the pregnant patient and to support attempts to avoid

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unnecessary surgery when feasible.10 Resuscitative delivery most commonly occurs via laparotomy and hysterotomy(eg, cesarean delivery), but deliv-ery can be achieved via assisted vaginal delivery if the cervix is fully dilated at the time of cardiac arrest. Associating the performance of resuscita-tive delivery and improved outcomes is challenging because selection bias favors better outcomes for those who achieve ROSC early enough in resus-citation that the procedure is no longer needed.Case series, a meta-analysis of case reports, and a prospective observational study all demonstrate an increased likelihood of survival of the pregnant patient and the newborn infant with shorter time intervals between cardiac arrest and resuscitative delivery.8,14,20

2.Resuscitative delivery initiated at 4 minutes and completed by 5 minutes from the onset of cardiac arrest was first proposed in 1986 and has remained the recommended time interval for this procedure based on practicality and available evidence.21 From a pragmatic standpoint, a time interval of 4 minutes allows for 2 rounds of CPR including administra-tion of epinephrine, defibrillation in the setting of a shockable rhythm, and attempts to address revers-ible causes. A population-based study evaluating cardiac arrest in obstetric hospitals in the United Kingdom demonstrated a shorter time interval between cardiac arrest and resuscitative delivery in surviving pregnant patients compared with non-survivors (3 versus 12 minutes; $P=0.001$ ). ${ }^{14}$ In a systematic review of 94 cases of cardiac arrest,resuscitative delivery within 10 minutes of cardiac arrest was associated with 5 times increased odds of survival of the pregnant patient. ${ }^{8}$ In the subgroup analysis of 57 people undergoing resuscitative delivery, time from arrest to delivery was shorter in neonatal survivors compared with nonsurvivors (14 versus 22 minutes; $P=0.02$ ). ${ }^{8}$ This was supported by a review of published cases, which found a con-sistent association between injury-free survival for the pregnant patient and newborn infant and early

resuscitative delivery. No delivery time inflection point or cut-off time was found.7

3. Moving the pregnant patient from the site of cardiac arrest for resuscitative delivery was associated with lower rates of ROSC in a small observational study,though results were potentially confounded by the inclusion of OHCA cases, which have overall poorer prognosis.20 A simulation-based study randomized multidisciplinary teams to perform resuscitative delivery at the location of the arrest or movement to the operating room for resuscitative delivery.The teams performing the delivery at the location of the arrest achieved delivery 3.5 minutes faster with fewer disruptions in chest compressions compared with those moving to the operating room for deliv-ery.22 In a simulation study evaluating the impact of transport on the quality of cardiopulmonary resusci-tation, teams randomized to transporting the mani-kin to the operating room showed lower rates of correct chest compressions with higher rates of interruption compared with the group randomized to stay in the location of simulated cardiac arrest.23

4.Manual left lateral uterine displacement (Figure 6)alleviates aortocaval compression while allowing the patient to remain in a supine position during the resuscitation. A prospective cohort study used quantitative cardiac magnetic resonance imag-ing to demonstrate that pregnant people have decreased cardiac output in the supine position compared with the left lateral position at 20 weeks and 32 weeks of pregnancy. ${ }^{18}$ Left ventricular end diastolic volume, left atrial volume, and stroke vol-ume were higher in the left lateral compared with supine position, supporting the ability of position to increase preload and cardiac output. A meta-analysis including 8 simulation-based crossover trials demonstrated superior chest compression technique when the manikin was placed in a supine as opposed to a left lateral tilt position. ${ }^{24}$ One of the included studies used a porcine model to demon-strate improved coronary perfusion pressure when chest compressions were performed when supine

 Figure 6. Manual left lateral uterine displacement performed with 2-handed technique(A) and 1-handed technique(B) during resuscitation.

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with left lateral uterine displacement versus supine positioning alone.25

5.The physiologic changes of pregnancy render pregnant people less tolerant of apneic oxygen-ation and more vulnerable to hypoxemia, hypercar-bia, and subsequent acidosis than other people in cardiac arrest. Providing adequate oxygenation and ventilation optimizes the resuscitation of the preg-nant patient while maintaining favorable gradients of oxygen and carbon dioxide across the uteropla-cental interface, which is critical to neonatal out-comes.3 Anatomic and hormonal changes increase the risk of aspiration in pregnancy, making endo-tracheal intubation ideal for airway management,but the likelihood of airway edema contributes to higher rates of difficult or failed intubation in pregnant patients.26,27 The "difficult" airway is navi-gated with a smaller endotracheal tube by a team member with expertise in laryngoscopy and con-sideration of a supraglottic airway after 2 failed intubation attempts.3,28

6. Theoretical concerns about bleeding and thrombo-sis in obstetric patients have delayed the use of ECLS in peripartum patients, but emerging data support its use. A systematic review of 358 obstet-ric patients managed with ECLS reported a 30-day survival rate of 75%.29 Fifty-seven of these patients were cannulated for the indication of cardiac arrest during pregnancy or in the first 24 hours after delivery with an 87% 30-day survival rate.29 Only 13% of patients in this study experienced severe bleeding necessitating laparotomy or hysterec-tomy, with a 3% rate of venous thromboembolism.A 2020 analysis of 277 obstetric patients in the ELSO Registry found a 55% rate of survival among the 42 patients receiving ECLS for the indication of cardiac arrest.30 This 55% survival rate among obstetric patients cannulated for an indication of cardiac arrest compares favorably with the 29%rate of survival for patients receiving ECRP in the ELSO Registry over a similar time period.31 ELSO guidelines suggest summoning available resources,including health care professionals, their expertise,and the necessary equipment, for evaluation for possible ECPR after 10 to 15 minutes of standard resuscitation without ROSC.32

<BeginOfPara>7. Although not directly studied, aortocaval compres-sion likely impedes delivery of resuscitation drugs administered in the lower extremities to the central circulation. A radionucleotide study in nonpregnant canines found that drugs instilled into the supe-rior vena cava32 However,studies from OHCA(excluding pregnant people)have not consistently demonstrated favorable neu-rologic outcomes when IO devices were placed

<EndOfPara>in the upper extremity compared to the lower extremity. ${ }^{33-35}$

8. Magnesium sulfate is a commonly utilized medica-tion in obstetrics, administered as a bolus dose fol-lowed by a continuous infusion for management of preeclampsia and for other specific patients at risk of preterm delivery. Life-threatening and fatal hyper-magnesemia due to medication error has been reported in obstetric and nonobstetric patients.36-38 A meta-analysis examining adverse effects from mag-nesium sulfate administration stratified by indication and regimen found an increased risk of respiratory depression in patients with preeclampsia receiving magnesium. ${}^{36}$ A study of patients on magnesium infusions for obstetric indications demonstrated that increasing concentrations of serum magnesium were associated with lower ionized calcium concentration and increased urinary calcium excretion. ${}^{39}$ Calcium administration may improve hemodynamics in the setting of magnesium toxicity, informing its use in car-diac arrest ${}^{40}$ Most patients in case reports received calcium along with multiple concurrent interventions,limiting the usefulness of these reports.

9. The physiologic dependence of the fetus on the circulation of the pregnant patient coupled with the high survival rate of newborn infants in the set-ting of ROSC prior to resuscitative delivery under-scores the importance of prioritizing resuscitation of the pregnant site. Fetal monitoring will not change management and may worsen outcomes by distracting the team and limiting timely defibril-lation and resuscitative delivery when indicated.3 Removal of external and internal fetal monitors at the diagnosis of cardiac arrest avoids these dis-tractions and minimizes risk of rescuer injury in the setting of defibrillation.

The 2025 treatment algorithm for the management of cardiac arrest in pregnancy is shown in Figure 5.

|Recommendations for Perpartum Patients With Life-Threatening Suspected Amniotic Fluid Embolism|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-LD|1. A massive transfusion protocol with a balanced transfusion strategy should be used for peripartum patients with life-threatening suspected amniotic fluid embolism.|| |2|C-LD|2. Tranexamic acid should be administered to peripartum patients with life-threatening suspected amniotic fluid embolism.|| |3|Ca-EO|3. It is reasonable to use VA-ECMO for peripartum patients with life-threatening suspected amniotic fluid embolism.|| |2a|C-EO|4. Use of inhaled pulmonary vasodilators is reasonable for peripartum patients with life-threatening suspected amniotic fluid embolism.|| |3: No Benefit|C-EO|5. Use of atropine in the absence of bradcardia is not recommended for peripartum patients with life-threatening suspected amniotic fluid embolism.||

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Synopsis

Amniotic fluid embolism (AFE) is a clinical diagnosis characterized by sudden hemodynamic and respiratory compromise during labor or shortly after delivery that can lead to cardiac arrest.41 The presence of disseminated intravascular coagulation and resultant hemorrhage is a hallmark feature of the disease.42,43 A key feature in the pathophysiology of AFE involves exposure to fetal antigens with proteins, such as tissue factor and en-dothelin.41 A complete understanding of the molecular mechanism triggering this hyperimmune response is still a topic of investigation, but the historic perspective of the pathophysiology of AFE characterized by fetal cells obstructing the pulmonary vasculature is incorrect.44,45

Tremendous overlap in the clinical features of AFE and other common causes of cardiac arrest make a high index of suspicion, timely diagnosis, and interven-tions addressing the underlying pathophysiology of critical importance.46 Echocardiography evaluating for increased pulmonary vascular resistance and right ven-tricular failure along with viscoelastic testing assessing for hyperfibrinolysis have been proposed to aid in timely diagnosis.47-50 National guidelines for the diagnosis vary without a reference standard clinical or pathologic diagnosis.51

These recommendations inform the management of pregnant patients with life-threatening AFE, including cardiac arrest.

Refer to Figure 5 for pregnancy modifications to stan-dard ALS.

Recommendation-Specific Supportive Text

1. Balanced transfusion characterized by the transfu-sion of red blood cells, fresh frozen plasma, and platelets equivalent to the constitution of whole blood is a cornerstone in the management of active bleeding and hemorrhagic shock in obstetric and nonobstetric patients.52,53 A massive transfu-sion protocol is an institution-specific response to expedite access to support a large-volume transfu-sion of whole blood components in the setting of life-threatening hemorrhage.53 The pathophysiol-ogy of hyperfibrinolysis alongside population-level data from multiple countries support the potential need for this intervention in the setting of sus-pected AFE.53,54 A population-based study evaluat-ing cases of suspected AFE in France reported 10 units of red blood cells as the median transfusion volume(range,0-22 units) while also noting 16 of 36 people received suboptimal hemorrhage man-agement.55 The importance of a balanced trans-fusion strategy that replaces coagulation factors along with red blood cells is underscored in a mul-tinational nested case-control study evaluating the association between hemorrhage management

and death in the setting of suspected AFE.51 An analysis of 216 subjects identified by the United Kingdom Obstetric Surveillance System demon-strated a reduced risk of death in the setting of transfusion of concentrated fibrinogen(aOR, 0.44;95% CI, 0.21-0.92) and platelets(aOR, 0.23; 95%CI, 0.10-0.52), noting the importance of coagula-tion factors in addition to red blood cells.

2. Tranexamic acid(TXA) works through competi-tive binding to limit the activation of plasmin-the enzyme that prevents excess clot formation in physiologic states by cleaving fibrinogen to fibrin and its split products. The hyperfibrinolysis of dis-seminated intravascular coagulation destabilizes existing blood clots while generating fibrin split products that cause microvascular injury.Therefore,the mechanism of action of TXA is to prevent clot degradation and downstream microangiopathy-not to promote clot formation. Two RCTs of more than 2000 adult patients each demonstrated a mortality benefit with TXA administration in the setting of hemorrhage. In the CRASH-2 trial,receipt of TXA reduced the risk of death in the setting of trauma without an increase in venous thromboembolism.56 The WOMAN trial showed a mortality benefit in obstetric patients with postpar-tum hemorrhage, but not specifically AFE, random-ized to receive TXA.57 International guidelines from the World Health Organization support the use of TXA in the setting of postpartum hemorrhage, with recommendations from the Society for Maternal-Fetal Medicine underscoring its unique role in the management of suspected AFE.58,59

3.ECLS with VA-ECMO has been used as a bridge to recovery in case reports and case series of peripartum women with suspected AFE refrac-tory to medical management.60,61 A retrospective case series from 2 high-volume ECMO centers in France evaluated outcomes for the 10 peripartum patients with suspected AFE placed on VA-ECMO over a 13-year period.60 Seven of the 10 patients suffered from cardiac arrest, 2 of whom were can-nulated during ECPR. Seven of the patients were alive at hospital discharge, representing 70% sur-vival in this case series. An ELSO Registry study reported a 62% rate of survival among the 34 patients placed on VA-ECMO in the setting of AFE over a 5-year period.62 Reported outcomes vary in the setting of AFE, with estimated survival rates predating more widespread use of ECMO rang-ing between 11% and 44%.63 The comparatively high rate of survival in patients with suspected AFE receiving ECLS suggests a role for this therapy as a bridge to recovery in this rare disease.

4. Inhaled pulmonary vasodilators selectively dilate pulmonary capillaries receiving alveolar gas

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exchange without causing systemic vasodilation, and case reports have described their use for the management of pulmonary hypertension during labor and delivery.64-66 A case report of the use of inhaled nitric oxide demonstrated rapid rever- sal of hemodynamic compromise in the setting of AFE.67 These limited data alongside biologic plau-sibility supporting the use of inhaled nitric oxide in the unique pathophysiology of AFE suggests a potential role for this therapy in this life-threatening disease.53

5. Case reports have highlighted the use of atro-pine in conjunction with ondsandronet and ketoro-lac for targeted therapy for peripartum patients with AFE.68,69 These case reports include patients receiving other interventions and hemodynamic support making the contribution of this novel regi-men to the reported outcome uncertain. Serotonin and thromboxane antagonism with onandse-ton and ketorolac, respectively, manifest limited hemodynamic consequence.68 Atropine has been included in this pathway regardless of the present-ing rhythm, presumably because of its role as a pulmonary vasodilator or its chronotropic effect.70 Atropine may cause nonselective pulmonary vaso-dilation, potentially worsening ventilation and per-fusion mismatch. The increased heart rate limits diastolic filling time, which can impact the coronary and systemic circulations, particularly in settings of right ventricular pressure overload. The lack of benefit alongside the availability of other vasoac-tive agents capable of providing chronotropic and inotropic support inform this recommendation.

REFERENCES

1. Ford ND, DeSisto CL, Galang RR, Kuklinal EV, Sperling LS, Ko JY. Car-diac Arrest During Delivery Hospitalation: A Cohort Study. Ann Intern Med 2023;176:472-479. doi:10.7326/M22-2750

2. Mhyre JM,Tsen LC,Einav S,Kuklinal E,Leffert LR,Bateman BT.Cardiac ar-rest during hospitalization for deliveryin in the United States, 1998-2011. Anes-thesiology.2014;120:810-818. doi:10.1097/AL000000000000159

3. Jeejeehboh FM,Zelop CM,Lipman S,Carvalho B,Joglar J,Mhyre JM,Katz VL,Lapinsky SE,Enav S,James CA,et on behalf of the American Heart Association Emergency Cardiovascular Care Committee, Coun-clin on Cardioplumary, Critical Care, Perioperative and Resuscitation,Council on Cardiovascular Diseases in the Young, and Council on Clini-cal Cardiology. Cardiac Arrest in Pregnancy: A Scientific Statement from the American Heart Association. Circulation 2015;132:1747-1773; doi-10.1161/CIRI-OFFardid/000000000000030

4.Zelop CM,Eavin S, Mhyre JM, Lipman SS, Arafeh J, Shaw RE, Edelson DP,Jeejteboh F; on behalf of the American Heart Association's Get With the Guidelines Resuscitation Observations. Characteristics and outcomes of ma-ternal cardiac arrest: A descriptive analysis of Get With the Guidelines Resuscitation.2018;132:17-20. doi:10.1016/j.resuscitation.2018.06:029

5.Zelop CM, Shaw RE, Edelson DP, Lipman SS, Myreh JM, Arafeh J, Jeejeshiophy FM, Eavin S; on behalf of the American Heart Association's Get With The Guidelines®-Resuscitation Factors. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With The Guidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Resuscitation's Resuscitation. Factors associated with non-survival from in-hospital maternal cardiac arrest: analysis of an Analysis of Get With TheGuidelines®-Re

6. Shields AD, Vidosh J, Minard C, Thomson B, Annis-Brayne K, Murphy M, Kavanagh L, Reth CK, Ludgendorf M, Barreslner ML, et al. Ob-

stetric Life Support Education for Maternal Cardiac Arrest: A Ran-domized Clinical Trial. JAMA Netw Open.2024;7:e2445295. doi: 10.1001/jamanetworkopen.2024.45295

7. Benson MD, Padovano A, Bourjeily G, Zhou Y. Maternal collapse: Chal-lenging the four-minute rule. EBioMedicine, 2016;6:253-257. doi:10.1016/j.jebiom.2016.02.042

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9. Panchal AR, Bartos JA, Cabanas JG, Donnino MW, Drennan IR, Hirsch KG,Kudenchuk PJ, Kurz MC, Lavonas EJ, Morley PT, et al; on behalf of the Adult Basic and Advanced Life Support: Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circu-lation.2020;142:S366-S468. doi: 10.1161/CIR.0000000000000916

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11. Vanden Hoek TL, Morrison LJ, Shuster M, Donnino M, Sinz E, Lavonas EJ,Jeejeebhoy FM, Gabrielli A. Part 12: cardiac arrest in special situations:2010 American Heart Association Guidelines for Cardiopulmonary Resus-sociation and Emergency Cardiopulmonary Resus-Circulation and Emergency Cardiopulmonary Care. Circulation.2010;122:S829-S861. doi:10.1016/CIRULATIONHA.110.971069

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13. Schaap TP, Overtoem E, van den Akker T, Zwart JJ, van Roosmalen J,Bloemenkamp KWM. Maternal cardiac arrest in the Netherlands: A nation-wide surveillance study. Eur J Obstet Gynecol Reprod Biol. 2019;237:145-150. doi: 10.1016/j.jeogrb.2019.04.028

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15.Dijkman A, Huisman CM, Smit M, Schutte JM, Zwart JJ, van Roosmalen JJ,Opekes D. Cardiac arrest in pregnancy: increasing use of perimortem cae-sarean section due to emergency skills training? BJOG.2010;117:282-287. doi: 10.1111/j.1471-0528.2009.02461.x

16. Alimena S, Freret TS, King C, Lassey SC, Economy KE, Easter SR.Simulation to improve trainee knowledge and comfort in manag-ing maternal cardiac arrest. AJOG Glob Rep. 2023;3:100182. doi:10.1016/j.xrag.2023.100182

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20.Kobori S, Toshitsu M, Nagaoka S, Yaegashi N, Mursotsi J. Utility and limitations of perimorteness cesarean section: A nationwide survey in Japan.J Obstet Gynecol Res.2019;45:325-330. doi:10.1111/jog.13819

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24. Enomoto N, Yamashita T, Furuta M, Tanaka H, Ng ESW, Matsunaga S,Sakurai A; on behalf of the Japan Resuscitation Council Maternal task force. Japan Resuscitation Council Maternal Task Force. Effect of ma-ternal positioning during cardiopulmonary resuscitation: a systematic

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25.Dohi S,Chizuka K,Matsuoka R,Seo K,Nagatsuka M,Sekizawa A.Coronary perfusion pressure and compression quality in maternal cardiopulmonary resuscitation in supine and left-lateral tilt positions: A prospective, crossover study using mannequins and swine models. Eur J Obstet Gynecol Rep Biol 2017/2169:98-103. doi:10.1016/j.jojogr.20170719

26. McDonnell NJ, Paech MJ, Clivais OM, Scott KL, Group AT. Difficult and failed intubation in obstetric anesthesia: an observational study of air-way management and complications associated with general anaesthe-sia for caesarean section. Int J Obstet Ansteh. 2008;17:292-297. doi:10.1016/j.ijoa.2008.01.107

27. Whitehead EM, Smith M, Dean Y, O'Sullivan G. An evaluation of gastric emp-ting times in pregnancy and the puerperium. Anaesthesia 1993;48:53-57.dol:1111/j.1365-2044.1993b06793x

28. Lipman S, Cohen S, Einos S, Eeejeeghb F, Myre JM, Morrison LJ,Natz K, Vten LC, Daniels K, Hamełak LP, et al; on behalf of the Society for Obstetric Anesthesis and Perinatology. In Stentropology, The Society for Obstetric Anesthesia and Perinatology consensus statement on the management of cardiac arrest in pregnancy. Anesth Analg. 2014;118:1003-1016. doi:10.1213/ANE.ANE0000000000000171

29. Naouom EE, Chalupka A, Haft J, MacEachern M, Vandeven CJ,Ester SR,Male M, Baestanl B, Vaner B, ME. Extracoreporal Life Support in Preg-nancy: A Systematic Review. J Am Heart Assoc. 2020;9:e016072. doi:10.1161/JAHA.119.016072

30. Ramanathan K,Tan CS,Rycus P, Anders M., Losuor R, Zhang JYJ,MacLaren G. Extracorporeal Membrane Oxygenation in Pregnancy: An Analysis of the Extracorporeal Life Support Organization Registry. Crit Care Med 2020;48:696-703.2011/109.1076/CC000000000002696

31. Richardson AS, Schmidt M, Bailey P, Lellegrino VA, Rycus PT, Pilcher DV.ECMC Cardio-Pulmonary Resuscitation (ECPR), trends in survival from an international multicentre cohort study over 12-year's Resuscitation.

32.Dalsey WC,Barsan WoyG.Jeendy M.Hedges,RJ.Lukes S.Doan LA. Compari-son of superior vena caval and inferior vena caue accessing using a radioisotopic technique during normal perfusion and cardiopulmonary resuscitation. Ann Emerg Med 1964;13:8841:884; doi:10.1015/6/1056-0644(84)80661-7

33. Brebner C, Asamoah-Boaheng M, Zaidel B, Yap J, Scheuermeyer F, Mok V,Christian M, Kawano T, Singh L, van Diep, S et al. The association of tibial vs. humeral intraosseous vascular access with patient outcomes in adult-out of hospital cardiac arrests. Resuscitation. 2023;193:110031. doi:10.1016/j.resuscitation.2023.110031

34. Smidra, CP to Rrows, Jar Litzc, T) Goebel E. Retrospective Comparison of Upper and Lower Extremia Intravenous Access During Out-of-Hospital Cardiac Areast Resuscitation. Prohem Energie Care 2024;28:779-786. doi:10.1080/1090312720.234221385.

35. Valentin MF, Granfeld A, Kiltagda TL, Mikkelsen S, Folke F, Christensen HC,Povlsen P, Taletersen A, Wilndert, Frilund W et al. Intravenous Vascular Access for Out-of-Hospital Cardiac Arrest. N Engl J Med.2025;392:349-360. doi:10.1056/NEJMo24076176.

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37. Hoffman RS, Smilkstein MJ, Rubenstein F, An'amp/ any by other name: the hazards of intravenous magnesium dosing J. JAMA 1989;261:557.

38. McCubbin S, Sibim, Bai BM, Endanna G. Cardiopulmonary ar-rest due to acute material hypermagnesasea. Lancet 191;1:1085. doi:10.1016/s0140-6736(81)92225-x

39. Cholst IN, Steinberg SF, Tropper F, Fox HE, Segre GV, Bilezikian JP. The influence of hypermagnesemia on serum calcium and parathyroid hor-mone levels in human subjects. N Engl J Med.1984;310:1221-1225. doi:10.1056/NEJM198405103101904

40. Van Hook JW. Endocrine crises. Hypermagnesia. Crit; Care Clin 1997;1:21-75.23.

41. Pacheco LD, Saade G, Hankins GD, Clark SL; Society for Maternal-Fetal Medicine(SMFM),Animotic fluid:embolism: diagnosis and management.Am J Obstet Gynecol.2016;215:B16-B24. doi:10.1016/j.jajog.2016.03.012

42.Asakura H. Diversity of disseminated intravascular coagulation and se-lection of appropriate treatments. Int J Hematol; 2021;11:13-10.14:10.1007/s12185-020-03030-5

43. Yamashita A, Daa T, Maman Wakala G,TiR I, Tde Y, Toru N, Yamra N,Sato Y, Itoh H, et al. Massive platelet-rich thrombus formation in small pulmonary vessels in amotic emloid mechanism: An autopsy. BJOG.2023;130:1685-1696. doi:10.1117/1411/781-17528-1585.

44.Clark SL, Pavlova Z, Greenspoon J, Horenstein J, Phelan JP. Squa-mous cells in the maternal pulmonary circulation. Am J Obstet Gynecol.1986;154:104-106. doi:10.1016/0002-9378(86)90402-3

45. Funki M, Damon A, Bandi V, Aagaard K, Sizegeti R, Clark S. Pulmonary vascular obstruction by squamous cells is not involved in amniotic fluid embolism. Am J Obstet Gynecol. 2018;18:460-461. doi: 10.1016/j.ajog.2017.12.225

46. Stafford IA, Moazabd A, Dildy GA, Klassen M, Berra A, Watters C, Belfort MA, Romero R, Clark S. Admiotic fluid embolism syndrome: analysis of the Unites States International Registry. Am J Obstet Gynecol MFM.2020;2:10083.8 doi:10.1016/j.ajogf.2019.100083

47. Amgalan A, Allen T, Othman M, Ahmadzia HK. Systematic review of visco-elastic testing(TEG/ROTEM) in obstetrics and recommendations from the women's SSC of the ISTH. J Thromb Haemost.2020;18:1813-1838. doi: 10.1111/j.14h.1882

48. Buggane N, Como JJ, Golani G, Freeman JJ, Sawhney JS, Vatsaas CJ,Yorkgit BK, Kreiner LA, Garcia NM, Aziz HA, et al. Thromboelastography and rotational thrombobastometry in bleeding patients with coagulopa-thy: Practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg. 2020;89:999-1017. doi:10.1097/TA00000000000000002944

49. Simard C, S Koolin M, Shear R, Rudski L, Lipes J. The role of echocardiography in amniotic fluid embolism: a case series and re-view of the literature. Can J Anaesth. 2021;68:1541-1548. doi: 10.10107/s12630-021-03065-4

50.Wiseman D, Simard C, Yang S, Koolian M, Abenhaim HA, Lipes J. Echocardiography findings in amniotic fluid embolism: a system-atic review of the literature. Can J Anaesth. 2023;70:151-160. doi: 10.1007/s12630-022-02343-9

51. Fitzpatrick KE, van den Akker T, Bloemenkamp KWM, Deneux-Tharaux C,Kristufova A, Li Z, Schaap TP, Sullivan EA, Tuffnell D, Knight M. Risk factors, management, and outcomes of amniotic fluid embolism: A multi-country population-based cohort and nested case-control study. PLoS Med.2019;16:e1002962. doi:10.1371/journal.pmed.1002962

52.Hombic Jo, BJ, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM,del Junco DJ, Basel KJ, Bulger EM, Callcut RA,et al.;PROPPR Study Group.Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs 1:1:2 ra-tio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015;313:471-482. doi: 10.1001/jama.2015.12

53. Pacheco LD, Clark SL, Klassen, Mankins, Hankins GDV. Anmiotic fluid em-bothism: principles of early clinical management. Am J Obstet Gynecol.2020;222:48-52. doi:10.1016/j.jajog.2019.07.036

54.Tanaka H, Katsuragi S, Osato K, Hasegawa J, Nakata M, Murakoshi Y, Yoshimatsu J, Sekizawa A, Kanayama N, Ishiwata I, et al. Value of fibringen in cases of maternal death related to amniotic fluid em-bolism. J. Matern Fetal Neonatal Med. 2017;30:2940-2943. doi:10.1010/80.14767058.2016.1269166

55. Bonnet MP, Zlotnik D, Saucedo M, Chassard D, Bouvier-Colle MH,Deneux-Thurax, C. French National Experts Committee on Mater-nal Mortality. Maternal Death Due to Amniotic Fluid Embolism: A National Study in France. Anesth Analg. 2018;126:175-182. doi: 10.1213/ANEON.00000000000002511

56. Shakur H, Roberts, B. Iaustista R, Caballero J, Coats T, Dewan Y, El-Sayed H. Gogichaishili T, Gupta S, Herrera J, et al; on behalf of the CRASH-2 trial collaborators. Effect of tranxamic acid on death, vascular occlu-sive events, and blood transfusion in trauma patients with significant haemorrhage(CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376:23-22. doi:10.1016/S0140-6736(10)60835-5

57. Woman Trial Collaborators. Effect of early tranexamic acid administra-tion on mortality. Hysterectomy, and other morbidities in women with post-partum haemorrhage(WOMAN): an international, randomised,double-blind, placebo-controlled trial. Lancet. 2017;389:2105-2116. doi:10.1015/S0140-6736(10)30638-4

58. Combs CA, Montgomery D, Toner LE, Dildy GA; on behalf of the Pa-tient Safety and Quality Committee, Society for Maternal-Fetal Medicine Safety Quality Committee, Society for Maternal-Fetal Medicine. Society for Maternal-Fetal Medicine. Special Statement: Checklist for initial manage-ment of amniotic fluid embolism. Am J Obstet Gynecol. 2021;224:B29-B32. doi:10.1016/jajog.2021.01.001

59. World Health Organization. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization;2012.

60.Assi James S,Klein T,Lebreton G,Nizard J,Chommeloux J,Brechot N Pineton de Chavranum M, Hekimian G, Luyt CE, Levy B,et al. Amniotic fluid embolism resued by vonoarterial extracorporeal membrane oxygenation.Crit Care 2022:2969.doi:10.1186/s13054-022-03969-3

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PULMONARY EMBOLISM

Introduction

PE is the occlusion of 1 or more pulmonary arteries and is a potentially reversible cause of hemodynamic instability or cardiac arrest. Partial or complete occlu-sion of pulmonary arteries results in ventilation and perfusion mismatch and increases in pulmonary artery pressures, causing impaired right ventricular function and, ultimately, cardiovascular collapse.1,2 In 1 large re-view of hospitalized patients diagnosed with PE, mor-tality of hemodynamically unstable patients was 76.6%and of hemodynamically stable patients was 10.8%,highlighting the severity of this disease process.3 Mor-tality in OHCA secondary to PE is reported as high as 91%.4 Most patients in cardiac arrest secondary to PE exhibit PEA(26%-75%) or asystole(19%-73%).4-6 Treatment of patients in cardiac arrest from PE include systemic and catheter-guided fibrinolysis, surgical and mechanical embolectomy, and ECMO. Each augments resuscitation by restoring pulmonary and systemic circulation.

The diagnosis of PE in children is often delayed because of diagnostic challenges and differences in symptomatology compared with adults.7 Considering children are able to compensate for shock states with increased systemic vascular resistance, hypotension is

a late sign of shock in children. ${}^{7}$ There are limited data available and no RCTs to inform the care of children.

These recommendations are modifications to stan-dard ACLS for adults and children in cardiac arrest from confirmed or suspected PE. The treatment of patients with life-threatening PE not in cardiac arrest are out-side of the scope of these recommendations, although several studies cited in the recommendations contain overlapping populations of hemodynamically unstable patients with PE in cardiac arrest.

|Recommendations for Adults in Cardiac Arrest From PE|||| |---|---|---|---| |COR|LOE|Recommendations|| |2a|8-BNR|1. For adults with confirmed PE as the precipitant of cardiac arrest, systemic fibrinolysis, surgical olectomy, and percutaneous mechanical olectomy are reasonable treatment options.|| |2a|B-NR|2. It is reasonable to use ECLS in adults with cardiac arrest from confirmed or suspected PE.|| |2b|B-NR|3. For adults in cardiac arrest from suspected PE, systemic fibrinolysis may be considered.|| |2b|C-EO|4. The optimal duration of CPR after administration of eclemic fibrinolytic to adults in cardiac arrest from confirmed or suspected PE is unclear.||

Recommendation-Specific Supportive Text

1. The treatment of adults in cardiac arrest from a confirmed PE may differ between institu-tions depending upon the available resources. In 1 retrospective multicenter study of 104 adult patients, including 70 patients in cardiac arrest who received systemic fibrinolytics, patients with confirmed PE had significantly greater survival to hospital discharge compared with those with a pre-sumed PE(26% versus 4%; P=0.01).8 A review of 153 adults who experienced cardiac arrest from PE who underwent surgical embolectomy showed 56% survival.9 One retrospective case series of hemodynamically unstable adults with confirmed PE, including patients who required CPR, showed lower in-hospital mortality for those who underwent percutaneous mechanical pulmonary embolectomy compared with no embolectomy(64.4% versus 76.8%; P<0.001).3 The benefit of systemic fibrino-lysis is weighed against the risk of bleeding com-plications. One study of adults with OHCA from PE observed the same risk of death from hemorrhage in patients who were treated with systemic fibrino-lytics compared with those who were not(6% ver-sus 5%; P=0.73).4 Another study observed 37.9%of adults developed bleeding complications, includ-ing intracranial hemorrhage in 9.1% of adults.10

2.ECLS,including VA-ECMO, for adults in cardiac arrest has become increasingly available. ${}^{11}$ In 1 ret-rospective before-and-after implementation study of ECPR in 39 adults who suffered cardiac arrest

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Special Circumstances: 2025 AHA Guidelines for CPR and ECC

due to suspected or confirmed PE, 19 underwent VA-ECMO cannulation during CPR.12 Adults who received VA-ECMO during CPR had higher ICU survival(26% versus 5%; P<0.01) and higher survival with favorable neurologic outcomes(21%versus 0%; P<0.05) than those patients receiving conventional CPR.12 In a systematic review and meta-analysis of 77 studies including 301 adults who suffered cardiac arrest from PE, 65% of patients placed on VA-ECMO during CPR survived to hospital discharge.13 Two separate retrospective reviews of adults treated with venovenous ECMO or VA-ECMO for hemodynamic instability or cardiac arrest from confirmed PE showed no difference in survival rate in adults who received unfractionated heparin alone compared with those who received systemic fibrinolysics or surgical or interventional thrombectomy.14,15 One meta-analysis showed no increased risk of mortality for adults who received systemic fibrinolysis prior to VA-ECMO or venove-nous ECMO cannulation. ${}^{13}$

3. Investigating the efficacy of systemic fibrinolytics to treat suspected PE is challenging due to varia-tions in patient enrollment, which often lead to the inclusion of many patients with cardiac arrest from causes unrelated to PE. The definition of sus-pected PE in reviewed studies is not well-defined,and research is conflicting. Two RCTs found that administration of systemic fibrinolytics did not improve survival in adults and children(>16 years of age) with undifferentiated cardiac arrest.16,17 In retrospective registry study of 58 adult OHCA patients treated with systemic fibrinolysis for suspected PE, systemic fibrinolytics provided no survival benefit at 24 hours versus control(66%versus 63%; P=0.76); however, a 30-day mortal-ity benefit was identified after the population was appropriately weighted(P=0.005; adjusted log-rank test).4 Two additional retrospective investiga-tions of adults with confirmed or suspected PE as a cause of cardiac arrest showed no increased rates of ROSC or 30-day survival with systemic fibrinolytics.10,18

4. There are no trials comparing different durations of continued resuscitation following systemic fibrino-lysis administration to adults in cardiac arrest from any cause, including confirmed or suspected PE.The 2019 European Society of Cardiology guide-lines for the diagnosis and management of acute PE recommend continuing CPR for at least 60 to 90 minutes after administration of a systemic fibri-nolytic based upon case reports and case series of adults who survived after 90 to 100 minutes of CPR.2,19,20 There is significant variation in the dura-tion of CPR after fibrinolysis between studies. One randomized trial investigating the use of systemic

fibrinolysis to treat adults in PEA arrest continued CPR for at least 15 minutes after systemic fibri-nolytic administration. ${}^{16}$ A second randomized trial continued CPR for at least 30 minutes after sys-temic fibrinolytic administration to adults in cardiac arrest. ${}^{17}$

|Recommendations for Children in Cardiac Arrest From PE||| |---|---|---| |COR|LOE|Recommendations| |2a|C-LD|1. For children with confirmed PE as the precipitant of cardiac arrest, systemic fibrinolysis, surgical embolectomy, and percutaneous mechanical embolectomy are reasonable treatment options.| |2a|C-LD|2. It is reasonable to use ECLS in children with cardiac arrest from confirmed or suspected PE.| |2b|C-EO|3. For children in cardiac arrest from suspected PE, systemic fibrinolysis may be considered.| |2b|C-EO|4. The optimal duration of CPR after administration of systemic fibrinolytic to children in cardiac arrest from confirmed or suspected PE is unclear.|

Recommendation-Specific Supportive Text

1. The recommendation for the treatment of children in cardiac arrest are first from confirmed PE is based on pediatric case series and data extrapolated from adults. One retrospective review of 33 children(<19 years of age) with confirmed PE included 3 children who underwent surgical embolectomy,3 who received catheter-based therapies, and 1 who received systemic thrombolysis.7 Of these children, 4 experienced cardiac arrest, 2 survived but the specific therapies they received were not described.7 Overall, 3 of the children died of PE-related causes.7 Another retrospective review of 170 children(≤18 years of age) with con-firmed PE included 25(15%) patients with shock or cardiac arrest.21 Twenty-two of these children received systemic fibrinolysis, catheter-directed therapies, or surgical thrombectomy.21 Eleven(6%)children in this case series died of PE-related causes.21 In 1 retrospective multicenter study of 104 adults, including 70 patients in cardiac arrest who received systemic fibrinolytics, patients with confirmed PE had significantly greater survival to hospital discharge compared with those with a pre-sumed PE(26% versus 4%; P=0.01).8 The benefit of systemic fibrinolysis is weighed against the risk of bleeding complications, which is conflicting in adult studies, ranging from 6% to 37.9% of cardiac arrest patients with suspected PE.4

2. The treatment of children who experience cardiac arrest from PE with ECLS, including VA-ECMO,is limited by resources available to individual institutions and individual patient factors. The recommendation for the treatment of children in cardiac arrest with ECLS is based on a pediatric

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registry study and data extrapolated from adults.One review of the ELSO Registry included 54 chil-dren≤18 years of age treated with ECMO who received a primary diagnosis code of PE.22 The number of children who experienced cardiac arrest prior to treatment with ECMO was not described,however,13 of the included children were treated with ECPR.22 Thirty-three(61%) children in this cohort survived to hospital discharge.22 In 1 retro-spective before- and after-ECPR implementation study of 39 adults who suffered cardiac arrest due to suspected or confirmed PE, 19 underwent VA-ECMO cannulation during CPR.12 Adults who received VA-ECMO during CPR had higher ICU survival(26% versus 5%; P<0.001) and higher survival with favorable neurologic outcomes(21% versus 0%; P<0.05) than those patients receiv-ing conventional CPR.12 In a systematic review and meta-analysis of 77 studies including 301 adults who suffered cardiac arrest from PE 65%of patients placed on VA-ECMO during CPR sur-vived to hospital discharge.13

3. Investigating the efficacy of systemic fibrinolytics to treat suspected PE is challenging due to varia tions in patient enrollment, which often lead to the inclusion of many patients with cardiac arrest from causes unrelated to PE. The definition of sus-pected PE in reviewed studies is not well-defined,and research is conflicting. Two RCTs found that administration of systemic fibrinolytics did not improve survival in adults and children(>16 years of age) with undifferentiated cardiac arrest.16,17 One retrospective registry study of 58 adult OHCA patients treated with systemic fibrinolysis for sus-pected PE found that systemic fibrinolysis pro-vided no survival benefit at 24 hours versus control(66% versus 63%; P=0.76); a 30-day mortality benefit was identified after the population was appropriately weighted(P=0.005; adjusted log-rank test).4 Two additional retrospective investiga-tions of adults with confirmed or suspected PE as a cause of cardiac arrest showed no increased rates of ROSC or 30-day survival with systemic fibrolinetics.10,18 Data for systemic fibrinolytics in children with cardiac arrest from suspected PE is lacking,and the recommendation is extrapolated from adult data).

4.There are no trials available to inform the optimal duration of continued resuscitation following sys-temic fibrinolysis administration to adults or chil-dren in cardiac arrest from any cause, including PE.The 2019 European Society of Cardiology guide-lines for the diagnosis and management of acute PE recommends continuing CPR for at least 60 to 90 minutes after administration of a systemic fibrinolytic based on case reports and case series

of adults who survived after 90 to 100 minutes of CPR.2,19,20 There is significant variation in time to continued CPR after fibrinolysis between studies.One randomized trial investigating the use of sys-temic fibrinolysis to treat adults in PEA arrest con-tinued CPR for at least 15 minutes after systemic fibrinolysis.16 A second randomized trial continued CPR for at least 30 minutes after systemic fibrinolytic administration to adults in car-diac arrest.17

REFERENCES

1. Hepburn-Brown M, Daravl I, Hammerschlag G. Acute pulmonary embolism:a concise review of diagnosis and management. Intern Med.J.2019;49:15-27.doi:10.1111/imj.14145

2.Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP,Huisman MV,Humbert M,Jennings CS,Jimenez D,et al;ESC Scientific Document Group.2019 ESC Guidelines for the diagnosis and manage-ment of acute pulmonary embolism developed in collaboration with the European Respiratory Society(ERS). Eur Heart J. 2020;41:543-603. doi:10.1093/eurheartj/ehz405

3. Keller K, Hobohm L, Esher M, Kresoja KP, Munzel T, Konstantides SV,Lankett M. Trends in thrombolytic treatment and outcomes of acute pul-monary embolism in Germany. Eur Heart J. 2020;41:522-529. doi:10.1093/eurheartj/ehz2386

4. Javaudin F, Lascarroua JB, Le Bastard Q, Bourry Q, Latour C, De Carvalho H, Le Conte P, Escutnairee J, Hubert H, Montassier E, et al. Thrombolysis During Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Pul-monary Embolism Increases 30-Day Survival: Findings From the French National Cardiac Arrest Registry. Chest 2019;156:1167-1175. doi:10.1016/j.chest2019.07.015

5.de Paz D,JieZr,Af S,Carpetta DP,Gulintero JA,Carvajal SM.Emergency Thrombolysis During Cardiac Arrest Due to Pulmonary Thromboembolism:Our Experience Over 6 Years. Open Access Emerg Med.2021;13:67-73. doi: 10.2147/OAEM.S275767

6. Henriksson CE, Frithiofsson J, Bruchfeld S, Bendz E, Bruzelius M, Djarv T. In-hospital cardiac arrest due to pulmonary embolism- Treatment and outcomes in a Swedish cohort study. Resuscus Plus.2021;8:100178. doi:10.1016/j.jreslu.2021.100178

7.Ross CE,Shih JA, Kleinman ME, Donnino MW. Pediatric Massive and Sub-massive Pulmonary Embolism: A Single-Center Experience. Hosp Pediatr.2020;10:2727-276. doi: 10.1542/hpeds.2019-0290

8. Gayen S, Katz A, Dikengil F, Kwok B, Zheng M, Goldenberg R, Benjamin C, Yuriditsky E, Bashir R, Lakhter V, et al. Contemporary practice pat-terns and outcomes of systemic thrombolysis in acute pulmonary em-bolism. J Vasc Surg Venous Lymphat Disord. 2022;10:1199-1127. doi:10.1016/j.jsvv.2022.04.014

9.Kon ZN, Pasrija C, Bittle GJ, Vemulapalli S, Grau-Sepulveda MV, Matsouaka R,Deatrick KB,Taylor BS, Gammie JS, Griffith BP. The Incidence and Out-comes of Surgical Pulmonary Emblochemist in North America. Ann Thorac Surg.2019;107:1401-1408. doi: 10.1016/j.athoratsur.2018.10.035

10.Dutta A, Tayal B, Kraghosh KH, Masmoudi Y, Azizian J, McDonald L, Goyal A, Sogaard P, Qureshi WT. Characteristics and outcomes of cardiac arrest survivors with acute pulmonary embolism. Resuscitation. 2020;155:6-12.doi: 10.1016/j.resuscitation.2020.06.029

11. Richardson ASC, Tonna JE, Nanjayya V, Nixon P, Abrams DC, Raman L, Bernard S, Finney SJ, Grunau B, Youngquist ST, et al. Extracorporeal Cardipulmonary Resuscitation in Adults: Interim Guideline Consensus Statement from the Extracorporeal Life Support Organization. ASAIO J.2021;67:221-228. doi:10.1097/MAT.0000000000001344

12.Mandiglers L,Scholetn E,Rietdijk WRR,Den Uil CA, van Thiel RJ,Rigter S, Heijnen B, Gommers D, Dos Reis Miranda D. Survival and neurologi-cal outcome with extracorporeal cardiopulmonary resuscitation for re-fractory cardiac arrest caused by massive pulmonary embolism: A two center observational study. Resuscitation. 2019;136:8-13. doi:10.1016/j.resuscitation.2018.12.008

13.Scott JH, Gordon M, Vender R, Pettigrew S, Desai P, Marchetti N, Mamary AJ, Panaro J, Cohen B, Bashir R, et al. Venoarterial Extracorporeal Mem-brane Oxygenation in Massive Pulmonary Embolism-Related Cardiac

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Arrest: A Systematic Review. Crit Care Med. 2021;49:760-769. doi: 10.1097/CC0000000000004828

14. Krciep L,Philipp A, Floerchinger B,Lubnow M,Unterbuchner C,Creutzenberg M,Lurz D,Mueller T,Schmi C,Camboni D,Extracorporeal Membroy-ogenation for Massive Pulmonary Emblosism as Bridge to Therapy. ASAIO J.2020;66:146-152. doi:10.1097/MAT000000000000953

15.Stabdauer A, Philipp A, Blech S, Lubnow M, Lurux D, Li J, Terrazas A,Schmid C, Lange TJ, Camboni D. Long-term follow-up and quality of life in patients receiving extracorporeal membrane oxygen for pulmonary embolism and cardiogenic shock. Ann Intensive Care. 2021:11:181: doi: 10.1186/s13613-021-00975-6

16. Abu-Laban RB, Christenson JM, Innes GD, van Beek CA, Wanger KP,McKnight RD, MacPhail PA, Iksarak J, Sadowski RP, Singer J, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med.2002;346:1522-1528.doi:10.1056/NEJMOa012885

17. Bottiger BW, Antz HR, Chamberlain DA, Bluhmki E, Belmans A, Danays T,Carli PA, Adgey JA, Bode C, Wenzel V; TROICA Trial Investigators. Throm-bolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med.2008;359:2651-2662. doi: 10.1056/NEJmoa070570

18. Kataria V, Kohman K, Jensen R, Mora A. Usefulness of thromboly-ism in cardiac arrest secondary to suspected or confirmed pulmo-nary embolism. Proc(Bayl Univ Med Cent). 2021;34:442-445. doi:10.1080/089982802/2021.1191449

19. Bottiger BW, Bode C, Kern S, Gries A, Gust R, Glatzer R, Bauer H, Motch J, Martin E. Efficacy and safety of thrombolytic therapy after initially unsuc-cessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet 2001;357:1583-1585. doi:10.1016/S0140-6736(00)047726-2001;537:1583-1585. doi:10.1016/S20140-6736(00)047726-2001;

20.Wu JP,Gu DY,Wang S,Zhang ZJ,Zhou JC,Zhou RF,Good neurologi-cal recovery after rescue thrombolysis of presumed pulmonary embolism despite prior 100 minutes CPR. J Thorac Dis. 2014;6:E289-E293. doi:10.3978/j.issn.2072-1439.2014.12:23

21. Pelland-Marcotte MC, Tucker C, Kalaassen A, Lamil A, Midam A, Airi N, Williams S, Halton J, Brandoe AL. Outcomes and risk factors of massive and submassive pulmonary embolism in children: a retro-spective cohort study. Lancet Haematol. 2019;6:e144-e153. doi:10.1016/S2352-3026(18)30224-2

22. Kim JS,Barrett CS, Hyslop RW,Buckvold SM,Gist KM.Sunival of Children With Pulmonary Embolism Supported by Extracorporeal Membrane Oxy-genation.Front Pediatr.2022;10:877637. doi:10.3389/fped.2022.877637

TOXICOLOGY

Introduction

Over 105000 people in the United States died from drug overdose in 2023.1 More than 92% of these deaths were unintentional. Over time, the population of people with fatal drug overdose is aging; overdose death rates are increasing in people aged≥35 years and decreasing in younger people. Although most deaths are due to syn-thetic and semisynthetic opioids, such as fentanyl, many different poisons are responsible for these deaths.

Poisoning in this guideline refers to the cellular injury or death that results from the exposure to an exogenous substance.2,3 Management of patients with critical poi-soning, defined as those in cardiac arrest, refractory shock, or other conditions posing an imminent threat of cardiac arrest, may require special techniques and antidotes in addition to standard resuscitation care to achieve survival and recovery. For example, patients may develop hypotension fromβ-adrenergic receptor antag-orist(β-blocker) or calcium channel antagonist(CCB)poisoning that does not respond to atropine, standard vasopressors, or cardiac pacing but is amenable to tar-geted therapies, such as high-dose insulin. Specific anti-dotes are available for many life-threatening poisonings

<EndOfPara>but are only safe and effective if given in the proper dose and with careful patient selection(Table 4). The ideal dose is rarely known, and in many cases, equally well-supported alternative dosing strategies exist. Many poisoned patients are often ideal candidates for ECLS techniques, such as VA-ECMO, because temporary cir-culatory support is a bridge to survival until the poison can be eliminated, either by natural or artificial means.

Research involving poisoned patients is ethically and logistically challenging. As a result, much data about human poisoning are descriptive and observational. Vari-ations and uncertainty in exposure, history, co-ingestions,and comorbidities make comparisons based on clini-cal observations challenging. High-quality animal stud-ies broaden understanding. Applying clinical research across species is challenging, and current evidence-based medicine structures discount the contribution of animal studies to the level or certainty of evidence about an intervention.

This section of the guidelines is designed primarily for health care professionals, but opioid overdose-by far the most common cause of poisoning death-can be treated by adults and adolescents in the community with brief training.

In the United States, Canada, and much of the rest of the world, regional poison centers can provide expert treatment guidance for the management of specific poi-soning cases. Each of the 55 poison centers operating in the United States and 5 in Canada is supported by board-certified medical and clinical toxicologists with specialized training in poisoning resuscitation. Poison centers provide clinical advice to clinicians and the gen-eral public about how to manage poison emergencies.A single number is used to reach the regional poison center in the United States (1-800-222-1222) and in Canada (1-844-764-7669 [1-844-POISON-X]).

We acknowledge the contributions of the authors of the 2023 American Heart Association Focused Update on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning.${}^{3}$

REFERENCES

1. Garnett MF, Minino AM. Drug Overdose Deaths in the United States, 2003-2023. Hyattsville, MD: National Center for Health Statistics; 2024.NCHS Data Brief, no 522. Accessed April 28, 2025. https://www.ccd.gov/nchs/products/databriels/db522.htm

2.World Report on Child Injury Prevention. Peden M, Oyegbite K, Ozanne-Smith J,Hyder AA, Branche C, Rahman A, Rivara F, Bartolomeos K, eds. Geneva;2008.

3.Lavonas EJ,Akpunonu PD,Arens AM,Babu KM,Cao D,Hoffman RS,Hoyte CO,MAzer-Amirshahi ME,Stolbach A,St-Ongre M,et al; on behalf of the American Heart Association.2023 American Heart Association Focused Up-date on the Management of Patients With Cardiac Arrest or Life-Threatening Toxicity Due to Poisoning: An Update to the American Heart Association Guide-lines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.Circulation.2023;148:e149.e184.doi:10.1161/CIR.0000000000001161

4. Chan BS, Isbister GK, Chiew A, Isoardi K, Buckley NA. Clinical ex-perience with titrating doses of digoxin antibodies in acute digox-in poisoning(ATOM-6). Clin Toxicol(Phila). 2022:60:433-439. doi:10.1080/15563650.2021.1968422

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Table 4.Commonly Used Doses of Antidotes for Resuscitation in Critical Poisoning

|Antidote|Indication|Initial dose(adult)*|Initial dose (pediatric)*|Maintenance infusion|Notes| |---|---|---|---|---|---| |Atropine|Organophosphates Carbamates|1-2 mg, doubled every 5 min|0.02 mg/kg, doubled every 5 min|10%-20% of the total loading dose per hour up to 2 mg-h-1(adults)|Titrate to reversal of bronchorhea, bronchospasm, and bradycardia.| |Calcium chloride|β-blockers|2000 mg|20 mg/kg|20-40 mg-kg-1.h-1|Titrate to blood pressure.| ||CCBs|28 mEq Ca2+ 20 mL 100 mg/mL solution|0.28 mEq Ca2+/kg 0.2 mL/kg 100 mg/mL solution|0.28-0.56 mEq Ca2+,kg-1.h-1 0.2-0.4 mL-kg-1.h-1 100 mg/mL solution|Do not exceed serum ionized calcium concentration 1.5-2 times the upper limits of normal. Administer through central line, especially in children.| |Calcium gluconate|β-blockers|6000 mg|60 mg/kg|60-120 mg-kg-1.h-1|Titrate to blood pressure.| ||CCBs|28 mEq Ca2+ 60 mL 100 mg/mL solution|0.28 mEq/kg Ca2+ 0.6 mL/kg 100 mg/mL solution|0.28-0.56 mEq Ca2+,kg-1.h-1 0.6-1.2 mL-kg-1.h-1 100 mg/mL solution|Do not exceed serum ionized calcium concentration 1.5-2 times the upper limits of normal. Administer through central line, especially in children.| |Digoxin immune Fab|Digoxin|Acute overdose: 1 vial for every 0.5 mg digoxin ingested Chronic poisoning: Use formula: dose in vials=serum digoxin concentration(ng/ mL)xweight(kg)/100 Acute overdose, critically il, ingested dose unknown: 10-20 vials|Same as adult|None|1 vial contains 40 mg Fab. Lower doses may be equally effective.4| |Digoxin immune Fab|Yellow oleander|1200 mg(30 vials)|Unknown|None|| ||venom and other cardioactive steroids||||| |Glucagon|β-blockers|2-10 mg|0.05-0.15 mg/kg|1-15 mg-h-1(adult)|Anticipate vomiting.| |Flumazenil|Benzodiazepines|0.2 mg, titrated up to 1 mg|0.01 mg/kg|None|Many contraindications| |Hydroxocobalamin|Cyanide|5g|70 mg/kg|Repeat doses may be necessary.|Transient hypertension| |Insulin|β-blockers CCBs|1 U/kg|Same as adult|1-10 U-kg-1-h-1|Regular human insulin. Monitor for hypoglycemia, hypokalemia, volume overload.| |Intravenous lipid emulsion|Local anesthetics|<70 kg: 1.5 mL/kg >70 kg: bolus 100 mL over 2-3 min|Same as adult|<70 kg: 0.25 mL-kg-1.min-1 for up to 30 min >70 kg:200-250 mL over 15-20 min|All studies use 20% lipid emulsion.| |Methylene blue|CCBs Methemoglobinemia|1-2 mg/kg, repeated every hour if needed|Same as adult|1 mg-kg-1.h-1(for vasodilatory shock)|Maximum 7 mg/kg| |Naloxone|Opioids|0.2-2 mg IV/IO/IM 2-4 mg intranasal Repeat every 2-3 min as needed|0.1 mg/kg|Two thirds of the waking dose per hour|Titrate to reversal of respiratory depression and restoration of protective airway reflexes.| |Pralidoxime|Organophosphates|2 g IV infusion over 15-30 min (do not bolus) or 0.6 g IM up to 3 doses|20-50 mg/kg|1 g-h-1(adult) 10-20 mg-kg-1.h-1 (pediatric)|| |Sodium bicarbonatet|Sodium channel blockers Cocaine Local anesthetics|50-150 mEq|1-3 mEq/kg|Prepare 150 mEq/L solution,infuse at 1-3 mL-kg-1.h-1|Watch for hypernatremia, alkalemia, hypokalemia, hypochloremia.|

(Continued)

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Table 4. Continued

|Antidote|Indication|Initial dose (adult)*|Initial dose (pediatric)*|Maintenance infusion|Notes| |---|---|---|---|---|---| |Sodium nitrite|Cyanide|300 mg|6 mg/kg|None|Watch for hypotension.| |Sodium thiosulfate|Cyanide|12.5 g|250 mg/kg|None||

$\beta$ -blockers indicates $\beta$ -adrenergic receptor antagonists; CCBs, calcium channel blockers; Fab, fragment antigen binding; IM, intramuscular; IO, intraosseous; IV, intra-venous; and U, units.

“Unless otherwise stated, the route of administration should be intravenous or intraosseous. Maximum pediatric dose should not exceed adult dose. Most antidotes should be repeated frequently and titrated to achieve control of critical signs and symptoms. The ideal dose of most antidotes is not known and is often controversial.Large doses are sometimes required to overcome competitive inhibition of molecular targets such as adrenergic receptors and ion channels. Consult a medical or clinical toxicologist, regional poison center, or topic-specific reference for detailed dosing and administration instructions.

tDifferent sodium bicarbonate are typically used for adults(1 mEq/mL) and children(0.5 mEq/mL).Both formulations are hypertonic.

TOXICOLOGY: BENZODIAZEPINES

Introduction

Benzodiazepines are commonly used sedative-hypnotics for treatment of anxiety,insomnia, seizures, and withdraw-al syndromes and as a component of general anesthesia and procedural sedation. Benzodiazepines are implicated in a large number of poisoning-related deaths, usually in combination with other central nervous system(CNS)depressants, such as opioids and alcohol.12 Benzodiaz-epine overdose causes CNS depression through agonist effects at the gamma-aminobutyric acid-A receptor with resultant respiratory compromise through loss of protec-tive airway reflexes. The subsequent hypoxemia and hy-percarbia cause tissue cellular injury or death.

Flumazenil, a competitive antagonist at the benzo-diazepine binding site on the gamma-aminobutyric acid-A receptor, reverses CNS and respiratory depres-sion, potentially preventing the need for intubation and mechanical ventilation.3,4 However, flumazenil admin-istration may precipitate refractory benzodiazepine withdrawal in patients with benzodiazepine tolerance,including seizures and arrhythmias, likely by removing benzodiazepine-mediated suppression of sympathetic tone.5

Overdose with multiple drugs is common. Flumazenil may not fully reverse respiratory depression, particularly in mixed overdoses, and it may increase the risk of sei-zures and arrhythmias in these situations.

These recommendations inform the management of adults and children with life-threatening benzodiazepine poisoning,including cardiac arrest.

|Recommendations for Adults With Life-Threatening Benzodiazepine Poisoning|||| |---|---|---|---| |COR|LOE|Recommendations|| |2a|B-NR|1. If combined opioid and benzodiazepine poisoning is suspected, it is reasonable to administer naloxone first(before other antidotes) in adults with respiratory depression or respiratory arrest.|| |2a|C-LD|2. Flumazenil can be effective in select adults with respiratory depression or respiratory arrest caused by pure benzodiazepine poisoning who do not have contraindications to flumazenil.||

|Recommendations for Adults With Life-Threatening Benzodiazepine Poisoning(Continued)|||| |---|---|---|---| |COR|LOE|Recommendations|| |3: No Benefit|C-EO|3. Flumazenil has no role in cardiac arrest related to benzodiazepine poisoning in adults.|| |3: Harm|B-R|4. Flumazenil administration is associated with harm in adults who are at increased risk for seizures or arrhythmias.||

Recommendation-Specific Supportive Text

1.While isolated benzodiazepine poisoning rarely causes life-threatening hypoventilation or hemo-dynamic instability in adults, overdoses usually occur with concomitant opioid, ethanol, or other CNS depressant poisoning.1,2 Flumazenil(Table 4)attenuates benzodiazepine-associated respiratory depression in healthy patients receiving a combi-nation of benzodiazepines and opioids, but this only produces partial restoration of respiratory func-tion. Naloxone reverses opioid poisoning, which is more common and causes more significant respi-ratory depression than benzodiazepine poisoning.This is particularly important given the presence of opioid-adulterated illicit drugs2,6(refer to the Toxicology: Opioid Overdose section).

2.Flumazenil(Table 4) is safe in some low-risk pre-sentations in adults(eg, iatrogenic overdoses during procedural sedation) and when high-risk conditions(eg, chronic benzodiazepine depen-dence and congestion of other dangerous sub-stances) can be reliably excluded. One healthy adult volunteer randomized crossover study of alfentanil plus midazolam-induced respiratory depression showed that 1 mg of flumenil sig-nificantly improved consciousness and respiratory depression over placebo.4

3. Flumazenil does not directly affect cardiac rhythm or restore spontaneous circulation in adults.7

4. In a meta-analysis of randomized clinical trials of adults with confirmed or suspected benzodiazepine overdose, higher rates of serious adverse effects,including seizures and arrhythmias, were observed in patients treated with flumazenil compared

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with standard care.${}^{5}$ There are few reports of flumazenil-provoked seizures in adults with preex-isting seizure disorder in the absence of other risk factors. ${}^{8}$ While the most common cardiac adverse event associated with flumazenil was supraven-tricular tachycardia, ventricular arrhythmias and asystole have also been reported in adults. ${}^{59,9-13}$The risks of flumazenil likely exceed the benefit in patients with undifferentiated coma for whom medical history and co-intoxications are unknown.

|Recommendations for Children With Life-Threatening Benzodiazepine Poisoning|||| |---|---|---|---| |COR|LOE|Recommendations|| |2a|B-R|1. Administration of flumazilen can be effective in select children with respiratory depression or respiratory arrest caused by pure benzodiazepine poisoning who do not have contraindications to flumazilen.|| |2a|C-EO|2. If combined opioid and benzodiazepine poisoning is suspected, it is reasonable to administer nalox-one first (before other antidotes) in children with respiratory depression or respiratory arrest.|| |3: No Benefit|C-EO|3. Flumazilen has no role in cardiac arrest related to benzodiazepine poisoning in children.|| |3: Harm|C-LD|4. Flumazilen administration is associated with harm in children who are at increased risk for seizures or arrhythmias.||

Recommendation-Specific Supportive Text

1. Flumazenil(Table 4) has been used safely in chil-dren when there is low risk of precipitating seizures or arrhythmias. Two RCTs of healthy children who received benzodiazepines as part of a procedural anesthetic demonstrated safety with no differ-ences in cardiorespiratory status and no seizures reported in those who received flumazenil com-pared with those who did not.14,15 Awakening was faster in children who received flumazenil after gen-eral anesthesia, but there was no difference with flumazenil use after conscious sedation,14,15 A pro-spective nonrandomized study of children receiving midazolam for conscious sedation showed 96%had a complete or partial response to flumazenil in which no significant adverse events, but children with risk factors for seizures were excluded.16 In a retrospective study of 83 children with clinical poisoning who received flumazenil after alleged benzodiazepine and nonbenzodiazepine poisoning,no flumazenil-related seizures occurred, and effec-tiveness was not reported. ${}^{17}$

2.There are no specific studies investigating the effects of flumazenil on respiratory depression for combination benzodiazepine and opioid overdose in children, thus, the pediatric recommendation is extrapolated from the adult data.

3. Flumazenil does not directly affect cardiac rhythm or restore spontaneous circulation in children. ${}^{7}$

4.There are reports of seizure recurrence after flu-mazenil use to reverse benzodiazepine-induced respiratory depression after prolonged seizures in children. ${}^{18,19}$ In a meta-analysis of random-ized clinical trials in mostly adults with presumed benzodiazepine overdose, higher rates of serious adverse effects, including seizures and arrhyth-mias, occurred with flumazenil compared with stan-dard care alone.5Harms were uncommon, and in most cases, readily managed. The risks of flumaze-nil likely exceed the benefit in children with undif-ferentiated coma for whom past medical history,substance use history, and the potential poison(s)involved are unknown.

REFERENCES

1. Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Bronstein AC, Rivers LJ, Pham NPT, Weber J. 2020 Annual Report of the American Asso-ciation of Poison Control Centers' National Poison Data System (NPDS):38th Annual Report. Clin Toxicol(Phila). 2021;59:1282-1501. doi: 10.1080/15563650.2021.1989785

2. Liu S, O'Donnell J, Gladden RM, McGlone L, Chowdhury F. Trends in Nonfatal and Fatal Overdoses Involving Benzodiazepines- 38 States and the District of Columnia, 2019-2020. MMWR Morb Mortal Wkly Rep.2021;70:1136-1141.doi: 10.15585/mmwr.mm7034a2

3.Flogel CM, Ward DS, Wada DR, Ritter JW. The effects of large-dose flu-mazen on midazolam-induced ventilatory depression. Anesth Analg.1993;77:1207-1214.doi:10.1213/00000539-199312000-00022

4. Gross JB, Blouin RT,Zandberg S,Conard PF,Haussler J.Effect of flumazenil on ventilatory drive during sedation with midazolam and antiferanil. Anesthe-siology.1996;85:713-720. doi:10.1097/000000542-199610000-00005

5. Penningna El, Graudal N, Ladekarl MB, Jungens G. Adverse Events As-sociated with Flumazenium Treatment for the Management of Suspected Benzodiazepine Intoxication--A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol. 2016;118:37-44. doi:10.1111/bcpt.12434

6.Arens AM, van Wijk XM, Vo KT, Lynch KL, Wu AH, Smollin CG. Ad-verse Effects From Counterfit Alprazolam Tablets. JAMA Intern Med.2016;176:1554-1555.doi:10.1001/jamainternmed.2016.4306

7. ROMAZICON® (flumazenil) INJECTION. 2007. Updated February 2007.Accessed January 22,2025. https://www.accessdata.fda.gov/drugsatfda docs/label/2007/020073s0161bl.pdf

8.$\_$ Spivey WH. Flumazenil and seizures: analysis of 43 cases. Clin Ther.1992;14:292-305.

9. Treatment of benzodiazepine overdose with flumazeen. The Flumaze-nil in Benzodiazepine Intoxationic Multicenter Study Group. Clin Ther.1992;14:978-995.

10. Katz Y, Boulos M, Singer P, Rosenberg B. Cardiac arrest associated with flumazenil. BMJ.1992;304:1415. doi:10.1136/bmj.304.6839.1415-b

11. Hulereux P, Vrankx M, Leduc D, Askenasi R. Flumazenil in mixed benzodiazepine/tricyclic antidepressant overdose:placebo-controlled study in the dog. Am J Emerg Med. 1992;10:184-188. doi:10.1016/0735-6757(92)990205-C

12.Marchant B, Wray R, Leach A, Nama M. Flumazenil causing con-vulsions and ventricular tachycardia. BMJ 1989;299:860. doi:10.1136/bmj.299.6703.860-b

13. Short TG, Maling T, Galletly DC. Ventricular arrhythmia precipitated by flumazenil. Br Med J(Clin Res Ed). 1988;298;1070-1071. doi: 10.1136/bmj.296.6628.1070-e

14.Jones RD, Lawson AD, Andrew LJ, Gunawardene WM, Bacon-Shone J.Antagonism of the hypnotic effect of midazolam in children: a random-ized, double-blind study of placebo and flumazenil administered after midazolam-induced anaesthesia. Br J Anaesth. 1991;66:660-666. doi:10.1093/bja/66.660

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15. Peters JM, Tolia V, Simpson P, Aravind MK, Kauffman RE. Flumaze-nil in children after esophagegastodroducosom. Am J Gastroenterol.1999;94:1857-1861. doi: 10.1111/j.1572-0241.1999.01218.x

16. Shannon M, Abers G, Burkhart K, Liebelt E, Kelley M, McCubbin MM,Hoffman J, Massarella J. Safety and efficacy of flumenil in the reversal of benzodiazepine-induced conscious sedation. The Flumenilan Pediatric Study Group. J.Pediatr.1997;131:582-586.doi:10.1016/s0022-3476(97)70066-0

17. Kreshak AA, Tomaszewski CA, Clark RF, Cantrell FL. Flumenil administra-tion in poisoned pediatric patients. Pediatr Emerg Care. 2012;28:448-450.doi:10.1097/PEC.0b013e3182531d0d

18. Brierley J. Danger of flumazenil use in pediatric status epilepticus. Pediatr Emerg Care.2002;22:168-169. doi:10.1097/0.007109/0.000202458.72602.85

19. Davis CO, Wax PM. Flumenilaz associated seizure in an 11-month-old child.J Emerg Med.1996;14:331-333. doi: 10.1016/0736-4679(96)00029-7

TOXICOLOGY:β-BLOCKERS

|Recommendations for Adults and Children With Life-Threatening β-Blocker P, B-BlockERS|||| |---|---|---|---| |COR|LOE|Recommendations|1. High-dose insulin or euglycemia therapy should be administered for hypotension refractory to vasopressor therapy in adults and children with life-threateningβ-blocker poisoning.| |1|C-LD|2. Varospressors should be administered for the treatment of hypotension in adults and children with life-threateningβ-blocker poisoning.|8.105-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.805-22.|

Synopsis

Direct antagonism of theβ-adrenergic receptors in patients withβ-blocker poisoning results in hypoten-sion from decreased cardiac contractility, bradycardia,and AV nodal blockade.'β-blocker poisoning has also been associated with hypoglycemia.2-6 A limited num-ber ofβ-blockers cause arrhythmias from blockade of cardiac sodium(eg, propranolol) or potastinine(eg, so-talol) channels and vasodilation from alpha-1 adrenergic

antagonism(eg, labelalol, carvedilol).7.8 Fortunately,while unintentional exposure to $\beta$ -blockers in children is common, severe toxicity including bronchospasm, car-diogenic shock, hypoglycemia, seizure, and symptom-atic bradycardia were not reported in 1 review of 208 children<6 years of age.5 No studies have evaluated the use of therapies specific to cardiac arrest due to$\beta$ -blocker poisoning. Therefore, recommendations are derived from studies in poisoned patients with severe$\beta$ -blocker-induced shock.

These recommendations inform the management of adults and children with life-threateningβ-blocker poi-soning, including cardiac arrest.

Recommendation-Specific Supportive Text

1. High-dose insulin(Table 4) improves inotropy in case series of adults and children in car-diogenic shock fromβ-blocker poisoning. ${}^{9,10}$In some case reports of adults and children,high-dose insulin therapy appears to be vaso-pressor sparing. Recurrence of vasopressor-resistant hypotension after insulin therapy was also reduced or stopped, although this is not reported consistently. ${}^{8,9,11,12}$ Protocolized care reduces the risk of hypoglycemia. ${}^{13,14}$Hypokalemia and volume overload are addi-tional concerns. ${}^{10,13}$

2.Successful use of inotropes and vasopressors is described in a systematic review of descrip-tive studies including adults and children as well as animal studies. ${}^{8}$ Because they are readily available and act quickly, vasopressors,such as norepinephrine and epinephrine, are almost always the initial therapy for $\beta$ -blocker-induced hypotension. Other nonadrenergic vasopressors, such as vasopressin, angioten-sin II, amrinone, milrinone, methylene blue, and hydroxocobalamin, are not supported by suffi-cient evidence to support a recommendation.

3. Intravenous glucagon(Table 4) increased con-tractility and improved hemodynamics in case reports and case series of adults and children withβ-blocker poisoning and in 1 adult trial involving a nontoxic dose of esmolol.8,11,15-17 However, 1 retrospective observational study of adults and children did not support these effects.18 The doses used to treat hemody-namic instability fromβ-blocker poisoning are larger than those used to treat hypoglycemia.Nausea and vomiting are common, and in 1 animal model, rapid tachyphylaxis occurred with continuous infusion.8,19

4 and 5. Adult and pediatric case reports, adult case series, and adult observational studies demon-strated VA-ECMO may be lifesaving for adults

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and children with persistent cardiogenic shock refractory to maximal supportive care.20-23 Limited pediatric data on the use of VA-ECMO for the treatment of children with $\beta$ -blocker poi-soning were identified; thus, the pediatric rec-ommendation for children is extrapolated from the adult data.

6 and 7. The Extracorporeal Treatments in Poisoning workgroup based on case reports and mech-anistic studies of adults with impaired kidney function provides weak recommendations for hemodialysis to aerodynamic critical poisoning due to atenolol or sotalol.24 Nadolol is also consid-ered dialysable, but clinical data are lacking.24 No pediatric data on the use of hemodialysis for the treatment of children with $\beta$ -blocker poi-soning were identified; thus, the recommenda-tion for children is extrapolated from the adult data.

8.Survival after ILE therapy (Table 4) has been described in adult case reports and case series with patients with $\beta$ -blocker poisoning. ${ }^{25-27}$ One case of a 7-month-old female did not have improved hemodynamics after ILE adminis-tration. ${ }^{28}$ Two adult cases of severe $\beta$ -blocker poisoning, combined with bupropion in 1 case and diltiazem in another, reported abrupt car-diac arrest immediately after ILE administra-tion. ${ }^{29}$ An expert consensus recommendation by international medical toxicology collabora-tors advises against the routine use of ILE for$\beta$ -blocker poisoning. ${ }^{25}$ Given pediatric data on the use of ILE therapy are limited, the recom-mendation for children is extrapolated from the adult data.

9.Survival after IV calcium administration(Table 4) has been described in adult case reports of cardiac arrest after $\beta$ -blocker over-dose. ${ }^{30,31}$ These cases are confounded by the concurrent administration of other vasoactive medications, and data for isolated calcium administration is lacking. ${ }^{30,31}$ No pediatric data on the use of calcium for $\beta$ -blocker poison-ing were identified, thus, recommendations for children are extrapolated from the adult case reports.

REFERENCES

1. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and manage-ment of calcium channel blocker and beta-blocker toxicity. Toxicol Rev.2004;23:223-238. doi:10.2165/00139709-200423040-00003

2. Casiglia E, Tikhonoff V. Long-Standing Problem of beta-Blocker-Elicited Hypoglycemia in Diabetes Mellitus. Hypertension. 2017;72:40-43. doi:10.1161/HYPERTENSIONHA.AHA.117.09378

3.Dungan K,Merril J, Long Binkey P.Effect of beta blocker use and type on hypoglycemia risk among hospitalized insulin requiring patients. Cardio-vasc Diabetol.2019;18:163. doi:10.1186/s12933-019-0967-1

4. Gokalp G, Nalbant T, Berksoy E, Bardak S, Demir G, Demir S, Sahin O Hocaaglu N. Is hypoglycemia really observed in pediatric beta-blocker intoxications? A case-control study. Arch Pediatr. 2022;29:56-60. doi: 10.1016/j.jarcped.2021.1.0006

5. Love JN, Howell JM, Klein-Schwartz W, Litovitz TL. Lack of toxicity from pediatric beta-blocker exposures. Hum Exp Toxicol. 2006;25:341-346. doi:10.1011/9690327106ht32oa

6. Murad MH, Coto-Yglesias F, Wang AT, Sheidae N, Mullan RJ, Elamin MB, Erwin PJ, Montori VM. Clinical review: Drug-induced hypoglyce-mia: a 1996 systematic review. J Clin Endocrinol Metab. 2009;94:741-745. doi:10.1210/jc.2008-1416

7. Pedersen ME, Cockcroft.JR. The vasodilatory beta-blockers. Curr Hypertens Rep.2007;9:269-277. doi: 10.1007/s11906-007-0050-2

8. Rotella JA, Greene SL, Koutsogiannis Z, Graudins A, Hung Leang Y,Kuan K, Baxter H, Bourke E, Wong A. Treatment for beta-blocker poi-soning: a systematic review. Clin Toxicol(Phila). 2020;58:943-983. doi: 10.1080/15563650.2020.1752918

9.Holger JS,Stellplfug SJ,Cole JB,Harris CR,Engebretsen KM.High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock. Clin Toxicol(Phila).2011;49:653-658. doi: 10.3109/15563650.2011.593522

10. Page CB, Ryan NM, Isbister GK. The safety of high-dose insulin eugin-caemia therapy in toxin-induced cardiac toxicity. Clin Toxicol (Philia).2018;56:389-396. doi: 10.1080/15563650.2017.1391391

11. Petersen KM, Bogevige S, Ris T, Andersson NW, Dalhoff KP, Holst JJ, Knop FK,Faber J, Petersen TS,Christensen MB. High-Dose Glucagon Has He-modynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade:A Randomized Clinical Trial. J Am Heart Assoc. 2020;9:e016828. doi: 10.1161/JAHA.120.016828

12. Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poison-ing, J.Toxicol Clinol Toxicol. 1999;37:463-474. doi: 10.1081/clt-100102437

13. Cole JB, Arens AM, LAes JR, Klein LR, Bangh SA, Olives TD. High dose insulin for beta-blocker and calcium channel-blocker poisoning. Am J Emerg Med.2018;36:1817-1824.24 doi:10.1016/j.ajem.2018.02.004

14.Schult RF, Macca N, Grannell TL, Jorgensen RM, Acquisto NM. Evaluation of high-dose insulin/euglycemia therapy for suspected beta-blocker or cal-cium channel blocker overdose following guideline implementation. Am J Health Syst Pharm.20229:57:547-555. doi:10.1093/ajhp/zxb439

15. Lvoff R, Wilcken DE. Glucagon in heart failure and in cardiogenic shock. Experience in 50 patients. Circulation. 1972;45:534-542. doi: 10.1161/01/cir.45.3.534.534

16. OMahony D, O'Leary P, Insilution M. Molloy MG. Severe oxprolol poisoning: the im-portance of glucagon infusion. Hum Exp Toxicol. 1990;9:101-103. doi: 10.1177/096032719000900208

17. Weinstein RS, Cole S, Kraster HB, Dahlbert T. Beta blocker overdose with propranolol and with atenolol. Ann Emerg Med. 1985;14:161-163. doi:10.1016/s0196-0644(8)81081-7

18. Senart AM,LeClair LA. Cardiovascular and Adverse Effects of Glucagon for the Management of Suspected Beta Blocker Toxicity: a Case Series.J Med Toxicol.2023;19:9-15. doi:10.1007/s13181-022-00919-x

19. Yao LF, MacLeod KM, McNeil JH. Glucagon-induced densitization: cor-relation between cyclic AMP levels and contractile force. Eur J Pharmacol.1982;79:147-150. doi: 10.1016/0014-2999(82)90588-x

20. Babatafi G, Massetti M, Verrier V, Lehoux P, Le Page O, Bruno PG, Khayat A.[Severe intoxication with cardiotoxic drugs: value of emergency percuta-neous cardiocirculatory assistance]. Arch Mal Coeur Vaiss. 2001;94:1386-1392.

21.Daubin C, Lehoux P, Ivassau C, Tasle M, Bousta M, Lepage O, Quentin C, Massetti M, Charbonneau P. Extracorporeal life support in severe drug intoxication: a retrospective cohort study of seventeen cases. Crit Care.2009;13:R138. doi: 10.1186/cc8017

22.Durcq T.,Goutay J.,Preau S.,Mugnier A.,Rousse N.,Moussa MD.,Vincentelli A.,Cuny J.,Parmentier-Decruç e, Poisy J., Venoarterial Extracorporeal Membrane Oxygenation in Severe Drug Intoxidization: A Retrospective Com-parison of Survivors and Nonsurvivors. ASAIO J. 2022;68:907-913. doi:10.1097/MAT.00000000000001583

23. Masson R, Colas V, Parenti JJ, Lehoux P, Massetti M, Charbonneau P, Saulnier F, Daubin C. A comparison of survival with and-out extracorporeal life support treatment for severe poisoning due to drug intoxication. Resuscitation. 2012;83:1413-1417. doi:10.1016/j.resuscitation.2012.03.028

24.Bouchard J, Shepherd G, Hoffman RS, Gosselin S, Roberts DM, Li Y,Nolin TD, Lavergne V, Ghanhoum M; EXTRIP workgroup. Extracorporeal treat-ment for poisoning to beta-adrenergic antagonists: systematic review and

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recommendations from the EXTRIP workgroup. Crit Care. 2021;25:201.doi:10.1186/s13054-021-03585-7

25. Gosselin S, Hoegberg LC, Hoffman RS, Graudins A, Stork CM,Thomas SH, Stelpfluse S, Hayes BD, Levine M, Morris M, et al.Evidence-based recommendations on the use of intravenous lipid emul-sion therapy in poisoning. Clin Toxicol(Phila). 2016;54:899-923. doi:10.1080/15563650.2016.1214275

26. Levine M, Hoffman RS, Lavergne V, Stork CM, Graudins A, Chuang R,Stellpfglu SJ, Morris M, Miller-Nesbitt A, Gosselin S; on behalf of the Lipid Emulsion Workgroup. Systematic review of the effect of intravenous lip-id emulsion therapy for non-local anesthetics toxicity. Clin Toxicol(Phila).2016;54:194-221. doi: 10.3109/1565360650.2015.1126286

27See. A Disel RC, Akarik Inpaminar A, Karakoc E. Role of intravenous lipid emulsions in the management of calcium channel blocker and beta-blocker overdose; 3 years experience of a universally hospital. Postgrad Med.2015;127:119-124. doi: 10.1080/00325481.2015.1012480

28. Montague AJ,Topeff JM,Katzung KG,Cole JB.High dose insulin to treat propranol toxicity in a 7-month-old infant. Clin Toxicol. 2015;53:740. doi: 10.3109/15563650.2015.1071025

29. Cole JB, Stellpfluse SJ, Engebretsen KM. Asystole immediately following intravenous fat emul for overdose. J Med Toxicol. 2014;10:307-310.doi:10.1007/s13181-014-0382-7

30. Brimcombe JR, Scully S. Swainston R. Propranolol overdose-ea-dra matic response to calcium chloride. Med J Aust.1991;155:267-268. doi:10.5694/j.1326-5377.1991.tb142238.x

31. Pertoldi F, D'Orlando L, Mercante WP: Electromechanical dissociation 48 hours after onelato overdose: usefulness of calcium chloride. Ann Emerg Med.1998;31:777-781.doi:10.1016/s0196-0644(98)70241-0

TOXICOLOGY: CALCIUM CHANNEL BLOCKERS

|Recommendations for Adults and Children With Life-Threatening CCB Poiponing|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|B-NR|1. High-dose insulin should be administered for hypotension in adults and children with life- threatening CCB poisoning.|| |2|C-LD|2. Vasopressors should be administered for hypotension in adults and children with life- threatening CCB poisoning.|| |3|2a|3. It is reasonable to use ECLS in adults with CCB poisoning that is refractory to pharmacological interventions.|| |2a|C-LD|4. It is reasonable to use ECLS in children with CCB poisoning that is refractory to pharmacological interventions.|2. Many adults and children with CCB-induced shock reported to a poison center registry and in 1 case series received vasopressor therapy.2,10| |2a|C-EO|5. It is reasonable to administer calcium in adults and children with life-threatening CCB poisoning.|| |2b|C-EO|6. The usefulness of a glucagon bolus followed by continuous infusion for adults and children with life-threatening CCB poisoning is uncertain.|| |2b|C-EO|7. The usefulness of methylene blue for adults and children with refractory vasoplasidatory shock due to CCB poisoning is uncertain.|| |2b|C-EO|8. The usefulness of ILE for adults and children with refractory shock due to CCB poisoning is uncertain.||

Synopsis

Antagonists of the L-type calcium channel(commonly called CCBs) are divided into 2 pharmacological class-es: dihydropyridines(eg, nifedipine, amlodipine) and

nondihydropyridines(eg, diltiazem, verapamil). At thera-peutic doses, nondihropyridines have more pronounced effects on cardiac tissue, including the atrioventricular node, resulting in negative chronotropy. In contrast, di-hydropyridines primarily cause peripheral vasodilation.Amlodipine can cause profound vasodilation mediated by nitric oxide release.1 These distinctions are often lost when therapeutic doses are exceeded, and patients present with severe shock from bradycardia, vasodilation, or loss of in-otropy. Prolonged effects are common given that CCBs are frequently prescribed in sustained-release forms(eg,diltiazem, verapami, nifedipine) or have long half-lives(eg,amlodipine). As a result, CCBs are a leading cause of poi-soning mortality reported to poison centers.2 Commonly used treatment modalities include atropine, calcium, vaso-pressors, high-dose insulin therapy, methylene blue(a ni-tric oxide synthase inhibitor), and ILE therapy.ECLS, such as VA-ECMO, has been used in refractory cases.

These recommendations inform the management of adults and children with life-threatening CCB poisoning,including cardiac arrest.

Recommendation-Specific Supportive Text

1. High-dose insulin(Table 4) improves inotropy in adults and children with severe cardiogenic shock from CCB poisoning.3-6 One large observational study including adults and chil-dren reported favorable outcomes with lower rates of vasoconstrictive complications than vasopressor-only therapy.3 One retrospective cohort study of adults and children suggested that patients with dihydropyridine toxicity may require more vasopressor support along with high-dose insulin because of additive vaso-dilation.7 Protocolized care reduces the risk of hypoglycemia.3,5 Hypokalemia and volume overload are additional concerns.3,8

2.Many adults and children with CCB-induced shock reported to a poison center registry and in 1 case series received vasopressor therapy.29,10 One retrospective case series of 48 adults and children demonstrated excellent survival rates with the primary use of vasopressors(most commonly morepinephrine at doses up to 100 mcg/min in adults), with low rates of ischemic complications.9 Three patients in this series had cardiac arrest before vasopressor therapy. There is no evidence to guide the choice of vasopres-sors. Other nonadrenergic vasopressors, such as vasopressin, angiotensin II, amrinone, milri-none, and hydroxocobalamin, are not supported by sufficient evidence for a recommendation.

3 and 4. The use of VA-ECMO for adults and children with refractory cardiogenic shock or cardiac arrest after CCB overdose is described in a

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case series with reported survival rates as high as 77%.11-16 A study using data from the ELSO Registry of adults with CCB poisoning found a mortality rate of 40.6%, which is lower than the general mortality rate of 50% for all adults on ECMO.17 The study also found that a pH<7.1 and the use of kidney replacement therapy prior to initiation of ECLS were associated with increased odds of mortality. ${}^{17}$

5.The available literature on calcium monother-apy for severe CCB toxicity is limited (Table 4).Improvements in heart rate, blood pressure,and conduction abnormalities are reported in adults and children.18,19 However, most patients require additional treatments.3,15,18,20 In case series of adults, high doses of calcium gluco-nate (targeting ionized calcium concentrations up to twice normal) appeared to be more effec-tive than lower doses.18

6. Glucagon is an adjunctive therapy for severe CCB poisoning in adults and children.39,20 Reported response rates are variable, vomiting is common, and tachyphylaxis may occur.19,21,22

7. Methylene blue (Table 4), a nitric oxide syn-thase inhibitor, is described in adult case series and case reports as an effective adjunct to treat refractory vasodilatory shock after CCB overdose (involving primarily amoplindee).23 However, responses are mixed, and the effects may be transient. Data for the treatment of chil-dren with methylene blue for CCB poisoning is lacking, and recommendations are extrapo-lated from adult data.

8.An adult case series and a systematic review of adult and pediatric case reports with CCB poisoning identified cases where ILE appeared beneficial.24-26 In 1 report of 2 adults, the use of ILE was associated with abrupt cardiac arrest.8 An expert consensus recommendation by international medical toxicology collabora-tors advises against the routine use of ILE for CCB poisoning.24 The role of ILE in patients who have failed other modalities and are in cardiac arrest or peri-arrest is unclear.21,24 Data for the treatment of children with ILE for CCB poisoning is limited, and recommendations are extrapolated primarily from adult data.

REFERENCES

1. Zhang X, Hintze TH. Amlodipine releases nitric oxide from canine coronary microvessens: an unexpected mechanism of action of a calcium channel-blocking agent. Circulation.1998;97:576-580.doi:10.1161/01.cirag.9756.76

2. Gummin DD, Mowry JB, Beuhler MC, Spyler DA, Rivers LJ, Feldman R,Brown K, Pham NPT, Bronstein AC, DesLauriers C. 2022 Annual Report of the National Poison Data System® (NPDS) from America's Poison Centers(R)). 40th Annual Report. Clin Toxicol (Phila). 2023;61:717-939.doi:10.1080/155636560.2023.2268981

3. Cole JB, Arens AM, Laes JR, Klein LR, Bangsh SA, Olives TD. High dose insulin for beta-blocker and calcium channel-blocker poisoning. Am J Emerg Med.2018;36:1817-1824.doi:10.1016/j.ajem.2018.02.004

4.Holger JS, Stellplfug SJ, Cole JB, Harris CR, Engebretsen KM.High-dose insulin: a consecutive case series in toxin-induced car-diogenic shock. Clin Toxicol(Phila). 2011;49:653-658. doi: 10.3109/156563650.2011.593522

5.Schult RF, Nacca N, Rannell TL, Jorgensen RM, Acquisto NM. Evalu-ation of high-dose insulin/euglycemia therapy for suspected beta-blocker or calcium channel blocker overdose following guideline implementation. Am J Health Syst Pharm. 2022;79:547-555. doi:10.1093/ajhp/zxab439

6. Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poison-ing. J Taxicol Clin Toxicol. 1999;37:463-474. doi: 10.1081/clt-100102437

7. Cole JB, Lee SC, Prekker ME, Kunzler NM, Considine KA, Driver BE, Puskarich MA, Olives TD. Vasodilation in patients with calcium channel blocker poisoning treated with high-dose insulin: a comparison of amlodip-ine versus non-dihydropyridines. Clin Toxicol(Phila). 2022;60:1205-1213. doi: 10.1080/15563650.2022.2131565

8. Cole JB, Stellflug SJ, Engebretsen KM. Asystole immediately following intravenous fat emulsion for overdose. J Med Toxicol. 2014;10:307-310. doi: 10.1007/s13181-014-0382-7

9.Levine M, Curry S, Radilla Jones A, Ruha AM. Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25-year experience at a single center. Ann Emerg Med.2013;62:252-258. doi:10.1016/j.jannermegred.2013.03.018

10. Ramoska EA, Spiller HA, Myers A. Calcium channel blocker toxicity. Ann Emerg Med.1990;19:649-653. doi: 10.1016/s0196-0644(05)82469-2

11. Babatasi G, Massetti M, Verrier V, Lehoux P, Le Page O, Bruno PG, Khayat A.[Sevoire intoxication with cardiotoxic drugs] of emergency percuta-neous cardiocirculatory assistance]. Arch Mal Coeur Vaiss. 2001;94:1386-1392.

12.Cole JB, Olives TD, Uili A, Litell JM, Bangh SA, Arens AM, Puskarich MA, Prekerk ME. Extracorporeal Membrane Oxygenation for Poisonings Reported to U.S. Poison Centers from 2000 to 2018: An Analysis of the National Poison Data System. Crit Care Med. 2020;48:1111-1119. doi: 10.1097/CCM.000000000000004401

13.Daubin C, Lehoux P, Ivassca C, Tasse M, Bousta M, Lepage O, Quentin C, Massetti M, Charbonneau P. Extracorporeal life support in severe drug intoxication: a retrospective cohort study of seventeen cases. Crit Care.2009;13:R138; doi:10.1186/cc8017

14.Durcbq T,Goutay J,Preau S,Mugnier A,Rousse N,Moussa MD,Vincentelli A,Cuny J, Parmentier-Decruç E, Poissy J. Venoarterial Extracorporeal Membrane Oxygenation in Severe Drug Intoxidation: A Retrospective Com-parison of Survivors and Nonsurvivors. ASAIO J. 2022;68:907-913. doi:10.1097/MAT.00000000000001583

15.Lewis J,Zarate M,Tran S,Albertson T.The Recommendation and Use of Extracorporeal Membrane Oxygenation(ECMO) in Cases Reported to the California Poison Control System. J Med Toxicol. 2019;15:169-177. doi:10.1007/s13181-09-010704-3

16. Voicu S, M'Rad A, Malisern I, Dyeer N, Megarbane B. Extracorporeal life sup-port in acidototoxic poisoning-a narrative review. Basic Clin Pharmacol Toxicol.2023;132:5-20. doi: 10.1111/bcp:13804

17.Subramanian R, Roebuch A, Joshi H, Drouin M. Predictors of Mortal-ity in Adults With Calcium Channel Blocker Toxicity Receiving Extra Corporeal membrane Oxygenation Support: An extracorporeal Life Sup-port Organization Registry Analysis. ASAIO J. 2024;71:200-203. doi:10.1097/mat 000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000

18.Howarth DM, Dawson AH, Smith AJ, Buckley N, Whyte IM. Calcium channel blocking drug overdose: Australian series. Hum Exp Toxicol.1994;13:161-166. doi: 10.1177/096032719401300304

19. Ramoska EA, Spiller HA, Winter M, Borys D. A one-year evaluation of cal-cium channel blocker overdoses: toxicity and treatment. Ann Emerg Med.1993;22:196-200. doi: 10.1016/s0196-0644(05)80202-1

20.Hofer CA,Smith JK,Tenholder MF. Verapamil intoxication: a literature review of overdoses and discussion of therapeutic options. Am J Med.1993;95:431-438.doi:10.1016/0002-9343(93)90314-f

21.St-Ongre M, Dube PA, Gosselin S, Guimont C, Godwin J, Archambault PM,Chauny JM,Frenette AJ,Darveau M,Le Sage N,et al.Treatment for cal-cium channel blocker poisoning: a systematic review. Clin Toxicol(Phila).2014:52:96-944.doi:10.3109/15563650.2014.965827

22.Yao LF, MacLeod KM, McNeill JH. Glucagon-induced densensitization: cor-relation between cyclic AMP levels and contractile force. Eur J Pharmacol.1982;79:147-150. doi:10.1016/0014-2999(82)90588-x

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23. Warrick BJ, Tataru AP, Smolinske S. A systematic analysis of methylene blue for drug-induced shock. Clin Toxicol(Phila). 2016;54:547-555. doi: 10.1080/15563650.2016.1180390

24. Gosselin S, Hoegberg LC, Hoffman RS, Graudins A, Stork CM,Thomas SH, Stellplfug SJ, Hayes BD, Levine M, Morris M, et al.Evidence-based recommendations on the use of intravenous lipid emul-sion therapy in poisoning. Clin Toxicol(Phila). 2016;54:899-923. doi: 10.1080/15563650.2016.1214275.

25. Levine M, Hoffman RS, Lavergne V, Stork CM, Graudins A, Chuang R,Stellplfgh SJ, Morris M, Miller-Nesbitt A, Gosselin S; on behalf of the Lipid Emulsion Workgroup. Systematic review of the effect of intravenous lip-id emulsion therapy for non-local anesthetics toxicity. Clin Toxicol(Phila).2016;54:194-221. doi: 10.3109/15563650.2015.1126286

26.Sebe A, Disel NR, Acikalin Akpinar, A Karakoc E. Role of intravenous lipid emulsions in the management of calcium channel blocker and beta-blocker overdose: 3 years experience of a university hospital. Postgrad Med.2015;127:119-124. doi:10.1080/00325481.2015.1012480

TOXICOLOGY: COCAINE

Introduction

The clinical manifestations of cocaine poisoning are mainly caused by sympathetic nervous system effects. Cocaine produces a sympathomistic toxicrome marked by tachy-cardia, hypertension, hyperthermia, diaphoresis, increased psychomotor activity, and seizures.1 Cocaine induces tachy-cardia (postynaptic (p-adrenergic receptor agonism) and hypertension (peripheral postsynaptic alpha-adrenergic re-ceptor agonism) by enhanced catecholamine release and catecholamine reuptake inhibition. The release and reup-take blockade of norepinephrine, epinephrine, dopamine,and serotonin also causes the CNS and neuropsychiatric symptoms of cocaine poisoning. ${}^{1,2}$ Cocaine-induced coro-nary atherosclerosis and vasospasm predisposes individu-als to acute coronary syndromes. ${}^{3}$

The electrocardiographic changes and dysrhythmogenic properties of cocaine are a result of the effect of cocaine on cardiac sodium and potassium channels.4 Sodium chan-nel blockade leads to slowed conductance during phase 0 of the cardiac action potential. As a result, patients may develop QRS complex prolongation and wide-complex tachycardia similar to what occurs with Vaughan-Williams la and lc medications.5,6 Cocaine also causes QT interval prolongation and torsade de pointes through potassium channel blockade.17 Cocaine-induced arrhythmias include asystolic cardiac arrest and pulseless VT. Like other local anesthetics, cocaine blocks neuronal sodium channels.

These recommendations inform the management of adults and children with life-threatening cocaine poison-ing, including cardiac arrest.

|Recommendations for Adults With Life-Threatening Cocaine Poisoning||| |---|---|---| |COR|LOE|Recommendations| |1|B-R|1. Sedation is recommended for adults with severe agitation from cocaine poisoning.| |1|C-LD|2. Rapid external cooling with ice water immersion is recommended for adults with life-threatening hyperthermia(Core Temperature>40°C[104°F]) from cocaine poisoning.|

|Recommendations for Adults With Life-Threatening Cocaine Poisoning (Continued)|||| |---|---|---|---| |COR|LOE|Recommendations|| |2a|C-LD|3. In adults with wide-complex tachycardia or cardiac arrest from cocaine poisoning, it is reasonable to administer sodium bicarbonate.|| |2a|C-LD|4. In adults with wide-complex tachycardia or cardiac arrest from cocaine poisoning, it is reasonable to administer lidocaine.|| |2a|C-LD|5. In adults with cocaine-induced coronary vasospasm or hypertensive emergencies, it is reasonable to administer vasodilators(eg,nitrates,holamine,CCBs).|| |2a|C-LD|6. It is reasonable to use ECLS in adults with cardiogenic shock from cocaine poisoning refractory to other treatment measures.|| |3: No Benefit|C-LD|7. In adults with cocaine-induced coronary vasospasm or hypertensive emergencies, administration ofβ-adrenergic antagonists is not recommended.|| |3: Harm|C-LD|8. Prolonged use of physical restraint in adults with life-threatening cocaine poisoning without sedation is potentially harmful.||

Recommendation-Specific Supportive Text

1. Sedatives(eg, benzodiazepines and antipsychot-ics) have been successful in treating adults with cocaine-induced agitation.8 Small animal pretreat-ment and rescue studies comparing chlorproma-zine to diazepam demonstrated improved survival with both compared with controls.9,10 One adult randomized clinical trial comparing droperidol ver-sus lorazepam for acutely agitated patients from cocaine or methamphetamine intoxication found adequate sedation with both medications, but dro-peridol had faster onset of sedation and required fewer repeat doses. ${}^{11}$

2. Hyperthermia(Core temperature>$40^{\circ} C\left[104^{\circ} F\right]$ )can be rapidly life-threatening in cocaine poison-ing. ${}^{12,13}$ High-quality data on cooling measures for hyperthermic cocaine-intoxicated adults are lack-ing, but immersion seems effective. ${}^{14}$ Evaporative or immersive cooling modalities reduce tempera-ture more rapidly in adults than cooling blankets,the application of cold packs, or endovascular cool-ing devices. ${}^{12,15-21}$ lce water immersion resulted in the fastest cooling rates in adults and may cool faster than 0.15°C/min(0.27°F/min), which has been associated with increased survival(refer to the Hyperthermia section). ${}^{16,22}$

3. Canine studies demonstrate the ability of sodium bicarbonate(Table 4) to reverse cocaine-induced QRS prolongation through competitive binding between sodium bicarbonate and cocaine at the sodium channel.23-25 Adult case reports and case series describe the successful use of hyper-tonic sodium bicarbonate to treat wide-complex

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tachycardia from severe cocaine poisoning. ${}^{26-30}$The successful use of hypertonic sodium bicar-bonate in the resuscitation has also been reported in an adult case report with asystolic cardiac arrest and subsequent wide-complex Brugada pattern. ${}^{28}$

4. Lidocaine administration has demonstrated safety in a multicenter retrospective observation study of 27 adults with cocaine-induced myocardial infarc-tion. ${}^{31}$ The use of lidocaine for cocaine-associated cardiac arrest with ventricular arrhythmias is sup-ported by 1 adult and a pediatric case report in a 17-year-old female patient. ${}^{32,33}$

5. Adult clinical trials demonstrate improvements in coronary blood flow and myocardial oxygen delivery in patients with cocaine-induced coro-nary vasospasm after treatment with vasodila-tors(eg, phentolamine, nitrates, verapamil).34-38 These studies did not include patients with cardiac arrest or in peri-arrest. Adults with refractory isch-emia from cocaine were successfully treated with phentolamine.35,39

6.ECLS,including VA-ECMO and intra-aortic bal-loon pump, has been used successfully to sup-port cardiac output in adults in cardiogenic shock after myocardial infarction.40,41 Evidence in patients with cocaine-associated circulatory failure is lacking.

7. While a 2008 AHA scientific statement suggests potential benefits of $\beta$ -adrenergic blockade after acute management of cocaine-related myocar-dial infarction, evidence to support the use of$\beta$ -adrenergic blockade in adults with acute life-threatening cocaine toxicity is lacking. ${ }^{42}$ In con-trolled animal trials, propranolol failed to prevent cocaine lethality. ${ }^{9,10,43}$ In adults who received cocaine while undergoing cardiac catheteriza-tion, propranolol exacerbated coronary vasocon-striction. ${ }^{44}$ In the same human model, labelatol was no better than saline at reversing coronary vasoconstriction. ${ }^{45}$ In at least 1 case report, the administration of metoprolol to an adult with persistent cocaine-induced hypertension and tachycardia resulted in crushing substernal chest pain, which was followed by PEA and death. ${ }^{46}$ In a case series of adults with acute cocaine toxic-ity, the effect of esmolol was inconsistent, fail-ing to treat tachycardia in 1 patient and raising diastolic blood pressure(possibly an unopposed alpha-adrenergic effect) in others, 1 of which was severe. ${ }^{47}$

8. Although physical restraints may be necessary temporarily, their sustained use without effective sedation is associated with death in adults with severe agitation from exposure to cocaine and other sympathomimetics. 48,49

|Recommendations for Children With Life-Threatening Cocaine Poisoning|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-EO|1. Sedation is recommended for children with severe agitation from cocaine poisoning.|| |2|C-EO|2. Rapid external cooling with ice water immersion is recommended for children with life-threatening hypertermia(Core Temperature>40°C[104°F]) from cocaine poisoning.|| |2a|C-EO|3. In children with wide-complex tachycardia or cardiac arrest from cocaine poisoning, it is reasonable to administer sodium bicarbonate.|| |2a|C-EO|4. In children with wide-complex tachycardia or cardiac arrest from cocaine poisoning, it is reasonable to administer lidocaine.|| |2a|C-EO|5. In children with cocaine-induced coronary vasospasm or hypertensive emergencies, it is reasonable to administer vasodilators(eg, nitrates, lentolamine, CCBs).|| |2a|C-EO|6. It is reasonable to use ECLS in children with cardiogenic shock from cocaine poisoning refractory to other treatment measures.|| |3: No Benefit|C-EO|7. In children with cocaine-induced coronary vasospasm or hypertensive emergencies, administration ofβ-adrenergic antagonists should not be performed.|| |3: Harm|C-EO|8. Prolonged use of physical restraint in children with life-threatening cocaine poisoning without sedation is potentially harmful.||

Recommendation-Specific Supportive Text

1. Sedatives(eg, benzodiazepines and antipsychot-ics) have been successful in treating adults with cocaine-induced agitation.8 Small animal pretreat-ment and rescue studies comparing chlorpromazine,an antipsychotic, to diazepam, a benzodiazepine,demonstrated improved survival with both compared with controls.9,10 One adult randomized clinical trial comparing droperidol versus lorazepam for acutely agitated patients with cocaine or methamphetamine intoxication found adequate sedation with both med-ications, but droperidol had faster onset of sedation and required fewer repeat doses.11 No pediatric data on the use of sedatives for life-threatening cocaine poisoning were identified, thus, the recommendation for children is extrapolated from the adult data.

2. Hyperthermia(Core Temperature>40°C[104°F])can be rapidly life-threatening in cocaine poison-ing. 12,13 Evaporative or immersive cooling modali-ties reduce temperature more rapidly in adults than cooling blankets, the application of cold packs, or endovascular cooling devices. 12,15-21 Ice water immersion resulted in the fastest cooling rates in adults and critically may cool faster than 0.15°C/min(0.27°F/min), which has been associated with increased survival. ${}^{16}$ High-quality data on cooling measures for hyperthermic cocaine-intoxicated adults are lacking, but immersion seems effec-tive. ${}^{14}$ No pediatric data on the use of rapid external

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cooling for life-threatening cocaine poisoning were identified, thus, the recommendation for children is extrapolated from the adult data(refer to the Hyperthermia section).

3.Canine studies demonstrate the ability of sodium bicarbonate(Table 4) to reverse cocaine-induced QRS prolongation through competitive binding between sodium bicarbonate and cocaine at the sodium channel.23-25 Adult case reports and case series describe the successful use of hypertonic sodium bicarbonate to treat wide-complex tachy-cardia from severe cocaine poisoning.26-30 The successful use of hypertonic sodium bicarbonate in resuscitation has also been reported in an adult with asystolic cardiac arrest and subsequent wide-complex Brugada pattern.28 No pediatric data on the use of hypertonic sodium bicarbonate for wide-complex tachycardia or cardiac arrest from cocaine poisoning were identified, thus, the recommenda-tion for children is extrapolated from the adult data.

4. Lidocaine administration has demonstrated safety in a multicenter retrospective observation study of 27 adults with cocaine-induced myocardial infarc-tion.31 The use of lidocaine for cocaine-associated cardiac arrest with ventricular arrhythmias is sup-ported by 1 adult and a pediatric case report in a 17-year-old female patient.32,33 No other pediat-ric data on the use of lidocaine for wide-complex tachycardia or cardiac arrest from cocaine poisoning were identified, thus, the recommendation for children is extrapolated from the adult data.

5. Adult clinical trials demonstrate improvements in coronary blood flow and myocardial oxygen delivery in patients with cocaine-induced coro-nary vasospasm after treatment with vasodila-tors(eg, phentolamine, nitrates, verapamil)34,37,38 These studies did not include patients with cardiac arrest or peri-arrest states. Adults with refractory ischemia from cocaine were successfully treated with phentolamine.35,39 No pediatric data on the use of vasodilators for cocaine-induced coronary vasospasm or hypertensive emergencies were identified, thus, the recommendation for children is extrapolated from the adult data.

6.ECLS, including VA-ECMO and intra-aortic bal-loon pump, has been used successfully to support cardiac output in adults in cardiogenic shock after myocardial infarction.40,41 Evidence in patients with cocaine-associated circulatory failure is lacking. No pediatric data on the use of ECLS for cardiogenic shock from cocaine poisoning were identified, thus,the recommendation for children is extrapolated from the adult data.

<BeginOfPara>7. While a 2008 AHA scientific statement sug-gests potential benefits ofβ-adrenergic block-ade after acute management of cocaine-related

myocardial infarction, evidence to support the use ofβ-adrenergic blockade in adults with acute life-threatening cocaine toxicity is lacking.42 In con-trolled animal trials, propranolol and labelatol failed to prevent cocaine lethality. In adults who receive cocaine while undergoing cardiac catheterization,propranolol exacerbates coronary vasoconstric-tion.9,10,43,44 In the same human model, labelatol was no better than saline at reversing coronary vaso-constriction.45 In at least 1 case report, the admin-istration of metoprolol to an adult with persistent cocaine-induced hypertension and tachycardia resulted in crushing substernal chest pain, which was followed by PEA and death. In a case series of adults with acute cocaine toxicity, the effect of esmolol was inconsistent, failing to treat tachycar-dia in 1 patient and raising diastolic blood pressure(possibly an unopposed alpha-adrenergic effect) in others, 1 of which was severe.47 No pediatric data on the use ofβ-adrenergic blockade for cocaine-induced coronary vasospasm or hypertensive emer-gencies were identified, thus, the recommendation for children is extrapolated from the adult data.

8. Although physical restraints may be necessary temporarily, their sustained use without effective sedation is associated with death in adults with severe agitation from exposure to cocaine and other sympathomometrics. 48,49 No pediatric data on the use of restraints for life-threatening cocaine poisoning were identified, thus, the recommenda-tion for children is extrapolated from the adult data.

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10. Guinn MM, Bedford JA, Wilson MC. Antagonism of intravenousocine lethality in nonhuman primates. Clin Toxicol. 1980;16:499-508. doi:10.3109/15563658008989979

11. Richards JR. Derelk W. Duncan DR. Chemical resterment for a agitated patient in the emergency departmentor:lazeponum separable 0. JEmerg Med. 1998;16:567-573. doi: 10.1016/s0196-4367-064(9)00045-6

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13. Roberts JR, Quattocchi E, Howland MA. Severe hyperthermia sec-ondary to intravenous drug abuse. Am J Emerg Med 1964;287:3937.

14. Laskowski LK, Landy A, Souchova, H. Hoffman RS. Ice water submersion for rapid cooling in severe drug-induced hyperthermia. Clin Toxicol (Phila)2015;53:181-184. doi: 10.3109/15563650.2015.1009994

15. Casa DJ, McDermott BP, Lee EC, Earygin SW, Armstrong LE, Maresh CM. Cold water immersion: the gold standard for exertional heat-stroke treatment. Exerc Sport Sci Rev. 2007;35:141-149. doi: 10.1097/jes/Ob3180a02bec.

16. Douma MJ,Aves T, Allan KS, Bendall JC, Berry DC, Chang WT, Epstein, EJ,Hood N, Singleary EM, Zideman D, et on; behalf of the First Aid Task Force of the International Lison Committee on Resuscitation. First and cooling techniques for heat stroke and exertional hyperthermia: A sys-tematic review and meta-analysis. Resuscitation 2020;148:173-190. doi:1016.1016/j.resuscitation.2020.01.007

17. Liao X,Zhou Z,Zhou M,Tang H,Feng M,Kou B,Zhu N,Liao F,Wu L.Effects of endovascular and surface cooling on resuscitation in patients with cardiac arrest and a comparison of effectiveness, stability, and safe-ty: a systematic review and meta-analysis. Crit Care. 2020;24:27. doi:10.1186/s13054-2020-7371z

18. McDermott BP, Casa DJ, Ganio MS, Lopez RM, Yeargin SW, Armstrong LE, Maresh CM. Acute whole-body cooling for exercise-induced hy-pertherm: a systematic review. A Ith Train. 2009;44:84-93. doi: 10.4085/1062-6050-44.1.84

19. Rosman J. Hentien M, Drine M. Roussel V, Just B, Jolly J, Diseat M, Mateu P.A comparison between intravascular and traditional cooling for induc-ing and maintaining temperature control in patients following car-diac arrest. Asana Chefir Cant Care Pain Med 2018;36:187:129-134. doi:10.1016/j.cpm.2016.08.009

20.Sonder P, Janssens GN, Beishuizen A, Henry CL, Rittenberger JC,Callaway CW, Dezufian C, Polderman KH. Efficacy of different cool-ing technologies for therapeutic temperature management: A pro-spective intervention study. Resuscitation: 2018;124:14-20.10.1016/j.resuscitation.2017.12.026

21. Zhang Y, Davis JK, Casa DJ, Bishop PA. Optimizing Cold Water Immersion for Exercise-Induced Hypertheriam: A Meta-analysis. Med Sci Sports Exerc 2015;47:2464-2472. doi:10.1249/MSS.000000000000693

22. Filep EM, Murata Y, Endres BD, Kim G., Steams RL, Casa DJ. Ex-erential Heat Stroke, Modality Cooling Rate, and Survival Out-comes: A Systematic Review. Medicina(Kaunas).2020;56:589. doi: 10.3390/medicina 511089.1185.

23. Beckman KJ, Parker RB, Harriman J.,Gallastegui JL,Javalid, BaUman JL,Hemodynamic and electrophysiological actions of cocaine. Effects of so-dium bicarbonate as an antidose in dogs. Circulation. 1991;83:1799-1807.doi: 10.1161/01.cir83.1599.

24. Wilson LD, Shelat C. Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication. J Toxicol Clin Toxicol 2003;41:777-788. doi: 10.1081/c1t-120025342

25. Parker RB, Perry GY, Horan LG, Flowers NC. Comparative effects of sodium bicarbonate and sodium chloride on reversing cocaine-induced changes in the electrocardiogram. J Cardiovasc Pharmacol. Neurosci 1999;34:864-869. doi:109.1075/0005344-199912000-00014

26Iani F, Kramani R, Kanjwal Y. Hyperkalemia and cocaine induced dynamic Brugada-type electrocardiogram.Eur JEmerg Med.2010;17:113-115.doi:10.1097/MEI/JoD013e02382e46d1

27. Kerns W 2nds W, Garvey L, Owens J. Cocaine-induced wide com-plex dysrhythmia. J Emerg Med. 1997;15:321-329. doi:10.1016/s0736-4679(97)0003-6

28. Ortega-Carnicer J, Bertos-Polo J, Gutierrez-Tirado C. Aborted sud-den death, transient Brugada pattem, and wide ORS dysrhythmias af-ter massive cocaine ingestion. J Electrodiol 2001;34:345-349. doi:10.1054/jelc.2001.26318

29. Tanen DA GAemea K, Curry SC. Crack cocaine ingestion with prolonged toxicity requiring electrical pacing. J Oxitlin Clin Toxicol 2000;38:653-657.doi:10.1081/cit-100102016

30. Wang RY, pH-dependent cocaine-induced cardiotoxicity. Am J Emerg Med.199917:1974-369-169. doi:10.1016/s0735-6757(99)90088-8

31. Shih RD, Hollander JE, Burstein JL, Nelson LS, Hoffman RS, Quick AM. Clinical safety of lidocaine in patients with cocaine-associated myocardial infarction. Ann Emerg Med. 1995;26:702-706. doi:10.1016/s0196-0644(9)70041-2

2023. Lormans P,Gaumann D, Schwieger I, Tassonyi E. Ventricular fibrillation fol-lowing local application of cocaine and epinephrine for nasal surgery. ORL J Otorhinolaryngol Relat Spec. 1992;54:160-162. doi: 10.1159/000276289

33.Wouplom JA, Tsimé R, Martie CR, Bailey AM, Baum RA, Akpunonu P.Use of lidocaine for treatment of pulseless ventricular tachycardia af-ter massive cocaine overdose. Toxicol Communcer. 2019;3:19-22. doi:10.1080/24734306.2019.1574391

34. Brogan WC 3rd, Lange RA, Kim AS, Moliterno DJ, Hillis LD. Alleviation of cocaine-induced coronary reconstituation by nitroglycerin. J Am Coll Car-diol.1991;18:581-586. doi: 10.1016/0735-1097(91)90617-i

35. Hollander JE, Carter WA, Hoffman RS. Use of phentolamine for cocaine-induced myocardial ischemia. N Engl J Med. 1992;327:361. doi:10.1015/NEJM199207303270517

36. Hollander JE, Hoffman RS, Gennis P,Fairweather P, DiSano MJ, Schumb DA, Feldman JA, Fish SDDyer S, Wax P. Nitroglycerin in the treatment of cocaine associated chest pain-clinical safety and efficacy. J Toxicol Clin Tensotol 1994;32243-2956. doi: 10.3109/15563659409017957

37. Pitts WR, Lange RA, Cigarroa JE, Hillis LD. Cdocaine-induced myocardial ischemia and infarction: pathophysiology, recogni-tion, and management. Prog Cardiovasc Dis. 1997;40:65-76. doi: 10.1016/s0033-0620(97)80023-0

88.Richards JR, Garber D, Laurin EG, Albertson TE, Derlet RW, Amsterdam EA,Olson KR,Roamska EA,Lange RA.Treatment of cocaine cardiovascu-lar toxicity: a systematic review. Clin Toxicol(Phila). 2016;54:345-364. doi:10.3109/155636502016.1142090

39. Chan GM, Sharma R, Price D, Hoffman RS, Nelson LS. Phentolamine therapy for cocaine-association acute coronary syndrome(CAACS). J Med Toxicol 2006:108-111. doi: 10.1007/BF0361019

40. Grimm J, Balsara KR, Kemp CD, Miller J, Myers M, Schulman SP,Scirtoim C. Extracorporal membrane oxygenation for profound cardio-genic shock due to cocaine toxicity. J Cardiol Cases.2015;11:28-31. doi:10.1016/j.jccase.2014.09.005

41. Javed F, Khan SA, Aziz EF, Abbasi T, Suryadevara R, Herzog E. Unusual towering elevation of troponin I after ST-elevation myocardial infarc-tion and intensive monitoring with echocardiography post-percutaneous coronary intervention: a case report. J Med Case Rep. 2010;4:137. doi:10.10175/19527-1947-4-137

42. McCord J, Jneid H, Hoffmane JE, de Lemos JA, Cercek B, Hsue P,Gibler WB, Ohman EM, Drew B, Phippilides G, et al; on behalf of the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117:1897-1907. doi:10.1016/CIRCULATIONAHA.107.188950

43. Smith M, Garner, N. Diemann JT. Pharmacologic interventions after an LD50 cocaine insult in a chronically instrumented rat model: are beta-blockers contraindated? Ann Emerg Med. 1991;20:768-771. doi:10.1016/s0196-0644(0)80839-x

44. Lange RA, Cigarova RG, Flores ED, McBride W, Kim AS, Wells RJ, Bedotto J,BDanziger R, Hills LD. Potentiation of cocaine-induced coronary vaso-constriction by beta-adrenergic blockade. Ann Intem Med. 1990;112:897-903. doi: 10.7326/0003-4819-112-12-897

45.Boehr JD, Moliterno DJ, Willard JE, Hillis LD, Lange RA. Influence of la-betallo on cocaine-induced coronary vaso-betallo on cocaine-orconial vasoconary coasconstriction in humans. Am J Med.1993;94:608-610. doi:10.1016/0002-9343(93)90212-8

46. Faredan F, Chan G, Hoffman RS. Death temporally related to the use of a Belta adneric receptor antagonist in cocaine associated myocardial in-farction. J Med. 2007;3:169-172. doi: 10.1007/BF03160934

47. Sand IC. Brody SL, Wrenn KD, Slovis CM. Experience with esmolol for the treatment of cocaine-associated cardiovascular complications. Am J Emerg Med.1991;9:161-163. doi: 10.1016/0735-6757(91)90182-j

48. Pollanen MS, Chasson DA, Cairns JT, Young JG. Unexpected death related to restraint for excited delirium: a retrospective study of deaths in police custody and in the community. CMAJ.1998;158:1603-1607.

49. Stromner EMF, Leith W. Zeegers MP, Freeman MD. The role of restraint in fatal excited: a renal research synthesis and pooled analysis. Forensic Sci Med Pathol.2020;16:680-692. doi:10.1007/s12024-020-00291-8

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TOXICOLOGY: CYANIDE

Introduction

Cyanide may be encountered through multiple industrial sources, including jewelry cleaning and electroplating or by the metabolism of naturally occurring cyanogens found in the pits of stone fruits, such as apricots. Cya-nide gas is liberated by the incomplete combustion of nitrogen-containing products, such as plastics and vinyl,during house fires. It may also be ingested as cyanide salts in poisonings.

Cyanide inhibits cellular respiration in the mitochon-dria, causing cardiovascular collapse, metabolic acidosis with elevated plasma lactate concentrations, depressed mental status, seizures, and death.1 Confirmatory testing is not rapidly available, and thus, diagnosis and manage-ment are dictated by clinical presentation.

Hydroxocobalamin(vitamin $B_{12 a}$ ) scavenges cyanide on an equimolar basis to form nontoxic cyanocobalamin.Hydroxocobalamin has a rapid onset of action, is simple to use, and is adequate when given alone for cyanide poisoning.2 Administration of hydroxocobalamin leads to deep red coloration of plasma and urine, which may interfere with laboratory analyses and erroneously trigger hemodialysis“blood leak” detectors.2

Alternatively, sodium nitrite and sodium thiosulfate have also been used to treat cyanide poisoning. Sodium nitrite oxidizes hemoglobin to methemoglobin, which then binds cyanide to form cyanethemoglobin.34 Sodium thiosulfate acts as a substrate for cyanide metabolism,slowly forming minimally toxic thiocyanate.3

These recommendations inform the management of adults and children with life-threatening cyanide poison-ing, including cardiac arrest.

|Recommendations for Adults With Life-Threatening Cyanide Poisoning|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-LD|1. Hydroxocobalamin should be administered to adults with life-threatening cyanide poisoning.|| |1|C-LD|2. The combination of sodium nitrite and sodium thiosulfate should be administered to adults with life-threatening cyanide poisoning when hydroxocobalamin is unavailable.|| |2a|C-EO|3. In adults with concurrent carbon monoxide and cyanide poisoning(eg, from a house fire), administration of sodium thiosulfate alone is reasonable when hydroxocobalamin is unavailable.|| |2b|C-EO|4. In addition to administering hydroxocobalamin, it may be reasonable to administer sodium thiosulfate to adults with cyanide poisoning.||

Recommendation-Specific Supportive Text

1. Hydroxocobalamin(Table 4) has been demon-strated to improve the survival of patients with cya-nide poisoning. One prospective observational case

series included 69 adults with suspected cyanide poisoning from house fires who were treated with hydroxocobalamin.5 Fifty(72\%) of the patients sur-vived. Fifteen patients received hydroxocobalamin while in cardiac arrest, and only 2(13%) survived.5 In a case series of 13 adults and a 14-year-old patient with cyanide poisoning not associated with house fires, 10(71%) patients survived, including 7(78%) patients who were treated with hydroxo-cobalamin alone.6 The 4 fatalities in this study were all patients who were in cardiac arrest when they received hydroxocobalamin.6 Overall, mortality of adults in cardiac arrest from cyanide poisoning is high despite hydroxocobalamin administration,highlighting the severity of disease. Adverse effects of hydroxocobalamin include transient hyperten-sion, skin discoloration, rash, acute kidney injury,interference with colorimetric laboratory assays,and erroneously triggering of hemodialysis“blood leak" detectors.5-9

2. The combination of sodium nitrite and sodium thiosulfate was more protective against lethal-ity in a canine model than either sodium nitrite or sodium thiosulfate alone.10 Adult cases of life-threatening cyanide poisoning have dem-onstrated survival using the sodium nitrite and sodium thiosulfate combination(Table 4).11 To avoid excessive methemoglobin formation, the dosing of sodium nitrite in patients with anemia must be precise; the prescribing information lists specifications.12

3.Sodium nitrite can produce methemoglobinemia,reduces oxygen-carrying capacity, and may worsen cellular hypoxia in adults with concomitant car-bon monoxide poisoninging. ${}^{10}$ The sodium thiosulfate alone was protective against lethality in a canine model compared with controls. ${}^{10}$ A conflicting por-cine model found sodium thiosulfate alone did not reverse shock in pigs with cyanide poisoning.No human clinical trial exists to inform the use of sodium thiosulfate alone to treat cyanide poison-ing. Adults with life-threatening cyanide poisoning have survived after treatment with sodium thiosul-fate alone(Table 4).14,15

4.Survival after hydroxocobalamin with sodium thiosulfate to treat cyanide poisoning has been reported in adult cases(Table 4).16,17 There are no human trials comparing the use of hydroxoco-balamin alone versus in combination with sodium thiosulfate. One porcine study showed no differ-ence in mean arterial pressures or survival when sodium thiosulfate was administered in combina-tion with hydroxocobalamin versus hydroxocobala-min alone. ${}^{13}$

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Recommendations for Children With Life-Threatening Cyanide Poisoning

|COR|LOE|Recommendations| |---|---|---| |1|C-EO|1. Hydroxocobalamin should be administered to children with life-threatening cyanide poisoning.| |1|C-EO|2. The combination of sodium nitrite and sodium thiosulfate should be administered to children with life-threatening cyanide poisoning when hydroxocobalamin is unavailable.| |2a|C-EO|3. In children with concurrent carbon monoxide and cyanide toxicity (eg, from a house fire), administration of sodium thiosulfate alone is reasonable when hydroxocobalamin is unavailable.| |2b|C-EO|4. In addition to administering hydroxocobalamin, it may be reasonable to administer sodium thiosulfate to children with cyanide poisoning.|

Recommendation-Specific Supportive Text

1. Hydroxocobalamin(Table 4) has been demon-strated to improve the survival of patients with cya-nide poisoning. One prospective observational case series included 69 adults with suspected cyanide poisoning from house fires who were treated with hydroxocobalamin.5 Fifty(72%) of the patients sur-vived. Fifteen patients received hydroxocobalamin while in cardiac arrest, and only 2(13%) survived.5 In a case series of 13 adults and a 14-year-old patient with cyanide poisoning not associated with house fires, 10(10/14; 71%) patients survived,including 7(7/9; 78%) patients who were treated with hydroxocobalamin alone.6 The 4 fatalities in this review were all patients who were in cardiac arrest when they received hydroxocobalamin.6 Overall, mortality of patients in cardiac arrest from cyanide poisoning is high despite hydroxocobala-min administration, highlighting the severity of dis-ease. Adverse effects of hydroxocobalamin include transient hypertension, skin discoloration, rash,acute kidney injury, interference with colorimetric laboratory assays, and erroneously triggering of hemodialysis “blood leak” detectors.5-9,18 Limited pediatric data on the treatment of life-threatening cyanide poisoning with hydroxocobalamin were identified, thus, the recommendation for children is extrapolated primarily from the adult data.

2.The combination of sodium nitrite and sodium thio-sulfate was more protective against lethality in a canine model than either sodium nitrite or sodium thio-sulfate alone.10 Adult cases of life-threatening cyanide poisoning have demonstrated survival using the sodium nitrite and sodium thiosulfate combination.11 To avoid excessive methemoglobin formation, the dosing of sodium nitrite in children or in patients with anemia must be precise; the prescribing information lists specifications.12 No pediatric data on the treatment of life-threatening

<EndOfPara>cyanide poisoning with the combination sodium nitrite and sodium thiosulfate were identified, thus,the recommendation for children is extrapolated from the adult data(Table 4).

3.Sodium nitrite can produce methemoglobinemia,reduces oxygen-carrying capacity, and may worsen cellular hypoxia in adults with concomitant car-bon monoxide poisoning. ${}^{10}$ The sodium thiosulfate alone was protective against lethality in a canine model compared with controls. ${}^{10}$ A conflicting por-cine model found sodium thiosulfate alone did not reverse shock in pigs with cyanide poisoning. ${}^{13}$No human clinical trial exists to inform the use of sodium thiosulfate alone to treat cyanide poison-ing. Adults and children in cases of life-threatening cyanide poisoning have survived after treatment with sodium thiosulfate alone(Table 4).14,15

4.Survival after hydroxocobalamin with sodium thiosulfate to treat cyanide poisoning has been reported in adult cases. ${}^{16,17}$ There are no human tri-als comparing the use of hydroxocobalamin alone versus in combination with sodium thiosulfate. One porcine study showed no difference in mean arterial pressures or survival when sodium thiosulfate was administered in combination with hydroxocobala-min versus hydroxocobalamin alone. ${ }^{13}$ No pediatric data on the treatment of life-threatening cyanide poisoning with the combination of hydroxocobala-min with sodium thiosulfate were identified, thus,the recommendation for children is extrapolated from the adult data(Table 4).

REFERENCES

1. Baud FJ, Barriot P, Toffis V, Riou B, Vicaut E, Lecarpentier Y, Bourdon R, Astier A, Bismuth C. Elevated blood cyanide concentrations in vic-tims of smoke inhalation. N Engl J Med. 1991;325:1761-1766. doi:10.1056/NEJM.199112193252502

2.CYANOKIT®(hydroxocobalamin for injection) for intravenous infusion.2018. Updated December 31,2018. Accessed January 16,2025.https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022041s019,%2000000000000058.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88.88

3. Petrikovics I, Budai M, Kovacs K, Thompson DE. Past, present and future of cyanide antagonism research: from the early remedies to the current thera-pies. World J Methodol. 2015;5:88-100. doi: 10.5662/wjm.v5.i2.88

4.Way JL.Cyanide antagonism. Fundam Appl Toxicol. 1983;3:383-386.

5. Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospective study of hy-droxcobanolal for acute cyanide poisoning in smoke inhalation. Ann Emerg Med.2007;49:794-801,801.e1.doi:10.1016/j.annemerged.2007.01.026

6. Borron SW, Baud FJ, Megarbane B, Bismuth C. Hydroxocobolamin for se-vere acute cyanide poisoning is inhalation. Am J Emerg Med.2007;25:551-558. doi: 10.1016/j.ajem.2006.10.010

7. Depret F, Hoffmann C, Daoud L, Thieffry C, Monplaisir L, Creveaux J,Annane D, Parmentier E, Mathieu D, Wramus S, et al. Association between hydroxocobalamin administration and acute kidney injury after smoke in-halation: a multitercretospective study. Crit Care. 2019;23:421. doi:10.1186/s13054-019-2706-0

8. Evans J, Pandya A, Ding Y, Yunibi WY. Hydroxocobalamin-Induced Oxa-late Nephropathy in a Patient With Smoke Inhalation. Kidney Int Rep.2021;6:2228-2231. doi: 10.1016/j.ekir.2021.05.019

9.Fortin JL, Giocanti JP, Rutftin M, Kowalski JJ. Prehospital administration of hydroxocobalamin for smoke inhalation-associated cyanide poisoning:

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8 years of experience in the Paris Fire Brigade. Clin Toxicol(Phila).2006;44:37-44. doi:10.1080/1556365600811870

10. Chen KK, Rose CL. Nitrite and thiosulfate therapy in cya-nide poisoning.J Am Med Assoc.1952;149:113-119. doi:10.1001/j.1952.02930190015004

11. Chen KK, Rose CL. Treatment of acute cyanide poisoning, J Am Med Assoc.1956;162:1154-1156. doi:10.1001/jama.1956/0927090050012

12 NITHIOTE(Sodium nitrite injection and sodium thiosulfate injection for intravenous infusion).2021. Updated January 13,2021. Accessed January 16, 2025. https://www.accessdata.govd/stusafda-docs/label/2021/201444s0261lbl.pdf

13. Bebara VS, Ptotti RL, Dixon P, Linaret JR, Bush A, Tanen DA. Hydroxoco-balamin versus sodium systrophas for the treatment of acute cyanide toxic-ity in a swine(Sus scrofa) model. Ann Emerg Med.2012;59:532-539. doi:10.1016/j.annemergmed2012.01022

14. Elhar Aasi, Panligai L, Lee M. Collapse and coma. Hosp Pract(Off Ed).1990;25:16-17. doi:10.1080/21548331.1990.11703941

15. Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydrocobacalamin for the empiric treatment of cyanide poisoning? Ann Emerg Med. 2007;49:806-813. doi: 10.1016/j.annemergmed.2006.09.021

16. Hall AH, Rumach BH. Hydroxobcalamin/sodium thiosulfate as a cyanide anti-dote.J Emerg Med.1987;5:115-121. doi:10.1016/0736-4679(87)90074-6

17. Zakharov S, Vaneckova M, Seidl D, Ziblik P, Khan P Urban P, Urban Nartil T, Pelclova D. Successful Use of Hydroxocobalamin and Sodium Thiosulfate in Acute Cyanide Poisoning: A Case Report with Follow-up. Basic Clin Phar-macol 2015;117:2009-212.doi:10.1111/bcp12387

18. Friedbar MT, Chen BC, Latimer AJ, Valento MJ. NLatoric pediatric hy-droxocobcalamin overdose. Am J Emerg Med. 2019;37:1394 e1391-1394 e1392. doi:10.1016/j.ajem.2019.04.012

TOXICOLOGY: DIGOXIN AND RELATED CARDIAC GLYCOSIDES

|Recommendations for Adults and Children with Life-Threatening Poisoning From Digoxin and Related Cardiac Glycosides||| |---|---|---| |COR|LOE|Recommendations| |1|B-NR|1. Digoxin-specific antibody fragments(digoxin-Fab) should be administered for adults and children with life-threatening digoxin or digitoxin poisoning.| |2a|C-LD|2. It is reasonable to administer digoxin-Fab for adults and children with life-threatening poisoning due to Bufo toad and yellow oleander to toxins.| |2b|C-EO|3. It may be reasonable to administer digoxin-Fab to treat adults and children with life-threatening poisoning from cardiac glycosides other than digoxin, digoxin, Bufo tooad toxins, and yellow oleander to toxins.| |2b|C-EO|4. It may be reasonable to administer lidocaine or phenytoin to treat adults and children with ventricular arrhythmias caused by digoxin and related cardiac glycoside poisoning until digoxin- Fab can be administered.| |3: No Benefit|B-NR|5. The use of hemodialysis, hemofiltration, hemoperfusion, or plasmapheresis to treat adults and children with life-threatening poisoning from life-threatening poisoning from digoxin and related cardiac glycosides is not recommended.|

Synopsis

Cardiac glycoside poisoning can be caused by medica-tions such as digoxin and digitoxin, plants such as fox-glove and oleander, and certain toad venoms ingested as ethnopharmaceuticals or hallucinogens. Patients with cardiac glycoside poisoning may develop gastrointestinal

symptoms, confusion, hyperkalemia, and cardiac conduc-tion abnormalities, including atrioventricular nodal block,VT,VF, or asystole. Although cardiac glycosides include a range of structurally similar cardioactive steroids, most data involve digoxin poisoning.

Digoxin-specific immune antibody fragments(eg,digoxin-Fab) bind to and inactivate digoxin and struc-turally similar cardiac glycosides. Different dosing regi-mens are advocated worldwide.1-3 The ideal empirical dose for cardiac arrest is unknown and likely differs for digoxin poisoning compared with other cardiac glycosides.

Standard ALS Measures for bradycardia, such as atro-pine and electrical pacing, have variable effectiveness in cardiac glycoside poisoning. Prior recommendations addressing these interventions were removed since they are included as part of standard ALS measures.

These recommendations inform the management of adults and children with life-threatening poisoning from digoxin and related cardiac glycosides, including cardiac arrest.

Recommendation-Specific Supportive Text

1. A systematic review of digoxin poisoning in adults and children found observational studies show-ing resolution of life-threatening arrhythmias after digoxin-Fab administration(Table 4).2 Most studies report responses of 50% to 90%, with arrhyth-mia resolution in 30 to 45 minutes in most cases.2 Although there are no RCTs studying cardiac arrest from digoxin or digitoxin poisoning, excellent sur-vival(30/56[54%] patients) was reported in an observational study of adults and children in car-diac arrest treated with digoxin-Fab.4

2.An RCT among hemodynamically stable adults and children with yellow oleander(Thevetia peru-viana, also known as Cascabela thevetia) cardio-toxicity(bradyocardia or atrial tachyarrhythmias)showed significant resolution of arrhythmia with digoxin-Fab, as do many case reports and case series including adults and children(Table 4).5,6 A Cochrane review did not identify any trials in adults or children with severe yellow oleander toxicity.7 In vitro studies showed affinity between cardiac gly-cosides found in Bufo tooad toxin and digoxin-Fab,murine studies showed protection, and some pub-lished case reports of adults and children showed apparent response.8-14

3.Survival after the administration of digoxin-Fab for poisoning from cardiac glycosides other than digoxin, digitoxin, Bufo toad toxin, and yellow ole-ander are limited to case reports in adults only.5,15-21 No pediatric data on the use of digoxin-Fab to treat poisoning from cardiac glycosides other than digoxin, digitoxin, Bufo toad toxin, and yellow

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oleander were identified, thus, the recommenda-tion for children is extrapolated from the adult data(Table 4).

4.There are multiple case reports including adults and children describing the use of antisysrhythmic medications, including lidocaine and phenytoin, to treat ventricular arrhythmias caused by digoxin poion-soning, with various responses.22-24 No high-quality cohort studies or randomized trials have evaluated their effect.

5. A systematic review of adults and children receiv-ing extracoreporal treatment for digoxin poisoning found that digox is not well removed because of its large volume of distribution.25

REFERENCES

1. Chan BS, Isbister GK, Ciew A, Isoardi K, Buckley NA. Clinical ex-perience with titrating doses of digoxin antibodies in acute digox-in poisoning (ATOM-6). Clin Toxicol (Phila). 2022;60:433-439. doi:10.1080/1556366502.201.1968422

2. Chan BS, Buckley NA. Digoxin-specific antibody fragments in the treat-ment of digoxin toxicity. Clin Toxic (Polith). 2016;42:82-836: doi:10.3109/15563656.2010.4.943907

3. Roberts DM, Gallapathy G, Dunwunille A, Chan BS. Pharmacological treat-ment of cardiac glycoside poisoning. Br J Clin Pharmacol 2016;81:488-495. doi:10.1111/bcp.12814

4. Antman EM, Wenger TL, Butler VP Jr., Haber E, Smith TW. Treatment of 150 cases of life-threatening digital intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation.1990;81:1744-1752.0:1016/1/01ir.816.1744

5. Bandara v, Weinstein SA, White J, Eddington M. A review of the natural history,toxicology diagnosis and clinical management of Nierium oleander(common/derander) and Thevetliup varniva (yellow erander) poisoning.Toxicon.2010;56-273:281.10.1016/j.toxicon.2010.03.026

6.Eddleston M,Rajapakse S,Rajakanathan,Sayerlath S,Sjostrom L,Santharaj W,Thenabad PN, Sheriff MH, Warrell NA. Anti-digoxin Fab fragments in car-dictotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000;355:967-972. doi:10.1016/s0140-6736(00)90014-x

7. Roberts DM, Buckley NA. Antidones for acute cardenolide cardiac glyco-side) poisoning. Cochrane Database Syst Rev.2006;2006;CD005490. doi:10.1002/14651858|CD005490.pub2

8. Bagrov A, Roukoykatina NI, Fedorovova O, Finaev AG, Ukhanova MV. Digitalis-like and vasoconstrict effects of endogenous digoxin-like factor(s) from the venom of Huvarlo manus to Eur J Pharmacol 1993;234:165-172. doi:10.1016/0014-2999(993)90950-5

9.Bressman M, Repppler D, Slater W, Patt M. Electrophysiologic similarities of overdose between digonin and buladorides found in a Chinese aproph-diacid. JArthrym.2017;33:76-78. doi:10.1016/j.10jaa.2016.05.004

10. Brubacher JR, Lachmanen D, Ravikumar PR, Hoffman RS. Efficacy of digox-in specific Fab fragments(Digind) in the treatment of road venom poison-ing. Toxicon.1999;37:931-942. doi:10.1016/s0041-0101(98)00224-4

11. Brubacher JR, Ravikumar P, BRania T, Heller M, Hoffman RS. Treat-ment of to adenum poisoning with digoxin-specific Fab fragments. Chest 1996;110:1282-1288. doi:10.1378/chest.110.5.1282

12. Dasgupta A. Lopez E, Wells A, Olsen M, Actor J. The Fab fragment of anti-digoxin antibody(digibind) binds digitoxin-like immunoreac-tive components of Chinese medicine Chan Su monitoring the ef-fect by measuring free digitoxin. Clin Chim Acta.2001;309:91-95. doi:10.1016/s0009-8981(01)0049-591.

13. Dasgupta A, Szelei Stevens K. Nautralization of free digoxin-like immu-noreactive components of oriental medicines Dan Shen and Lu-Shen-Wan by the Fab fragment of antidigox antibody(Digibind). Am J Clin Pathol 2004;1217:261-281. doi:10.1309/93UF-4YEL-EMG9V-548

14.Trakulshri S, Chumvanchaya K, Sriapha C, Tongpoo A, Wananukul W.Tooad Poisoning: Clinical Characteristics and Outcomes. Ther Clin Risk Man-ag.2020;16:1235-1241. doi:10.21/1274/TCRM.S272863

15. Alarfaj M, Goswami A. Cardiotoxicity in yew berry poisoning. Am J Emerg Med.2021;50:812.e1-812.e4.doi:10.1016/j.ajem.2021.05.043

16. Bernshteyn M, Adams Sh; Gada K. A Case of Attempted Suicide by Cer-bera odollar Seed ingestion. Case Rep Crit Care.2020;2020:7367191. doi: 10.1155/2020/7367191

17. Combe C,Guitton J, Daude A, Le Bricton T, Guibert N, Bosset C, Girardot T,Multidisciplinary management of voluntary pink oleander poisoning: How to estimate the quantities ingested?. Ann Pharm Fr. 2022;80:76-80. doi:10.1016/j.pharma.2021.04.003

18. Maillaud C, Bargul Y, Mikulski M, Cheze M, Pivert C, Deveaux M, Lapostolle F. First successful curative use of digoxin-specific Fab antibody fragments in a life-threatening cocoon crab(Birgus latro L) poisoning. Toxicon.2012;60:1013-1017.doi: 10.1016/j.toxicon.2012.06.017

19. Rouault E,Ghnonia C,Filippi-Codaccioni E, Maillard N. Dose and efficacy of repeated administrations of digoxin-specific antibody fragments: Case report of foxgo violenceing. Basic Clin Pharmacol Toxicol. 2021;128:183-186. doi: 10.1111/bcpt.13473

20. Vermeth M, Vehra R, Bowman N, Furbee RB, Rusyniak DE, Cardiac Tox-icity from Intentional Ingestion of Pong-Pong Seeds(Cerbera Odollam). J Emerg Med.2018;55:507-511.doi:10.1016/j.jemmered.2018.05.021

21. Wu Ll, Yu JH, Lin CC, Seak CJ, Olson KR, Chen HY. Fatal cardiac glyco-side poisoning due to mistaking foxglove for comfrey. Clin Toxicol(Chila).2017;55:670-673. doi: 10.1080/15563650.2017.1317350

22. Batteggay M, Cottier C, Burckhardt D, Ritz R. [Acute digitoxin poisoning].Schweiz Rundsch Med Prax 1989;78:880-882.

23. Chi HT, Hung DZ, Hu WH, Yang DY. Prognostic implications of hyperka-lemia in toad toxin intoxivation. Hum Exp Toxicol. 1998;17:343-346. doi:10.1177/096032719801700610

24. Rumack B. BH, Rundell RR, Gilrich H. Phenytoin(diphenylhydantion) treat-ment of massive digoxin overdose. Br Heart J. 1974;36:405-408. doi: 10.1136/hrt36.4.405

25.Mowry JB, Burdmann EA, Anseeuw K, Ayoub P, Ghannoum M, Hoffman RS, Lavergne V, Nolin TD, Gosselin S; EXTRIP Workgroup. Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin Toxicol(Phila). 2016;54:103-114. doi:10.3109/15563650.2015.51118488

TOXICOLOGY: LOCAL ANESTHETICS

|Recommendations for Adults and Children With Life-Threatening Local Anesthetic Poisoning|||| |---|---|---|---| |COR|LOE|Recommendations|| |COR|1.CL|1. For adults and children with life-threatening local anesthetic poisoning, ILE should be administered.|| |1|C-LD|2.Benzodiazepines should be used to treat adults and children with seizures associated with local anesthetic systemic toxicity(LAST).|| |2a|C-EO|3. It is reasonable to administer sodium bicarbonate and children for life-threatening wide complex tachycardia associated with local anesthetic toxicity.|| |3a|C-EO|4. It is reasonable to use ECLS in adults and children is long anesthetic toxicity with refractory 2a||

Synopsis

Local anesthetics reversibly bind sodium channels to dis-rupt nerve transmission and block pain signals. Patients with local anesthetic poisoning present with a constellation of CNS and cardiovascular symptoms termed local anesthet-ic systemic toxicity(LAST). CNS toxicity includes agitation,confusion, obtunation, and seizures, whereas cardio-vascular symptoms include asystole, bradycardia, cardiac

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collapse, conduction delays, hypertension, hypotension,and ventricular arrhythmias ${}^{1-3}$ Cardiovascular and CNS toxicity can occur both in isolation and concomitantly. ${}^{3-5}$

Local anesthetics vary in toxicity depending on the potency associated with their lipophilic side chains. At equal doses(eg, mg/kg), bupivacaine is a more potent cardiotoxin than lidocaine and ropivacaine through its greater affinity and binding durations to cardiac sodium channels.67 However, at equipotent doses, all local anes-thetics can precipitate toxicity.2-4.8

Both hypoxia and acidemia are associated with increased toxicity from bupivacaine in animal models.9-11 As such,airway management and circulatory support are critical to resuscitation from LAST. Pharmacological interventions (eg,ILE, sodium bicarbonate) and mechanical support (eg,VA-ECMO) in addition to ACLS have been used for LAST.

Evidence-based dosing recommendations for ILE are lacking. The majority of animal studies and human expe-rience for the treatment of LAST use 20% ILE.9 Attempts to reproduce this dose using propofol (which contains 10 mg/mL propofol in 10% ILE) would be at 10 to 20 times the induction dose for general anesthesia and lead to serious CNS and cardiovascular adverse effects.

Local anesthetic poisoning can also produce methe-moglobinemia; treatment recommendations are provided in the Toxicology: Methemobineginia section.

These recommendations inform the management of adults and children with life-threatening local anesthetic poisoning, including cardiac arrest.

Recommendation-Specific Supportive Text

1.Early administration of 20% ILE(Table 4) in patients with LAST is supported by animal studies,case reports(including in children and pregnant women), and registry studies.1,4,9,12-19 In conjunction with prevention of hypoxia and acidemia through standard ALS measures, administration of ILE has been associated with successful resuscitation in these studies. The descriptive studies are subject to publication bias with only a few case reports where ILE failed to resuscitate patients with LAST associated with lidocaine, mepivacaine, and ropiva-caine.20-23 Three RCTs(n=40 volunteers) demon-strate a potential pharmacokinetic benefit of ILE for ropivacaine, levobupivacaine, bupivacaine, and lidocaine.These 3 studies found that coadministra-tion of ILE decreased the maximum plasma con-centration of ropivacaine, the concentration curve for lidocaine, and the context-sensitive half-life of bupivacaine.12,24,25 This is consistent with animal models of the same phenomenon.26,27

2.In the case of isolated CNS toxicity,LAST may prog-ress rapidly to cardiovascular toxicity. Seizures asso-ciated with LAST may worsen hypoxia and acidemia,increasing the risk of cardiotoxicity.11 Administration

of benzodiazepines can abort seizure-like activity and is commonly reported as part of a therapeutic regimen in adults and children.2,15,28

3.Sodium bicarbonate administration(Table 4) may overcome sodium channel blockade by local anes-thetics and correct acidemia. Evidence to support the use of sodium bicarbonate is limited to case reports in adults and children as part of a thera-peutic regimen.15,28 However, some case reports showed limited efficacy in adults already in cardiac arrest.29,30 There are multiple porcine RCTs demon-strating effective shortening of the QRS interval in bupivacaine and ropivacaine toxicity.31,32

4. Several case reports in adults and children describe successful use of mechanical circulatory sup-port, such as CPB or VA-ECMO, for patients with LAST and refractory cardiogenic shock.29,30,33-36 Unfortunately, lack of widespread availability of VA-ECMO limits use of these interventions.

REFERENCES

1.Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical pre-sentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009. Reg Anesth Pain Med. 2010;35:181-187. doi: 10.1097/aap.0b01381d31230b

2. Gitman M, Barrington M.J. Local Anesthetic Systemic Toxicity: A Review of Recent Case Reports and Registries. Reg Anesth Pain Med.2018;43:124-130. doi: 10.1097/AAP0000000000000721

3. Macfarlane AJR, Gitman M, Bornstein KJ, El-Boghadlyad K, Weinberg G. Up-dates in our understanding of local anaesthetic systemic toxicity: a narrative review. Anaesthesia.2021;76(Suppl 1):27-39. doi: 10.1111/anae.15282

4. Schweitzer-Chaput A, Calot D, Bouazza N, Lesage F, Oqualha M, Paret N,Boyer-Geroise M, Treluyer JM, Chouchana L. Local anesthetics systemic toxicity in children: analysis of the French pharmacovigilance database.BMC Pediatr. 2023:23:321. doi: 10.1186/s12887-023-0412-7

5.Singaravelu Ramesh A, Boretsky K. Local anesthetic systemic toxicity in children: a review of recent case reports and current literature. Reg Anesth Pain Med.2021;46:909-914. doi: 10.1136/rapm-2021-102529

6. Groban L, Deal DD, Vernon JC, James RL, Butterworth J. Cardiac resuscita-tion after incremental overdosage with lidocaine, bupivacaine, levobupiva-caine, and ropivacaine in anesthetized dogs. Anesth Anal. 992;32:37-43.doi:10.1097/00000539-200101000-00008

7. Knudsen K, Beckman Surukula M, Blomberg S, Sjovall J, Edvardsson N.Central nervous and cardiovascular effects of IV infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth. 1997;78:507-514.

8.Fuzier R, Lapeyre-Mestre M, Samii K, Montastruc JL; French Association of Regional Pharmacovigilance Centres. Adverse drug reactions to local an aesthetics: a review of the French pharmacovigilance database. Drug Saf.aesthetics: a review of 0.2165/00002018-200932040-00008

9. Gosselin S, Hoegberg LC, Hoffman RS, Graudins A, Stork CM,Thomas SH, Stellplfug SJ, Hayes BD, Levine M, Morris M, et al.Evidence-based recommendations on the use of intravenous lipid emul-sion therapy in poisoning. Clin Toxicol(Phila). 2016;54:899-923. doi:10.1080/15563650.2016.1214275

10.Heavner J,Edryen CF,Jr,Sanghani V,Huemer G,Bessire A,Badgwell JM.Severe hypoxia enhances central nervous system and cardiovascular toxic-ty of bupivacaine in lightly anesthetized pigs. Anesthesiology.1992;77:142-147. doi:10.1097/000000542-199207000-00020

11.Heinonen JA, Skrifvaris MB, Haasio J, Backman JT, Rosenberg PH, Litonius E. Intravenous lipid emulsion for levobupivacaine intoxication in acidotic and hypoxaemic pigs. Anaesthes Intensive Care. 2016;44:270-277. doi:10.1177/0310057X1604400214

12.Dureau R,Charbit B,Nicolas N,Benhamou D,Mazoit JX.Effect of Intralipid@on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers: A Clinical and Pharmacokinetic Study. Anesthesiology. 2016;125:474-483.doi:10.1097/ALN.00000000000000000000000

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13. Fettplace MR, McCade DJ. Lipid emulsion improves survival in animal models of local anestheticity to a meta-analysis. Clin Toxicol(Phila),2017;55:617-623. doi: 10.1080/15563650.2017.1288911

14. Fpetixture MP, Richurko AB, Heterogeneity and bias in animal models of lipid emulsion therapy: a systematic review and meta-analysis. Clin Toxicol(Phila),2021;59:11-11. doi: 10.1080/15563650.2020.1814316

18. Hoogberg LC, Tania, L退valve, Bailey A. Bailey N, Bergurov JA, Burgurov A, Thomas S,Morris M, Miller-Nesbit A, Mgarbagen, B Magder S, et al; on behalf of the Lipid Emulsion Workgroup. Systematic review of the effect of intrave-nous lipid emulsion therapy for local anesthetic toxicity, Clin Toxicol(Phila),2016;54:167-193. doi: 10.3109/15563650.2015.1121270

16. Jermoljevale J, Razelevi, Gursis V, Kirnevinide DE, Lukosene I,Macas A. Local Anesthetic Syntotic Toxicity Following Invertent Intrave-nous Levobupivacaine Infusion in Infants: A Case Report. Medicina(Kaunas).2023:5998:01. doi:30.3990/mediacena59050981

17. Davado P, Carvalho E, Almeida M, Taveira I, Padua F, A Myriad of Symptoms:After Spinal Anesthesia: A Case Report of Local Anesthetic Systemic Toxicity. U2urey. C2024;1990e2; doi:10.7039/cureus.29902

18. Tsuji M,Ni M,Furuta M,Baba S, Maenaka T,Matsunaga S,Tanaka H,Sakurai A; on behalf of the Japan Resuscitation Council (JRC) of the Guideline Edi Tonal Committee. Intravenous lipid emulation for local anaesthetic systemic toxicity in pregnant women: a scoping review. BMC Pregnancy Childirth.2024:138: doi:10.1186/318824-06306-19.

19. Weinberg GL. Treatment of local anesthetic systemic toxicity(LAST). Reg Ansth Pain Med. 2010;35:188-193. doi: 10.1097/AAPOb:01e381a318d246c3

20. Amiri MA, Mohammad F, Dezofoli SAT, Naderkhani M. Fatal Systemic To-icity with Topical Lidocaine Spray J. J Pharm Negat Results. 2022;13:611-613.

21. Aveline C, Cognet F, Bonnet F. Ineffectiveness of intralipid infusion for cen-tral nervous toxicity following ultrasound-guided sciatic nerve block with lidorac-ivopacine-ravitation: interaction between carbamasezapine, local anaesthetic and intralipid? Eur J Anaesthesiol. 2010;27:1070-1072. doi:10.1097/EJA:010b013e328331711

22. Calenda E, Dinescu SA. Failure of lipid emulsion to reverse neurotoxicity after an ultrasound-guided axillary block with ripovacine and mepivacine.J Anesth.2009;23:472-473. doi:10.1007/s00450-009-0755-2.

23. Cao D, Heard K, Foran M, Koyman A. Intravenous lipid emulsion in the emergency department: a systematic review of recent literature. J Emerg Med.2015;48:387-397. doi:10.1016/j.jemmeder.2014.10.009

24. Heinenon JA, Litonius E, Salmi, Thaia O, Jartkila P, Backman JT,Rosenberg PH. Intravenous lipid emulsion given to volunteers does not affect symptoms of lidocaride brain toxicity. Basic Clin Pharmacol Toxicol 2015;116:378-383. doi:10.1111/bcpct12321

25. Litonius, E. Tarkala R, Puonov RJ, Rosenberg PH. Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans. Anaesthesia.2012;67:600-605. doi:10.1111/j.1365-2044.2012.07056.x

6. Fettiplace MR,Lis R,Pirker R, Kowal P.,Chikurov A, Vietold D, Rubinstein I,Schwartz D,Akpa BS,Weinberg G. Multi-modal contributions to detoxifica-tion of acute pharmacotoxicity by a triglyceride micro-emission. J. Control Release.2015;198:62-70. doi:10.1016/j.jconrel.2014.11.018

27. Shi K, Xia Y, Wang Q, Wu Y, Dong X, Chen C, Tang W, Zhang Y, Luo M,Wang X,et al.The effect of lipid emulsion on pharmacokinetics and tissue distribution of bupivacaine in rats. Anesth Anal. 2013;116:804-809.doi:10.1213/ANE.013e318284132e

28. Mallampat SR, Liu PRLn RM. Covrams and ventricular tachyardia from bupivacine with epinephriser: successful resuscitation. Anesth Anal.1984;63:856-859.

29. Long WB. Rosenbum, S Grady IP. Successful resuscitation of bupivacaine-induced cardiac arrest using cardiopulmonary bypass. Anesth Anal. 1989:43-406. doi:10.1213/0000559-198909000-00026

30. Tsai MH, Tseng CK, Wong KC. Successful resuscitation of a bupivacaine-induced cardiac arrest using cardiopulmonary bypass and mitral valve replacement. J Cardiothorane Ashne: 1987:1454-456. doi:10.1016/s0888-6296(87)97090-6

31. Zaballos M, Callejo D, Sevilla R, Quintela O, Lopez-Menchaca R, Melone A,Rareva O, Adonan Baselga MJ, Alminal J. Comparative Effects of Sodium Bicarbonate and Intravenous Lipid Emulsions on Reversing Bupacivaine,Induced Electrophysiological Toxicity in a Porcine Experimental Model.Anesth Anal.2019;129:63-72. doi:10.1213/ANE.000000000003875

32. Zaballos M, Fernandez l, Melone A, Rodriguez L, Varela O, Garcia S, Quintela O,Vazquez E, Anadon MJ, Alendral J. Somic bicarbonate reverts elec-trophysiologic cardiotoxicity of ripovacine faster than lipid emulsions in porcine model. Basic Clin Pharmacol Toxicol. 2023;132:211-222. doi:10.1111/bct:13822

33. Bacon A, Silverton N, Kaitz M, Heath E, Bull DA, Harig J, Tonna JE. Local Anesthetic Systemic Toxicity Induced Cardiac Arrest After Topicalization for Transesophageal Echocardiography and Subsequent Treatment With Ex-tracorpocardium Dopplarumary Resuscitation. J Cardiothorac Vasc Anesth.2019;33:162-165. doi:10.1053/j.jvca.2018.01.044

34. Froehle M, Haas NA, Kircner G, Kececioglu D, Sandica E. ECMO for Car-diac rescue after Accidental Intravenous Mepivacaine Application. Case Rep Pediatr.2012;2012:491692.doi:10.1155/2012/491692

35. Samuels LE, Casanova-Ghosh E, Droogan C. Cardiogenic shock as-sociated with loco-regular anesthesia rescued with left ventricu-lar assist device implantation. J Cardiothorac Surg. 2010;5:126. doi:10.1186/1749-8090-5-126

36.Soltez EG, van Pelt F, Byrne JG. Emergent cardiopulmonary bypass for bupivacine cardiotoxicity. J Cardiothorac Vasc Anesth. 2003;17:357-358.doi:1016/5103/070(03)00062-4

TOXICOLOGY: METHEOLOBINEMIA

|Recommendations for Adults and Children With Life-Threatening Methemoglobinemia|||| |---|---|---|---| |COR|LOE|Recommendations for Aduities|| |COR|1-BNR|For adults and children with life-threatening methemoglobinemia, methylene blue should be administered.|| |2b|C-EO|2. Exchange transfusion may be reasonable as a treatment for adults and children with life- reattening methemoglobinemia that is not responsive to methylene blue.|| |2b|C-EO|3. Hyperbaric oxygen therapy may be reasonable as a treatment for adults and children with life- reattening methemoglobinemia that is not responsive to methylene blue.|| |2b|C-EO|3. Hyperbaric oxygen therapy may be reasonable as a treatment for adults and children with life-reattening methemoglobinemia that is not responsive to methylene blue.|| |2b|C-EO|4. For adults and children with life-threatening methemoglobinemia, it may be reasonable to administer ascorbic acid only when methylene blue is contraindicated or not available.|| |3: No Benefit|B-R|5. N-acetylcycysteine is not recommended as a treatment for adults with life-threatening methemoglobinemia.||

Synopsis

Acquired methemoglobinia occurs after exposure to an oxidant stress that oxidizes iron in the hemoglobin molecule from the ferrous $\left(Fe^{2+}\right)$ state to the ferric $\left(Fe^{3+}\right)$state.In the ferric state, hemoglobin no longer effectively binds and delivers oxygen to end organs. Common sourc-es of oxidant stress that can cause methemoglobinemia include nitrates, nitrites, and many pharmaceuticals(eg,benzocaine, dapsone, phenazopyridine).1-9 Patients with methemoglobinemia can appear cyanotic and dusky and complain of shortness of breath and fatigue. Frequently,a difference is observed between the oxygen saturation measured by pulse oximetry versus arterial blood gas.Although moderate methemoglobinemia is generally well-tolerated, severe methemoglobinemia can lead to cardiovascular collapse and death.5,6,9

The most widely accepted treatment for methemoglo-binemia is methylened blue, which acts as a cofactor to reduce methemoglobin to hemoglobin.10 Other treatment modalities that have been described include exchange transfusion, hyperbaric oxygen therapy, and ascorbic

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acid.No studies have examined the treatment of methe-moglobinemia in the context of cardiac arrest.

These recommendations inform the management of adults and children with life-threatening methemoglobin-emia, including cardiac arrest.

Recommendation-Specific Supportive Text

1.No randomized trial has evaluated methylene blue for the treatment for methemoglobinemia; however,observational studies and published case reports in adults and children consistently demonstrate that methylene blue effectively reverses methe-moglobinemia(Table 4).1-47,11-13 Methylene blue may not improve methemoglobinemia and may lead to hemolysis in patients who have glucose-6-phosphate dehydrogenase deficiency, which is present in about 2% of the US population.13-17

2.Exchange transfusion has been used success-fully in case reports and case series in adults and children to treat methomoglobinemia and may be appropriate in patients for whom methylene blue is ineffective.18-24

3. Hyperbaric oxygen therapy has been used as monotherapy and in conjunction with other thera-pies in adults. Reduction of methemoglobinemia concentrations, however, can be delayed up to several hours.25-27 Not all health care facilities will have hyperbaric oxygen therapy available, and its use may be impractical in the setting of cardio-pulmonary collapse or cardiac arrest. There are no published pediatric cases of the use of hyper-baric oxygen therapy for methemoglobinemia.Recommendations for children are extrapolated from adult case reports.

4.Ascorbic acid, or vitamin C, has been used to treat methemoglobinemia.23,28-32 Most published case reports in adults and children demonstrate its use in conjunction with other treatment modalities or as an alternative when methylene blue is contrain-dicated or unavailable. The clinical effect of ascor-bic acid, however, is slow, often requires multiple doses over several hours, and might require higher doses to achieve similar reductions on methemo-globin.5,28-30,32-34 It is, therefore, unlikely to have benefit when used alone in resuscitation situations.

5.N-acetylcyteine did not reduce sodium nitrite-induced methemoglobinemia in a double-blind crossover adult volunteer study.35 No pediatric data on the use of N-acetylcyteine were identified.

REFERENCES

1.Curtis LA, Dolan TS, Seibert HE. Are one or two dangerous? Lidocaine and topical anesthetic exposures in children. J Emerg Med. 2009;37:32-39. doi:10.1016/jjeremmed.2007.11.005

2.Edwards RJ,Ujma J. Ethreme methaemoglobinaemia secondary to rec-reational use of any nitrite. J Accid Emerg Med. 1995;12:138-142. doi:10.1136/emj.122.138

3. Ferguson AJ, Lavery GG. Deliberate self-poisoning with dapsone. A case report and summary of relevant pharmacology and treatment. Anaesthesia.1997;52:359-363. doi:10.1111/j.1365-2044.1997.98-az0094b.x

4. Finan A, Keenan P, Donovan FO, Mayne P, Murphy J. Methaemoglobinae-mia associated with sodium nitrite in three siblings. BMJ. 1998;317:1138-1139. doi:10.1136/bmj.317:1766.1138

5.Gupta A,Jain A, Ngrawal A, Khanna A, Gutch M. A fatal case of severe methaemoglobulinia due to nitrobenzene poisoning. Emerg Med J.2012;29:70-71.doi:10.1136/emj.07.2011.4431rep

6. Harvey M, Cave G, Chanwai G. Fatal methaemobliinaemia induced by self-poisoning with sodium nitrite. Emerg Med Australas.2010;22:463-465.doi:10.1111/j.1742-6723.2010.01335.x

7. Huang A, Terry W, Guido F, Torres JC, Lipsman J, Derobertis N, Cola C,Didio V, Vincent C, Long H, et al. Methemoglobulinemia following uninten-tonal ingestion of sodium nitrite--New. MMWR Morb Mortal Wky Rep.2002;51:639-642.

8. Kreutz RW, Kinni ME. Life-threatening toxic methemoglobinemia induced by prilocaine. Oral Surg Oral Med Oral Pathol. 1983;56:480-482. doi:10.1016/0030-4220(83)90092-0

9. Margulies DR, Manokian CM. Methemoglobinemia as a cause of respiratory fail-ure.J.Trauma.2002;52:796-797. doi:10.1097/00005373-200204000-00037

10.Clifton J 2nd,Leibin J.B.Methylene blue.Am J Ther.2003;10:289-291.doi:10.1097/00045391-200307000-00009

11. Herman MI, Chyka PA, Butler AY, Rieger SE. Methylene blue by intraosse-ous infusion for methemoglobinemia. Ann Emerg Med. 1999;33:111-113.doi:10.1016/s0196-0644(99)70427-0

12. Mun SH, Park GJ, Lee JH, Kim YM, Chai HS, Kim SC. Two cas-es of fatal methemoglobinemia caused by self-poisoning with so-dium nitrite: A case report. Medicine (Baltim). 2022;101:e28810. doi: 10.1097/MD.0000000000028810

13. Rothenberg R, Biary R, Hoffman RS. Effectiveness and tolerability of me-thythonium chloride(methylene blue) for the treatment of methemo-globinia: twenty-four years of experience at a single poison center. Clin Toxicol.2025;63:284-291. doi:10.1080/15563650.2025.2470428

14.Chinevere TD, Murray CK, Grant E Jr., Johnson GA, Duelm F, Hospenthal DR. Prevalence of glucose-6-phosphate dehydrogenase deficiency in U.S. Army personnel. Mil Med. 2006;171:905-907. doi:10.7205/milmed.171.9.905

15.Karadshhe NS, Shaker Q, Ratroat B. Metoclopramide-induced methemo-globinia in a patient with co-existing deficiency of glucose-6-phosphate dehydrogenase and NAD-hytochrome b55 reductase: failure of methylene blue treatment. Haematologica 2001;86:659-660.

16.McDonagh EM, Bautista JM, Youngster I, Altman RB, Klein TE. Phar-mGKB summary: methylene blue pathway. Pharmacogenet Genomics.2013;23:498-508. doi: 10.1097/FPC.0b013e32836498f4

17. Mullick P, Kumar A, Dayal M, Babbar S, Kumar A. Aniline-induced me-haetombinaebinia in a glucose-6-phosphate dehydrogenase en-zyme deficient patient. Anaesth Intensive Care.2007;35:286-288. doi:10.1177/0310057X0703500222

18.Bhat P, Sisler I, Collier AB 3rd. Exchange transfusion as treatment for rasbirase induced methoglobinemia in a glucose-6-phosphate de-hydrogenase deficient patient. Pediatr Blood Cancer. 2008;51:568. doi:10.1002/pbc.21582

19. Golden PJ,Weinstein R.Treatment of high-risk,refractory acquired methemo-globinemia with automated redblood cellexchange.J ClinApher.1998;13:28-31. doi: 10.1002/(sci)1098-1101(1998)13:1<28::aid-jca6>3.0.co;2-b

20.Lien YH,Lin YC,Chen R.J.A case report of acquired methemoglobinemia rescued by veno-venous extracorporeal membrane oxygenation. Medicine(Baltim).2021;100:e25522. doi: 10.1097/MD.0000000000025522

21.Perera M, Shihana F, Kularathne K, Dissanayake D, Dawson A. Acute methaemlobiinaemia after massive nitrobenzene ingestion. BMJ Case Reports.2009;2009:bcr0720080515-bcr0720080515 doi:10.1136/bcr:07.2008.0515

22.Prus-Czarnecka Z, Fuenay Al, Noga T, Lau VI. Methaemalbumin: a diag-nostic surrogate for methaemoglobinaemia and treatment with red cell ex-change in a patient with thalassemaia. BMJ Case Rep.2023;16:e252885 doi:10.1136/bcr-2022-252855

23.Shihana F, Dawson R, Dobbins T, Dissanayake D, Buckley NA A beside test for methaemoglobinemia improved antidote use in propanil poisoning. Clin Toxicol(Phila). 2016;54:576-580. doi:10.1080/15563650.2016.1177651

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24. Singh P, Rakesh K, Agarwal R, Tripathi PP, Dhooria S, Sehgal IS, Prasad KT,Hans R, Sharma R, Sharma N, et al. Therapeutic whole blood exchange in the management of methaemoglobimonia: Case series and systematic review of literature. Transis Med 2020;303:231-239. doi: 10.1111/tm.12666

25. Altintlop I, Sanri E, Tatti M, Alkin E, Mezenbiz A. Methemoglobinemia treated with hyperbaric oxygen therapy: A case report. Turk J Emerg Med 2018;18:176-178.doi: 10.1016/j.jtem.2018.03/00305

26. Cho Y, Park SW, Han SK, Kim HB, Yeom SR. A Case of Methemobulinemia Successfully Treated with Hyperbaric Oxygenation Monotherapy. J Emerg Med.2017;53:685-687. doi:10.1016/j.emjendered.2017040.336

27. Lindrenmann J, Matzi V, Kaufmann P, Krisper P, Maier A, Porubsky C,Smolle-Juetner FM. Hyperbolic oxygenation in the treatment of life-threatening isobutyl nitrite-induced `jemethomobvina-a-case report`.Inhal Toxicol.2006;18:1047-1049. doi:10.1080/08958370600904629

28. Hamza A. Nasrulah A, Singh R. Difsiv D. Behnyaopluridine-Inde:haemobtinaemia The Aftermolds of Waters Treatment Eur J Case Rep Intern Med.2022:9:003191. doi:10.12890/2022_003191

29. Karacoban G, Gurbavan A, Ozen H, Gun E, Fathin Cakskii H, Kendritl T.Success451 Metarsov Acidic acid in a case of Methemoglobinemia.Dus Due to Glucose-6-Phosphate Dehydrogenase Deficiency. Turk Arch Pediatr.2024;59:112-113. doi: 10.152/1015/TurkArchPediatr.2024.23112

30. Keats KR, Robinson R, Patel M, Wallace A, Albrecht S. Ascorbic Acid for Methemobginaemia Treatment: A Case Report and Literature Review. J Pharm Pract. 2024;37:1015-1020. doi: 10.1177/089719002311188834

31. Rehman A, Shehadeh M, Khirfan D, Jones A, Severe acute haemo-lytic anemia associated with severe methemobiaxinemia in a G6PD-deficient man. BMJ Case Rep. 2018;2018:bcr2017223369. doi: 10.1136/bcr-2017-223369

32. Rino PB, Scolink D, Fustinana A, Mitelpunkt A, Glastriak M. Ascor-bic acid for the treatment of methemoglobinemia: the experience of a large tertiary care pediatric hospital. Am J Ther. 2014;21:240-243: doi:10.1097/MJT.200000000000028

33. Park EJ, Lee M, Min YG. Successful treatment of NO-induced methemo-globinemia with low-dose vitamin C. Clin Toxic Cholph(4).2017;55:686. doi: 10.1080/15563650.2017.1315126

34. Park SY, Lee KW, Kang TS. High-dose vitamin C management in dapsone induced methemoglobinemia. Am J Emerg Med 2014;32:684 e681-684 e683. doi: 10.1016/j.ajem.2013.11.036

35. Tanen DA, LoVecchio F, Curry SC. Failure of intravenous N-acetylcysteine to reduce methemoglobin produced by sodium nitrite in human volunteers:A randomized controlled trial. Ann Emerg Med.2000;35:369-373. doi: 10.1016/s0196-0644(00)70056-4

TOXICOLOGY: OPIOID OVERDOSE

Introduction

Opioid poisoning continues in the United States and other countries at epidemic levels.1 Most opioid overdose deaths are unintentional, which underscores the need to develop and implement evidence-based interventions for primary prevention, emergency treatment, and re-covery support for people with substance use disorder.Response to life-threatening opioid overdose is a critical resuscitation skill.

In formulating these recommendations, the writing group reviewed prior AHA publications about opioid over-dose resuscitation and a 2024 ILCOR systematic review and performed a structured literature review through November 2024.2-9 We acknowledge the contributions of the authors of prior AHA opioid overdose recommen-dations, members of the 2025 Adult Basic Life Support Writing Group, and Dr. Matthew Neth for their contribu-tions to the Toxicology: Opioid Overdose section.2-4,6-9

Recommendations about training of the lay rescuers for opioid overdose recognition and response are pro-vided in“Part 12: Resuscitation Education Science.” The

treatment of opioid-induced respiratory depression in newborn infants is outside the scope of these guidelines.

|Recommendations for Adults and Children With Life-Threatening Opioid Overdose|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|B-NR|1. For trained rescuers assisting an adult or child with suspected opioid overdose who has respiratory de- pression or respiratory arrest and has a definite pulse, breaths or bag-mask ventilation should be provided.|| |2|B-NR|1. For lay rescuers assisting an adult or child with suspected opioid overdose who is unresponsive and not breathing normally, CPR with breaths should be provided.|| |3|For trained rescuers assisting an adult or child with suspected opioid overdose in respiratory ar- rest with a definite pulse, an opioid antagonist(eg, naloxone) should be administered.||| |4|Lay and trained rescuers should not delay per- forming standard resuscitation or activating the emergency response system while administering emergency response system while administering opioid antagonist(eg, naloxone) or awaiting the person's response to an opioid antagonist.||| |5|For lay and trained rescuers, opioid antagonist administration may be reasonable for adults in cardiac arrest with suspected opioid overdose, provided that opioid antagonist(eg, naloxone) suppression-ventilation CPR.||| |2b|B-NR|6. For lay and trained rescuers, opioid antagonist administration may be reasonable for children in cardiac arrest with suspected opioid overdose, provided that opioid antagonist(eg, naloxone) suppression-ventilation CPR.|| |5|2b|6. For lay and trained rescuers, opioid antagonist administration may be reasonable for children in cardiac arrest with suspected opioid overdose, provided that opioid antagonist(eg, naloxone) suppression-ventilation CPR.||

Synopsis

Opioid overdose causes CNS and respiratory depression,progressing to respiratory arrest and ultimately cardiac arrest.4 Most opioid deaths involve additional substances that contribute to respiratory respiratory depression.10-15 Differenti-ating opioid overdose from other causes of cardiac and respiratory arrest can be difficult without an accurate his-tory, which is often unavailable.16 The mainstay of care remains early recognition, activation of the emergency response system,provision of breaths or ventilations, and the administration of opioid antagonists for adults and children in respiratory arrest(Figures 7 and 8).

Opioid antagonists can restore spontaneous respira-tions and protective airway reflexes in adults and children with respiratory depression or respiratory arrest from opi-oid overdose. For adults with cardiac arrest from opioid overdose, observational studies of naloxone administra-tion have mixed results.

Two opioid antagonists, naloxone and nalmefene, are currently available for reversal in the United States.17 Both are high potency antagonists of the mu-opi-oid receptor.Naloxone is currently available for purchase with or with-out a prescription in the United States and Canada.18,19

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 Figure 7. Adult Basic Life Support Lay Rescuer Infographic.

Intranasal nalmefene is available by prescription only.20 To date, the published clinical data are more robust for naloxone than nalmefene.

These recommendations inform the management of adults and children with life-threatening opioid poison-ing, including respiratory depression, respiratory arrest,and cardiac arrest.

Recommendation-Specific Supportive Text

1,2, and 4. Initial management of opioid overdose should focus on support of the person's air-way and breathing, as described in“Part 6: Pediatric BLS” and“Part 7: Adult BLS.”Respiratory depression and respiratory arrest can be treated by opening the airway and providing breaths or ventilations, which may be all that is needed to prevent deterioration to cardiac arrest. CPR is indicated for any adult or child in known or suspected cardiac arrest, including in trained rescuer situations in which a definite pulse is not felt and in lay rescuer situations in which a pulse check is not performed. Opioid antagonists may

require several minutes and repeated doses to reverse respiratory arrest, particularly when administered by the intranasal or IM route.21-23 Nonopioid sedatives commonly contribute to respiratory depression and are typically not reversed by opioid antagonists.Opioid antago-nists are extremely unlikely to benefit an adult or child in cardiac arrest who is not receiving CPR and do not reverse VF.For these reasons,standard BLS or ALS resuscitation should be provided immediately and continued until the adult or child is awake and breathing normally Initiating compression-ventilation CPR before opioid antagonist administration differs from that of the prescribing information for nalox-one or nalmefene.19,20 The rationale to initi-ate standard resuscitation first and continue until the adult or child is breathing normally is articulated in this chapter and in prior AHA publications.3

3.Opioid antagonists restore protective airway reflexes and reverse respiratory arrest from opioid overdose in adults and children.More than 30 observational studies report return

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of alertness and resolution of respiratory depression in adults and children with opi-oid overdose when opioid antagonists are administered(for dosing, see Table 4).22-56 No studies compared opioid antagonist administration to standard resuscitation or ventilatory support alone. Major complica-tions are rare and dose related.

5 and 6. No clinical trials have evaluated the role of opioid antagonists in adults or children with cardiac arrest. The results of animal studies and adult observational studies of naloxone administration in undifferentiated cardiac arrest or cardiac arrest with suspected opioid overdose are conflicting and highly suscep-tible to confounding by indication.57-64 As a result, the overall certainty of the evidence surrounding a potential role for opioid antago-nist administration for adults in cardiac arrest is very low.5 However, no human study has clearly demonstrated harm from naloxone administration in cardiac arrest. Pediatric data are sparse, and recommendations for children are extrapolated from adult studies. Identifying opioid overdose as the underlying cause of cardiac arrest may not always be obvious to the rescuer. Furthermore, resuscitation emer-gencies are task-saturated events. It is impor-tant that interventions with proven benefit,such as high-quality compression-ventilation CPR, be prioritized over interventions such as opioid antagonists, which do not have established benefit for adults and children in cardiac arrest and are unlikely to work in the absence of cardiac output5 For dosing infor-mation in adults and children, refer to Table 4.

|Recommendations for Adults and Children With Opioid Overdose Following Successful Response to Opioid Antagonists|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-LD|1. Adults with opioid overdose who respond to opioid antagonists(eg, naloxone) should be observed in a health care setting until a low risk of recurrent respiratory depression, normal level of consciousness, and normal vital signs are achieved.|| |1|C-EO|2. Children with opioid overdose who respond to opioid antagonists(eg, naloxone) should be observed in a health care setting until a low risk of recurrent respiratory depression, normal level of consciousness, and normal vital signs are achieved.|| |2a|C-LD|3. Repeated doses of opioid antagonists(eg, naloxone) can be beneficial in adults with opioid overdose who respond to opioid antagonists and develop recurrent respiratory depression.|| |2a|C-EO|4. Repeated doses of opioid antagonists(eg, naloxone) can be beneficial in children with opioid overdose who respond to opioid antagonists and develop recurrent respiratory depression.||

Synopsis

People with opioid overdose who respond to opioid an-tagonist therapy may develop recurrent respiratory de-pression if the duration of action of the opioid exceeds the duration of the antagonist.

Recommendation-Specific Supportive Text

1-4. Adults and children with respiratory depression or respiratory arrest who respond to an opioid antagonist may develop recurrent CNS and respi-ratory depression.In 1 study, recurrent respiratory depression occurred in 72% of patients treated with titrated low doses of IV naloxone.65 The ideal duration of observation is unknown and likely dif-fers based on the substance involved, which may be unknown; the dose and route of opioid antag-onist administration; and whether the patient received naloxone or nalmefene. Although abbre-viated observation periods may be adequate for adults with fentanyl, morphine, or heroin over-dose, a period of observation may be required to safely discharge an adult with a life-threatening overdose of a long-acting or sustained-release opioid.26,49,53,66-74 Treatment options for recurrent respiratory depression include repeat doses of an opioid antagonist or an IV infusion of nalox-one(Table 4).49,67,69,74,75 No studies were identified to inform the minimum safe observation period for a child treated with opioid antagonists or the efficacy of opioid antagonists for recurrent respi-ratory depression in children, thus, recommenda-tions are extrapolated from adult data.

|Recommendations for Opioid Antagonist Education and Distribution Following Treatment for Opioid Overdose|||| |---|---|---|---| |COR|LOE|Recommendation|| |1|C-LD|1. Adults who are treated for opioid overdose receive an opioid antagonist(eg, naloxone) and teaching at the time of discharge from a health care setting.|| |1|C-EO|2. Children who are treated for opioid overdose, or their caregivers as appropriate, should receive an opioid antagonist(eg, naloxone) and teaching at the time of discharge from a health care setting.||

Synopsis

People who survive an opioid overdose are at increased risk of a subsequent overdose. Secondary and tertiary pre-vention strategies include screening, brief intervention, and referral to treatment(SBIRT); providing or prescribing opi-oid antagonists such as“take-home naloxone” programs;and prescribing medications for opioid use disorder.76 These recommendations specifically relate to provision or prescribing of naloxone to opioid overdose survivors at the time of discharge from the emergency department

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 Figure 8. Adult* Basic Life Support for Health Care Professionals Algorithm.

*If signs of puberty,treat as adult. AED indicates automated external defibrillator; ALS,advanced life support; and CPR, cardiopulmonary resuscitation.

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or hospital. A 2024 scoping review summarizes 12 stud-ies of programs that distribute("take-home naloxone")or prescribe opioid antagonists to patients at the time of discharge from the emergency department or hospital fol-lowing treatment for opioid overdose." Although the pro-grams contained many different components, naloxone distribution was widely accepted by adults and children in these studies. Naloxone kits were used more than 90000 times over a 4-year period to reverse opioid overdoses in British Columbia.78 In a US emergency medical ser-vices-based study, 24 000 adults and children received layperson-administered naloxone over a 2-year period.79 Observational studies show that community-based nalox-one distribution programs are associated with lower opioid overdose death rates and are cost-effective.80,81

Recommendation-Specific Supportive Text

1 and 2. Adults and children who survive opioid over-dose are at high risk of subsequent fatal over-dose.82-85 The highest risk period is the first several days after the initial overdose, and the risk of overdose mortality remains high for at least a year. A 2016 systematic review found that take-home solxone programs align with the Bradford Hill viewpoint for causality between exposure(opioid antagonist distribu-tion) and outcome(reduced opioid overdose mortality).86 In those studies that reported the age of participants, the majority of participants were adults. Pediatric recommendations are,therefore, extrapolated from adult data.

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77. Sindhwani MK,Friedman A,O'Donnell M,Stader D,Weiner SG.Naloxone distribution programs in the emergency department: A scoping review of the literature. J Am Coll Emerg Physicians Open.2024;5e13180. doi:10.1002/emp2.13180

78. Lei F,Verguson M, Geiger R, Williams S, Liu L, Workton JA. Factors associ-ated with take-home naloxone kit usage in British Columbia: an analysis of administrative data. Subt abuse Treat Prev Policy. 2022;17:25. doi:10.1186/13011-022-00452-4

79.Gage CB, Powell JR, Ulintz A, Cash RE, Lyons MS, Wang H, Panchal AR.Layperson-Admisterated Naolaxone Trends Reported in Emergency Medical Service Activations,2020-2022.JAMA Netw Open.2024;7:e2439427.2011.1001/jamanetworkopen.2024.39427

80. Cherrier N,Kearon J,Tetrault R,Garasia S,Ginduon E.Community Distri-bution of Naloxone: A Systematic Review of Economic Evaluations. Pharma-coEcon Open.2022;6:329-342.doi:10.1007/s41669-021-00309-z

81. Naumann RB, Durance CP, Ranapurwala SI, Austin AE, Proescholdbell S,ChidRs R, Marshall SW, Kanasgra S, Shanahan ME. Impact of a community-based naloxone distribution program on opioid overdose death rates.Drug Al-cohol Depend. 2019;204:107536.doi: 10.1016/j.drugalcdep.2019.06.038

82. Ashburn NP, Ryder CW, Angi RM, Snavely AC, Nelson RD, Bozeman WP, McGinnis HD, Winslow JT, Stopyra JP. One-Year Mortality and As-sociated Factors in Patients Receiving Out-of-Hospital Naloxone for Presumed Opioid Overdose. Ann Emerg Med. 2020;75:559-567. doi:10.1016/j.annemergmed.2019.11.022

83. Eide D, Gjersing L, Darielsen AW, Schulberg AK, Dale O, Braarud AC,Yeherdah F, Tylleskar l. Heightened mortality risk after a non-fatal opioid overdose: Risk factors for mortality in the week following emergency treat-ment. Addition.2024;119:2131-2138. doi:10.1111/add.16632

84. Hood JE, Aleshin-Guendel S, Poel A, Liu J, Collins HN, Sadinle M,Avoundian T, Sayre MR, Rea TD. Overdose and mortality risk following a non-fatal opioid overdose treated by Emergency Medical Services in King County, Washington. Drug Alcohol Depend. 2023;253:111009. doi:10.1016/j.drugcadep.2023.111009

85. Weiner SG, Baker O, Bernson D, Schuur JD. One-Year Mortal-ity of Patients After Emergency Department Treatment for Non-fatal Opioid Overdose. Ann Emerg Med.2020;75:13-17. doi:10.1016/j.annemergmed.2019.04.020

86. McDonald R, Strang J. Are take-home naloxone programmes effective?Systematic review utilizing application of the Bradford Hill criteria. Addiction.2016;11:1117-1187.doi:10.1111/add.13326

TOXICOLOGY: ORGANOPHOSPHATES AND CARBAMATES

|Recommendations for Adults and Children With Life-Threatening Organophosphate or Carbamate Poisoning|| |---|---| |COR|LOE| |A|Recommandations| |1|A| |2|Early endotracheal intubation is recommended for adults with life-threatening organophosphate or carbamate poisoning.| |3|Early endotracheal intubation is recommended for adults with life-threatening organophosphate or carbamate poisoning.| |4|3. Early endotracheal intubation is recommended for children with life-threatening organophosphate or carbamate poisoning.| |5|3. Early endotracheal intubation is recommended for children with life-threatening organophosphate or carbamate poisoning.| |6|4. Benoziazepines should be administered to treat seizures and agitation for adults and children with life-threatening organophosphate or carbamate poisoning.| |7|4. Benoziazepines should be administered to treat seizures and agitation for adults and children with life-threatening organophosphate or carbamate poisoning.| |8|9. Use of neuromuscular blockers metabolized or clinesterase(eg, succinylcholine and mivacurium) is not recommended for adults and children with life-threatening organophosphate or carbamate poisoning.| |1|6. Dermal decontamination for external organophosphate or carbamate exposure is recommended for adults and children with life-reattening organophosphate or carbamate exposure is recommended for adults and children with life-attening organophosphate or carbamate exposure.| |1|7. For adults with life-threatening organophosphate or carbamate exposure.| |2a|A| |2a|B-R| |3: No Benefit|8. Use of neuromuscular blockers metabolized or clinesterase(eg, succinylcholine and mivacurium) is not recommended for adults and children with life-threatening organophosphate or carbamate poisoning.|

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Synopsis

Organophosphates and carbamates-found in pesticides,neveg agents, and some medications-inhibit acetylcho-linesterase, resulting in muscarinic and nicotinic toxic-ity.They produce parasympathetic excess (bradycardia,bronchorhea, bronchospasm, diaphoresis, diarrhea,hypersalivation, lacrimation, miosis, unination, vomiting),nicotinic excess (mydriasis, tachycardia, muscle fascicu-lations progressing to depolarizing neuromuscular block-ade and paralysis), and CNS effects (altered mental status, central apnea, seizures).

Early and effective treatment may prevent dete-rioration to respiratory and cardiac arrest. Treatments include decontamination,atropine,benzodiazepines,and oximes.1

Atropine blocks parasympathetic overstimulation,mitigating bronchorhea, bradycardia, bronchospasm,and CNS effects. Atropine does not block acetylcholine excess at the neuromuscular junction or nicotinic ganglia and, therefore, does not reverse paralysis. When admin-istered early, oximes reactivate the acetylcholinesterase enzyme, reversing nicotinic effects to slowly improve respiratory and skeletal muscle strength, although this effect may be organophosphate specific.2-5 Hemoperfu-sion or adsorption for organophosphate poisoning has been evaluated but is not available in North America.6

The evidence for the treatment of cholinesterase poisoning primarily involves adults and children with organophosphate poisoning. The basis for the treatment of patients with life-threatening carbamate poisoning is extrapolated from the limited evidence for carbamate poisoning and indirectly from evidence for organophos-phate poisoning.

These recommendations inform the management of adults and children with life-threatening organophos-phate or carbamate poisoning, including cardiac arrest.

Recommendation-Specific Supportive Text

1. For adults and children with life-threatening organophosphate or carbamate poisoning including cardiac arrest, bradycardia, hypoten-sion, bronchorrhea, or bronchospasm, early atropine administration improved survival in 1 clinical trial.7 Much larger doses of atropine are often required for this indication than for typical bradycardia(Table 4). The initial dose is doubled every 5 minutes until full atropinization is achieved (clear chest on auscultation; heart rate >80/min; systolic blood pressure >80 mm Hg). Maintenance of atropinization can be achieved by an atropine infusion (Table 4).7

2 and 3. Observational data, mostly in adults, show that patients who are intubated early in the course of organophosphate or carbamate poisoning have

shorter durations of intubation than those who are intubated later in their course.8.9 Whether this is due to prevention of aspiration pneumo-nia, differences in pathophysiology of respira-tory failure, or some other cause is not known.Minimal pediatric data on airway management with organophosphate or carbamate poisoning were identified; thus, the recommendation for children is extrapolated from adult data.

4. Benzodiazepines, such as diazepam(first line) or midazolam, have demonstrated efficacy for treating organophosphate or carbamate-induced seizures and agitation in adults and children, and they effectively man-age organophosphate-induced status epilep-ticus and mitigate neuronal injury in animal models.10,11

5. Health care professionals not wearing appro-priate PPE have developed symptoms con-sistent with organophosphate exposure after being in close contact with adults and chil-dren poisoned by organophosphates, including patients with respiratory and dermal exposures only.12-15 Appropriate health care professional PPE depends on the circumstances of the organophosphate exposure and potency of the involved organophosphate.

6. Dermal decontamination through removal of contaminated clothing and copious irrigation with soap and water performed by people wear-ing protective barriers is effective at preventing further absorption and prevents contamination of caregivers and the care environment.

7 and 8. Metanalysis of 3 RCTs of primarily adults with organophosphate poisoning treated with oximes versus placebo did not find a mortal-ity benefit. The 3 studies were heterogenous,used lower doses of pralidoxime, and all had risks of biases.16 Two high-dose versus low-dose pralidoxime RCTs of primarily adults with moderate to severe organophosphate poison-ing favored the high-dose groups with greater survival, lower rates of pneumonia, and lower mean atropine doses(see Table 4 for dosing information).17 These findings are consistent with pralidoxime-induced protection with and without atropine against lethality in a rodent model of organophosphate poisoning.18 Oximes are not universally effective; their effective-ness may be limited by rapid aging of some organophosphates(eg, tabun), their inability to cross the blood-brain barrier, structural dif-ferences among organophosphates, and rapid reinactivation of regenerated acetylcholines-terase in the presence of poison.4.5 Although the available data are not sufficient to support

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a recommendation for or against oxime use in carbamate poisoning, oximes should not be withheld in cases of cholinesterase poisoning when the class of poison is unknown. A limited number of children were included in the RCTs of pralidoximes for organophosphate poison-ing, thus, the recommendation for children is extrapolated from the adult data.

9. Neuromuscular blockade from medications metabolized by butryylcholinesterase(pseu-docholinesterase), such as succinylcholine and mivacurium, can be prolonged by several hours in the context of organophosphate or carbamate poisoning in adult and pediatric cases.19-21 Other aminosteroid(eg, rocurronium,evuronium) and benzylisquinololin(eg, atracurium, cisatracurium) neuromuscular blockers are not primarily metabolized by cholinesterases.

REFERENCES

1. Cibulsky SM, Kirk MA, Ignacio JS, Leary AD, Schwartz MD. Patient De-contamination in a Mass Chemical Exposure Incident: National Planning Guidance for Communities. Washington, D.C.: US Department of Homeland Security; US Department of Health and Human Services; 2014. Accessed December 1, 2024. https://www.dhs.gov/sites/default/files/publica-tions/Patient%20Decon%20National%20Planning%20Guidance_Final/December%202014.pdf

2. Hobbiger F. Protection against the lethal effects of organophosphates by pyridine-2-aldoxime methiodide. Br J Pharmacol Chemother. 1957;12:438-446. doi:10.1111/j.1476-5381.1957tb0012.x

3.Hulse EJ, Davies JO, Simpson AJ, Scuiit AM, Eddleston M. Respiratory complications of organophosphorus nerve agent and insecticide poisoning.Implications for respiratory and critical care. Am J Respir Crit Care Med.2014;190:1342-1354. doi:10.1164/rccm.201406-11500C

4.Masson P. Nachon F. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning.J Neu-rochem.2017;142:26-40.doi:10.1111/jnc.14026

5. Worek F, Thiermann H, Srinucz L, Eyer P. Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophospho-nus compounds and oximes. Biochem Pharmacol. 2004;68:2237-2248. doi:10.1016/jbcip.2004.07038

6.Omar S, Sooka PN, Khoza S, Van Roeyen MC, Mashamba L, Madi S,Mathika H, George JA, Hemopiferusion for Clinically Suspected Organo-phosphate and Carbamate Poisoning in Critically III Patients: A Randomized Trial. Blood Purif.2023;52:157-165. doi:10.1159/000525936

7. Abedin MJ, Sayed AA, Basher A. Maude RJ, Hoque G, Faz M. Open-label randomized clinical trial of atropine bolus inversion robust bolus splines plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol.2012;8:108-117. doi:10.1007/s1811-012-012-014-8

8.Eddleston M, Mohamed F, Davies Jo, Eyer P, Worek F, Sheriff MH, Buckley NA. Respiratory failure in acute organophosphorus pesticide self-poisoning. QIM,2009;69:513-522. doi: 10.1093/qmed/hcl065

9. Tsao TC, Juang YC, Lan RS, Shieh WB, Lee CH. Respiratory failure of acute organophosphate and carbamate poisoning. Chest 1990;98:631-636. doi:10.1378/chest983.631

10. Eddleston M, Buckley NA, Eyer, Pawson AH. Management of acute or-ganophosphorus pesticide poisoning, Lancet 2008;371:597-607; doi:10.1016/S0140-6736(07)61202-1

11. McCarren HS, McDonough JH Jr. Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides. Ann N Y Acad Sci 2016;1374:144-150. doi:10.1111/ryas.13092

12. Calvert GM, Barnett M, Mehler LN, Becker D, Asac R, Beckman J, Male D,Sievert J,Thomsen C, Morrissey B. Acute pesticide-related illness among

emergency responders,1993-2002. Am J Ind Med.2006;49:383-393. doi:10.1002/ajim.20286

13. Centers for Disease Control and Prevention. Nosocomial poisoning associ-ated with emergency department treatment of organophosphate toxicity-Georgia,2000.MMWR Morb Mortal Wky Rep.2001;49:1156-1158.

14.Koksal N, Buyukbese M, Guven A, Cetinkaya A, Hasanoglu HC. Organo-phosphate intoxication as a consequence of mouth-to-mouth breathing from an affected case. Chest 2002;122:740-741.doi:10.1378/chest122.2740

15.Stacey R, Morfey D, Payne S. Secondary contamination in organophos-phate poisoning: analysis of an incident. Q.M. 2004;97:75-80. doi: 10.1093/qmed/hch020

16. Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. Oximes for acute organophosphate pesticide poisoning. Cochrane Database Syst Rev.2011;2,CDC005085. doi: 10.1002/14651858.CD005085.pub2

17. Pawar KS, Bhoite RR, Pilay CP, Chavan SC, Malshikare DS, Garad SG Continuous pralidoxime infusion versus repeated bolus injection to treat or-ganophosphorus pesticide poisoning: a randomised controlled trial. Lancet.2006;368:2136-2141.doi:10.1016/S0140-6736(06)69862-0

18. Kewitz H, Nachmansohnson D, Wilson IB. A specific antidote against lethal alkyl phosphate intoxication. II.Antidotal properties. Arch Biochem Biophys.1956;64:456-465. doi: 10.1016/0003-9861(56)90288-0

19. Perez Guillermo,Fartinz Pretel CM,Tarin Royo F,Fena Macias MJ,Alvarez Ossorio R, Alvarez Gomez JA, Vidal CJ. Prolonged suaxethonium-induced neuromuscular blockade associated with organophosphate poison-ing. Br J Anaesth.1988;61:233-236. doi: 10.1093/bja/61.233

20.Selden BS, Curry S. Prolonged succinylcholine-induced paralysis or in-ganophosphate insecticide poisoning. Ann Emerg Med.1987;16:215-217.doi:10.1016/s0196-0644(87)80018-5

21. Sener EB, Ustun E, Kocamanoglu S, Tur A. Prolonged apnea follow-ing succinylcholine administration in undiagnosed acute organophos-phate poisoning. Acta Anaesthesiol Scand. 2002;46:1046-1048. doi:10.1034/j.1399-6576.2002.460821.x

TOXICOLOGY: SODIUM CHANNEL BLOCKERS

|Recommendations for Adults and Children With Life-Threatening Sodium Channel Blocker Poisoning|||| |---|---|---|---| |COR|LO|Recommendations for Aduits and Children With Life-Threatening Sodium Channel Blocker Poisoning|| |1|B-NR|1. Sodium bicarbonate should be used to treat adults with life-threatening cardiotoxicity from tricyclic and tetracyclic antidepressant poisoning.|| |2a|C-LD|2. It is reasonable to use sodium bicarbonate to treat children with life-threatening cardiotoxicity from tricyclic and tetracyclic and tetracyclic antidepressant poisoning.|| |3b|It is reasonable to use hyperverilation in combination with sodium bicarbonate for mechanically ventilated adults and children with life-threatening sodium channel blocker poisoning.||| |2a|C-EO|4. It is reasonable to use ECLS in adults and children refractory cardiogenic shock from life- threatening sodium channel blocker poisoning.|| |2a|C-EO|5. It is reasonable to use sodium bicarbonate to treatment adults and children with life-threatening tetracyclic and tetracyclic and tetracyclic antidepressants.|| |2b|C-EO|6. It may be reasonable to use Vaughan-Williams class lb antiarrhythmics(eg, lidocaine) to treat adults and children with life-threatening blockers. If the antiarrhythematics (eg, lidocaine) to treat adults and children with life-threatening blockers. If the antiarrhythemating blockers.|| |2b|C-EO|7. It may be reasonable to use ILE to treat adults and children with life-threatening sodium channel blocker poisoning.|| |2c|C-EO|6. It may be reasonable to use ULE to treat adults and children with life-threatening sodium channel blocker poisoning.||

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Synopsis

Many poisons block cardiac sodium channels with prop-erties similar to Vaughan-Williams class la or lc antiar-rhythmics. Sodium channel blocker poisoning causes QRS prolongation, hypotension, seizures, ventricular ar-rhythmias, and cardiovascular collapse. Characteristic electrocardiogram changes usually precede ventricular arrhythmias in patients with sodium channel blocker poi-soning. These include intraventricular conduction delay(QRS complex prolongation) and the development of a terminal rightward axis deviation, best appreciated in lead aVR(Figure 9). Many sodium channel blockers have additional effects on other cardiac receptors and ion channels.1 Although poisoning from tricyclic antidepres-sants(TCAs) is best studied, many other poisons cause life-threatening sodium channel blockade.2 Treatment recommendations for poisoning by other sodium channel blockers are often extrapolated from TCA studies. Man-agement of life-threatening poisoning from local anes-thetics, whose pharmacologic action is similar to class lb antiarrhythmics, is discussed in the Toxicology: Local Anesthetics section. The treatment of cocaine poisoning,which has toxicity unique from other local anesthetics, is discussed in the Toxicology: Cocaine section. Manage-ment of chloroquine and hydroxychloroquine poisoning,which is unique, is outside the scope of these guidelines.

These recommendations inform the management of adults and children with life-threatening sodium channel blocker poisoning, including cardiac arrest.

Recommendation-Specific Supportive Text

1 and 2. Sodium loading and increasing the serum pH are each supported for the treatment of hypo-tension and arrhythmia from TCA poisoning by in vitro studies, animal studies, and case series and cohort studies of adults and children.3-6 Administration of hypertonic sodium bicarbon-ate achieves both of these physiologic goals,though its mechanism is not fully elucidated.For dosing information, refer to Table 4. This practice is supported by case series in TCA poisoning, involving mostly adults.4.5 Whether the target endpoints of initial hypertonic sodium bicarbonate bolus therapy should be biochemical (pH≈7.50) or physiologic(resolu-tion of hypotension and QRS prolongation) is debated.37-9 After the goals of alkalinization are achieved, it is not known whether it is superior to monitor the patient and administer additional sodium bicarbonate boluses as needed or start a continuous infusion.6 Experts recommend avoiding extremes of hypernatremia (serum sodium not to exceed 155 mEq/L) and alka-lemia (serum pH not to exceed 7.55) to avoid iatrogenic harm.3,6,10 If pH exceeds 7.55 and serum sodium is below 155 mEq/L, serum sodium can be increased by administration of hypertonic saline; if serum sodium exceeds 155 mEq/L and pH is below 7.55, pH can be 155 mEq/L and pH is below 7.55, pH can be

 Figure 9. Sodium channel blocker electrocardiogram.

Reproduced with permission from Robert Hoffman, MD.

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controlled by adjusting minute ventilation in intubated adults and children.5,11,12

3. Observational data from adults and children(≥15 years of age) suggest that patients with tricyclic antidepressant poisoning who are treated with mechanical hyperventilation in addition to sodium bicarbonate may be more likely to achieve controlled alkalemia and cor-rection of QRS prolongation compared with those receiving sodium bicarbonate alone.5 The clinical threshold for intubation is unclear;in adults and children who are intubated, min-ute ventilation can be adjusted to achieve pH targets.5,11

4. ECLS, including VA-ECMO, has been used successfully in adult cases with refractory car-diogenic shock from sodium channel blocker poisoning.13-17 One retrospective cohort study comparing 14 poisoned adults (7 poisoned by sodium channel blockers) treated with ECLS with 48 poisoned adults (14 poisoned by sodium channel blockers) with conventional therapies found that ECLS was associated with a lower mortality rate in the overall cohorts. ${ }^{18}$ The study did not have a subgroup analysis of only sodium channel blocker poisoning. There is a single case report of a child with cardiac arrest secondary to TCA poisoning who was successfully treated with VA-ECMO. ${ }^{19}$ No con-trolled observational studies or clinical trials were identified. Further discussion of the use of VA-ECMO in poisoning is provided in the Toxicology:ECMO section.

5.The use of sodium bicarbonate to treat sodium channel blocker poisoning other than from TCAs is based on case reports of adult poison-ing by other sodium channel blockers.320-23 No pediatric data were identified, thus, the recom-mendation for children is extrapolated from the adult data. For dosing information in adults and children, refer to Table 4.

6. Lidocaine, a class lb antisyrhythmic, competes with la and lc antiarrhythmic hromics for binding at the sodium channel. Class lb antiarrhythmic dis-sociate from the receptor more rapidly than la or lc agents, such as TCAs, and, therefore,do not depress phase 0 depolarization.24 The use of lidocaine to treat wide-complex tachy-cardia from TCA overdose is supported by animal studies and case reports of adults and children.24 A similar role for phenytoin, another class lb antiarrhythmic, is supported by adult case reports, though not consistently by animal studies.24-27

<BeginOfPara>7. Most sodium channel blockers are highly lipophilic. Several case reports in adults and

children describe temporal improvement fol-lowing ILE administration, including suc-cessful treatment of TCA-induced cardiac arrest.28-37 However, an RCT published in abstract form only found no benefit from ILE administration in treatment of hypotension or electrocardiogram abnormalities from TCA poisoning.38. The administration of ILE may increase drug absorption in oral overdose in an animal model, and results of animal stud-ies are inconsistent.39-43 Nonetheless, existing evidence-based recommendations suggest ILE administration after failure of standard therapies for life-threatening anmitripline poisoning, particularly if VA-ECMO or other forms of mechanical circulatory support are not readily available.44

REFERENCES

1. Lei M, Wu L, Terrar DA, Huang CL. Modernized Classification of Car-diac Antiarrhythmic Drugs. Circulation. 2018;138:1879-1896. doi:10.1161/CIRCULATIONHA.118.035455

2. Lenkey N, Karoly R, Lukacs P, Vizi ES, Sunesen M, Fodor L, Mike A. Clas-sification of drugs based on properties of sodium channel inhibition: a com-parative automated patch-clamp study. PLoS One. 2010;5:e15568. doi:10.1371/journal.pone.0015568

3. Brucolereri RE, Burns MM A. Literature Review of the Use of Sodium Bicar-bonate for the Treatment of QRS Widening.J Med Toxicol.2016;12:121-129. doi: 10.1007/s13181-015-0483-y

4. Hoffman JR, Voiter SR, Bayer M, Silver L. Effect of hypertonic so-dium bicarbonate in the treatment of moderate-to-severe cyclic an-tidepresent overdose. Am J Emerg Med. 1993;11:336-341. doi:10.1016/0735-6757(93)990163-6

5. Pai K, Buckley N, Isoardo KZ, Isbister GK, Becker T, Chiew AL, Cairns R,Brown JA, Chan BS. Optimising alkalination and its effect on QRS narrow-ing in tricyclic antidepressant poisoning. Br J Clin Pharmacol. 2002;88:723-733. doi: 10.1111/bcp.19008

6. Seger DL. A critical reconsideration of the clinical effects and treatment recommendations for sodium channel block-ing drug cardiotoxicity. Toxicol Rev. 2006;25:283-296. doi:10.2165/00139709-200625040-00008

7. Chan BS, Buckley NA. Common pitfalls in the use of hypertonic so-dium bicarbonate for cardiac toxic drug poisonings. Clin Toxicol(Phila).2024;62:213-218. doi: 10.1080/15563650.2024.2337028

8. Liebelt EL. Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalization and so-dium loading. Pediatr Emerg Care.1998;14:293-298.

9.Mirrakhimov AE, Ayach T, Barbary A, Talari G, Chadra H, Gray A. The Role of Sodium Bicarbonate in the Management of Some Toxic Ingestions. Int J Nephrol.2017;2017;7831358. doi:10.1155/2017/7831358

10. Greene SL, Dargan Pi, Jones AL. Acute poisoning: understanding 90% of cases in a nutshell. Postgrad Med J. 2005;81:204-216. doi: 10.1136/pgmj.2004.024794

11. Blackman K, Brown SG, Wilkes GJ. Plasma alkalinization for tricyclic antidepressant toxicity: a systematic review. Emerg Med (Fremantle).2001;13:204-210. doi:10.1046/j.1442-2026.2001.00213.x

12.McKinney PE, Rasmussen R. Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution. Ann Emerg Med.2003;42:20-24. doi:10.1067/mem.2003.233

13.de Lange DW, Sikma MA, Meulenbelt J. Extracorporeal membrane oxygenation in the treatment of poisoned patients. Clin Toxicol(Phila).2013:51.385-393. doi: 10.3109/15563650.2013.800876

14. Duburcq T.,Goutay J.,Preau S.,Mugnier A.,Rousse N.,Moussa MD,Vincentelli A, Cuny J., Parmentier-Decruc [E, Poissy J., Venoarterial Extracorporeal Membrane Oxygenation in Severe Drug Intoxation: A Retrospective Com-parison of Survivors and Nonsurvivors. ASAIO J. 2022;68:907-913. doi:10.1097/MAT.00000000000001583

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15. Ikejiri K, Akama Y, Ikej Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K,Imai H. Veno-arterial extracoreporal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest:A case report and literature review. Medicine (Baltin) 2021;1100e24980. doi: 10.1097/MD.00000000000024980

16. Reynolds JC, Judge BS. Successful treatment of flecine-induced cardiac arrest-arest with extracorporeal membrane oxygen in the ED. Am J Emerg Med.1542;33:1542.e2-1542.e2.d. doi:10.1016/j.ajem.2015.0705.048

17. Williams JM, Hollingshed MJ, Yaslakis A, Morales M, Prescott JE, Graber EM. Extracorporeal circulation in the management of severe tri-cyclic antidepressant overdose. Am J Emerg Med. 1994;12:456-458. doi: 10.1016/0735-6757(94)90062-0

18. Masson R, Colas V, Parientji, LLJehou P, Massetti M, Charbonneau P, Saulner F, Daubin C. A comparison of survival with and-out extracorporeal life support treatment for severe poisoning due to drug intoxication. Resuscitation. 2012;83;1413-1417. doi: 10.1016/j.resuscitation.2012.03.028

19. Goodwin DA,Lally KP N,PRt N,Diff Etracoreal membrane oxygen sup-port for cardiac dysfunction from tricyclic antidepressant-induced. Crit Care Med 1993;21:625-627. doi:10.1097/0003246-199304000-00025

20. Brubacher J. Bicarbonate therapy for unstable proposfene-induced wide complex tachycardia. CJ. 2004;6:349-356. doi: 10.1017/s181480300009635

2011. Farooq M, Qureshi F, Kamkoum W, Abuzeyad F. Propafenane and proprano-diol dual toxicity, J. Am Coll Emerg Physicians Open 2020;1:1104-1107. doi:10.1002/emp2.12126.

22. Vu NM, Hill TE, Summers MR, Vranian MN, Faul X. Manage-ment of life-threatening feinucleid overdose: A case report and re-view of the literature. HeartRhythm Case Rep. 2016;2:228-231: doi:10.1016/j.hrc.2015.12.013

23.Winkelmann BR, Reinberger H. Life-threatening disearcinide toxicity, A pharmacodynamic approach. Ann Intem Med. 1987;106:807-814. doi:10.7326/0003-4819-106-6-807

24 Foinami A, Joseph Weagant, T. Benowitz N. What is the role of idocaine or phenoryin to triacyclic antidepressant-induced cardiotoxicity? Clin Toxicol(Phila).2010;48:325-330. doi: 10.3109/1556365020.1487050

25.Calaham M, Schumaker H, Pentell P. Phenomy trophisic of cardieto toxicity in experimental antitriply poisoning. J Pharmacol Exp Ther.1988;245:216-220.

26. Hageran GA, Hanashiro PK. Reversal of tricyclic-ideanterrastant-induced cardiac conduction abnormalities by phenytoin. Ann Emerg Med.1981;10:82-86. doi:10.1016/s0196-0644(86)80342-3

27. Rayon R, Ruiz E. Phenomyotit: does reverse tricyclic-antipidernast-induced cardiac conduction abnormalities? Ann Emerg Med.1986;15:876-880. doi:10.1016/s0196-0644(86)80342-3

28. Agarwala R, Ahmed SZ, Wegand J. Prolonged use of intravenous lipid emulsion in a severe tricyclic antideepant oxidose. J Med Toxicol.2014;10:210-214. doi:10.1007/s13181-013-0353-4.

20.92. Angel-Isaza AM, Bustamante-Cristano LA, Uribe BF. Successful Out-come Following Intravenous Lipid Emulsion Rescue Therapy in a Pa-tient with Cardiac Arrest Due to Amitriply Overdose. Am J Case Rep.2020;21:e922206. doi: 10.12659/AJCR.922206

36. Engels PT, David JS. Intravenous fat emulsion to reverse haemoyd-namic instability from intentional amriptiline overdose. Resuscitation.2010;81:1037-1039. doi: 10.1016/j.resuscitation.2010.04.009

11. Harvey M, Cave G. Case report: successful lipid resuscitation in multi-drug overdose with predominant tricycideant oxidometer. Int J Emerg Med.2012;5:8. doi: 10.1186/1865-1380-5-8

32.Khiwata P, Clark L, Khunger A, Rijal BB, Ritter J. A Case Report of File-cainide Toxicity With Review of Literature. Cureus. 2022;14:e22261. doi: 10.7759/cureus.22261

33. Lee SH, Kim S, Sohn JT. Lipid Emulsion Treatment for Drug Tox-icity Caused by Nonlocal Anesthetic Drugs in Pediatric Patients:A Narrative Review. Pedafar Emerg Care 2023:393-53:69. doi: 10.1097/PEC/0000000000002828

34. Levine M, Hoffman RS, Laverveng V, Stork CM, Graudins A, Chuang R,Stellplfbr SJ, Morris M, Miller-Neibtash A, Gosevin S, on behalf of the Lipid Emulsion Workgroup. Systematic review of the effect of intravenous lip-id emulsion therapy for non-local anesthetics to city. Clinotoxil(Phila)2016;54:194-221. doi:10.3109/15563650.2015.1126286

35. Radley D, Droog S, Barragry J, Bigham C. Survival following massive amplitrixy overdose: The use of intravenous lipid emulsion therapy and the occurrence of acute respiratory distress. J. Intensive Care Soc.2015;16:181-182.doi:10.1177/175114371456836

36. Le Fevre P, Gosling M, Acharya K, Georgiou A. Dramatic resuscitation with Intralipid in an epinephrine unresponsive cardiac arrest following overdose of amitriptiline and proprandol. BMJ Case Rep.2017;2017:bc2016218281.doi:10.1136/ber-2016-218281

$\text{37.}$Levine M, Brooks DE, Franken A,Graham R. Delayed-onset seizure and cardi-ac arrest after antitriply. Anideepose overdose, treated with intravenous lipid emulsion therapy. Pediatrics 2012;130:e432-e438. doi: 10.1542/peds.2011-2511

38. Kasnavieh MH, Noudoushan SJ, Ghafoir HB, Abazarian N, Behnam M, Omid Y, Mollaifar A. Intravenous lipid emulsion for treatment of tricyclic antidepressant toxicity a randomized controlled trial. Paper presented at:VIllth Mediterranean Emergency Medicine Conference; September 8-11,2013.

930. Cave G, Havey M, Quin P, Heys D. Hypertonic sodium bicarbonate ver-sus intravenous lipid emulsion in a rabbit model of intravenous fleacide to toxicity: no difference, no sink. Clin Toxicol(Phila).2013;51:394-397. doi: 10.3109/15563650.2013.794282

40. Harvey M, Gave O, Gng B. Intravenous lipid emulsion-augmented plasma exchange in a rabbit model of clomprime toxicity; survival, but no sink. Clin Toxicol(Phila).2014;52:13-19. doi:10.3109/15563650.2013.866242

41. Litonius E, Niiya T, Neuronen RJ, Rosenberg PH. No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication de-spite significant entrainment of amitriptyline. Basic Clin Pharmacol Toxicol.2012;110:379-883; doi: 10.1111/j.1742-7843.2011.00826.x

42. Perichon D, Tursf S, Gustamopoulos D, Graudins A. An assessment of the in vivo effects of intravenous lipid emulsion on blood drug concentration and haemodynamics following or gano-satric amitriptline overdose. Clin Toxiol(Phil).2013;51:208-215. doi:10.3109/15563650.2013.778994

43. Varney SM, Bebarta VS, Vargas TE, Boudreau S, Castaneda M. Intravenous lipid emulsion therapy does not improve hypotension compared to sodium bicarbonate for tricyclic antidepressant toxicity: a randomized, controlled pilot study in a swine model. Acad Emerg Med.2014;21:1212-1219. doi:10.1111/acem.12513

44. Gosselin S, Hoegberg LC, Hoffman RS, Graudins A, Stork CM,Thomas SH, Stelpflug SJ, Hayes BD, Levine M, Morris M, et al.Evidence-based recommendations on the use of intravenous lipid emulision therapy in poisoning. Clin Toxicol(Phila). 2016;54:899-923. doi:10.1080/1565365020.2016.61214275

TOXICOLOGY: SYMPATHOMIMETICS

Introduction

The hallmark of sympathomimetic poisoning is increased activity of the adrenergic nervous system.Amphetamines,cathinones, and some synthetic cannabinoids produce sympathomimetic poisoning. Management of severe cocaine poisoning is discussed separately(refer to the Toxicology: Cocaine section). Complications of sympa-mathomeric poisoning result from excessive catechol-amine release and an attendant increase in metabolic and psychomotor activity. Clinical manifestations include tachyocardia, hypertension, agitation, seizures, hyperther-tachyocardia, hypertension, agitation, seizures, hyperther-mia,habrydolysis, and acidosis.1-4

Sympathomimetic poisoning can cause sudden car-diac arrest, presenting as VF,VT, or PEA.5-9 Vasospasm can cause myocardial infarction, even in patients with normal coronary arteries.6,8,10,11 A stress(takotsubo)cardiomyopathy is also reported in sympathomimetic-poisoned patients; this condition can be fatal, but it resolves spontaneously in survivors.10,12-15 Hyperther-mia is a severe and rapidly life-threatening clinical manifestation.3-5,16,17

These recommendations inform the management of adults and children with life-threatening sympathomi-metic poisoning, including cardiac arrest.

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|Recommendations for Adults With Life-Threatening Sympathomimetic Poisoning|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|B-NR|1.Sedation is recommended for adults with severe agitation from sympathomimetic poisoning.|| |2|C-LD|2.Rapid external cooling with ice water immersion is recommended for adults with life-threatening hyperthermia (Core Temperature >40 ℃ [104°F]) from sympathomimetic poisoning.|| |2a|C-EO|3. Vasodilators (eg,nitrates, phentolamine,CCBs) are reasonable for adults with coronary vasospasm from sympathomimetic poisoning.|| |2a|C-EO|4. It is reasonable to use ECLS in adults with cardiogenic shock from sympathomimetic poisoning refractory to other treatment measures.|| |2b|C-LD|5. The usefulness of dantrolene is uncertain for adults with life-threatening hyperthermia from MDMA toxicity.|6. Although physical restraints may be necessary temporarily, their sustained use without effective sedation is associated with death in adults with severe agitation from exposure to cocaine and other sympathomimetics.37,43-45| |3: Harm|C-LD|6. Prolonged use of physical restraint without sedation for adults is potentially harmful.||

2a C-EO 3. Vasodilators(eg, nitrates, phentolamine, CCBs) are reasonable for adults with coronary vasospasm from sympathomimetic poisoning.

2a-EO 4. It is reasonable to use ECLS in adults with cardiogenic shock from sympathomimetic poisoning of reactivity for other treatment measures.

2b C-LD

3:Harm C-LD

Recommendation-Specific Supportive Text

1. Sedatives(eg, benzodiazepines, antipsychotics)have been used in animal experiments to treat sympathomimetic poisoning.18.19 Sedatives con-trol psychomotor agitation that produces heat and rhabdomyolysis. Antipsychotics control agitation.Benzodiazepines mitigate agitation, relax muscles,and treat seizures. Although several adult clinical trials compare specific therapies for severe psycho-motor agitation, it is difficult to separate patients with sympathomimetic poisoning from other patients in these studies, and cardiac arrest was rare.20-24

2. Hyperthermia(Core Temperature>40°C[104°F])is rapidly life-threatening in sympathomimetic poi-soning.25 External and immersive, cooling has been used to treat hyperthermia in adults and a 17-year-old patient with sympathomimetic poisoning. 5,26-28 Evaporative or immersive cooling modalities reduce temperature more rapidly in adults than cooling blan-kets, the application of cold packs, or endovascular cooling devices. 29-33 Ice water immersion resulted in the fastest cooling rates in adults and critically may cool faster than 0.15°C/min(0.27°F/min), which has been associated with increased survival.34,35 High-quality data on cooling measures for hyperthermic sympathomimetic patients are lacking, but immersion seems effective (refer to the Hyperthermia section). 28

3. Vasodilators, including alpha-adrenergic receptor antagonists, CCBs, and nitrates, have been used to treat coronary vasospasm, reversing electrocar-diographic and biochemical markers of ischemia in sympathomimetic-poisoned adults.36-38

4.ECLS, including VA-ECMO and intra-aortic bal-loon pump, has been used successfully to support cardiac output in adults in cardiogenic shock while

$\text{stress}\,\text{ cardiomyopathy}\,\text{ resolves.}^{10,13,39,40}\,\text{ Stress}$$(\text{takotsubo) cardiomyopathy can be fatal, but it}$$\text{ often spontaneously resolves in days to weeks}$$\text{with circulatory support.}$$

5.Data on dantrolene for MDMA-induced hyper-thermia is conflicting. A meta-analysis of patients aged≥15 years only identified case reports and series totaling 71 cases and found that dantrolene use was associated with improved survival, but a nonrandomized series of 9 adults with MDMA-induced hyperthermia did not find clinical differ-ences between patients who received dantrolene and those who did not.41,42

6.Although physical restraints may be necessary temporarily, their sustained use without effective sedation is associated with death in adults with severe agitation from exposure to cocaine and other sympathomimetics.37,43-45

|Recommendations for Children With Life-Threatening Sympathomimetic Poisoning|||| |---|---|---|---| |COR|LOE|Recommendations|| |1|C-EO|1. Sedation is recommended for children with severe agitation from sympathomimetic poisoning.|| |2|C-EO|2. Rapid external cooling with ice water immersion is recommended for children with life-threatening hyperthermia(Core Temperature>40°C(104°F)) from sympathomimetic poisoning.|| |2a|C-EO|3. Vasodilators(eg, nitrates, phentolamine, CCBs) are reasonable for children with coronary vasospasm from sympathomimetic poisoning.|| |2a|C-EO|4. It is reasonable to use ECLS in children with cardiogenic shock from sympathomimetic poisoning refractory to other treatment measures.|| |2b|C-EO|5. The usefulness of dantrolene is uncertain for children with life-threatening hyperthermia from MDA toxicity.|| |3: Harm|C-EO|6. Prolonged use of physical restraint without sedation for children is potentially harmful.||

Recommendation-Specific Supportive Text

1. Sedatives(eg, benzodiazepines, antipsychotics) have been used in animal experiments to treat sympatho-mimetic poisoning.18,19 Sedatives control psychomo-tor agitation that produces heat and rhabdomyolysis.Antipsychotics control agitation. Benzodiazepines mitigate agitation, relax muscles, and treat seizures.Although several adult clinical trials compare spe-cific therapies for severe psychomotor agitation, it is difficult to separate patients with sympathomimetic poisoning from other patients in these studies, and cardiac arrest was rare.20-24 No high-quality pediat-ric data on the sedatives for sympathomimetic were identified, thus, the recommendation for children is extrapolated from the adult data.

2. Hyperthermia(Core Temperature >40°C[104 $^{\circ}F$]) is rapidly life-threatening in sympathomimetic

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poisoning.25 External and immersive cooling has been used to treat hyperthermia in adults and a 17-year-old patient with sympathomimetic poison-ing.5,27,28 Evaporative or immersive cooling modali-ties reduce temperature more rapidly in adults than cooling blankets, the application of cold packs,or endovascular cooling devices.29-33 Ice water immersion resulted in the fastest cooling rates in adults and critically may cool faster than 0.15°C/min(0.27°F/min), which has been associated with increased survival.34,35 High-quality data on cool-ing measures for hyperthermic sympathomimetic patients are lacking, but immersion seems effec-tive.28 Limited pediatric data on the rapid external cooling for life-threatening sympathomimetic poi-soning were identified, thus, the recommendation for children is extrapolated primarily from the adult data(refer to the Hyperthermia section).

3. Vasodilators, including alpha-adrenergic recep-tor antagonists, CCBs, and nitrates, have been used to treat coronary vasospasm, reversing electrocardiographic and biochemical mark-ers of ischemia in sympathomimetic-poisoned adults.36-38 No pediatric data on the use of vaso-dilators for life-threatening sympathomimetic poisoning were identified, thus, the recommen-dation for children is extrapolated from the adult data.

4.ECLS,including VA-ECMO and intra-aortic bal-loon pump, has been used successfully to sup-port cardiac output in adults in cardiogenic shock while stress cardiomyopathy resolves,10,13,39,40 Stress(takotsubo) cardiomyopathy can be fatal,but it often spontaneously resolves in days to weeks with circulatory support. No pediatric data on the use of ECLS for life-threatening sympa-thomimetic poisoning were identified, thus, the recommendation for children is extrapolated from the adult data.

5.Data on dantrolene for MDMA-induced hyper-thermia is conflicting. A meta-analysis of patients aged≥15 years only identified case reports and series totaling 71 cases and found that dantrolene use was associated with improved survival, but a nonrandomized series of 9 adults with MDMA-induced hyperthermia did not find clinical differ-ences between patients who received dantrolene and those who did not ${ }^{41,42}$ Limited pediatric data on the use of dantrolene to treat life-threatening sympathominetic poisoning were identified, thus,the recommendation for children is extrapolated primarily from the adult data.

6.Although physical restraints may be necessary temporarily, their sustained use without effective sedation is associated with death in adults with severe agitation from exposure to cocaine and

other sympathomimetics.37,43-45 No pediatric data on the use of physical restraint for life-threatening sympathomimetic poisoning were identified, thus,the recommendation for children is extrapolated from the adult data.

REFERENCES

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2. Mueller PD, Korey WS. Death by"ecstasy": the serotonin syndrome? Ann Emerg Med. 1998;32:377-380. doi: 10.1016/s0196-0644(98)70018-6

3. Potocka-Banas B, Janus T, Majdanik S, Banas T, Dembinska T, Borowiak K.Fatal Intoxication with alpha-PVP, a Synthetic Cathinone Derivative.J Foren-sic Sci.2017;62:553-556. doi: 10.1111/1556-4029.13326

4. Refstad S. Paramethoxyramphetamine(PMA) poisoning; a‘party drug’with lethal effects. Acta Anaesthesiol Scand. 2003;47:1298-1299. doi:10.1046/j.1399-6576.2003.00245.x

5. Dagli C, Duman I. Successful Use of Early Therapeutic Hypothermia in an MDMA and Amphetamine Intoxication-Induced Out-of-Hospital Cardiac Arrest: A Case Report. J Emerg Med. 2020;59:e89-e92. doi:10.1016/j.jemermed.2020.06.019

6. Hong R, Matsuyama E, Nur K. Cardiomyopathy associated with the smok-ing of crystal methamphetamine. JAMA 1991;265:1152-1154. doi:10.1001/jama.1991.03460090100040

7. Mende L, Bohm R, Regenthal R, Klein N, Grond S, Radke J. [Cardiac ar-rest caused by an ecastasy intoxication]. Anasthesiol Intensivmed Notfallmed Schamerization. 2005;40:762-765. doi: 10.1055/s-2005-870500

8. Packe GE, Garton MJ, Jennings K. Acute myocardial infarction caused by intravenous amphete abuse. Br Heart J. 1990;64:23-24. doi:10.1136/hrt.64.123.

9.Tsai C, Quidgley-Martin M, Laub N, Polsky TG, Osterhoudt KC.Methamphetamine-associated pulseless electrical activity in a young child. Am J Energ Med. 2001;39:257 e251-257 e259. doi:10.1016/j.ajem.2020.06.081

10.Chen JP. Methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary arteries of nontrormal coronary arteries: refractory global coronary microvascular spasm. J Invasive Cardiol.2007;19:E89-E92.

11. Wijetunga M, Bhan R, Lindsay J, Karch S. Acute coronary syndrome and crystal methamphetamine use: a case series. Hawaii Med J. 2004;63:8-13,25.

12. Aly SM, Deheul S, Puymirat E, Richeval C, Allorge D, Gaulier JM. Takot-subo cardiomyopathy as a consequence of 4-fluoroamphetamine Mono-intoxication documented by toxicological analyses. Clin Toxicol(Phila).2021;59:73-74. doi: 10.1080/15563650.2020.1757695

13. Cotinet PA, Bizouarn P, Roux F, Rozec B. Management of cardiogenic shock by circulatory support during reverse Tako-Tsubo following amphetamine exposure: A report of two cases. Heart Lung. 2021;50:465-469. doi:10.1016/j.jhrting.2020.10.007

14.Simoes MV, Maciel BC, Marin-Neto JA. Reversible segmental left-ventricular dysfunction caused by accidental administration of sym-pathometricic drug in human. Int J Cardiol. 1997;61:93-96. doi: 10.1016/s0167-5273(97)00126-5

15. White C,Jeanmonod R.Reverse Takotsubo Cardiomyopathy After Accidental Exposure to an Ilicit Substance: A Case Report. Cureus. 2022;14:e24282 doi:10.7759/cureus.24282

16.Castro AL,Tarelho S,Almeida D,Sousa L,Franco JM,Teixeira HM.MDMA Intissocation in a Potential Organ Donor with Cardiac Arrest. J Anal Toxicol.2020;44:923-926. doi: 10.1093/jat/bkaa042

17. Thirakul P, Hair LS, Bergen KL, Pearson JM. Clinical Presentation, Autopsy Results and Toxicology Findings in an Acute N-Ethylpentylone Fatality.J Anal Toxicol. 2017;41:342-346. doi: 10.1093/jat/bkx004

18. Derlet RW,Albertson TE,Rice P.Protection against d-amphetamine toxicity.Am.J Emerg Med.1990;8:105-108. doi:10.1016/0735-6757(90)90194-5

19. Derlet RW,Albertson TE,Rice P.Antagonism of cocaine,amphetamine, and methamphetamine toxicity. Pharmacol Biochem Behav. 1990;36:745-749.doi: 10.1016/0091-3057(90)90071-0

20. Cole JB,Moore JC,Nystrom PC,Orozos BS,Stellplfug SJ,Kornas RL,Fryza BJ,Steinberg LW, O'Brien-Lanthert A, Bache-Wig P, et al. A prospective study of ketamine versus haloperidol for severe prehospital agitation. Clin Toxicol(Phila).2016;54:556-562. doi 10.1080/15563650.2016.1177652

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21. Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intra-venous midazolam and doporid for sedolium of the acutely agitated pa-tient in the emergency department. Ann Emerg Med. 2006;47:61-67. doi:10.1016/j/enmergmed2005.07/0303

22. Martel M, Steringer A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droplet. Ziridospin, and midazolam. Acad. Emerg Med.2005;12:1167-1172. doi:10.1197/jaem.2005.07.017

23. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind,randomized trial of midazolium versus haloperidol versus Iarepazum in the chemical restraint of violent and severely agitated patients. Acad Emerg Med 2004;11:744-749. doi:10.1197/jaem.2003.06.015

424 Richards. JR der� RW, Dunran DR. Chemical restraint for the agitated patient in the emergency department: lorazepas versus sporodidol. J. Eergmed Med 1998;16:567-573; doi: 10.1016/0376/4876/0389/0008455

5.Mastsum Roche, Semierini MJ, Turner RC, Robson MJ, Nguyen L, Miller DB,O'Callaghan JP. Methamphetamine-induced toxicity: an updated review on issues related to hyperthermia. Pharmacol Ther. 2014;144:28-40. doi:1016/j.pharmata.2014.05.001

26. Armenian P,Ramantov TM,TsotaokaBT,GeronaRR,SilmanEF,Wu AH,Olson KR.Mt< Multiple MD(EMCystas) overdystone at a rare event a case series. J In-tensive Care Med.2013;28:252-258. doi:10.1177/0885066612445982

27. Douglas Gare, John J. Bosman D, Green M. Wilson N, Donovan J, Muhinere T, Holbery-Morgan, Bourke E, Smith E. Safety and Efficacy of an On-Site Intensive Treatment Protocol for Mild and Moderate Sympathormitotic To-icity at Australian Music Festivals. Phorep Disaster Med 2020:35:41-45. doi:10.1017/S1049023X19005089

28. Laskowski LK, Landry A, Vassallo SU, Hoffman RS. Ice water submersion for rapid cooling in severe drug-induced hyperthermia. Clin Toxicol (Phila)2015;53:181-184. doi: 10.3109/15563650.2015.1009994

29. Casa DJ, McDermott BP, Lee EC, ERigny SW, Armstrong LE, Aresh CM. Cold water immersion: the gold standard for external heat-stroke treatment. Exerc Sport Sci Rev. 2007;35:141-149. doi:10.1097/jes.0b3180a02bec

30. Croutin A. Emergency treatment of exertional heatstroke and comparison of whole body cooling techniques. Med Sci Sports Exerc.1990;22:15-18.doi:10.124/0006768-19800200004

31. Liao X,Zhou Z,Zhou M,Tang H,Feng M,Kou B,Zhu N,Liao F,Wu L.Effects of endovascular and surface cooling on resuscitation in patients with cardiac arrest and a comparison of effectiveness, stability, and safe-ty: a systematic review and meta-analysis. Crit. Care. 2020;24:27. doi:10.1186/s13054-020-2731z

32. Rosman J, Hentzien M, Drane M, Russel V, Juster B, Jolly D, Mateu P.A comparison between intravascular and traditional cooling for in-ducing and maintaining temperature control in patients following cardiac arrest. Anaesth Crit Care Pain Med. 2018;37:129-134. doi:10.1016/j.acccpm.2016.08.009

33.Sonder P.Janssens GN, Beishuizen A. Henny CL, Rittenberger, C. Callaway CW,Dezufian C.,Polderman KH.Efficacy of different cooling technologies for therapeutic temperature management A prospective intervention study.Resuscitation 2018;124:14-20. doi:10.1016/j.resuscitation.2017.12.026

34. Douma MJ. Aves T, Allan KS, Bendall JC, Berry DC, Chang WT, Epstein J,Hood N. Singletary EM. Zideman D, et on/ behalf of the First Aid Task Force of the International Liaison Committee on Resuscitation. First aid cooling techniques for heat stroke and exertional hypertheria: A sys-tematic review and meta-analysis. Resuscitation 2020;148:170-190. doi:10.1016/j.resuscitation.2020.01.007

35. Filep EM, Murata Y, Endres BD, Kim G., Stearns RL, Casa DJ. Ex-ertional Heat Stroke, Modality Cooling Rate, and Survival Out-comes: A Systematic Review. Medicina(Kaunas). 2020;56:589. doi:10.3390/medicina56110589

36. Minh JaFSh, Multr RF,Dovarak P,NaccaN.Amethylamine and ClonidineToxicity Resulting in Posterior Reversible Encephalopathy Syndrome. Pediatr Emerg Care 2021;37:e1721-e1723: doi 10.1097/PEG/OnalRepaticity 00000000000000000000000000000000000

37. Asaimou J, Wendard J, Davies K. Asteclyst induced acute myocardial infarc-tion. Heart 2001;85:E10. doi: 10.1136/heart.85.6e10

38.Richards JR, Albertson TE, Derif Wang, Lange CR Alo, ORner Risk-BZ.Treatment of toxicity from amphetamines, related derivatives, and ana-logica: a systematic clinical review. Drug Alcohol Depend. 2015;150:1-13.doi:10.1016/j.drugalcdep.2015.01.040

39. Al-Abri S, Meier KH, Colby JM, Smollin CG, Benowitz NL. Cardio-genic shock after use of fluoroamphetamine confirmed with se-rum and urine levels. Clin Toxolico(Phila). 2014;52:1292-1295. doi:10.3109/15563650.2014.974262

40. Morrison LK, Kromm J, Gaudet J, Zuege D, Button B, Warshawski F, Lucyk SN. Rescue extracorporeal membrane oxygenation therapy in methamphet-amine toxicity, CJEM.2018;8:20:S14-S19. doi:10.1017/cem.2017.356

41.Grunau BE, Wiens MO, Brubacher JR. Dantrolene in the treatment of MDMA-related hyperpexia: a systematic review. CJEM. 2010;12:435-442. doi:10.1017/s1481803500012598

42. Nikomanesh K, Phan AT, Choi J, Arabian S, Neeki MM. Dantrolene Administration in the Management of the Prehospital Patient with Methylenedioxethymphorhetamine Overdose: A Case Series and Literature Review. Case Rep Crit Care. 2022;2022:5346792. doi: 10.1155/2022/5346792

43. Otabhach C, Mevik C, Bagdugd S, Nugent K. Excited delirium, restraints and unexpected death: a review of pathogenesis. Am J Forensic Med Pathol.2010;31:107-112. doi: 10.1097/PAF0b0b3181d76cdd

44. Pollanen MS, Chiasson DA, Cairns JT, Young JG. Unexpected death related to restraint for excited delilmer: a retrospective study of deaths in police custody and in the community. CMAJ.1998;158:1603-1607.

45. Stromner EMF, Leith W, Zeegers MP, Freeman MD. The role of restraint in fatal excited delilium: a research synthesis and pooled analysis. Forensic Sci Med Pathol.2020;16:680-692. doi: 10.1007/s12024-020-00291-8

TOXICOLOGY: VOLATILES

|Recommendation for Adults and Children With Life-Threatening Poisoning Following Volatile Hydrocarbon Exposure||| |---|---|---| |COR|LOE|Recommendation| |2b|C-EO|1. It may be reasonable to use $\beta$ -adrenergic| |2b|CA|antagonists for adults and children with ventricular arrhythmias refractory to standard therapy.|

Synopsis

Cardiac arrest following volatile hydrocarbon use has been termed sudden sniffing death.1 While the exact mechanism is unknown, in vitro and animal experiments suggest that hydrocarbons sensitize cardiac potassium sodium, and calcium channels.2-5 Hypoxia, catecholamine surge, or hypocalcemia(from fluorinated hydrocarbons)may also contribute to lethal arrhythmias. Animals treat-ed with chloroform, a nonhydrocarbon volatile, have en-hanced sensitivity to epinephrine, which led to death in some animals.6.7 In a large case series, sudden death was frequently reported following exertion or a stressful situation.

This recommendation informs the management of adults and children with life-threatening arrhythmias from volatile hydrocarbon exposure, including cardiac arrest.

Recommendation-Specific Supportive Text

1.$\beta$ -adrenergic antagonists decrease myocardial sensitivity to epinephrine. Several case reports describe resuscitation with aβ-adrenergic antago-nist for cardiac arrest from volatile hydrocarbons. A 23-year-old patient suffered perseed pulseless VT cardiac arrest following inhalation of 1,1-difluoroethane.In addition to amiodarone and defibrillation, recur-rent VT was successfully treated with calcium,dexmedetomidine, esmolol, and cardiac bypass.8 Another adult case report described myocardial

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infarction and VT after inhalation of a keyboard cleaner containing difluoroethane. Despite amino-adorone, lidocaine, and metropolot, the patient died of refractory cardiogenic shock.9 The use ofβ-adrenergic antagonists is further supported by the extrapolation of data from withholding epi-nephrine. In a case series of 22 patients aged≥13 years with cardiac arrest from volatile hydrocar-bons, none of the 8 patients receiving epineph-rine survived, while 5 of the 6 patients who did not receive epinephrine survived with good neurologi-cal outcome.10

REFERENCES

1. Bass M. Sudden sniffing death. JAMA 1970;212:2075-2079. doi:10.1001/jama.1970.03170250031004

2. Brock WJ, Rusch GM, Trochimochiz H.J. Cardiac sensitization: method-ology and interpretation in risk assessment. Regul Toxic Pharmacol.2003;38:78-90. doi: 10.1016/s0273-2300(03)00072-2

3. Himmel HM. Mechanisms involved in cardiac sensitization by volatile anes-tics: general applicability to halogenated hydrocarbons? Crit Rev Toxicol.2008;38:773-803. doi:10.1080/10408440802237664

4. Jiao Z, De Jesus VR, Iravian S, Campbell DP, Xu J, Vitali JA, Banach K,Fahrenbach J, Dudley SC Jr. A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias.J Mol Cell Cardiol.2006;41:698-705. doi:10.1016/j.ymcc.2006.07.003

5.Scholz EP,Alter M,Zitron E,Kiesecker C,Kathofer S,Thomas D,Kreye VA,Kreuzer J,Becker R,Katus HA,et al.In vitro modulation of HERG chan-nels by organochlorine solvent trichornethroma as potential explanation for proarthmythic effects of chloroform. Toxicol Lett.2006;165:156-166. doi:10.1016/j.toxlet.2006.03.004

6. Levy AG.The exciting causes of ventricular fibrillation in animals under chlo-roform anesthesia. Heart 1913;4:319-378.

7. Levy AG, Lewis T. Heart irregularities resulting from the inhalation of low percentages of chloroform vapour and their relationship to ventricular fibril-lation. Heart 1911;3:999-111.

8'D'OraJio, Bassett R, Boroughft W, Kowalski JM. Hypocalcemia associ-ated with 1,1-difluoroethane inhalation. Clin Toxicol. 2014;52:702. doi:10.3109/15563650.2014940163

9.Nguyen N,Kleiman RJ,Punja M,Demesthias M.ACMT 2020 Annual Scien-tific Meeting Abstracts- New York, NY. J Med Toxicol. 2020;16:116-168.dol:10.1007/s13181-020-00759-7

10. Schultz BV,Rolley A,Doan TN, Bodnar D,Isodi K.Epidemiology and sur-vival outcomes of out-of-hospital cardiac arrest following volatile substance use in Queensland, Australia. Clin Toxicol(Phila).2023;61:649-655. doi:10.1080/15563650.2023.2267172

TOXICOLOGY: ECMO

|Recommendations for the Use of VA-ECMO in Adults and Children With Life-Threatening Poisoning||| |---|---|---| |COR|LOE|Recommendations| |2a|B-NR|1. It is reasonable to use VA-ECMO in adults and children with persistent cardiogenic shock or cardiac arrest due to poisoning that is refractory to pharmacological interventions.| |2a|C-EO|2. It is reasonable to use VA-ECMO in adults and children with persistent arrhythmias due to poisoning when other treatments fail.| |2b|C-LD|3. For adults and children with life-threatening poisoning, the effectiveness of VA-ECMO for poisoned patients with cardiovascular collapse from causes other than cardiogenic shock or arrhythmia has not been established.|

Synopsis

VA-ECMO is a resusitative measure providing both car-diac and pulmonary support.1 In the setting of poisoning,VA-ECMO treats refractory cardiogenic shock by provid-ing mechanical circulatory support while the offending poison is eliminated. The use of VA-ECMO in both poi-soned adults and children is limited by availability, logis-tics of transport, patient comorbidities, and risks inherent to the procedure. Decisions to initiate VA-ECMO involve the understanding of both the pathophysiology of the specific poisoning and the clinical features of the patient and may include consultation from a poison center or medical toxicologist.

Other forms of mechanical circulatory support, such as implanted LVADs and percutaneous mechanical circu-latory support devices(eg,intra-aortic balloon pump) are beyond the scope of this recommendation.

These recommendations inform the management of adults and children with life-threatening poisoning,including cardiac arrest.

Recommendation-Specific Supportive Text

1.In a retrospective cohort study of 64 adults treated with VA-ECMO for cardiac arrest or refractory shock regardless of cause, cardiotoxic poisoning was independently associated with sur-vival? A nonrandomized observational study of adults in cardiac arrest due to poisoning treated with VA-ECMO showed lower mortality than other patients treated with VA-ECMO and lower mor-tality compared with poisoned patients treated with standard critical care and antidotal therapy alone.3 In a prospective observational study of 32 adults placed on VA-ECMO to treat cardiogenic shock or refractory cardiac arrest from poisoning,78% of patients survived to hospital discharge.4 A review of 407 patients with poisoning treated with either VA-ECMO or venovenous ECMO reported to the National Poison Data System included 75 patients<12 years of age and found similar mor-tality rates for adults and children(29.5% versus 32.0%, respectively).5 Significant complications with VA-ECMO treatment include limb ischemia,bleeding, stroke, and infection.1,4,6 Studies have reported complications of VA-ECMO following administration of lipid emulsion therapy, includ-ing cracking of stopcocks, clogging and malfunc-tion of the membrane oxygenator, and increased blood clot and lipid aggregation in the circuits.78 However, multiple case reports reported success-ful treatment with VA-ECMO concurrent with lipid emulsion therapy.8,9

2.For adults and children with persistent nonperfus-ing arrhythmias, VA-ECMO provides antegrade blood flow to allow poison elimination. Case reports

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describe neurologically intact survival with the use of VA-ECMO to support adult cases of poisoning with persistent arrhythmias.10-13 One adult case resulted in return to normal sinus rhythm, but the patient subsequently suffered multisystem organ failure.14 Similar to adults, there are case series and case reports of the use of VA-ECMO to treat children with persistent arrhythmias thus following poisoning.15,16

3.The mortality benefit of VA-ECMO is mixed in poi-sonings that cause refractory vasodilatory shock with preserved cardiac function, direct cellular toxicity, disruption of cellular oxygen use, or poi-sonings that are almost universally fatal despite temporary cardiac support. One retrospective registry study of patients reported to the National Poison Data System, including 75 children<12 years of age, showed that patients with hemato-logical and metabolic poisons had higher mortality on ECMO compared with patients with other poi-sonings; however, this study was unable to deter-mine the mode of ECMO utilized.5 In contrast, in 1 retrospective case series, 80% of children<18 years of age who were treated with VA-ECMO(with or without continuous kidney replacement therapy) for vasodilatory shock from poisoning survived.17 Similarly, multiple case reports have demonstrated mortality benefit of VA-ECMO for adults with cardiogenic shock, hypotension, and arrhythmias in the setting of aluminum phos-phide poisoning, a pesticide and rodenticide that when exposed to water produces phosphine gas,a direct cellular toxin that causes depression of myocardial contractility and ventricular arrhyth-mias.18 The pathophysiology of these poisons is not expected to differ significantly between adults and children, including aluminum phosphide.

REFERENCES

1. Johnson NJ, Gaiescki DF, Allen SR, Perone J, DeRoos F. A review of emer-gency cardiopulmonary bypass for severe poisoning of cardiac drugs. J Med Toxicol. 2013;9:54-60. doi: 10.1007/s13181-012-0281-8

2. Brunet J, Valette X, Ivascau C, Lehoux P, Sauneul B, Dalbert Y, Masson R,Sabatier R, Lubos D, Seguin A et al. Extracorporeal Life Support for Re-fractory Cardiac Arrest or Shock: A 10-Year Study. ASA/0 J. 2015;61:676-681. doi: 10.1097/MAT00000000000282

3. Masson R, Colas V, Parienti JJ, Lehou P, Massett M, Charbonneau P,Saulnier F, Daubin C. A comparison of survival with and without extracorpolo real life support treatment for severe poisoning due to drug intoxication, Re-suscitation.2012;83:1413-1417.doi:10.1016/j.resuscitation.2012.03.028

4. Pozzi M, Koffel C, Djaref C, Grinberg D, Fellahi JL, Hugon-Vallet E, Prieur C,Robin J,Obadia J.FH rate of arterial complications in patients supported with extracorporeal life support for drug intoxication-induced refractory car-dogenic shock or cardiac arrest.J Thorac D: 2017:98-1998. doi: 10.21037/jtd.2017.06.81.

5.Cole JB, Olives TD, Ulici A, Litell JM, Bangh SA, Arens AM, Puskarich MA, Prekerk ME. Extracorporeal Membrane Oxygenation for Poisonings Reported to U.S. Poison centers from 2000 to 2018: An Analysis of the National Poison Data System. Crit Care Med. 2020;48:1111-1119. doi: 10.1097/CCM.0000000000004401

6.Duburcq T.,Goutay J.,Preau S.,Mugnier A.,Rousse N.,Moussa MD,Vincentelli A, Cuny J., Parmenter-Decrucc E.,Poisy J.,Venoarter Extracorpool

Membrane Oxygenation in Severe Drug Intoxication: A Retrospective Com-parison of Survivors and Nonsurvivors. ASAIO J. 2022;68:907-913. doi: 10.1097/MAT.00000000000001583

7. Hayes BD, Gosselin S, Calelolo DP, Nacca N, Rollins CJ, Abourbih D, Morris M, Nesbitt-Miller A, Morais JA, Lavergve N; on behalf of the Lipid Emul sion Workgroup. Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol(Phila).2016;54:365-404. doi: 10.3109/15563650.2016.1151528

8. Lee HM, Archer JR, Dargan PI, Wood DM. What are the adverse effects as-sociated with the combined use of intravenous lipid emulsion and extracor-poral membrane oxygenation in the poisoned patient? Clin Toxicol(Phila).2015;53:145-150. doi: 10.3109/15563650.2015.1004582

9.Escaleda JT, Katz KD, Rittenberger JC. Successful treatment of metropolil-induced cardiac arrest with high-dose insulin, lipid emul-sion, and ECMO. Am J Emerg Med.1111;33:1111.e1-1111.e4. doi:10.1016/j.ajem.2015.01.012

10. Hermes-Laufer J,Meyer M,Rudiger A,Henze J,Enselmann K,Kupferschmidt H,Muller D,Herzog A,Bettex D,Keller Dl,et al.Extracorporeal life support as bridge to recovery in yew poisoning: case reports and literature review.ESC Heart Fail.2021:8:705-709.doi:10.1002/ehf2.12828

11. Ikejiri K, Akama Y, Ieki Y, Kawamoto E, Suzuki K, Yokoyama K, Ishikura K,Imai H. Veno-arterial extracorporeal membrane oxygenation and targeted temperature management in tricyclic antidepressant-induced cardiac arrest:A case report and literature review. Medicine (Baltim). 2021;100:e24980.doi:10.1097/MD.000000000024980

12.Kato Y, Kuriyama A, Hata R, Ikegami T, Extracorporeal Membrane Oxy-genation for Hypokalemia and Refractory Ventricular Fibrillation As-sociated with Caffeine Intoxication. J Emerg Med. 2020;58:59-62. doi:10.1016/j.jemmered.2019.09.023

13. Mu HW, Chen CH, Yang KW, Hung DZ. Cerbera manghas poisoning sur-vied by using extracorporeal life support. Clin Toxicol(Phila).2018;56:153-154. doi: 10.1080/15563650.2017.1343478

14. Vo KT,Tabas JA,Smollin CG. Alternating Ventricular Complexes After Over-dose from an Herbal Medication. JAMA Intem Med.2017;177:1199-1201.doi:10.1001/jamintermeded.2017.1839

15. Labarinas S, Meulmester K, Greene S, Thomas J, Virk M, Erkonen G. Extra coporardic Pulmonary Resuscitation After Diphenhydramine Ingestion.J Med Toxicol.2018;14:253-256. doi: 10.1007/s13181-018-0672-6

16. Lewis JC, Sutter ME, Albertson TE, Owen KP, Ford JB. An 11-year re-view of bupropion insuffusion exposures in adults reported to the Cali-fornia Poison Control System. Clin Toxicol(Phila). 2014;52:969-972. doi:10.3109/15653602014.969372

17. Depin L, Nguyen H, Kilgore S, Wang GS, Kim JS. Venoarterial Extracoro-real Membrane Oxygenation for Support of Vasodilatory Shock in Children Due to Toxicological Ingestions[published online January 10,2025]. ASA/O J. doi: 10.1097/mat 0000000000002374

18. Voicu S, M'Rad A, Malissin I, Deye N, Megarbane B. Extracorporeal life sup-port in cardiotoxic positroning-A narrative review. Basic Clin Pharmacol Toxicol.2023;132:5-20. doi: 10.1111/bcpt.13804

KNOWLEDGE GAPS AND PRIORITIES OF RESEARCH

Cardiac arrest and life-threatening states due to special circumstances are vastly under-researched. As part of the overall work for the development of these guidelines,the writing group reviewed a large amount of literature concerning the management of cardiac arrest and life-threatening states due to special circumstances. One expected challenge faced through this process was the lack of data in many areas. With some exceptions, car-diac arrests due to special circumstances are rare events and challenging to study. As a result, only the majority of guideline recommendations were based on low-grade evidence(LOC)

Some critical knowledge gaps identified by the writing group are summarized in Table 5.

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Table 5. 2025 Adult and Pediatric Special Circumstances of Resuscitation Key Knowledge Gaps

|Alternative CPR|| |---|---| |Are there situations when a precordial stump can be used safely in adults and children in cardiac arrest in a well-monitored setting when a defibrillator is not immediately available? Is percussion pacing more effective than transcutaneous pacing in adults and children with witnessed, monitored, in-hospital onset of asystole or a nonperfusing bradyrhythmia before loss of consciousness? Can cough CPR effectively prevent cardiac arrest after the onset of a hemodynamically significant arrhythmia before loss of consciousness in the out-of- hospital setting? In which circumstances does interposed abdominal compression enhance the effectiveness of CPR in adults and children?|| |Anaphylaxis|| |Does early administration of epinephrine in adults and children offer benefit over standard ALS support protocols in shockable rhythms from anaphylaxis? Does a higher dose of epinephrine, such as 5 mg administered intramuscularly in adults, confer benefit in cardiac arrest from anaphylaxis? Do escalating doses of intravenous epinephrine in adults and children improve outcomes?|| |Asthma|| |What is the optimal timing of ECLS in adults and children with life-threatening asthma? For adults and children in cardiac arrest, what is the benefit of active exhalation maneuvers? What is the optimal timing of the addition of volatile anesthetics to the treatment of adults and children with life-threatening asthma?|| |Cardiac intervention laboratory|| |What interventions to treat adult cardiac arrest in the cardiac intervention laboratory are beneficial in RCTs? Is there a survival benefit to immediate rapid defibrillation for shockable rhythms(prior to chest compressions) for adult cardiac arrest in the cardiac intervention laboratory?|| |Is there harm if chest compressions or CPR for adults in cardiac arrest in the cardiac intervention laboratory are paused during arrest to perform a corrective procedure(eg, pericardiocentesis)? Which adults in cardiac arrest in the cardiac intervention laboratory are most likely to benefit from ECLS? Is the use of intracona epinephrine to treat adult cardiac arrest in the cardiac intervention laboratory beneficial?|| |Cardiac surgery|| |What is the benefit to 3 stacked shocks in VF in adults after cardiac surgery compared with standard ALS? What is the incidence of capture from pacing asystole or bradycardia with temporary wires in adults and children in the immediate postoperative period?|| |Drowning|| |Are untrained lay rescuers competent to distinguish respiratory arrest for cardiac arrest for adults and children following drowning? Are lifeguards competent to use bag-mask or supraglottic ventilation for adults or children following drowning? What is the competency level of different types of rescuers to perform in-water breathing following drowning? What is the competency and associated training required of lifeguards to perform resuscitation in cardiac arrest following drowning on rescue crafts(eg, surfboards, stand-up paddleboards, personal watercrafts, boats)? What is the outcome of resuscitation for adults and children in cardiac arrest following drowning? How does resuscitation with and without oxygen affect the outcomes for adults and children in cardiac arrest following drowning? How does resuscitation using airway-breathing-circulation versus circulation-airway-breathing affect outcomes for adults and children in cardiac arrest following drowning?|| |How does resuscitation with and without oxygen affect the outcomes for adults and children in cardiac arrest following drowning? How does resuscitation using airway-breathing-circulation versus circulation-airway-breathing affect outcomes for adults and children in cardiac arrest following drowning?|| |How does the use of an AED in the early stage versus in a later stage of the resuscitation affect outcomes for adults and children in cardiac arrest following drowning? Does the use of oxygen during transport of a drowned adult or child to the hospital improve outcomes?|| |What is the outcome of different airway techniques(endotracheal intubation, supraglottic airway, bag-mask ventilation, noninvasive ventilation) during transport of a drowned adult or child to the hospital? How does ECPR for adults and children in cardiac arrest following drowning? Does targeted temperature management during or after resuscitation improve neurological outcomes for adults and children in cardiac arrest following drowning?|| |Does admission to a drowning center versus other health facilities(eg, regionalization of the treatment of drowned persons) affect outcomes in cardiac arrest following drowning?|| |following drowning? Is drying the chest before using an AED on a drowned adult or child necessary for safe defibrillation? Does drying the chest affect defibrillation success?|| |Electrocution|| |What is ideal resuscitation management for a given type of electrical injury in adults and children? Is antiarrhythmic therapy earlier in the resuscitation of adults and children in cardiac arrest after electrocution beneficial?||

(Continued)

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Table 5. Continued

|Gas embolism|| |---|---| |Does supplemental oxygen benefit adults and children after gas embolism?|| |High-consequence respiratory respiratory pathogens|| |How can teams mitigate the effects of PPE on resuscitation team performance and health care professional fatigue? What factors contribute to PPE noncompliance, and how can these be addressed without compromising team performance? How do we support lay rescuers in providing CPR and AED application in the safest way possible during a pandemic with a high-consequence respiratory pathogen?|| |Hyperkalemia|| |What is the benefit/harm of calcium in treatment of adults and children in cardiac arrest from hyperkalemia? What is the benefit/harm of sodium bicarbonate in treatment of adults and children in cardiac arrest from hyperkalemia?|| |Hyperthermia|| |What is the survival benefit of cooling for adults and children in cardiac arrest from hyperthermia? What is the survival benefit of the various types of cooling systems for adults and children in cardiac arrest from hyperthermia?|| |Hypothermia|| |In adults and children in cardiac arrest due to environmental hypothermia, what is the optimal temperature to rewarm to prior to defibrillation and administration of epinephrine? Are there circumstances in which CPR can be safely delayed in adults and children in cardiac arrest due to environmental hypothermia until rewarming is initiated? What is the best prognostication score or variable in children in cardiac arrest due to environmental hypothermia? What is the farthest distance that an adult or child in cardiac arrest due to environmental hypothermia should be transported in order to utilize ECLS for rewarming?|| |Left ventricular assist device|| |What is the best method to confirm cardiac arrest in an adult or child with an LVAD? What is the best sequence for resuscitation of an adult or child with an LVAD when a single rescuer is present(eg, prioritizing chest compressions versus assessing and restarting LVAD function)? What is the role of ECLS in an adult or child with an LVAD with sustained cardiac arrest?|| |Is there a period of time from known LVAD stoppage after which it should not be restarted due to risk of thrombosis?|| |Pregnancy|| |What is the optimal management of cardiac arrest during pregnancy? What are the survival benefits of airway management techniques in cardiac arrest in pregnancy, including placement of advanced airway, intubation, and use of video laryngoscopy? What is the optimal management of out-of-hospital pregnancy cardiac arrest, especially when transport delays perimortem or resuscitative delivery? For pregnant patients, who are the best candidates for ECLS to balance bleeding and clotting complications? What is the optimal post-cardiac arrest care during pregnancy?|| |PE|| |What is the best diagnostic criteria for adults and children in cardiac arrest to suspect PE? What is the optimal amount of time chest compressions should be continued after an adult or child receives systemic fibrinolytics? Should there be monitoring of fibrin activity or other laboratory markers of fibrinolysis after receiving fibrinolytics to ensure the treatment has been effective?|| |Benzodiazepines|| |For which adults and children does the benefit of flumazenil exceed the risk of seizure?|| |β-Blockers and CCBs|| |Does high-dose insulin therapy, administered in addition to or instead of standard vasopressors, reduce mortality or ischemic complications of adults and children with life-threateningβ-blocker or CCB poisoning?|| |What is the ideal vasopressor or inotropic strategy for adults and children in refractory shock fromβ-blocker or CCB overdose? Does tailoring therapy to cardiogenic versus vasopressic outcomes? Are nonadrenergic vasopressors effective? What are the benefits of glucagon for adults and children with life-threatening $\beta$ -blocker or CCB poisoning? What is the mortality benefit of hemodialysis for adults and children with life-threatening atolenol, solotal, or nadolol poisoning? What are the benefits of ILE for adults and children after oral overdose of lipophilicβ-blockers or CCBs? What are the benefits of gastrointestinal decontamination for adults and children with life-threatening $\beta$ -blocker or CCB poisoning, particularly when extended- release formulations are involved?||

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Table 5. Continued

|Cocaine|| |---|---| |What is the ideal management of cocaine-induced myocardial ischemia, hypertensive emergency, or arrhythmia?|| |Cyanide|| |Does the addition of sodium thiosulfate to either hydroxocobalamin or sodium nitrite therapy improve outcomes of adults and children with life-threatening cyanide poisoning?|| |Is there a carbon monoxide level for which sodium nitrite therapy is appropriate for adults and children with life-threatening cyanide poisoning? Should adults and children with cyanide ingestion be treated differently than patients with hydrogen cyanide gas exposure? Is there a role for VA-ECMO for adults and children with persistent shock from cyanide poisoning?|| |Digoxin|| |What is the best empirical dose of digoxin-Fab for adults and children in cardiac arrest from digoxin poisoning? What is the appropriate dose of digoxin-Fab for adults and children in critical poisoning from cardiac glycosides other than digoxin?|| |Local anesthetics|| |What is the benefit of ILE when given in addition to standard resuscitation with vasopressors and sodium bicarbonate for adults and children with life-threatening local anesthetic motidotoxicity? What is the ideal dose of ILE for adults and children with life-threatening local anesthetic poisoning? Is the optimal treatment for adults and children with life-threatening poisoning from other local anesthetics the same as for poisoning from bupivacaine?|| |Methemoglobinemia|| |What is the true risk of methylene blue therapy in adults and children with glucose-6-phosphate dehydrogenase deficiency? How does methylene blue adults and children in cardiac arrest from methemoglobinemia?|| |Opioids|| |What is the ideal initial dose of naloxone for adults and children with life-threatening opioid poisoning in settings of high fentanyl analog prevalence? What is the benefit of naloxone when given to adults and children in cardiac arrest with suspected opioid overdose? What is the minimum safe observation period for patients with opioid overdose treated with naloxone? In addition to "take-home naloxone," what are the other effective forms of secondary prevention for adults and children with opioid use disorder who survive overdose?|| |Organophosphates and carbamates|| |What PPE and decontamination protocols are necessary to protect health care professionals caring for adults and children with organophosphate and carbamate exposures? Which adults and children with life-threatening organophosphate poisoning benefit from oxime therapy? What is the most effective oxime for adults and children with life-threatening organophosphate poisoning? What is the most appropriate dose of oximes? Do adults and children with life-threatening poisoning from highly toxic carbamates(eg, aldicarb) benefit from oxime therapy?|| |Sodium channel blockers|| |What is the ideal treatment for adults and children with life-threatening poisoning from sodium channel blockers other than TCAs?|| |What physiological or electrocardiographic targets are most appropriate for adults and children with sodium channel blocker poisoning to prevent deterioration to cardiac arrest?|| |Sympathomimetics|| |What factors predict which adults and children with sympathomimetic poisoning will suddenly decompensate to cardiac arrest? What is the ideal medication or combination of medications for sedation of adults and children with severe psychomotor agitation?|| |Volatiles|| |Are there other heart rate control medications that would portend better outcomes for adults and children with hydrocarbon exposure?|| |Role of VA-ECMO in poisoning|| |Which adults and children with poisoning have improved outcomes from VA-ECMO compared with standard critical care plus antidotal therapy? In what situations can VA-ECMO benefit adults and children with distributive shock or cellular injury from poisoning? What is the optimal timing of VA-ECMO initiation for adults and children following poisoning? Are outcomes better when VA-ECMO is initiated in the peri-arrest period or earlier in the course of illness?||

AED indicates automated external defibrillator; ALS, advanced life support;β-blockers,β-adrenergic receptor antagonists; CCBs, calcium channel blockers; CPR,diipulmonary resuscitation; Fab, fragment antigen binding;ECLS,extracorporeal life support; ECRP, extracorporeal cardiopulmonary resuscitation; ILE, intravenous lipid emulsion; LVAD, left ventricular assist device;PE, pulmonary embolism; PPE, personal protective equipment; RCT, randomized controlled trial; TCA, tricyclic antide-pressant; VA-ECMO, venoarterial extracorporeal membrane oxygenation; and VF, ventricular fibrillation.

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ARTICLE INFORMATION

The American Heart Association requests that this document be cited as follows: Cao D, Arens AM, Chow SL, Easter SR, Hoffman RS, Lagina AT III, Lavonas EJ, Patil KD, Sutherland LD, Tijssen JA, Wang GS, Zelop CM, Rodriguez AJ,Drennan IR, McBride ME. Part 10: adult and pediatric special circumstances of resuscitation:2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2025;152(suppl 2):S578-S672.doi:10.1161/ClR.0000000000001380

Acknowledgments

We acknowledge the contributions of Nhat Chau, MD; Bharghavess Gottam, MD;and Olivia Williams, MD, who assisted the authors in the evidence review of these recommendations.

We acknowledge the contributions of the librarians Abdul Pullattayil, Amy Sisson,Caitlin Plovnick,Joey Nicholson,Laura Haygood,and Peace Ossom,who assisted with systematic searches.

Contributors

Amber V.Hovero,RN,MSN;Andrea Nillas,MD;Philip Jarrett,MD,MBA;Avi Ru-derman,MD;Matthew D.McEvoy,MD;Michael R.Fettiplace,MD;PhD;Mark S.Link,MD;Matthew R.Neth,MD;Gurpreet S.Dhillon,MD;Marina Del Rios,MD,MS;Jason A.Bartos,MD,PhD;Ashish R.Panchal,MD;PhD;Comilla Sasson,MD,PhD;PhD

Disclosures

Appendix 1. Writing Group Disclosures

|Writing group member|Employment|Research grant|Other research support|Speakers noronia|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Dazhe Cao|University of Texas Southwestern Medical Center|Medical Toxicology Foundation*|None|None|None|None|None|None| |Mary E. McBride|Lurie Children's Heart Center|None|None|None|None|None|American Heart Associationt|None| |Ann M. Arens|Ochsner Health|None|None|None|None|None|None|None| |Sheryl L Chow|Western University of Health Sciences|None|None|None|None|None|None|None| |lan R. Drennan|University of Toronto; Ornge Critical Care and Transport Medicine; Sunnybrook Health Sciences (Canada)|ZOLL Medalt|None|ZOLL Medalc|None|None|None|None| |Sarah Rae Easter|Brigham and Women's Hospital, Harvard Medical School|None|None|None|None|None|None|None| |Robert S. Hoffman|NYU School of Medicine|None|None|None|None|None|None|None| |Anthony T. Lagina III|Wayne State University|None|None|None|None|None|None|None| |Eric J. Lavonas|Denver Health|None|None|None|None|None|American Heart Associationt|None| |Kaustubha D. Patil|Northwestern Medicine|None|None|Zoll Medical* Abbott Laboratories*|None|None|None|None| |Amber J. Rodriguez|American Heart Association|None|None|None|None|None|None|None| |Lauren D. Sutherland|Columbia University Irving Medical Center|None|None|None|None|None|None|None| |Janice A. Tijssen|London Health Sciences Center(Canada)|AMOSO Innovations Fund* Children's Health Research Institute*; Western Strategic Support Fund*; Physician Services Incorporated*|None|None|None|None|None|None|

$\text{(Continued)}$

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Writing Group Disclosures Continued

|Writing group member|Employment|Research grant|Other research support|Speakers|Expert bureau/ honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---|---| |George Sam Wang|Children's Hospital Colorado|NIH/NIDA*|None|None|None|Plaintiff, case involving drug-exposed children and concern for maltreatment*|None|UpToDatet'; Schmitt-Thompson Clinical Contentt|None| |Carolyn M. Zelop|The Valley Hospital and NYU|AHA/MERCK*|None|None|None|None|UpToDate*|None||

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$5000 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$5000 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.

tSignificant.

Appendix 2. Reviewer Disclosures

|Reviewer|Employment|Research grant|Other research support|Speakers bureau/ honoraria|Expert witness|Ownership interest|Consultant/advisory board|Other| |---|---|---|---|---|---|---|---|---| |lan B. Hollis|University of North Carolina|None|None|None|None|None|None|None| |Elizabeth Mack|Medical University of South Carolina|None|None|None|None|None|None|Vizient(consultant[FT employee])*| |Carl H. Rose|Mayo Clinic|None|None|None|None|None|None|None| |Kelly N. Sawyer|University of Pittsburgh|None|None|None|None|None|None|None|

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Ques-tionnaire, which all reviewers are required to complete and submit. A relationship is considered to be“significant” if(a) the person receives$5000 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$5000 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.*Significant.