Resuscitation

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Available online at http://www.sciencedirect.com

journal homepage: http://www.elsevier.com/locate/resuscitation

                             

Adult Advanced Life Support
2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations$

Jasmeet Soar, Katherine M. Berg, Lars W. Andersen, Bernd W. Bo ̈ttiger, Sofia Cacciola, Clifton W. Callaway, Keith Couper, Tobias Cronberg, Sonia D’Arrigo,
Charles D. Deakin, Michael W. Donnino, Ian R. Drennan, Asger Granfeldt,
Cornelia W.E. Hoedemaekers, Mathias J. Holmberg, Cindy H. Hsu, Marlijn Kamps, Szymon Musiol, Kevin J. Nation, Robert W. Neumar, Tonia Nicholson, Brian J. O’Neil, Quentin Otto, Edison Ferreira de Paiva, Michael J.A. Parr, Joshua C. Reynolds, Claudio Sandroni, Barnaby R. Scholefield, Markus B. Skrifvars, Tzong-Luen Wang, Wolfgang A. Wetsch, Joyce Yeung, Peter T. Morley, Laurie J. Morrison, MichelleWelsford,MaryFranHazinski,JerryP.Nolan,
onbehalfoftheAdultAdvanced Life Support Collaborators 1

Abstract

This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations for advanced life support includes updates on multiple advanced life support topics addressed with 3 different types of reviews. Topics were prioritized on the basis of both recent interest within the resuscitation community and the amount of new evidence available since any previous review. Systematic reviews addressed higher-priority topics, and included double-sequential defibrillation, intravenous versus intraosseous route for drug administration during cardiac arrest, point-of-care echocardiography for intra-arrest prognostication, cardiac arrest caused by pulmonary embolism, postresuscitation oxygenation and ventilation, prophylactic antibiotics after resuscitation, postresuscitation seizure prophylaxis and treatment, and neuroprognostication. New or updated treatment recommendations on these topics are presented. Scoping reviews were conducted for anticipatory charging and monitoring of physiological parameters during cardiopulmonary resuscitation. Topics for which systematic reviews and new Consensuses on Science With Treatment Recommendations were completed since 2015 are also summarized here. All remaining topics reviewed were addressed with evidence updates to identify any new evidence and to help determine which topics should be the highest priority for systematic reviews in the next 1 to 2 years.

Keywords: AHA Scientific Statements, arrhythmias, cardiopulmonary arrest, cardiopulmonary resuscitation and emergency cardiac care, echocardiography, post-cardiac arrest care, postresuscitation care, prognostication, sudden cardiac arrest, ventricular fibrillation

$

1

https://doi.org/10.1016/j.resuscitation.2020.09.012

0300-9572/© 2020 European Resuscitation Council, American Heart Association, Inc. and International Liaison Committee on Resuscitation. Published by Elsevier B.V. All rights reserved.

This article has been co-published in Circulation.

The list of collaborators is given in the Acknowledgements.

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Overview

The International Consensus on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) Science With Treatment Recommendations (CoSTR) is the fourth in a series of annual International Liaison Committee on Resuscitation (ILCOR) publications. This 2020 CoSTR for advanced life support (ALS) includes new topics addressed by systematic reviews performed within the past 12 months and prioritized by the ALS Task Force. In addition, it includes updates of the ALS treatment recommendations that were published from 2010 through 2019,1 8 as needed, and were based on additional evidence evaluations. As a result, this 2020 CoSTR for ALS is the most comprehensive update since 2010. The 3 major types of evidence evaluation supporting this 2020 publication are the systematic review (SysRev), the scoping review (ScopRev), and the evidence update (EvUp).

The SysRev is a rigorous process following strict methodology to answer a specific question, and each of these ultimately resulted in generation of the task force CoSTR included in this publication. The SysRevs were performed by a Knowledge Synthesis Unit, an Expert Systematic Reviewer, or by the ALS Task Force, and many resulted in separate published SysRevs.

To begin the SysRev, the question to be answered was phrased in

terms of the population, intervention, comparator, outcome, study

design, time frame (PICOST) format. The methodology used to

identify the evidence was based on the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA).9 The approach

used to evaluate the evidence was based on the one proposed by the

Grading of Recommendations, Assessment, Development and

Evaluation (GRADE) working group.10 Using this approach, the task

force rated as high, moderate, low, or very low the certainty/

confidence in the estimates of effect of an intervention or assessment

across a body of evidence for each of the predefined outcomes.

Randomized controlled trials (RCTs) generally began the analysis as

high-certainty evidence, and observational studies generally began

the analysis as low-certainty evidence; examination of the evidence by

using the GRADE approach could result in downgrading or upgrading

of the certainty of evidence. For additional information, refer to Part 2:

Evidence Evaluation Process and Guidelines Development in this supplement.11 ,11a

When we have quoted unchanged treatment recommendations from the 2010 CoSTR, the language used differs from that in the GRADE approach because GRADE was not used before 2015.12,13

Draft 2020 CoSTRs for ALS were posted on the ILCOR website14 for public comment between January 3 and January 4, 2020, with comments accepted through January 18, 2020. These new draft 2020 CoSTR statements for ALS were viewed a total of 4205 times with 11 comments received.

This summary statement contains the final wording of the CoSTR statements as approved by the ILCOR task forces and by the ILCOR member councils after review and consideration of comments posted online in response to the draft 2020 CoSTRs. Within this publication, each topic includes the PICOST as well as the CoSTR, an expanded Justification and Evidence-to-Decision Framework Highlights section, and a list of knowledge gaps requiring future research studies. An evidence-to-decision table is included for each CoSTR in Appendix A in the Supplemental Materials of this publication.

The second major type of evidence evaluation performed to support this 2020 CoSTR for ALS is a ScopRev, which identifies the extent,

range, and nature of evidence on a topic or a question. The ScopRevs were performed by topic experts in consultation with the ALS Task Force. The task force analysed the identified evidence and determined its value and implications for resuscitation practice or research. The rationale for the ScopRev, the summary of evidence, and task force insights are all highlighted in the body of this publication. The most recent treatment recommendation is included. The task force notes whether the ScopRev identified substantive evidence that may result in a change in ILCOR treatment recommendations. If sufficient evidence was identified, the task force suggested consideration of a future systematic review to supply sufficient detail to support the development of an updated CoSTR. All ScopRevs are included in their entirety in Appendix B in the Supplemental Materials of this publication.

The third type of evidence evaluation supporting this 2020 CoSTR for ALS is an EvUp. EvUps are generally performed for topics previously reviewed by ILCOR to identify new studies published after the most recent ILCOR evidence evaluation, typically through use of search terms and methodologies from previous reviews. These EvUps were performed by task force members, collaborating experts, or by members of council writing groups. The EvUps are cited in the body of this publication with reiteration of the original PICOST (if available) and a note as to whether the evidence suggested the need to consider a SysRev; the existing ILCOR treatment recommendation is quoted. In this publication, no change in ILCOR treatment recommendations resulted from an EvUp; if substantial new evidence was identified, the task force recommended consideration of a SysRev. All EvUps are included in Appendix C in the Supplemental Materials of this publication.

The ALS Task Force considered the availability of new evidence as well as the evidence needed to create, confirm, or revise treatment recommendations. The chapter topics are organized in sections according to the approximate order of the steps of resuscitation, postresuscitation care, and prognostication. For each reviewed topic, the method of review (SysRev, ScopRev, EvUp) is clearly labelled, with links to the relevant review documents in the Appendix.

Topics Reviewed in This 2020 ALS CoSTR

Note: As indicated above, the ALS CoSTR evidence reviews were all completed by January 18, 2020. As a result, this document does not address the topic of potential influence of coronavirus disease 2019 (COVID-19) on resuscitation practice. In the spring of 2020, an ILCOR writing group was assembled to identify and evaluate the published evidence regarding risks of aerosol generation and infection transmission during attempted resuscitation of adults, children, and infants. This group developed a consensus on science with treatment recommendations and task force insights. This statement is published as a separate document.15 As new evidence emerges, the ILCOR task forces will review and update this statement, so the reader is referred to the ILCOR website14 for the most up-to-date recommendations.

Defibrillation Strategies for Ventricular Fibrillation or Pulse- less Ventricular Tachycardia

Anticipatory defibrillator charging (ALS 2001: ScopRev)
Double sequential defibrillation (ALS 2003: SysRev)
Automated external defibrillator versus manual defibrillator (ALS

495: EvUp)
Waveform analysis for predicting successful defibrillation (ALS

601: EvUp)

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Airway, Oxygenation, and Ventilation During CPR

Airway management during cardiac arrest (ALS 576, 783, 432, 496, 711, 714: 2019 SysRev, CoSTR update)
Confirmation of correct tracheal tube placement (ALS 469: EvUp) Oxygen dose during CPR (ALS 889: EvUp) AutomaticventilatorsversusmanualventilationduringCPR(ALS 490: EvUp)

Circulatory Support During CPR

ECPR versus manual or mechanical CPR (ALS 723: 2018 Sys- Rev, 2019 CoSTR)

Physiological Monitoring During CPR

Monitoring physiological parameters during CPR (ALS 656: Adopted From Pediatric Task Force ScopRev)

Drugs During CPR, Including Timing of Administration

Vasopressors during cardiac arrest (ALS 788, 659, 789, 784, 778: 2019 SysRev, CoSTR)
Antiarrhythmic drugs for cardiac arrest (ALS 428, 493: 2018 SysRev, CoSTR)

Intravenous versus intraosseous drug delivery (ALS 2046: SysRev) Steroids during cardiac arrest (ALS 433: EvUp)
Buffering agents for cardiac arrest (ALS 483: EvUp)
Drugs for torsades de pointes (ALS 457: EvUp)

Intra-arrest Prognostication

Point-of-care echocardiography for prognostication during CPR (ALS 658: SysRev)
ETCO2 to predict outcome of cardiac arrest (ALS 459: EvUp)

Cardiac Arrest in Special Circumstances

Cardiac arrest associated with pulmonary embolism (ALS 435, 581: SysRev)
Cardiac arrest in pregnancy (ALS 436: EvUp)
Opioid toxicity (ALS 441: EvUp)

Postresuscitation Care

Oxygen dose after return of spontaneous circulation (ROSC) in adults (ALS 448: SysRev)
Ventilation strategy after ROSC in adults (ALS 571: SysRev) Postresuscitation haemodynamic support (ALS 570: EvUp) Postresuscitation steroids (ALS 446: EvUp)

Prophylactic antibiotics after cardiac arrest (ALS 2000: SysRev) Post-cardiac arrest seizure prophylaxis and treatment (ALS 431, 868: SysRev)
Targeted temperature management (ALS 455, 790, 791, 802, 879: EvUp)

Neurophysiological tests for prognostication (ALS 450, 713, 460: SysRev)

Blood biomarkers for prognostication (ALS 450, 713, 484: SysRev)

Imaging for prognostication (ALS 450, 713, 458: SysRev)

Defibrillation Strategies for Ventricular Fibrillation or Pulseless Ventricular Tachycardia

The task force restricted its review to 2 new topics that were based on trends in current clinical practice. These deal primarily with manual defibrillation in adults. The CoSTRs for the use of automated external defibrillators for adults can be found in Adult Basic Life Support, and for infants and children in Pediatric Life Support.

Anticipatory Defibrillator Charging (ALS 2001: ScopRev)

Rationale for Review

This topic was chosen because the timing of the rhythm check in relation to manual defibrillator charging varies by country and region. The standard method described in the 2010 American Heart Association Guidelines for CPR and ECC16 and the 2015 European Resuscitation Guidelines17 consists of briefly pausing compressions to analyse the rhythm then resuming compressions while charging the defibrillator, then pausing compressions briefly to deliver the shock. With the anticipatory method, the defibrillator is charged near the end of a compression cycle but before the rhythm is checked; then, compressions are paused briefly both to analyse the rhythm and deliver a shock. The ScopRev methodology was chosen given the limited published evidence.18

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Prognostication in Comatose Patients After Resuscitation From Cardiac Arrest

Clinical examination for prognostication (ALS 450, 713, 487: SysRev)

Population:Adultswithcardiacarrestinanysetting(in-hospitalor out-of-hospital)
Intervention: Charging the defibrillator before rhythm analysis during manual defibrillation

Comparator: Charging the defibrillator after rhythm analysis during manual defibrillation
Outcome: Survival with favourable neurological/functional out- come at discharge, 30 days, 60 days, 180 days, and/or 1 year; survival only at discharge, 30 days, 60 days, 180 days, and/or 1year; ROSC were defined as critical or important outcomes. Other outcomes were termination of arrhythmia, defibrillation success, preshock pause, postshock pause, perishock pause, hands-off time, hands-on time, compression fraction, inappropri- ate shocks, shocks during chest compression (shock to rescuer), or any other defibrillation measure.

Study design: Human and manikin studies were included. RCTs and nonrandomized studies (non-RCTs, interrupted time series, con- trolled before-and-after studies, cohort studies) were eligible for inclusion. Unpublished studies (eg, conference abstracts, trial protocols) were excluded. In addition, gray literature (evidence not published in traditional journals) was included in this ScopRev.19,20 Time frame: All years and languages were included. Studies without a title in English were excluded. MEDLINE, Embase, and Cochrane databases were updated to October 7, 2019.

Summary of Evidence

We identified no clinical studies addressing the critical or important outcomes specified in the PICOST question. Three manikin and 1 multicentre retrospective human study were identified. In the only human study,21 both methods resulted in relatively short pre- and postshock pauses, whereas anticipatory charging was associated with a shorter total hands-off time in the 30 seconds preceding shock delivery. The results of the 3 manikin studies showed reduced overall pause duration during the compression cycle, but increased pre, post, and perishock pause duration with anticipatory charging.22 24

Task Force Insights

TheScopRevisincludedin SupplementAppendixB-1.Thetaskforce noted that although anticipatory charging can reduce overall chest compression pause duration during the compression cycle, it can increase pre, post, and perishock pause duration. The clinical relevance of these findings is undetermined. Further high-quality evidence is required to evaluate the relative importance of the different typesofpausedurationforcriticalandimportantpatientoutcomes, and the role of new defibrillator technologies and methods. There are insufficient data for a SysRev to be of use at this time.

Treatment Recommendation

There was no treatment recommendation on timing of defibrillator charging previously, and in the absence of sufficient evidence, none was added.

Double Sequential Defibrillation (ALS 2003: SysRev)

Rationale for Review

This is a new topic in response to the increasing use of double (dual) sequential defibrillation (DSD). At least 20% of patients with ventricular fibrillation (VF)/pulseless ventricular tachycardia (pVT) will remain in a shockable rhythm after 3 shocks.25 28 Survival decreases as the number of defibrillation attempts required increases. DSD, or the use of 2 defibrillators to deliver 2 overlapping shocks or 2 rapid sequential shocks, one with standard pad placement and the other with either anteroposterior or additional anterolateral pad placement, has been suggested as a possible means of increasing VF termination rates.

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

 Population: Adults with cardiac arrest in any setting (in-hospital or out-of-hospital) with a shockable rhythm

 Intervention: DSD

 Comparator: Standard defibrillation

 Outcome: Favourable neurological outcome at hospital discharge,
survival to hospital discharge or admission, ROSC, or termination
of VF

 Study design: RCTs and nonrandomized studies (non-RCTs,
interrupted time series, controlled before-and-after studies, cohort
studies with 5 patients or more) are eligible for inclusion.

 Time frame: There was no date restriction, and the literature
search was updated to September 27, 2019.

 International Prospective Register of Systematic Reviews

Consensus on Science

For the critical outcomes of survival with favourable neurological outcome29 31 and survival to hospital discharge29 34 and the important outcomes of survival to hospital admission,29,30,32,33 ROSC,29 35 and termination of VF,31,34,35 we identified only observational studies. The overall certainty of evidence was rated as very low for all outcomes, primarily because of a very serious risk of bias. The individual studies were all at a critical or serious risk of bias because of confounding (due to inadequate adjustment for cardiac arrest characteristics and other factors). Because of this and a high degree of heterogeneity, no meta-analyses could be performed, and individual studies were difficult to interpret.36

TreatmentRecommendation

We suggest against routine use of a DSD strategy in comparison with a standard defibrillation strategy for cardiac arrest with a shockable rhythm (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontableisincludedin SupplementAppendixA-1. There is no strong evidence to favour one intervention compared with the other. The evidence available (very low certainty) suggests lower rates of survival and neurological outcome for patients treated with DSD, but any odds ratios (ORs) or other results reported are difficult to interpret given the very high risk of bias.36 There is no consensus standardized approach to double defibrillation, in that a double-dose strategy could be 2 overlapping shocks or 2 sequential shocks. The ALS Task Force discussed whether any potential benefit might arise from increased shock energy, the fact that 2 shocks were delivered sequentially, different pad placement and vector for the second shock, or some other reason. The task force is aware of recently published data from a small pilot RCT comparing standard defibrillation to DSD (adding a second set of defibrillator pads in the anteroposterior position) or to vector change defibrillation (replacing anterolateral pads with anteroposterior pads).37 The study found differences in VF termination (DSD 76%, vector change 82%, and standard placement 66%) and ROSC (DSD 40%, vector change 39%, and standard defibrillation 25%). This pilot RCT was not designed to formally test differences between the groups, and no survival data were reported. These results have informed a larger, ongoing RCT (NCT04080986) that will provide further data about DSD.

Implementation of DSD requires training of staff and availability of defibrillators. It is important to monitor the intervention to determine effectiveness, and to track adverse events such as harm to the patient, defibrillator damage, and the increase in resource utilization.

Knowledge Gap

High-quality studies comparing DSD with standard defibrillation in terms of survival and neurological outcome at hospital discharge

Automated External Defibrillator Versus Manual Defibrillator (ALS 495: EvUp)

Population, Intervention, Comparator, and Outcome

Population: Adults who are in cardiac arrest in any setting (in- hospital or out-of-hospital)

Intervention: Use of an automated external defibrillator or a multifunctional defibrillator in automatic mode

Comparator: Standard resuscitation (using a manual defibrillator)

(PROSPERO) Registration: CRD42020152575

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Outcome:Favourableneurologicaloutcomeathospitaldischarge, survival to hospital discharge or admission, ROSC, or termination of VF
This topic was last reviewed in 2010.43,44 The evidence update is includedin SupplementAppendixC-1andthesearchconducted was limited to January 2008 to December 2019. We identified 5 observational studies (only 2 of which included a comparison group) and no randomized trials.38 42 After consideration, a SysRev was not suggested.

Airway, Oxygenation, and Ventilation During CPR

AirwayManagementDuringCardiacArrest(ALS576,783, 432, 496, 711, 714: 2019 SysRev, CoSTR Update)

Airway management during cardiac arrest was addressed by a 2019 SysRev66 and a 2019 CoSTR summary.2,3 Consensus on science, justification and evidence-to-decision highlights, and knowledge gaps can be found in the 2019 CoSTR summary.2,3

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adults with cardiac arrest from any cause and in any setting (in-hospital or out-of-hospital)

Intervention: A specific advanced airway management method (eg, tracheal intubation or a supraglottic airway) during cardiac arrest

Comparator: A different advanced airway management method or no advanced airway management method (eg, bag-mask ventilation) during cardiac arrest

Outcome: ROSC, survival, or survival with favourable neurological outcome at discharge/28 days or longer

Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) that compared at least 2 airway strategies were eligible for inclusion. Studies with 10 or fewer patients in either group were excluded.

Time frame: All years and languages were included; unpublished studies (eg, conference abstracts, trial protocols) were excluded. The literature search was updated to October 30, 2018.

Treatment Recommendations

We suggest using bag-mask ventilation or an advanced airway strategy during CPR for adults with cardiac arrest in any setting (weak recommendation, low to moderate certainty of evidence).

If an advanced airway is used, we suggest a supraglottic airway for adults with out-of-hospital cardiac arrest (OHCA) in settings with a low tracheal intubation success rate (weak recommendation, low- certainty evidence).

If an advanced airway is used, we suggest a supraglottic airway or tracheal intubation for adults with OHCA in settings with a high trachealintubationsuccessrate(weakrecommendation,verylow- certainty evidence).

If an advanced airway is used, we suggest a supraglottic airway or tracheal intubation for adults with in-hospital cardiac arrest (IHCA) (weak recommendation, very low-certainty evidence).2,3

Confirmation of Correct Tracheal Tube Placement (ALS 469: EvUp)

Population, Intervention, Comparator, and Outcome

Population: Adults with cardiac arrest in any setting (in-hospital or out-of-hospital) requiring tracheal intubation

Intervention: Use of devices (eg, waveform capnography, CO2 detection device, esophageal detector device, or tracheal ultrasound)

Treatment Recommendation

This treatment recommendation (below) is unchanged from 2010.43,44 No significant survival differences have been demonstrated between defibrillation in semiautomatic and manual modes during out-of-hospital or in-hospital resuscitation; however, the semiauto- matic mode is preferred because it is easier to use and may deliver

fewer inappropriate shocks.
Trained personnel may deliver defibrillation in manual mode. Use

of the manual mode enables chest compressions to be continued during charging, thereby minimizing the preshock pause. When using the defibrillator in manual mode, frequent team training and ECG recognition skills are essential.

The defibrillation mode that results in the best outcome will be influenced by the system of care and by provider skills, training, and ECG recognition.

Waveform Analysis for Predicting Successful Defibrillation (ALS 601: EvUp)

Population, Intervention, Comparator, and Outcome

Population: Adults with cardiac arrest in any setting (in-hospital or

out-of-hospital)

 Intervention: Use of techniques for prediction of the likelihood of
success of defibrillation (analysis of VF, etc)

 Comparator: Standard resuscitation (without such prediction)

 Outcome: Survival with favourable neurological/functional out-
come at discharge, 30 days, 60 days, 180 days, and/or 1 year; survival only at discharge, 30 days, 60 days, 180 days, and/or 1 year; ROSC; termination of VF

 This topic was last reviewed in 2010.43,44 Two EvUps were completedfor2020andareincludedin SupplementAppendixC- 2a and C-2b. The evidence updates restricted the search to January 2008 to January 2020 and identified one large RCT conducted in 201345 and 20 observational studies.46 65 In addition, there is an ongoing multicentre RCT of real-time amplitude spectrum area to guide defibrillation (NCT03237910). Although the VF waveform analyses and outcomes studied were highly heterogeneous, given the amount of data available, an updated SysRev was suggested.
Treatment Recommendation
This treatment recommendation (below) is unchanged from 2010.43,44 There is insufficient evidence to support routine use of VF waveform analysis to guide defibrillation management in adult cardiac
arrest in- or out-of-hospital.

 Comparator: Not using these devices

 Outcome: Tracheal intubation success

 This topic was last reviewed in 2015.1,7 This EvUp is included in
Supplement Appendix C-3. An updated SysRev was not considered necessary.
Treatment Recommendations
This treatment recommendation (below) is unchanged from 2015.1,7 We recommend using waveform capnography to confirm and continuously monitor the position of a tracheal tube during CPR in addition to clinical assessment (strong recommendation, low-quality
evidence).
We recommend that if waveform capnography is not available, a
nonwaveform CO2 detector, esophageal detector device, or ultra- sound in addition to clinical assessment is an alternative (strong recommendation, low-quality evidence).1,7
Oxygen Dose During CPR (ALS 889: EvUp)
Population, Intervention, Comparator, and Outcome

 Population: Adults with cardiac arrest in any setting (in-hospital or out-of-hospital)

 Intervention: Administering a maximal oxygen concentration (eg, 100% by face mask or closed circuit)

 Comparator: No supplemental oxygen (room air) or an alternative supplemental oxygen concentration (eg, 40% to 50%)

 Outcome: Survival with favourable neurological/functional out- come at discharge, 30 days, 60 days, 180 days, and/or 1 year; survival only at discharge, 30 days, 60 days, 180 days, and/or 1 year; ROSC

 This topic was last reviewed in 2015.1,7 This EvUp is included in SupplementAppendixC-4andthesearchwasconducted from October 30, 2013, to December 2, 2019. The search identified 2 observational studies relevant to this topic published since 2015.67,68 There are no adult studies of oxygen titration during CPR. An updated SysRev was not considered necessary.
Treatment Recommendation
This treatment recommendation (below) is unchanged from 2015.1,7 We suggest using the highest possible inspired oxygen concen- tration during CPR (weak recommendation, very low-certainty
evidence).
Automatic Ventilators Versus Manual Ventilation During CPR (ALS 490: EvUp)
Population, Intervention, Comparators and Outcome

 Population: Adults and children in cardiac arrest in any setting (in- hospital or out-of-hospital) and who have advanced airways in place

 Intervention: The use of automatic ventilators

 Comparator: Use of manual ventilation

 Outcome: Ventilation, oxygenation, hands-off time, continuous
compressions, survival

 This topic was last reviewed in 2010.6,8 An evidence update is
includedin SupplementAppendixC-5.Asearchrestrictedto January 1, 2008, to December 7, 2019, identified 1 very small RCT

and 3 observational studies.69 72 An updated SysRev was not considered necessary.

Treatment Recommendation

This treatment recommendation (below) is unchanged from 2010.6,8 There is insufficient evidence to support or refute the use of an automatic transport ventilator over manual ventilation during resusci-

tation of the cardiac arrest victim with an advanced airway.

Circulatory Support During CPR

ECPR Versus Manual or Mechanical CPR (ALS 723: 2018 SysRev, 2019 CoSTR)

Extracorporeal CPR (ECPR) was addressed by a 2018 SysRev73 and a 2019 published CoSTR summary.2,3 Consensus on Science, Values, Preferences, and Task Force Insights and Knowledge Gaps can be found in the 2019 CoSTR summary.2,3

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adults (18 years or older) and children (younger than 18 years) with cardiac arrest in any setting (in-hospital or out-of- hospital)

Intervention: ECPR, including extracorporeal membrane oxygen- ation or cardiopulmonary bypass, during cardiac arrest

Comparator: Manual CPR and/or mechanical CPR
Outcome: Short-term survival and neurological outcomes (eg, hospital discharge, 28 days, 30 days, and 1 month) and long-term survival and neurological outcomes (eg, 3 months, 6 months, and

1year)
Study design: Randomized trials, non-RCTs, and observational

studies (cohort studies and case-control studies) with a control group were included. Animal studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, and letters to the editor were not included.

Timeframe:AllyearsandlanguageswereincludeduptoMay22, 2018.

Treatment Recommendations

We suggest that ECPR may be considered as a rescue therapy for selected patients with cardiac arrest when conventional CPR is failing in settings in which it can be implemented (weak recommendation, very low-certainty evidence).2,3

Physiological Monitoring During CPR

The ability to monitor physiological variables and tailor ALS interventions to the patient’s precise physiological state is appealing and hence the ongoing interest in this area.

Monitoring Physiological Parameters During CPR (ALS 656: Adopted From Pediatric Task Force ScopRev)

Rationale for Review

Physiological monitoring during CPR, including measurement of end- tidal CO2 (ETCO2) and arterial blood pressure among other

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parameters, is growing in popularity. There is limited evidence to-date on whether use of such parameters improves outcomes. This topic was last updated in 2015.1,7 A Pediatric Task Force ScopRev of physiological monitoring during CPR for 2020 also included review of the adult evidence. The adult portion of the ScopRev was included in this update.

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

 Population: Adults who are in cardiac arrest in any setting (in- hospital or out-of-hospital)

 Intervention: The use of physiological feedback in regard to CPR quality(eg,arterialcatheter,ETCO2monitoring, SpO2waveforms, or others)

 Comparator: No use of physiological feedback

 Outcome: Survival with favourable neurological/functional out-
come at discharge, 30 days, 60 days, 180 days, and/or 1 year; survival only at discharge, 30 days, 60 days, 180 days, and/or 1 year; ROSC

 Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies). If it is anticipated that there will be insufficient studies from which to draw a conclusion, case series may be included. The minimum number of cases for a case series to be included was set by the taskforce at 5. Unpublished studies (eg, conference abstracts, trial protocols) are excluded.

 Time frame: For Step 1, all languages are included if there is an English abstract. We searched articles from 2015 onward. For Step 2, if a SysRev or ScopRev of high quality (as per AMSTAR 2 tool) is identified, the search can be limited to beyond data and/or scope of that review.
Summary of Evidence
ETCO2 or Arterial Blood Pressure Monitoring. The ScopRev is includedin SupplementAppendixB-2aand2b.Weidentified 1 observational propensity-matched cohort study of adult IHCA by using data from the AHA Get With the Guidelines-Resuscitation registry.74 In this study, 3032 physiologically monitored patients (either by ETCO2 or arterial catheter) were compared with 6064 patients without such monitoring. Those monitored showed a higher rate of ROSC (OR, 1.22 [95% CI, 1.04; 1.43]) but not survival to discharge (OR, 1.04 [95% CI, 0.91; 1.18]) nor survival with favourable neurological outcome. The study did not specifically look at diastolic blood pressure. Even when an arterial catheter was in place, only about one third reported using the diastolic blood pressure to guide their CPR efforts.
Near-InfraredSpectroscopy.TheScopRevisincludedin Supple- ment Appendix B-2c. Two SysRevs were identified; the latest was published in 2018 and comprised studies published before February 2017. The SysRevs concluded that a higher cerebral oxygen saturation measured with near-infrared spectroscopy (NIRS) is associated with a higher chance of ROSC and survival and a lower NIRS is associated with an increased mortality.75,76 However, there is no consensus on specific thresholds of cerebral oxygen saturation.75 There was a wide overlap of mean or median cerebral oxygen saturation values between patients with and without ROSC, and this was also reflected in the cohort studies.77 79 Only 1 observational study80 compared the rates of

ROSC with and without NIRS monitoring and found no difference between the groups. All other studies compared NIRS values in patients who achieved ROSC with those without ROSC. Many different NIRS devices with noninterchangeable saturation indices were used across the studies, complicating comparisons.81 The findings of the observa- tional studies published since February 2017 correlate with those published in both SysRevs.

The ScopRev did not suggest the existence of sufficient new data to proceed to a SysRev.

Task Force Insights

Physiological monitoring during CPR is increasingly popular and potentially useful for both outcome prediction and real-time improve- mentinCPRquality.Theheterogeneityandobservationalnatureof available studies continues to limit the task force’s ability to make specific recommendations. The 2015 treatment recommendation is therefore unchanged.1,7

Treatment Recommendation

This treatment recommendation (below) is unchanged from 2015.1,7 We make no treatment recommendation for any particular physiological measure to guide CPR because the available evidence

would make any estimate of effect speculative.

Drugs During CPR, Including Timing of Administration

Since the 2015 CoSTR, there have been RCTs of antiarrhythmics and vasopressors during CPR82,83 and subsequent publications compar- ing the intravenous (IV) and intraosseous (IO) route for drugs.84,85

Vasopressors During Cardiac Arrest (ALS 788, 659, 789, 784, 778: 2019 SysRev, 2019 CoSTR)

The topic of vasopressors during cardiac arrest was addressed by a 2019SysRev86andapublishedCoSTRsummary.Consensuson science, justification and evidence to decision highlights, and knowledge gaps can be found in the 2019 CoSTR summary.2,3

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adults (older than 18 years) with cardiac arrest in any setting (in-hospital or out-of-hospital)

Intervention: Any vasopressor or combination of vasopressors provided intravenously or intraosseously during CPR

Comparator: No vasopressor, a different vasopressor, or a combination of vasopressors provided intravenously or intra- osseouslyduringCPR

Outcome: Short-term survival (ROSC and survival to hospital admission), midterm survival (survival to hospital discharge, 28 days, 30 days, or 1 month), midterm favourable neurological outcomes (Cerebral Performance Category [CPC] 1 2 or modified Rankin Scale [mRS] score 0 3 at hospital discharge, 28 days, 30 days, or 1 month), and long-term unfavourable and poor (mRS score 4 5) neurological outcomes (after 1 month)

Study design: Randomized trials, nonrandomized trials, and observational studies (cohort and case-control studies) with a comparison group were included.

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Time frame: All years and languages were included if there was an English abstract to November 23, 2018.

Treatment Recommendations

We recommend administration of epinephrine during CPR (strong recommendation, low to moderate certainty of evidence).

For nonshockable rhythms (pulseless electric activity/asystole), we recommend administration of epinephrine as soon as feasible during CPR (strong recommendation, very low-certainty evidence).

For shockable rhythms (VF/pVT), we suggest administration of epinephrine after initial defibrillation attempts are unsuccessful during CPR (weak recommendation, very low-certainty evidence).

We suggest against the administration of vasopressin in place of epinephrine during CPR (weak recommendation, very low-certainty evidence).

We suggest against the addition of vasopressin to epinephrine during CPR (weak recommendation, low-certainty evidence).2,3

Additional Task Force Commentary

Concerns have been expressed about epinephrine increasing the number of survivors with unfavourable neurological outcome in the PARAMEDIC2 trial (Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest). The opinion of the ALS Task Force, however, is that any drug that increases the rate of ROSC and survival, but is given after several minutes of cardiac arrest when some degree of neurological damage may already have occurred, will likely increase the number of survivors with both favourable and unfavourable neurological outcome. Determining the likelihood of favourable or unfavourable neurological outcome at the time of starting resuscita- tion is currently not feasible. Therefore, the task force consensus is that continuing to use a drug that increases survival and focusing efforts on providing earlier CPR, earlier drug administration, and improved postresuscitation care for all patients is likely to increase survival with a favourable neurological outcome.

Antiarrhythmic Drugs for Cardiac Arrest (ALS 428, 493: 2018 SysRev, CoSTR)

This topic was addressed by a 2018 SysRev87 and a published 2018 CoSTR summary.4,5 Consensus on Science, Values and Prefer- ences, Task Force Insights, and Knowledge Gaps can be found in the 2018 CoSTR summary.4,5

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

 Population: Adults and children in cardiac arrest in any setting (in- hospital or out-of-hospital) and a shockable rhythm at any time during CPR or immediately after ROSC

 Intervention: Administration (intravenously or intraosseously) of an antiarrhythmic drug during CPR or immediately (within 1 hour) after ROSC

 Comparator: Administration of another anti-arrhythmic drug or placebo or no drug during CPR or immediately after ROSC

 Outcome: Survival to hospital discharge with good neurologic outcome and survival to hospital discharge were ranked as critical outcomes. ROSC was ranked as an important outcome. For antiarrhythmic drugs after ROSC, rearrest was included as an important outcome.

Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion.

Time frame: All years and languages were included if there was an English abstract; unpublished studies (eg, conference abstracts, trial protocols) were excluded. The literature search was updated to August 15, 2017.

Treatment Recommendations

We suggest the use of amiodarone or lidocaine in adults with shock- refractory VF/pVT (weak recommendation, low certainty evidence).

We suggest against the routine use of magnesium in adults with shock-refractory VF/pVT (weak recommendation, very low-certainty evidence).

The confidence in effect estimates is currently too low to support an ALS Task Force recommendation about the use of bretylium, nifekalant, or sotalol in the treatment of adults in cardiac arrest with shock refractory VF/pVT.

The confidence in effect estimates is currently too low to support an ALS Task Force recommendation about the use of prophylactic antiarrhythmic drugs immediately after ROSC in adults with VF/pVT cardiac arrest.4,5

IV Versus IO Drug Delivery (ALS 2046: SysRev)

Rationale for Review

This is a new ALS question that was based on the increasing use of IO access during adult resuscitation. It can often be difficult to obtain IV access, especially in the prehospital setting. IO access as an alternative to IV access is increasingly used during cardiac arrest. However, whether drugs are as effective when administered intra- osseously versus intravenously is unknown. This 2020 CoSTR is informed by a 2020 SysRev.88

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population:Adultswithcardiacarrestinanysetting(in-hospitalor out-of-hospital)

Intervention: Placement of an IO cannula and drug administration through this IO during cardiac arrest

Comparator: Placement of an IV cannula and drug administration through this IV during cardiac arrest

Outcome: ROSC, or survival/survival with a favourable neurologi- cal outcome at hospital discharge, 30 days, or longer

Study design: Randomized trials, non-RCTs, and observational studies (cohort studies and case-control studies) comparing IO with IV administration of drugs were included. Randomized trials assessing the effect of specific drugs (ie, epinephrine and amiodarone/lidocaine) in subgroups related to IO versus IV administration were also included. Ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, and unpublished studies were not included. Studies assessing cost-effectiveness were included for a descriptive summary.

Time frame: The literature search was performed on September 12, 2019, and updated on December 17, 2019, with no date restrictions.

PROSPERO Registration: CRD42020150877

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Consensus on Science

For the important outcome of ROSC, we identified very low-certainty evidence (downgraded for risk of bias and inconsistency) from 4 observational studies89 92 including 70 419 adults with OHCA, demonstrating an association of worse outcomes with the use of IO access when compared with IV access (adjusted OR, 0.72 [95% CI, 0.68 0.76]; P < 0.00001; absolute risk difference, 6.1% [95% CI, 7.1 to 5.2] or 61 fewer per 1000 cardiac arrests had ROSC with IO access compared with IV access [95% CI, 71 fewer to 52 fewer]).

For the critical outcome of survival to hospital discharge, we identified very low-certainty evidence (downgraded for risk of bias and inconsistency) from 4 observational studies89 92 including 70 419 adult OHCAs, demonstrating an association of worse outcomes with the use of IO access when compared with IV access (adjusted OR, 0.71 [95% CI, 0.63 0.79]; P<0.00001; absolute risk difference, 2.0% [95% CI, 2.5 to 1.4] or 20 fewer per 1000 cardiac arrests with survival to hospital discharge with use of IO access compared with IV access [95% CI, 25 fewer to 14 fewer]).

For the critical outcome of survival to hospital discharge with a favourable neurological outcome, we identified very low-certainty evidence (downgraded for risk of bias and inconsistency) from 3 observational studies89,91,92 including 68 619 adult OHCAs, demonstrating an association of worse outcomes with the use of IO access when compared with IV access (adjusted OR, 0.60 [95% CI, 0.52 0.69]; P < 0.00001; absolute risk difference, 1.9% [95% CI, 2.3 to 1.5] or 19 fewer per 1000 cardiac arrests with survival to hospital discharge with a favourable neurological outcome with use of IO access compared with IV access [95% CI, 23 fewer to 15 fewer]).

In addition to these findings from observational studies, we identified2RCTsofdrugadministrationduringcardiacarrestthat performed subgroup analyses according to IO versus IV route of administration.84,85 None of the comparisons showed statistically significant effect modification. The point estimates generally favored IV access as compared with IO access, except for the outcome of ROSC in the PARAMEDIC2 trial where the effect of epinephrine was similar when given IV or IO. These 2 trials were underpowered to assess such interactions for any outcomes other than ROSC.

Treatment Recommendations

We suggest IV access as compared with IO access as the first attempt for drug administration during adult cardiac arrest (weak recommen- dation, very low-certainty evidence).

If attempts at IV access are unsuccessful or IV access is not feasible, we suggest IO access as a route for drug administration during adult cardiac arrest (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontableisincludedin Supplement Appendix A-2. Although the overall certainty in the evidence is very low, the current evidence suggests that outcomes might be better with IV versus IO drug administration. The task force discussed the possibility of unaccounted-for confounders in comparing patients for whom an IV could be obtained with those who required IO placement for access. The task force also discussed that 2015 council guidelines suggest that IO access should be used only if IV access is “difficult or impossible”17 or “not readily available.”93 The included studies did not enable meaningful analysesofspecificsubgroups.ThedocumentedIOsitewasprimarily tibial, but the site was often not documented. As such, no statements can be made about difference between tibial and humeral (or other) IO sites.

All studies were conducted in OHCA patients. Although IHCA patients are likely to have existing IV access, this is not universally true. Although there might be differences in provider skills and patient characteristics between OHCA and IHCA, we consider it unlikely that these would lead to substantial effect modification. As such, the above recommendations apply to both IHCA and OHCA.

Knowledge Gap

The overall certainty in the evidence is very low. As such, there is clinical equipoise for additional trials related to IV versus IO drug administration during cardiac arrest. These could include trials that directly compare IV to different sites of IO access (eg, tibial, humeral).

Steroids During CPR (ALS 433: EvUp)

Population, Intervention, Comparator, and Outcome

Population: Adults who are in cardiac arrest in any setting (in- hospital or out-of-hospital)

Intervention: Corticosteroid or mineralocorticoid administration during CPR

Comparator: Not using steroids
Outcome: Survival with favourable neurological/functional out-

come at discharge, 30 days, 60 days, 180 days, and/or 1 year; survival only at discharge, 30 days, 60 days, 180 days, and/or 1 year; ROSC

Intra-arrest steroid use was last reviewed in 2015.1,7 The EvUp for intra-arreststeroiduseisincludedin SupplementAppendixC-6. The search identified 2 large, population-based observational studies published since the 2015 CoSTR,94,95 both of which suggest a possible association between the use of corticosteroids during CPR and improved survival. Three ongoing clinical trials on this topic were also identified (NCT02790788, NCT03640949, NCT03317197). The task force will prioritize a SysRev when the results of these trials become available.

Treatment Recommendation

This treatment recommendation (below) is unchanged from 2015.1,7 For IHCA, the task force was unable to reach a consensus recommendation for or against the use of steroids during cardiac arrest. We suggest against the routine use of steroids during CPR for

OHCA (weak recommendation, very low-certainty evidence).

Buffering Agents for Cardiac Arrest (ALS 483: EvUp)

Population, Intervention, Comparator, and Outcome

Population: Adults with cardiac arrest in any setting (in-hospital or out-of-hospital)

Intervention: The use of buffering agents alone or combination with other drugs

Comparator: Not using drugs (or a standard drug regimen)
Outcome: ROSC, survival, survival with favourable neurological

outcome
This topic was last reviewed in 2010.6,8 An EvUp was completed

for2020andisincludedin SupplementAppendixC-7.Onesmall RCT and 4 observational studies were identified.96 100 An updated SysRev was not considered necessary.

Treatment Recommendation

This treatment recommendation (below) is unchanged from 2010.6,8 Routine administration of sodium bicarbonate for treatment of

IHCA and OHCA is not recommended.

Drugs for Torsades de Pointes (ALS 457: EvUp)

Population, Intervention, Comparator, and Outcome

 Population: Adults with torsades de pointes in any setting (in- hospital or out-of-hospital)

 Intervention: Any drug or combination of drugs

 Comparator: Not using drugs or alternative drugs

 Outcome: ROSC, survival, or survival with favourable neurological
outcome ThisPICOwaslastreviewedin2010.6,8AnEvUpisincludedin
Supplement Appendix C-8. No studies meeting inclusion criteria were identified, and thus consideration of an updated SysRev was not suggested.
Treatment Recommendation
This treatment recommendation (below) is unchanged from 2010.6,8 Polymorphic wide-complex tachycardia associated with familial long QT may be treated with IV magnesium, pacing, and/or beta
blockers; however, isoprenaline should be avoided.
Polymorphic wide-complex tachycardia associated with acquired
long QT may be treated with IV magnesium.
Addition of pacing or IV isoprenaline may be considered when
polymorphic wide-complex tachycardia is accompanied by bradycar- dia or appears to be precipitated by pauses in rhythm.
Intra-arrest Prognostication
Point-of-Care Echocardiography for Prognostication During CPR (ALS 658: SysRev)
Rationale for Review
In 2015, the question of whether the use of cardiac ultrasound during CPR changed outcomes was reviewed.1,7 This question has not been reviewedforthe2020CoSTRforALS,andthe2015CoSTRcurrently remains: We suggest that if cardiac ultrasound can be performed without interfering with standard advanced cardiovascular life support protocols, it may be considered as an additional diagnostic tool to identify potentially reversible causes (weak recommendation, very low-quality evidence).1,7
The current question is different from that mentioned above and was prioritized by the ALS Task Force due to the increasing popularity of the use of point-of-care echocardiography during cardiac arrest as a prognostic tool, as well as concern about potential pitfalls for misinterpretation of ultrasound findings. A task

force led SysRev of the intra-arrest prognostic capabilities of point- of-care echocardiography was performed to inform the 2020 CoSTR for ALS.101

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adults with cardiac arrest in any setting (in-hospital or out-of-hospital).

Intervention: A particular finding on point-of-care echocardiogra- phy during CPR

Comparator: The absence of that finding or a different finding on point-of-care echocardiography during CPR

Outcome:Clinicaloutcomesinclude,butarenotnecessarilylimited to, ROSC, survival to hospital admission, (both important) and the critical outcomes of survival/survival with a favourable neurological outcome at hospital discharge, and survival/survival with a favourable neurological outcome beyond hospital discharge.

Study design: Randomized trials, non-RCTs, observational studies (cohort studies and case-control studies), registries, and prognosis studies. Ecological studies, case series, case reports, reviews, abstracts, editorials, comments, letters to the editor, or unpublished studies will not be included.

Time frame: All years and languages were included if there was an Englishabstract,andtherewerenodaterestrictions.Theliterature search was updated to September 18, 2019.

PROSPERO Registration: CRD42020150677.

Consensus on Science
The SysRev identified no RCTs and 15 relevant observational studies.102 116 The overall certainty of evidence was rated as very low for all outcomes primarily due to risk of bias, inconsistency, and/or imprecision. There was a substantial risk of bias due to prognostic factor measurement, outcome measurement, adjustment for prog- nostic factors, or confounding. Because of this and a high degree of clinical heterogeneity, no meta-analyses could be performed, and individual studies are difficult to interpret. The consensus on science is summarized in Table 1. The summary of each outcome is separated by the ultrasonographic finding (organized contractility versus non- organized and/or unspecified motion) and timing of image acquisition (initial, every, any, or subsequent evaluation; or unspecified) because these also varied considerably across studies.

Treatment Recommendation

We suggest against the use of point-of-care echocardiography for prognostication during CPR (weak recommendation, very low- certainty evidence)

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontableisincludedin Supplement Appendix A-3. This CoSTR specifically addresses the role of ultrasound in prognostication, and in particular prognostication of a favourable outcome that is based on the presence of cardiac motion. In 2015, the task force stated that ultrasound had a potential role in diagnosing reversible causes of cardiac arrest if it could be done without interfering with high-quality CPR, and this recommendation was not reassessed for 2020.1,7

Given the increasing popularity of the use of point-of-care echocardiography for prognostication during attempted resuscitation after cardiac arrest, this comprehensive and rigorous summary of its intra- arrest prognostic capabilities provides valuable information to both the resuscitation science community and bedside clinicians. In making these recommendations, the ALS Task Force considered the following:

There were inconsistent definitions and terminology about the sonographic evidence of cardiac motion. This included wide variation in the classification of anatomy, type of motion, and timing of point-of- care echocardiogram. The task force encourages the establishment of uniform definitions and terminology to describe sonographic findings of cardiac activity during cardiac arrest.

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Table 1 – Estimated Prognostic Test Performance and Prognostic Association for Sonographic Findings on Point-of- Care Echocardiography During Cardiac Arrest to Predict Clinical Outcomes.

Outcome Author, Year Total Subjects (n), Sensitivity Specificity Odds Ratio
IHCA or OHCA (Range or 95% CI) (Range or 95% CI) (Range or 95% CI)

Organized Cardiac Motion (Unspecified Timing of Echocardiography)

Survival 180 days
Survival to hospital discharge Survival to hospital admission ROSC

Flato, 2015113 Atkinson, 2019108

Flato, 2015113 Atkinson, 2019108 Blaivas, 2001109 Atkinson, 2019108 Flato, 2015113

49, IHCA
229, IHCA and OHCA 349, OHCA
229, IHCA and OHCA

1.0 (95% CI, 0.4 1.0) 0.67 1.00
0.39 1.00
0.34 0.79

0.49 (95% 0.64) 0.51 0.89

0.91 0.91 0.68 0.96

0.78 (95% 0.89) 0.49 0.94

0.55 0.85

0.78 1.00

0.92 1.00

0.49 (95% 0.64) 0.86 (95% 0.93) 0.77 (95% 0.83) 0.60 0.84

0.33 0.98

0.79 (95% 0.94) 1.00 (95% 1.00)

0.45 (95% 0.68) 0.21 (95% 0.51)

0.89 0.98 0.95 0.99

0.84 0.94

CI, 0.34

CI, 0.62

8.62 (95% CI, 0.44 169.38)
13.60 16.63

6.73 414.56 8.07 13.21

10.26 (95% CI, 0.39 273.09)
0.38 17.00

0.75 27.56

6.33 16.11

45.33 148.20

8.62 (95% CI, 0.44
169.38)
17.00 (95% CI, 0.65 446.02)

3.09 (95% CI, 1.29 7.37)
9.14 14.00

23.18 289.00

3.75 (95% CI, 0.19
74.06)
52.50 (95% CI, 2.10 1300.33)

0.13 (95% CI, 0.01 3.11)
0.02 (95% CI, 0.00 0.53)

1.32 4.25 0.61 4.70

0.38 125.00

Nonorganized and/or Unspecified Cardiac Motion on Initial Echocardiogram

Good neurological outcome at discharge
Survival to hospital discharge

Survival to hospital admission

ROSC

Aichinger, 2012107 Gaspari, 2016114

Varriale, 1997106 Zengin, 2016116 Aichinger, 2012107 Gaspari, 2016114 Salen, 2001104 Zengin, 2016116 Gaspari, 2016114 Kim, 2016115 Varriale, 1997106

42, OHCA

1171, y IHCA and OHCA

1295,y IHCA and OHCA

861, IHCA and OHCA

1.00 (95% 1.00) 0.06 0.91

0.11 0.92

0.25 0.64

0.50 0.80

CI, 0.03

Nonorganized and/or Unspecified Cardiac Motion on Every Echocardiogram

Survival to hospital admission

Aichinger, 2012107 134,* OHCA Salen, 2001104

Nonorganized and/or Unspecified Cardiac Motion (Unspecified Timing of Echocardiography)

Good neurological outcome at 180 days
Good neurological outcome at discharge

Survival to hospital discharge Survival to hospital admission

ROSC

Flato, 2015113

Salen, 2005103

Lien, 2018102

Breitkreutz, 2010110 Chua, 2017112 Salen, 2001104 Chardoli, 2012111 Lien, 2018102 Salen, 2005103 Tayal, 2003105

49, IHCA 70, OHCA 177, OHCA 291,* OHCA

317, OHCA

1.00 (95% CI, 0.40 1.00)
1.00 (95% CI, 0.03 1.00)

0.48 (95% CI, 0.28 0.69)
0.72 0.86

0.62 1.00

0.50 (95% CI, 0.01 0.99)
0.67 (95% CI, 0.22 0.96)

CI, 0.34 CI, 0.75 CI, 0.69

CI, 0.54 CI, 0.77

CI, 0.23 CI, 0.05

Return of Organized Cardiac Motion on Subsequent Echocardiogram

Survival to hospital discharge ROSC

Varriale, 1997106 Varriale, 1997106

20, IHCA 20, IHCA

Coalescent Echo Contrast (ie, Visible Clotted Intra-Cardiac Blood) After 20 30 min of CPR

Survival to hospital discharge ROSC

Varriale, 1997106 Varriale, 1997106

20, IHCA 20, IHCA

1130,y IHCA and OHCA 531,y IHCA and OHCA

317,y IHCA and OHCA

0.00 (95% 0.84) 0.00 (95% 0.46)

0.00 0.15 0.03 0.04

0.00 1.00

CI, 0.00 CI, 0.00

Sonographic Evidence of Treatable Pathology

Survival to hospital discharge

Survival to hospital admission ROSC

Gaspari, 2016114 Varriale, 1997106 Zengin, 2016116 Zengin, 2016116 Chardoli, 2012111 Lien, 2018102 Tayal, 2003105 Varriale, 1997106

IHCA indicates in-hospital cardiac arrest; OHCA, out-of-hospital cardiac arrest; and ROSC, return of spontaneous circulation.
* Studies did not report these data for all enrolled subjects; n is lower than the total of all subjects enrolled.
y Gaspari et al and Zengin et al report multiple sonographic findings within a given category on the same subjects; n reflects composite variable “subject-

assessments ”.

Most of the identified studies suffer from high risk of bias related to prognostic factor measurement, outcome measurement, lack of adjustment for other prognostic factors, and confounding from self- fulfilling prophecy and unspecified timing of point-of-care echocardi- ography. Because the risk of bias and heterogeneity across studies was high, no meta-analyses were performed. The evidence support- inguseofpoint-of-careechocardiographyasaprognostictoolduring cardiac arrest is uniformly of very low certainty. Clinicians should interpret sonographic findings during cardiac arrest in light of these limitations. The task force encourages subsequent investigators studying point-of-care echocardiography during cardiac arrest to identify methodology that mitigates these risks of bias.

Only 2 studies113,114 reported estimates of inter-rater reliability (Kappa 0.63 and 0.93). More uniform reporting of inter-rater reliability of point-of-care echocardiography interpretation in future investiga- tions is important.

No sonographic finding had sufficient and/or consistent sensitivity for any clinical outcome for its absence to be used as a sole criterion to stop resuscitation, but the certainty of this evidence is very low.

Some sonographic findings had higher ranges of specificity for clinical outcomes, but the certainty of this evidence is very low.

The impact of ECPR on the prognostic accuracy of point-of-care echocardiography is uncertain.

Point-of-care echocardiography may still be useful to diagnose treatable etiologies of cardiac arrest or to intermittently assess response to resuscitative treatments. These applications are not within the scope of this particular PICOST question. We do, however, caution against overinterpreting the finding of right-ventricular dilation in isolation as a diagnostic indicator of massive pulmonary embolism. Right-ventricular dilation begins a few minutes after onset of cardiac arrest as blood shifts from the systemic circulation to the right heart along a pressure gradient.117,118 Right-ventricular dilation was uniformly observed in a porcine model of cardiac arrest across etiologies of hypovolemia, hyperkalemia, and primary arrhythmia.119

Clinicians should be cautious about potentially prolonging interruptions in chest compressions when using point-of-care echocardiography during cardiac arrest.120,121 Several strategies to minimize these interruptions have been proposed.122,123

Point-of-care echocardiography is subject to availability of equipment and skilled operators.

Knowledge Gaps

 There is no standardized or uniform definition of cardiac motion visualized on point-of-care echocardiography during cardiac arrest.

 There are very few prognostic factor studies of point-of-care echocardiography during cardiac arrest performed with method- ology that minimizes risk of bias.

 The inter-rater reliability of point-of-care echocardiography during cardiac arrest is uncertain.

 The relative roles and feasibility of transesophageal versus transthoracic echocardiography during CPR require research.
ETCO2 to Predict Outcome of Cardiac Arrest (ALS 459: EvUp)
Population, Intervention, Comparator, and Outcome
Population: Adults who are in cardiac arrest in any setting (in- hospital or out-of-hospital)

Intervention: Any ETCO2 level value, when present
Comparator: Any ETCO2 level below that value
Outcome: ROSC, survival, survival with favourable neurological

outcome
This topic was last updated in a published 2015 CoSTR,1,7 and the

SysRev that informed this CoSTR was published in 2018.124 The 2 EvUpsareincludedin SupplementAppendixC-9aandC-9b.A search from December 2013 to November 2019 identified 7 new observational studies74,80,125 129 in addition to the previous SysRev.124 The task force discussed the low likelihood of an updated SysRev leading to a change in treatment recommenda- tions based on the available studies, and therefore did not prioritize this topic for a SysRev at this time. Future studies and SysRevs should consider trends and changes in ETCO2 values during CPR in addition to the significance of single ETCO2 values. The 2015 treatment recommendations remain unchanged.1,7

Treatment Recommendations

This treatment recommendation (below) is unchanged from 2015.1,7 We recommend against using ETCO2 cutoff values alone as a mortality predictor or for the decision to stop a resuscitation attempt

(strong recommendation, low-quality evidence).
We suggest that an ETCO2 of 10 mm Hg or greater measured after

tracheal intubation or after 20minutes of resuscitation may be a predictor of ROSC (weak recommendation, low-quality evidence).

We suggest that an ETCO2 of 10 mm Hg or greater measured after tracheal intubation, or an ETCO2 of 20 mm Hg or greater measured after 20 minutes of resuscitation, may be a predictor of survival to discharge (weak recommendation, moderate-quality evidence).

Cardiac Arrest in Special Circumstances

Cardiac Arrest Associated With Pulmonary Embolism (ALS 435, 581: SysRev)

Rationale for Review

Pulmonary embolism (PE) is a potentially reversible cause of cardiac arrest. Whether chances for ROSC and survival may be significantly higher if a PE is present and can be treated is not well established because research has been limited to-date. This topic was last reviewed in 2015.1,7 The specific role of ECPR was not addressed in this updated SysRev because ECPR was addressed in the previous 2019 CoSTR summary.2,3 The role of ECPR for the treatment of PE and cardiac arrest is discussed in the justification section that follows.

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adults in cardiac arrest due to PE or suspected PE in any setting (in-hospital or out-of-hospital)

Intervention: Any specific alteration in the ALS treatment algorithm (eg, fibrinolytics or any other)

Comparator: Standard ALS care
Outcome: Survival with favourable neurological outcome at

discharge, 30 days, 60 days, 180 days, and/or 1 year; survival at discharge, 30 days, 60 days, 180 days, and/or 1year (all critical); ROSC (important)

Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort

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studies) are eligible for inclusion. Unpublished studies (eg, conference abstracts, trial protocols) are excluded.
Time frame: All years and languages were included if there was an English abstract. Literature search was updated to October 2019. PROSPERO Registration: Registered with ILCOR Science Advisory Committee October 6, 2019. This SysRev was done as an update of the 2015 CoSTR SysRev and PROSPERO registration was not done.

The overall certainty of evidence was rated as very low primarily due to a very serious risk of bias and inconsistency. For this reason, no meta-analyses were performed.

Treatment Recommendations

These recommendations (below) are unchanged from 2015.1,7 We suggest administering fibrinolytic drugs for cardiac arrest when PE is the suspected cause of cardiac arrest (weak recommendation, very low-certainty evidence).

We suggest the use of fibrinolytic drugs or surgical embolectomy or percutaneous mechanical thrombectomy for cardiac arrest when PE is the known cause of cardiac arrest (weak recommendation, very low- certainty evidence).

Consensus on Science

Fibrinolysis. For the critical outcome of survival with favourable
neurological outcome at 30 days, we identified very low-certainty
evidence (downgraded for serious imprecision and very serious risk of
bias) from a subgroup of 37 patients with confirmed PE from 1 RCT comparingfibrinolyticswithplaceboduringcardiacarrest130findingnoTheevidence-to-decisiontableisincludedin Supplement difference between groups [tenecteplase 2/15, (13.3%) versus

placebo, 0/22 (0%)] [risk ratio (RR), 7.19; 95% CI, 0.37 139.9]. We also identified very low-certainty evidence (downgraded for risk of bias) from a single observational study that found no difference (10% with fibrinolysis versus 5% without; adjusted RR [ARR], 1.97; 95% CI, 0.70 5.56).131

For the critical outcome of survival at 30 days, very low-certainty evidence (downgraded for risk of bias) from one observational study showed an association between improved survival and administration of fibrinolysis (16% with fibrinolysis versus 6% without; P = 0.005).131

For the critical outcome of survival to hospital discharge, very low- certainty evidence (downgraded for very serious risk of bias and imprecision) from 3 retrospective observational studies showed no association between administration of fibrinolysis and survival (10.5% survival with fibrinolysis versus 8.7% without;132 9.5% survival with fibrinolysis versus 4.8% without133 and 19.4% survival with fibrinolysis versus 6.7% without (RR, 2.9; 95% CI, 0.75 13.8).134

For the important outcome of ROSC, very low-certainty evidence from 1 study (downgraded for very serious risk of bias) showed benefit associated with the use of fibrinolytic drugs compared with no fibrinolytic drugs in patients with PE (81.0% with fibrinolysis versus 42.9% without; P = 0.03).133 Two other studies provided very low- certainty evidence (downgraded for very serious risk of bias) of no difference in ROSC (66.7% with fibrinolysis versus 43.3% without [RR, 1.5; 95% CI, 0.8 8.6] and 47.4% with fibrinolysis versus 47.8% without; P = 0.98).132,134

For the outcome of survival at 24hours, very low-certainty evidence (downgraded for risk of bias) from 1 observational study showed no difference associated with fibrinolysis (66% with fibrinoly- sis versus 63% without; P = 0.76),131 whereas another study showed benefit associated with fibrinolysis (52.8% with fibrinolysis versus 23.3% without; RR, 2.3; 95% CI, 1.1 4.7).134

Surgical Embolectomy. We found very low-certainty evidence (downgraded for very serious risk of bias) from 2 case series135,136 with no control groups and a total of 21 patients requiring CPR with a 30-day survival rate of 12.5% and 71.4%, respectively.

Percutaneous Mechanical Thrombectomy. For the important outcome of ROSC, very low-certainty evidence (downgraded for very serious risk of bias and very serious imprecision) from 1 case series of 7 patients with cardiac arrest with no control group,137 ROSC wasachievedin6of7patients(85.7%)treatedwithpercutaneous mechanical thrombectomy.

Appendix A-4. The task force considered that mechanical or surgical thrombectomy would be used only if the patient had a confirmed PE. No RCTs were identified and no meta-analysis was undertaken given the limited evidence.

The task force considered that 2% to 7% of patients with OHCA have a PE,130,131 and this figure is probably higher for patients with IHCA. The task force acknowledged that ECPR techniques are now frequently used in patients with cardiac arrest from suspected PE in those settings where it is feasible. This role of ECPR for advanced life support was addressed by the 2019 CoSTR summary, and the considered studies included patients with PE.2,3 Specifically in patients with PE, ECPR may potentially facilitate the use of fibrinolysis or mechanical or surgical embolectomy, but the evidence is of very low certainty.

The task force considered the increased risk of bleeding from fibrinolysis if it is administered to patients without PE. The Thrombolysis in Cardiac Arrest (TROICA) Study—which is the largest study of thrombolysis during cardiac arrest—showed an increased risk of bleeding in the thrombolysis group (any intracranial hemorrhage, 2.7% versus 0.4%; RR, 6.95 [95% CI, 1.59 30.41]; P = 0.006), but major bleeding complications did not occur more often (symptomatic intracranial hemorrhage, 0.8% versus 0%; RR, 8.93 [95% CI, 0.48 165.45]; P = 0.13; major nonintracranial hemorrhage, 7.7% versus 6.4; RR, 1.21 [95% CI, 0.77 1.88]; P = 0.48; ischemic stroke, 0.8% versus 0.6%; RR, 1.32 [95% CI, 0.30 5.88]; P = 1.00).130 Patients are far more likely to die from the cardiac arrest than from the treatment.

Knowledge Gap

OptimaldruganddosingstrategyforfibrinolysisduringCPRwitha suspected or actual PE

Intra-arrest prediction of PE during CPR
Cardiac Arrest in Pregnancy (ALS 436: EvUp) Population, Intervention, Comparator, and Outcome

Population: Pregnant women who are in cardiac arrest in any setting Intervention: Any specific intervention(s)
Comparator: Standard care (usual resuscitation practice)
Outcome: ROSC; survival to discharge, 30 days, or longer;

survival with favourable neurological outcome at discharge, 30

days, or longer AnEvUpisincludedin SupplementAppendixC-10.Sincethe

2015 CoSTR,1,7 7 new small observational studies were identified,

Justification and Evidence-to-Decision Framework Highlights

5 of which focused on association of timing of delivery with outcome of cardiac arrest and other factors associated with maternal and fetal mortality.138 142 Due to the very small size of most studies, an updated SysRev was not suggested. The 2015 treatment recommendation remains unchanged.1,7

Treatment Recommendation

This treatment recommendation (below) is unchanged from 2015.1,7 We suggest delivery of the fetus by perimortem cesarean delivery for women in cardiac arrest in the second half of pregnancy (weak

recommendation, very low-quality evidence).
There is insufficient evidence to define a specific time interval by

which delivery should begin.
High-quality usual resuscitation care and therapeutic interventions

that target the most likely cause(s) of cardiac arrest remain important in this population.

There is insufficient evidence to make a recommendation about the use of left-lateral tilt and/or uterine displacement during CPR in the pregnant patient.

Opioid Toxicity (ALS 441: EvUp)

Death from opioid toxicity is an important public health issue in many countries. The issue of first aid education for opioid toxicity has been addressed by the EIT Task Force ScopRev 891.142a,142b

Population, Intervention, Comparator, and Outcome

 Population: Adults who are in cardiac arrest or respiratory arrest due to opioid toxicity in any setting (in-hospital or out-of-hospital)

 Intervention: Any specific therapy (eg, naloxone, bicarbonate, or
other drugs)

 Comparator: Usual ALS care

 Outcome: Survival with favourable neurological/functional
outcome at discharge, 30 days, 60 days, 180 days, and/or 1 year; survival only at discharge, 30 days, 60 days, 180 days, and/or 1year; ROSC were defined as critical or important outcomes
Thistopicwaslastreviewedin2015.1,7TheEvUpisincludedin Supplement Appendix C-11. The search was conducted for studies published from September 1, 2013 to September 13, 2019. There was insufficient evidence to support consideration of a stand-alone ALS SysRev, but an updated SysRev with other task forces was suggested.
Treatment Recommendations
This treatment recommendation (below) is unchanged from 2015.1,7 We recommend the use of naloxone by IV, intramuscular, subcutaneous, IO, or intranasal routes in respiratory arrest associated with opioid toxicity (strong recommendation, very low-quality
evidence). The dose of naloxone required will depend on the route. We can make no recommendation about the modification of
standard ALS in opioid-induced cardiac arrest.
Postresuscitation Care
The last update of postresuscitation care was published in the 2015 CoSTR.1,7 Since that publication, there have been many reported studies of postresuscitation care.143

Oxygen Dose After ROSC in Adults (ALS 448: SysRev)

Rationale for Review

Both hypoxemia and hyperoxemia during postresuscitation care have been associated with worse outcomes. Hypoxemia may worsen ischemic brain injury and injury to other organs, and hyperoxemia may lead to increased oxidative stress and organ damage after reperfu- sion. A SysRev was conducted to inform this 2020 CoSTR for ALS.144

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Unresponsive adults with sustained ROSC after cardiac arrest in any setting

Intervention: A ventilation strategy targeting a specific oxygen saturation and/or Pao2

Comparator: Treatment without specific targets or with an alternate target to the intervention

Outcome: Critical outcomes include survival/survival with a favourable neurological outcome at hospital discharge or 30 days; and survival/survival with a favourable neurological outcome after hospital discharge or 30 days (eg, 90 days, 180 days, 1 year).

Study design: Randomized trials, non-RCTs, and observational studies (cohort studies and case-control studies) with a control group (ie, patients treated with no specific oxygen saturation and/or Pao2 targets or an alternative target to the intervention) were included. Animal studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, and letters to the editor were not included. There were no limitations on publication period or study language, if there was an English abstract. The population included patients with IHCA or OHCA of any origin. Unpublished studies (eg, conference abstracts, trial protocols) were excluded. The cited SysRev144 was perfomed without age restriction, and the evidence from adult studies (generally defined as older than 16 years or 18 years or older) is included here.

Time frame: All years and languages were included. The literature search was updated to August 22, 2019.

PROSPERORegistration:CRD42020150877

Consensus on Science

The evidence from the 6 RCTs identified in the SysRev is summarized in Table 2. Trials generally failed to show a benefit of a titrated (lower percentage of oxygen) approach compared with standard care (higher percentage of oxygen). A subgroup analysis of postresuscitation patients in one larger RCT, however, found better survival in patients for whom hyperoxemia was aggressively avoided.145 In addition, results from 10 observational studies rated as having only serious risk of bias were inconsistent. Four146 149 found an association between hyperoxemia (variable definitions, but most often PaO2 greater than 300mm Hg) and either worse survival or worse survival with neurological outcome, whereas the other 6150 155 found no such association. Hypoxemia was found to be associated with worse outcome in adjusted analysis in 1 of these studies.149

Treatment Recommendations

We suggest the use of 100% inspired oxygen until the arterial oxygen saturation or the partial pressure of arterial oxygen can be measured reliably in adults with ROSC after cardiac arrest in any setting (weak recommendation, very low-certainty evidence).

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94 RESUSCITATION 156 (2020) A80 A119

Table 2 – Overview of Included Randomized Trials of Oxygen Dose after ROSC.

Study, Year Country Years of Number Intervention Comparator Relative Absolute Risk Certainty Inclusion of Risk [95% CI] Reduction [95% CI]

Patients

Favourable Neurological Outcome at 6 mo*—ICU Initiation

Jakkula, 2018156 Mackle, 2019145

Finland and Denmark

2016 2017

120 Normoxia for 36 h (10 15 kPa)

Moderate hyperox- ia for 36 h (20
25kPa) Standard oxygen (O2 Sat >90%)

1.13 [0.87 1.47] 1.40 [0.93 2.13]

0.56 [0.14 2.29] 1.33 [0.63 2.84]

1.07 [0.84 1.36]

1.39 [1.01 1.92]

0.97 [0.68 1.37]

3.15 [1.04 9.52] 1.13 [0.41 3.08]

79 more per 1000 [79 fewer to 287 more]
128 more per 1000 [22 fewer to 361 more]

196 fewer per 1000 [382 fewer to 573 more]
141 more per 1000 [159 fewer to 789 more]

46 more per 1000 [106 fewer to 238 more]

160 more per 1000 [4 more to 377 more]

18 fewer per 1000 [194 fewer to 224 more]

379 more per 1000 [7 more to 1000 more]
58 more per 1000 [262 fewer to 924 more]

Moderatey Very lowz

Very low{ Lowx

Moderatex Lowyy

Very lowx

Very low{ Very low{

2015 2018
Survival to Hospital Discharge With Favourable Neurological Outcome#—Prehospital Initiation

Young, 2014157 Kuisma, 2006158

New Zealand

Finland

2012 2013 17

Not recorded 28

97%)
Titrated oxygen for

Standard oxygen for 72 h (O2 Sat >95%)
High oxygen pre- hospital (100%)

Moderate hyperox- ia for 36 h (20
25kPa)

Standard oxygen (O2 Sat >90%)

High oxygen pre- hospital (100% or 10 L/min)

Standard oxygen prehospital (O2 Sat 100%)
Standard oxygen for 72 h (O2 Sat >95%)

Australia and New Zealand

164 Conservative oxy- gen (O2 Sat 90%

Survival to Hospital Discharge—ICU Initiation

Jakkula, 2018156 Finland and Denmark

Survival to 90 Days—ICU Initiation

Mackle, 2019145 Australia and New Zealand

2016 2017 120

2015 2018 164

Survival to Hospital Discharge—Prehospital Initiation

Meta-analysis Kuisma 2006158/ Bray, 2018159

Thomas, 2019160 Young,**

2014157

Finland, Australia

United Kingdom New Zealand

Not re- 89
corded,158
2015 4 L/min) 2017159
2014 2015 35

72h(O2Sat90% 94%)
Low oxygen pre- hospital (30%)

Normoxia for 36 h (10 15kPa)

Conservative oxy- gen (O2 Sat 90% 97%)

2012 2013 17

Low oxygen pre- hospital (30% or 2

Titrated oxygen prehospital (O2 Sat 94% 98%) Titrated oxygen for 72h(O2Sat90% 94%)

ICU indicates intensive care unit; Sat, saturation.
* Defined as either Cerebral Performance Category (CPC) 1 2 or Extended Glasgow Outcome Score of 5 8. y Downgraded for imprecision.
z Downgraded for risk of bias and imprecision.
x Downgraded 2 levels for imprecision.

{ Downgraded for indirectness and 2 levels for imprecision.
# Defined as CPC 1 2 or discharge to home.
** Intervention initiated prehospital but continued after admission. yy Downgraded 2 levels for risk of bias.

We recommend avoiding hypoxemia in adults with ROSC after cardiac arrest in any setting (strong recommendation, very low- certainty evidence).

We suggest avoiding hyperoxemia in adults with ROSC after cardiac arrest in any setting (weak recommendation, low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontableisincludedin SupplementAppendixA-5. In making the recommendation to avoid hypoxemia, the task force acknowledges that the evidence is of very low certainty. The task force concluded that the known harm that can result from hypoxia justifies its avoidance, and detection of hypoxemia may be the best surrogate for or precursor of tissue hypoxia. The suggestion to avoid hyperoxemia is based on low- to moderate-certainty evidence that showed either harm or no benefit from hyperoxemia. The definitions used for hyperoxemia varied, ranging from an oxygen saturation greater than 97% measured by pulse oximeter to a PaO2 up to 20 to 25 kPa (150 188 mm Hg) in the available RCTs. In light of the possible benefit and lack of evidence for harm, the task force suggests targeting normoxemia and avoiding hyperoxemia. The task force acknowledges that the primary randomized

trial evidence suggesting benefit from avoiding hyperoxemia is from a subgroup analysis only, and data from the 3 ongoing trials (NCT03138005, NCT03653325, NCT03141099) will be helpful.

The task force felt that titration of oxygen should not be attempted until oxygen levels (peripheral oxygen saturation or partial pressure of oxygen in arterial blood) could be measured reliably. Some of the randomized trials conducted in the prehospital setting, although very small, reported more desaturation of arterial blood in the lower oxygen group, which reinforces the task force suggestion to administer 100% oxygen until reliable measurement of oxygen level is possible. This is likely to be more important in the prehospital setting.

Knowledge Gap

Randomized trials comparing lower oxygen target strategies with higher oxygen target strategies or usual care in postarrest patients have thus far been small and therefore inconclusive. More trials are needed, and 3 trials are underway currently (NCT03138005, NCT03653325, NCT03141099).

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95

Ventilation Strategy After ROSC in Adults (ALS 571: SysRev)

Rationale for Review

Hypocapnia causes cerebral vasoconstriction and hypercapnia leads to cerebral vasodilation. Exactly how variations in Paco2 affect intracranial pressure and perfusion in the brains of postarrest patients, and whether this affects outcome, remains unclear.161 This topic was last reviewed in 2015.1,7 A SysRev144 was conducted to inform this 2020 ALS CoSTR.

Population, Intervention, Comparators, Outcomes, Study Designs, and Time Frame

 Population: Unresponsive adults with sustained ROSC after cardiac arrest in any setting

 Intervention: A ventilation strategy targeting a specific Paco2

 Comparators: Treatment without specific targets or with an
alternate target to the intervention

 Outcome: Critical outcomes include survival/survival with a
favourable neurological outcome at hospital discharge or 30 days; and survival/survival with a favourable neurological outcome after hospital discharge or 30 days (eg, 90 days, 180 days, 1 year).

 Study design: Randomized trials, non-RCTs, and observational studies (cohort studies and case-control studies) with a control group (ie, patients treated with no specific PaCO2 targets or an alternative target to the intervention) were included. Animal studies, ecological studies, case series, case reports, reviews, abstracts, editorials, comments, and letters to the editor were not included. There were no limitations on publication period or study language, if there was an English abstract. The population included patients with IHCA or OHCA of any origin. Unpublished studies(eg,conferenceabstracts,trialprotocols)wereexcluded. The cited SysRev144 was done without age restriction, and the evidence from adult studies (generally defined as older than 16 years or 18 years or older) is included here.

 Time frame: All years and languages were included. The literature search was updated to August 22, 2019.

 PROSPERO Registration: CRD42020150877.
Consensus on Science
The task force concluded that differences in the PaCO2 targets used in the arms of the 2 RCTs identified156,162 precluded meta-analysis.
For the critical outcome of favourable neurological outcome (defined as CPC 1 2) at 6 months, we identified low-certainty evidence from 1 RCT enrolling 120 patients and comparing a ventilation strategy targeting high-normal PaCO2 (5.8 6.0 kPa/43.5- 45 mmHg) with one targeting low-normal PaCO2 (4.5 4.7 kPa/33.7- 35.2 mmHg) and failing to show benefit from the higher PaCO2 strategy (RR, 0.84; 95% CI, 0.64 1.10; ARR, 113 fewer per 1000; 95% CI, from 254 fewer to 70 more).156 For the critical outcome of favourable neurological outcome (defined as an extended Glasgow Outcomes Scale 5) at 6 months, we identified low-certainty evidence (down- graded for inconsistency and imprecision) from 1 RCT enrolling 83 patients and comparing a ventilation strategy targeting moderate hypercapnia (PaCO2 50 55 mm Hg/6.7-7.3 kPa) with one targeting normocapnia (PaCO2 35 45 mm Hg/4.7-6.0 kPa) and failing to show benefit from the higher PaCO2 strategy (RR, 1.28; 95% CI, 0.83 1.96; ARR, 129 more per 1000; 95% CI, from 78 fewer to 443 more).162
For the critical outcome of survival to 30 days we identified low- certainty evidence (downgraded for inconsistency and imprecision)

from 1 RCT enrolling 120 patients and comparing a ventilation strategy targeting high-normal PaCO2 (5.8 6.0 kPa/43.5-45 mmHg) with one targeting low-normal PaCO2 (4.5 4.7 kPa/33.7-35.2 mmHg) and failing to show benefit from the higher PaCO2 strategy (RR, 0.81; 95% CI, 0.63 1.05; ARR, 143 fewer per 1000; 95% CI, from 279 fewer to 38 more).156

For the critical outcome of survival to discharge we identified low- certainty evidence (downgraded for inconsistency and imprecision) from 1 RCT enrolling 83 patients and comparing a ventilation strategy targeting moderate hypercapnia (PaCO2 50 55 mm Hg/6.7-7.3 kPa) with one targeting normocapnia (PaCO2 35 45 mm Hg/4.7-6.0 kPa) and failing to show benefit from the higher PaCO2 strategy (RR, 1.16; 95%CI,0.87 1.56;ARR,101moreper1000;95%CI,from82fewer to 355 more).162

Results were inconsistent across the 6 observational studies rated as having less than critical risk of bias. Hypercapnia was associated with improved outcomes in 2 studies155,163 and worse outcomes in 2 studies.149,164 There was no association between hypercapnia and outcomes in the remaining 2 studies.152,165 Results were similar for hypocapnia although no studies found an association with improved outcomes.

Treatment Recommendations

There is insufficient evidence to suggest for or against targeting mild hypercapnia compared with normocapnia in adults with ROSC after cardiac arrest.

We suggest against routinely targeting hypocapnia in adults with ROSC after cardiac arrest (weak recommendation, low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontableisincludedin SupplementAppendixA-6. Evidence from existing randomized trials and observational studies is very inconsistent. Both randomized trials failed to show any effect from different Paco2 targets, but the trials were small and used different target ranges, precluding meta-analysis. Observational studies were evenly distributed in showing benefit, harm or no effect associated with hypercapnia. Hypocapnia results were also inconsistent, although no studies found an association with benefit. In light of the lack of evidence for benefit, and lack of consistent evidence for harm from Paco2 levels higher than normal, the task force did not think there was sufficient evidence to suggest for or against targeting mild hypercapnia compared with normocapnia. An ongoing trial investigating this comparison may bring clarity to this issue (NCT03114033).

For hypocapnia, very limited evidence suggests either no benefit or harm, supporting the task force’s suggestion against targeting hypocapnia.

Although the task force discussed whether patients with baseline chronic lung disease and chronic CO2 retention might respond differently to different Paco2 targets, no evidence addressing this subgroup was found. The task force agreed it would be reasonable to adjust PaCO2 targets in patients with known chronic CO2 retention, but this is expert opinion only because no evidence was identified on this topic.

The prior treatment recommendation (2015)1,7 was a suggestion to maintain normocapnia. The updated treatment recommendation allows for continuing this approach, while emphasizing that we do not currently know if targeting normocapnia is beneficial, harmful, or equal in comparison to targeting hypercapnia. The task force discussed the possible complication of acidemia from hypercapnia. The presence or

96 RESUSCITATION 156 (2020) A80 A119

absence of metabolic acidosis requires consideration when choosing a ventilation strategy and PaCO2 target, and metabolic acidosis is common in postarrest patients. The PaCO2 targets or ranges also differed somewhat across studies. For this reason, the task force chose not to define specific numeric targets because no optimal target or range has been made clear. Additionally, opinions vary on whether arterial blood gas analysis in patients receiving targeted temperature management(TTM)shouldbeadjustedfortemperature.Onceagain, trials differed in their approach. Approaches to blood gas interpreta- tion in regard to temperature also varied across the observational studies. These variations in methodology and in definitions of target ranges prohibit the task force from being able to recommend specific numbers or a specific method for blood gas analysis for systems implementing these recommendations.

Knowledge Gaps

 Randomized trials comparing strategies targeting mild hypercap- nia with strategies targeting normocapnia have thus far been small and therefore inconclusive. A much larger randomized trial is currently underway (NCT03114033).

 How PaCO2 targets should be adjusted in those with chronic CO2 retention is unknown.
Postresuscitation Haemodynamic Support (ALS 570: EvUp)
Population, Intervention, Comparator, and Outcome

 Population: Adults with ROSC after cardiac arrest in any setting

 Intervention: Titration of therapy to achieve a specific haemody-
namic goal (eg, mean arterial pressure greater than 65 mm Hg)

 Comparator: No haemodynamic goal

 Outcome: Any clinical outcome AnEvUpforthistopicwasperformedandisincludedin
Supplement Appendix C-12. Two RCTs completed since 2015156,166 did not find that targeting a specific mean arterial pressure affected outcome, although the studies were not powered for clinical outcomes of survival or neurological outcome. In the absence of ongoing RCTs, and controversy about the targeting of higher blood pressure, the task force suggests that this topic be considered for a SysRev.
Treatment Recommendations
This treatment recommendation (below) is unchanged from 2015.1,7 We suggest haemodynamic goals (eg, mean arterial pressure, systolic blood pressure) be considered during postresuscitation care and as part of any bundle of postresuscitation interventions (weak
recommendation, low-certainty evidence).
There is insufficient evidence to recommend specific haemodynamic
goals; such goals should be considered on an individual patient basis and are likely to be influenced by post-cardiac arrest status and preexisting comorbidities (weak recommendation, low-certainty evidence).
Postresuscitation Steroids (ALS 446: EvUp)
Population, Intervention, Comparator, and Outcome

 Population: Adult patients with ROSC after cardiac arrest (prehospital or in-hospital)

 Intervention: Treatment with corticosteroids

Comparator: Standard care
Outcome: Survival to hospital discharge with good neurological

outcome or survival to hospital discharge ( time to shock

reversal/shock reversal)
The 2010 CoSTR addressed steroid use both intra-arrest and

postresuscitation.6,8 The 2015 CoSTR included only intra-arrest steroid use.1,7 The EvUp for postresuscitation steroid use is includedin SupplementAppendixC-13.ThreesmallRCTsanda large observational study were identified.94,167 169 Two of the RCTs used steroids both during CPR and after ROSC.167,168 One recently completed trial that is not yet published was also identified (NCT02790788). The task force recommends a SysRev be undertaken once the recently completed trial is published.

Treatment Recommendations

This treatment (below) is unchanged from 2010.6,8
There is insufficient evidence to support or refute the use of

corticosteroids for patients with ROSC after cardiac arrest.

Prophylactic Antibiotics After Cardiac Arrest (ALS 2000: SysRev)

Rationale for Review

This is a new topic prioritized by the ALS Task Force. Infective complications are common in patients admitted to intensive care units (ICUs). After cardiac arrest, pneumonia has been reported in 50% to 60% of patients,170,171 which is thought to result in part from aspiration during the cardiac arrest and resuscitation. In these patients, early and accurate identification of infection is challenging. Standard criteria for identifying infection are affected by patient treatment (ie, TTM) and the pathophysiology of the post-cardiac arrest syndrome (ie, including the systemic inflammatory response). The decision to treat a possible infection needs to be balanced by the need for prudent antibiotic administrationtoavoidantibioticresistance.Thisnewtopicwas prioritized by the ALS Task Force due to the recent publication of a SysRev on the topic.172 The published SysRev was updated by using the ADOLOPMENT process.173

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adult patients after ROSC from cardiac arrest in any setting (in-hospital or out-of-hospital)

Intervention: Early/prophylactic administration of antibiotics
Comparator: Delayed/clinically driven administration
Outcome: Survival or survival with good neurological outcome at

hospital discharge or longer, (critical), and important outcomes of critical care length of stay, infective complications, or duration of mechanical ventilation

Study design: Observational and interventional studies if they compared the effect of administration of early or prophylactic antibiotics with delayed or clinically driven administration of antibiotics in adult patients after cardiac arrest. All study types that included a control group were included. Case reports and case series were not eligible for inclusion. There was no restriction on language.

Timeframe:Therewasnorestrictiononpublicationdate,andthe literature search was completed/updated in October 2019.

PROSPERO Registration: CRD42016039358 for the original SysRev.172

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Consensus on Science

For the critical outcome of survival with favourable neurological outcome at ICU discharge or 30 days, we identified low-certainty evidence (downgraded for serious risk of bias and serious impreci- sion) from 2 RCTs171,174 enrolling 254 patients, which showed no benefit of early/prophylactic antibiotic administration (RR, 0.89; 95% CI, 0.71-1.12; P = 0.31; risk difference, 0.06; 95% CI, 0.19-0.06; P = 0.30).

For the critical outcome of survival at ICU discharge or 30 days, we identified low-certainty evidence (downgraded for serious risk of bias and serious imprecision) from 2 RCTs171,174 enrolling 254 patients, whichshowednobenefit(RR,0.95;95%CI,0.79 1.14;P=0.60;risk difference, 0.03; 95% CI, 0.15 to 0.08; P = 0.58). We also identified very low-certainty evidence (downgraded for serious indirectness) from 2 observational studies. One study175 enrolling 1604 patients showed no benefit associated with early or prophylactic antibiotic administration compared with delayed/clinically driven administration (OR, 1.16; 95% CI, 0.94-1.13; P = 0.18). The second observational study176 enrolling 138 patients showed a benefit (data presentation precludes reporting of OR, P = 0.01).

For the important outcome of infective complications (pneumonia) we identified low-certainty evidence (downgraded for serious risk of bias and serious imprecision) from 2 RCTs171,174 enrolling 254 patients, which showed no benefit (RR, 0.75; 95% CI, 0.43-1.32; P = 0.32; risk difference, 0.12; 95% CI, 0.23-0.00; P = 0.05). There were differences between the studies in methods used to diagnose pneumonia. We found very low-certainty evidence (downgraded for serious risk of bias, serious indirectness, and serious imprecision) from 2 observational studies175,177 enrolling 2245 patients, which showed no association between early/prophylactic administration compared with delayed/clinically driven administration (OR, 0.61; 95% CI, 0.61-1.62; P = 0.98). These studies, too, differed in methods used to diagnose pneumonia.

For the important outcome of critical care length of stay we identified low-certainty evidence (downgraded for serious risk of bias and serious imprecision) from 2 RCTs171,174 enrolling 248 patients, which showed no benefit (mean difference, 0.47 days; 95% CI, 1.31- 2.24; P = 0.61).

For the important outcome of duration of mechanical ventilation we identified very low-certainty evidence (downgraded for very serious risk of bias and serious imprecision) from 1 RCT174 enrolling 60 patients, which showed no benefit (mean difference, 0.20 days; 95% CI, 1.53-1.93; P = 0.82).

Treatment Recommendation

We suggest against the use of prophylactic antibiotics in patients after ROSC (weak recommendation, low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontableisincludedin AppendixASupplement Appendix A-7. Meta-analyses of both randomized trials and observational studies showed no overall benefit in the use of prophylactic antibiotics during post-cardiac arrest care. The task force did review the findings of 1 RCT at low overall risk of bias that reported reduced incidence of early pneumonia in patients treated with prophylactic antibiotics.171 Although this study demonstrated the potential efficacy of prophylactic antibiotics, there was no improve- ment in other clinical outcomes, such as survival or critical care length of stay. Pneumonia affects approximately 50% of ICU patients after

cardiac arrest, but this is unlikely to contribute to mortality because most deaths are attributable to neurological failure, cardiovascular failure, or multiorgan failure.170,171 A strategy of prophylactic antibiotic use would likely expose a large number of patients to antibiotics with no specific benefit and increase the risk of development of resistant organisms. The decision to administer antibiotics after cardiac arrest, particularly in the context of gastric aspiration, is challenging and clinicians may have different clinical thresholds for prescribing antibiotics. We did not identify any RCTs enrolling patients after IHCA.

Knowledge Gaps

Studies of post-ROSC antibiotics after IHCA.
RCTs that evaluate this question in patients treated with TTM at

temperatures other than 32 C to 34 C.
RCTs powered to determine the effect of prophylactic antibiotics

on outcomes such as critical care length of stay or duration of mechanical ventilation.

Post-Cardiac Arrest Seizure Prophylaxis and Treatment (ALS 431, 868: SysRev)

Rationale for Review

Hypoxic-ischemic brain injury is a common cause of death in comatose cardiac arrest survivors. Clinical convulsions and epilepti- form activity in the electroencephalogram (EEG) are common, with substantial overlap and an approximate incidence of 20% to 30%.178 181 The prognosis for patients with clinical and electrographic seizures is usually poor, but some patients recover and may ultimately have a good neurological outcome.180,181 This CoSTR is based on an update of the 2015 SysRev and CoSTR1,7 for seizure prophylaxis and treatment in cardiac arrest survivors.

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Unresponsive adults (older than 18 years) with sustained ROSC after cardiac arrest in any setting (in-hospital or out-of-hospital)

Intervention: One strategy for seizure prophylaxis or treatment Comparator: Another strategy or no seizure prophylaxis or

treatment
Outcome: Survival with favourable neurological/functional out-

come at discharge, 30 days, 60 days, 180 days, and/or 1 year; survival at discharge, 30 days, 60 days, 180 days, and/or 1 year (all critical); and the important outcome of seizure incidence during index hospitalization (for seizure prophylaxis only)

Study design: RCTs and nonrandomized studies (non-RCTs, interrupted time series, controlled before-and-after studies, cohort studies) are eligible for inclusion. Unpublished studies (eg, conference abstracts, trial protocols) are excluded.

Time frame: All years and languageswere included if therewas an English abstract; unpublished studies (eg, conference abstracts, trial protocols) were excluded. The literature search was updated to September 26, 2019.

PROSPERO Registration: Registered with ILCOR Science Advisory Committee October 3, 2019. This SysRev was done as an update of the 2015 CoSTR SysRev and PROSPERO registration was not done.

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Consensus on Science

Post-Cardiac Arrest Seizure Prophylaxis. For the critical outcomes of survival with favourable neurological outcome to discharge/30 days or longer, and survival to discharge/30 days or longer, 2 prospective RCTs involving a total of 562 subjects provided very low-certainty evidence (downgraded for risk of bias, indirectness and imprecision) 182,183 of no benefit from seizure prophylaxis. One nonrandomized prospective clinical trial with 107 subjects that used historic controls provided very low-certainty evidence (downgraded for risk of bias, indirectness, and imprecision) of no benefit.184

For the important outcome of seizure prevention, we identified very low-certainty evidence (downgraded for risk of bias and indirectness and imprecision) from 2 prospective double-blinded RCTs182,183 showing no benefit of seizure prophylaxis.

Post-Cardiac Arrest Seizure Treatment. For the critical outcomes of survival with favourable neurological outcome or survival at discharge/ 30 days or longer, we identified no RCTs or nonrandomized studies that addressed the effect of post-cardiac arrest seizure treatment, compared with no seizure treatment, on outcomes.

Treatment Recommendations

This treatment recommendation has been updated from 2015.1,7 We suggest against seizure prophylaxis in adult post-cardiac arrest survivors (weak recommendation, very low-certainty evidence). We suggest treatment of seizures in adult post-cardiac arrest

survivors (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontableisincludedin Supplement Appendix A-8. The task force decision to suggest against post- cardiac arrest seizure prophylaxis was primarily based on the absence of direct evidence that prophylactic therapy with antiepi- leptic drugs prevents seizures or improves important outcomes in adult comatose cardiac arrest survivors. However, the task force did recognize the very low certainty of the evidence from RCTs. The task force also considered that seizure prophylaxis in other forms of acute brain injury is not associated with improved outcomes, and that most drugs used for seizure prophylaxis can have significant side effects. Finally, the task force acknowledged that most comatose cardiac arrest survivors routinely receive sedatives such as propofol or benzodiazepines that are known to have antiepileptic effects. However, the task force identified no controlled studies that examined whether different sedation strategies or choices of sedation drugs had an impact on the incidence of post-cardiac arrest seizures.

The task force decision to suggest treatment of seizures in post- cardiac arrest survivors takes into consideration the absence of direct evidence that seizure treatment improves critical outcomes in this patient population. However, there are no published controlled clinical studies. Therefore, the task force weighed the fact that ongoing seizures have the potential to worsen brain injury, and treatment of recurrent seizures and status epilepticus constitutes “standard of care” in other patient populations. A large randomized trial is currently underway investigating the benefit of systematic antiepileptic drug therapy with the goal of suppressing all epileptiform activity on the EEG versus standard treatment of clinical seizures only in post-cardiac arrest

status epilepticus. (TELSTAR trial [Treatment of Electroencepha- lographic Status Epilepticus After Cardiopulmonary Resuscitation], NCT02056236)

Indirect evidence from case series suggests that sedatives such as propofol are effective in suppressing both clinical convulsions and epileptiform activity on EEG in these patients.185 187 A recent retrospective study provides some evidence that conventional antiepileptic drugs (specifically valproate and levetiracetam) also have an effect in suppressing epileptiform activity in the EEG.188 In a recent comparison of valproate, levetiracetam, and fosphenytoin for convulsive status epilepticus, the 3 drugs were equally effective but fosphenytoin caused more episodes of hypotension and need for tracheal intubation.189 However, it is important to note that this study excluded post-cardiac arrest patients. On the basis of these results, the task force discussed using valproate and levetiracetam as first-line drugs in post-cardiac arrest seizure treatment.

There is no direct evidence of undesirable effects of antiepileptic drug therapy in comatose post-cardiac arrest survivors. Treatment with sedatives and conventional antiepileptic drugs in high doses has the potential to cause delayed awakening, prolonged need for mechanical ventilation, and increased critical care days. Importantly, generalized myoclonus in combination with epileptiform discharges may be manifestations of Lance-Adams syndrome, which is compatible with a good outcome.187,190 In such cases, overly aggressive sedation and treatment with high doses of conventional antiepileptic drugs may confound the clinical examination and lead to overly pessimistic prognostication.

The relative benefit of continuous EEG compared with intermittent EEG monitoring was not specifically reviewed. Continuous EEG monitoring is labor intensive and likely to add significant cost to patient care.Thenetcost-effectivenessofthisapproachiscontroversialand may depend substantially on the setting.191,192 The task force also discussed the potential cost of delayed neurological prognostication and prolonged ICU care associated with active treatment of seizures because of the need to continue sedation.

Knowledge Gaps

There is no high-certainty evidence of a positive effect of antiepileptic drugs on the outcome of post-cardiac arrest patients with seizures.

There are no RCTs specifically designed to evaluate the impact of post-cardiac arrest seizure prophylaxis on the incidence of seizures and on neurological outcome.

There are inadequate data about the timing, duration, dosing, and choice of antiepileptic drugs for seizure prophylaxis in comatose post-cardiac arrest patients.

The utility of continuous EEG versus intermittent EEG monitoring in the diagnosis and treatment of seizures in comatose post- cardiac arrest patients remains controversial.

The threshold for treating epileptiform activity other than convulsive seizures (eg, generalized epileptiform discharges) is poorly defined.

Standardized terminology for classification of epileptiform activity in the EEG of comatose post-cardiac arrest patients is increasingly used. There remains a need to develop consensus on the definition of post-cardiac arrest status epilepticus.

The value of using volatile anesthetics to treat refractory status epilepticus on post-cardiac arrest patients is currently unknown.

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Targeted Temperature Management (ALS 455, 790, 791, 802, 879: EvUp)

A comprehensive SysRev of TTM193,194 was conducted for the 2015 CoSTR.1,7 The task force chose to delay updating this SysRev until the completion and publication of the Targeted Hypothermia Versus Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) RCT (NCT02908308). EvUps for use of TTM and TTM duration were completed andappearin SupplementAppendixC-14andC-15.

The results of the HYPERION trial (Therapeutic Hypothermia After Cardiac Arrest in Nonshockable Rhythm) were recently published.195 In this French trial, 581 adult patients who were comatose after resuscitation from either an IHCA or OHCA with an initial non- shockable rhythm were randomized to either TTM with a target temperature of 33 C or TTM with a temperature of 37 C, both for 24 hours. The primary outcome (the proportion of patients with a CPC of either 1 or 2 at 90 days after the cardiac arrest) significantly favored the 33 C group. At 90 days, 29 of 284 patients (10.2%) in the 33 C group were alive with a CPC of 1 or 2, as compared with 17 of 297 (5.7%) in the normothermia group (risk difference, 4.5%; 95% CI, 0.1 8.9; P = 0.04). There was no difference in mortality at 90 days (81.3% versus 83.2%; risk difference, 1.9%; 95% CI, 8.0 to 4.3).

This trial does not lead to any immediate changes to the 2015 ILCOR treatment recommendations1,7 but reinforces the suggestion to consider TTM, targeting a constant temperature between 32 C and 36 C, in patients who remain comatose after resuscitation from either IHCA or OHCA with an initial nonshockable rhythm.

Treatment Recommendations

These treatment recommendations are unchanged from 2015.1,7 We recommend selecting and maintaining a constant target temperature between 32 C and 36 C for those patients in whom temperature control is used (strong recommendation, moderate-quality evidence). Whether certain subpopulations of cardiac arrest patients may benefit from lower (32 C 34 C) or higher (36 C) temperatures

remains unknown, and further research may help elucidate this.
We recommend TTM as opposed to no TTM for adults with OHCA with an initial shockable rhythm who remain unresponsive after ROSC

(strong recommendation, low-quality evidence).
We suggest TTM as opposed to no TTM for adults with OHCA with

an initial nonshockable rhythm who remain unresponsive after ROSC (weak recommendation, very low-quality evidence).

We suggest TTM as opposed to no TTM for adults with IHCA with any initial rhythm who remain unresponsive after ROSC (weak recommendation, very low-quality evidence).

We suggest that if TTM is used, duration should be at least 24 hours (weak recommendation, very low-quality evidence).

We recommend against routine use of prehospital cooling with rapid infusion of large volumes of cold IV fluid immediately after ROSC (strong recommendation, moderate-quality evidence).

We suggest prevention and treatment of fever in persistently comatose adults after completion of TTM between 32 C and 36 C (weak recommendation, very low-quality evidence).

Prognostication in Comatose Patients After Resuscitation From Cardiac Arrest

Combined Prognostic Systematic Reviews

Many comatose post-cardiac arrest patients will not survive or will survive with an unfavourable neurological outcome. In some regions,

family and treating teams may limit or withdraw life-sustaining treatment when unfavourable neurological outcomes are expected. Therefore, reliable strategies for timely prognostication are a critical component of any cardiac arrest system of care. The 2015 CoSTR distinguished between studies of prognostication among patients treated with or without hypothermia. For this 2020 CoSTR for ALS, these treatment recommendations apply regardless of the TTM strategy used. The reason for this is that in all of the studies we assessed,thepopulationincludedamixofTTM-treatedandnon TTM-treated patients, and the potential impact of TTM on prognostication could not be assessed separately.

On May 31, 2013, a new search was launched, using the search strategies used for previous SysRevs on neuroprognostication. For the SysRev informing the 2020 CoSTRs, the search included studies published from January 1, 2013, to December 31, 2019 [PROSPERO Registration: CRD42019141169].

This review identified clinical signs, neurophysiological measure- ments, blood biomarkers, and imaging studies that had high specificity for poor neurological outcome, defined as CPC score of 3 to 5 or mRS score of 4 to 6 at hospital discharge, 1 month, or later.

The decision to limit treatment of comatose post-cardiac arrest patients should never rely on a single prognostication element. The consensus of the task force was that in patients who remain comatose in the absence of confounders (eg, sedative drugs), a multimodal approach should be used, with all supplementary tests considered in the context of the clinical examination. The most reliable combination and timing for each assessment are still to be determined and require further research.

The SysRevs supporting this CoSTR defined prediction as imprecise when the upper limit of 95% CIs for false-positive rate was above 5%.196 However, there is no universal consensus on what the acceptable limits for imprecision should be. In a recent survey of 640 medical providers, Steinberg et al197 reported that 56% considered an acceptable false-positive rate for withdrawal of life sustaining treatment from patients who might otherwise have recovered was 0.1% or less. In addition, 59% of respondents felt that an acceptable false-positive rate threshold for continuing life- sustaining treatment in patients with unrecognized unrecoverable injury was 1% or less.

Clinical Examination for Prognostication (ALS 450, 713, 487: SysRev)

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adults who are comatose after resuscitation from cardiac arrest (either in-hospital or out-of-hospital), regardless of target temperature

Intervention: Pupillary light reflex (PLR), pupillometry, corneal reflex, myoclonus, and status myoclonus assessed within 1 week after cardiac arrest

Comparator: None
Outcome: Prediction of poor neurological outcome defined as

CPC 3 to 5 or mRS 4 to 6 at hospital discharge, 1 month, or later Study design: Prognostic accuracy studies where the 2 2 contingency table (ie, the number of true/false negatives and positives for prediction of poor outcome) was reported, or where those variables could be calculated from reported data, are eligible for inclusion. Unpublished studies, reviews, case reports,

100 RESUSCITATION 156 (2020) A80 A119

case series, studies including fewer than 10 patients, letters, editorials, conference abstracts, and studies published in abstract form were excluded.

 Time frame: In 2015, an ILCOR evidence review identified 4 categories of predictors of neurological outcome after cardiac arrest, namely clinical examination, biomarkers, electrophysiolo- gy, and imaging. In the last 4 years, several studies have been published and new predictors have been identified, therefore the topic needs an update.

 The most recent search of the previous SysRevs on neuro- prognostication was launched on May 31, 2013. We searched studies published from January 1, 2013, to December 31, 2019.

 PROSPERO Registration: CRD42019141169
Consensus on Science
Pupillary Reflex. The association of a bilaterally absent standard PLR, measured at various time points, with outcome was investigated in 17 observational studies.198 214 Although all of this evidence was rated as very low certainty, studies that evaluated the prognostic value of absent standard PLR at time points of 72 hours or more after ROSC had greater specificity (ranging from 90% to 100%) for unfavourable neurological outcome at time points from discharge to 12 months than studies that used the absence of PLR at less than 72 hours (specificity ranging from 48% to 92%). Sensitivity appeared to decrease when using a time point of 72 hours or more, but specificity was identified as the higher priority given the critical importance of avoiding false positives.
Pupillometry. Automated assessment of PLR can be made by measuring either of the following variables:

 The percent reduction in pupillary size, which is reported as qPLR, or

 The neurological pupil index (NPi), which is based on several variables such as pupillary size, percentage of constriction, constriction velocity, and latency.
Automated Pupillometry Using Percent of Pupillary Size Reduction (qPLR). In 3 observational studies using various time points,209,215,216 qPLR from 0% to 13% at 24hours predicted poor neurological outcome from 3 months to 12 months with specificity ranging from 77.8% to 98.9% and sensitivity from 17% to 66% (certainty of evidence from moderate to very low). When evaluated at 48 hours, specificity ranged from 95.7% to 100% and sensitivity from 18.1% to 58.5% (certainty of evidence from low to very low). In 1 study of 234 patients209 qPLR = 0% at 72 hours predicted poor neurological outcome at 3 months with 100% specificity and 4.9% sensitivity (moderate certainty of evidence).
Automated Pupillometry Using Multiple Variables (NPi). In 3 observational studies,209,217,218 NPi from 0 to 2.40 within 24hours predicted poor neurological outcome from hospital discharge to 3 months with 100% specificity and sensitivity ranging from 22% to 43.9% (certainty of evidence from moderate to very low). For the same outcome, 1 study with 361 patients209 found that NPi 2 or less at 48 hours had 100% specificity and 18.8% sensitivity, and NPi 2 or less at 72 hours had 100% specificity, and 16.9% sensitivity (moderate certainty of evidence).
Corneal Reflex. Corneal reflex at various time points was investigated in 11 observational studies.198,200,202,204

206,210,211,213,214,219 Although all of the evidence was rated as very low certainty, studies that evaluated the prognostic value of absent corneal reflex at time points of 72 hours or more after ROSC had greater specificity (ranging from 89% to 100%) for unfavourable neurological outcome from hospital discharge to 12 months after ROSC than studies that used the absence of corneal reflex at less than 72 hours (specificity ranging from 25% to 89%). Sensitivity appeared to decrease when using a time point of 72 hours or more, but specificity was determined to be a higher priority given the critical importance of avoiding false positives.

Myoclonus. Presence of myoclonus within 96 hours after ROSC was investigated in 6 studies200,210,219 222 and predicted poor neurologi- cal outcome from hospital discharge to 6 months with specificity ranging from 77.8% to 100% and sensitivity ranging from 18.2% to 44.4% (very low-certainty evidence). However, definitions of myoclo- nus were provided in only 1 study.220

Status Myoclonus. Presence of status myoclonus within 72 hours after ROSC was investigated in 2 studies178,223 and predicted poor neurological outcome from hospital discharge to 6 months with specificity ranging from 99.8% to 100% and sensitivity ranging from 12.2% to 49.1% (very low-certainty evidence). The definitions of status myoclonus differed between these 2 studies.

Treatment Recommendations

We recommend that neuroprognostication always be undertaken by using a multimodal approach because no single test has sufficient specificity to eliminate false positives (strong recommendation, very low-certainty evidence).

We suggest using PLR at 72hours or more after ROSC for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence).

We suggest using quantitative pupillometry at 72 hours or more after ROSC for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, low-certainty evidence).

We suggest using bilateral absence of corneal reflex at 72 hours or more after ROSC for predicting poor neurological outcome in adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence).

We suggest using presence of myoclonus or status myoclonus within 7 days after ROSC, in combination with other tests, for predicting poor neurological outcome in adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence). We also suggest recording EEG in the presence of myoclonic jerks to detect any associated epileptiform activity (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

As noted in the previous CoSTR on this topic in 2015,1,7 the task force consensus is that a multimodal approach should be used in all cases with all supplementary tests considered in the context of the clinical examination.

Theevidence-to-decisiontablesareincludedin Supplement Appendixes A-9, 10, 11, and 12. For standard PLR, NPi, and corneal reflex, the suggestion to use these findings at 72 hours or more after ROSC was based both on the specificity found in different studies and on the perceived importance of eliminating confounding effects of sedatives or muscle relaxants as much as possible. Only some of the

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101

included studies specifically excluded the presence of residual sedation at the time the pupillary or corneal reflex was assessed.

For assessment of the pupillary reflex, the task force felt that NPi has the potential for being more accurate and less prone to bias and subjectivity. This benefit, however, may be counterbalanced by the need for more equipment and specialized training to obtain the NPi.

Results of clinical examination usually cannot be concealed from the treating team. Therefore, a risk of self-fulfilling prophecy exists even when index tests that are based on clinical examination are not explicitly included in the criteria for withdrawal of life-sustaining therapy.

Although definitions of both myoclonus and status myoclonus are missing from most studies and are inconsistent in others, the presence of myoclonus is associated with poor outcome in patients who are comatose after ROSC from cardiac arrest and the finding may be useful within the context of a multimodal prognostic assessment. Myoclonus and status myoclonus are inconsistently associated with epileptiform activity on the EEG. Importantly, generalized myoclonus associated with favourable clinical features, such as a continuous or reactive EEG background or preserved brain stem reflexes, may be manifestations of Lance-Adams syndrome, which is compatible with a good outcome.187,190

Knowledge Gaps

 Absence of residual effects from sedatives must be specifically assessed in studies evaluating the accuracy of predictors on the basis of clinical examination after cardiac arrest.

 The interrater agreement for the assessment of standard PLR, corneal reflex, and myoclonus/status myoclonus in patients resuscitated from cardiac arrest deserves investigation.

 The number of studies documenting pupillometry for predicting poor outcome after cardiac arrest is still low. A consistent threshold for 100% specificity has not been identified for qPLR or NPi.

 Achieving a uniform and consensus-based definition of both myoclonus and status myoclonus is necessary. The role of EEG as an additional tool to investigate the nature and the prognostic significance of myoclonus deserves investigation.

 The most reliable combination and timing for each assessment remains to be determined.

 The potential impact of TTM on prognostication remains to be determined.
Neurophysiological Tests for Prognostication (ALS 450, 713, 460: SysRev)
Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

 Population: Adults who are comatose after resuscitation from cardiac arrest in any setting (in-hospital or out-of-hospital) and regardless of target temperature

 Intervention: Electrophysiology studies assessed within 1 week after cardiac arrest

 Comparator: None

 Outcome: Prediction of unfavourable neurological outcome
defined as CPC 3 to 5 or mRS 4 to 6 at hospital discharge, 1
month, or later

 Study design: Prognostic accuracy studies where the
2 2 contingency table (ie, the number of true/false negatives and positives for prediction of poor outcome) was reported, or

where those variables could be calculated from reported data, are eligible for inclusion. Unpublished studies, reviews, case reports, case series, studies including fewer than 10 patients, letters, editorials, conference abstracts, and studies published in abstract form are excluded.

Time frame: In 2015,1,7 an ILCOR evidence review identified 4 categories of predictors of neurological outcome after cardiac arrest, namely clinical examination, biomarkers, electrophysiolo- gy, and imaging. In the last 4 years, several studies have been published and new predictors have been identified, therefore the topic needs an update.

The most recent search of the previous SysRevs on neuro- prognostication was launched on May 31, 2013. We searched studies published from January 1, 2013, to December 31, 2019.

PROSPERO Registration: CRD42019141169

Consensus on Science

Somatosensory Evoked Potentials. The prognostic value of somatosensory evoked potentials (SSEPs) was investigated in 14 observational studies.199,205,208 211,214,224 230 In 4 stud- ies,205,224,228,229 bilaterally absent N20 SSEP wave within 24 hours after ROSC predicted poor neurological outcome from hospital discharge to 6 months. Specificity was 100% and sensitivity ranged from 33.3% to 57.7% (very low-certainty evidence). In 1 study,199 an absent N20 wave on one side and an absent or low-voltage N20 wave on the other side within 24hours after ROSC predicted poor neurological outcome at 6 months. Specificity was 100% and sensitivity was 49.6% (very low-certainty evidence).

In 12 studies,205,208 211,214,225 230 bilaterally absent N20 SSEP wave at 24 to 96hours after ROSC predicted poor neurological outcome from hospital discharge to 6 months. Specificity ranged from 50% to 100% and sensitivity ranged from 18.2% to 69.1% (very low- certainty evidence).

Unreactive EEG. The prognostic value of an unreactive EEG was investigated in 10 observational studies.210,219,229,231 237 In 9 of these studies,210,219,229,232 237 an unreactive EEG within 72hours after ROSC predicted poor neurological outcome from hospital discharge to 6 months. Specificity ranged from 41.7% to 100% and sensitivity ranged from 50% to 97.1% (certainty of evidence from moderate to very low). Specificity was below 90% in most of these studies, reaching 100% in only 2 of them.

In 1 study,231 an unreactive EEG at a median of 77hours after ROSC (interquartile range [IQR], 53 102) predicted poor neurologi- cal outcome at 6 months with 70% specificity and 88.1% sensitivity (very low-certainty evidence).

Rhythmic/Periodic Discharges. The prognostic value of rhythmic/ periodic discharges were investigated in 9 observational stud-

ies.199,210,228,231,237 241

In 2 studies,199,238 rhythmic/periodic discharges within 24 hours after ROSC predicted poor neurological outcome from 3 months to 6 months. Specificity was 100% and sensitivity ranged from 2.4% to 7.9% (certainty of evidence from moderate to very low).

In 4 studies,210,228,238,239 rhythmic/periodic discharges within 48hours after ROSC predicted poor neurological outcome from 3 months to 6 months. Specificity ranged from 97.2% to 100% and sensitivity ranged from 8.1% to 42.9% (certainty of evidence from moderate to very low).

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In 3 studies,228,237,239 rhythmic/periodic discharges at 48 to 72hours after ROSC predicted poor neurological outcome from 1 month to 6 months. Specificity ranged from 66.7% to 96.1% and sensitivity ranged from 11.4% to 50.8% (certainty of evidence from low to very low).

In 2 studies,231,240 rhythmic/periodic discharges at the median time of 76 to 77hours after ROSC predicted poor neurological outcome at 6 months. Specificity ranged from 97% to 100% and sensitivity ranged from 5% to 40% (certainty of evidence from low to very low).

In 1 study,241 rhythmic/periodic discharges within 5 days after ROSC predicted poor neurological outcome at 6 months. Specificity was 100% and sensitivity was 15.7% (moderate certainty of evidence).

Sporadic, Nonrhythmic/Periodic Discharges. The prognostic value of sporadic, nonrhythmic/periodic discharges was investigated in 5 observational studies.199,226,228,237,238 In 3 studies,199,226,238 sporad- ic, nonrhythmic/periodic discharges within 24hours after ROSC predicted poor neurological outcome from 3 months to 6 months. Specificity ranged from 84.6% to 100% and sensitivity ranged from 0.5% to 7.9% (certainty of evidence from moderate to very low).

In 3 studies,226,228,238 sporadic, nonrhythmic/periodic discharges within 48 hours predicted poor neurological outcome from 3 months to 6 months. Specificity ranged from 95.8% to 99.5% and sensitivity ranged from 0.4% to 13.3% (certainty of evidence from moderate to very low).

In 3 studies,226,228,237 sporadic, nonrhythmic/periodic discharges at 48 to 72 hours predicted poor neurological outcome from 1 month to 6 months. Specificity ranged from 88.9% to 97.3% and sensitivity ranging from 0.6% to 38.5% (certainty of evidence from low to very low).

In 1 study,226 sporadic, nonrhythmic/periodic discharges at 96 to 120hours predicted poor neurological outcome at 6 months. Specificity ranged from 66.7% to 82.1% and sensitivity ranged from 17.6% to 21.3% (very low-certainty evidence).

Seizures. The prognostic implications of seizures were investigated in 5 observational studies.220,231,236 238 In 4 of these studies, seizures were recorded within 72hours after ROSC, and in 1 study,231 they were recorded at a median of 77 (53 102) hours after ROSC. In these studies, the presence of seizures predicted poor neurological outcome from hospital discharge to 6 months with 100% specificity and sensitivity ranging from 0.6% to 26.8% (certainty of evidence from moderate to very low).

The prognostic implications of status epilepticus were investigated in 6 studies.202,225,236,241 243 The definitions of status epilepticus were inconsistent across studies. In these studies, status epilepticus within 5 days after ROSC predicted poor neurological outcome from hospital discharge to 6 months. Specificity ranged from 82.6% to 100% and sensitivity ranged from 1.8% to 50% (certainty of evidence low to very low).

In 3 of these studies,202,225,236 EEG was recorded within 72 hours after ROSC and specificity was 100%. In another study,243 specificity was 100% only when status epilepticus originated from a discontinu- ous or burst-suppression background.

Burst Suppression. The possible prognostic value of burst suppres- sion was investigated in 6 observational studies.202,220,225,231,233,240 In 2 studies,220,233 burst suppression within 24hours after ROSC

predicted poor neurological outcome to hospital discharge with 50% to 100% specificity and 50% to 51.5% sensitivity (certainty of evidence very low).

In 5 studies,202,225,231,233,240 burst suppression at 24 to 120 hours after ROSC predicted poor neurological outcome at hospital discharge to 6 months. Specificity ranged from 91.7% to 100% and sensitivity ranged from 13.9% to 55.6% (certainty of evidence from low to very low).

Definitions of burst suppression used in these studies varied when they were included at all. In 2 studies,231,240 the American Clinical Neurophysiology Society definition244 was used. In 1 study, a non-American Clinical Neurophysiology Society definition was used, while in the remaining studies, no specific definition was used.

Synchronous Burst Suppression. In 1 study,226 a synchronous burst suppression at 6 to 96hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and sensitivity ranging from 1.1% to 31.7% (certainty of evidence from moderate to low).

Heterogeneous Burst Suppression. In 1 study,226 heteroge- neous burst suppression at 6 to 120 hours after ROSC predicted poor neurological outcome at 6 months. Specificity ranged from 90.7% to 100% and sensitivity ranged from 1.1% to 16.2% (certainty of evidence from moderate to very low).

Treatment Recommendations

We recommend that neuroprognostication always be undertaken by using a multimodal approach because no single test has sufficient specificity to eliminate false positives (strong recommendation, very low-certainty evidence).

We suggest using a bilaterally absent N20 wave of SSEP in combination with other indices to predict poor outcome in adult patients who are comatose after cardiac arrest (weak recommenda- tion, very low-certainty evidence).

We suggest against using the absence of EEG background reactivity alone to predict poor outcome in adult patients who are comatose after cardiac arrest (weak recommendation, very low- certainty evidence).

We suggest using the presence of seizure activity on EEG in combination with other indices to predict poor outcome in adult patients who are comatose after cardiac arrest (weak recommenda- tion, very low-certainty evidence).

We suggest using burst suppression on EEG in combination with other indices to predict poor outcome in adult patients who are comatose and effects of sedation after cardiac arrest have cleared (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

The evidence-to-decision tables are included in Supplement Appen- dixes A-13, 14, 15, 16, and 17.

In making a recommendation about use of SSEPs for prognosti- cation, the task force considered that SSEPs have a low risk of confounding from TTM or sedation and a large size of effect (high precision). However, to limit the risk of self-fulfilling prophecy, combining evaluation of SSEPs with other indices of poor neurological outcome is prudent.

In almost all studies, we reported the specificity of unreactive EEG background for predicting poor outcome, and its precision was low. In addition, both definitions of stimuli to induce EEG reactivity were inconsistent across studies.

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In most of the studies, we included the specificity of rhythmic/ periodic epileptiform activity for predicting poor outcome as 100%. Specificity was lower for sporadic epileptiform discharges.

In all studies, we included the specificity of American Clinical Neurophysiology Society-defined seizures on EEG for predicting poor outcome as 100%.244 This specificity was consistent throughout the first 72 hours after ROSC.

Specificity of status epilepticus for predicting poor outcome was 100% in only half of the studies we included. An additional challenge for use of studies of status epilepticus for prognostication is the inconsistency of its definitions in reported studies.

In all studies we included, the presence of burst suppression on EEG predicted poor neurological outcome with a specificity above 90%, and in most studies, the specificity was 100%. Because sedative agents can affect the EEG, the most prudent strategy is to assess burst suppression for prognostication when any effects of sedation medications have cleared.

Knowledge Gaps

 Further studies are needed to evaluate the added value of assessing SSEPs in combination with other predictors of poor neurological outcome after cardiac arrest.

 It is desirable that future studies adopt a standard definition of background EEG reactivity. An international consensus statement on EEG reactivity testing (eg, stimulus protocol) has been proposed.245

 It is desirable that future studies adopt a standard definition of epileptiform discharges.

 The specific predictive value of the different epileptiform subtypes, their prevalence, and their combination with background EEG deserves further investigation.

 Precision was low or very low in most studies of the association of seizures with outcome. Further studies are needed to confirm the predictive value of seizures for poor outcome after cardiac arrest.

 A standard definition of status epilepticus is urgently needed.

 It is desirable that future studies adopt a standard definition of burst suppression, such as the one included in the American Clinical Neurophysiology Society’s Standardized Critical Care
EEG Terminology.244

 The accuracy of synchronous burst suppression for prognostication
(identical/highly epileptiform bursts) deserves further investigation.

 It is desirable to achieve a consensus definition of the term, “highly malignant EEG patterns” in patients who are comatose after
resuscitation from cardiac arrest.

 The potential impact of TTM on prognostication remains to be
determined.
Blood Biomarkers for Prognostication (ALS 450, 713, 484: SysRev)
Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

 Population: Adults who are comatose after resuscitation from cardiac arrest in any setting (in-hospital or out-of-hospital) and regardless of target temperature

 Intervention: The use of neuron-specific enolase (NSE), S-100B, glial fibrillary acidic protein, serum tau protein, and neurofilament light chain assessed within 1 week after cardiac arrest

Comparator: None
Outcome: Prediction of unfavourable neurological outcome,

defined as CPC 3 to 5 or mRS 4 to 6 at hospital discharge, 1

month, or later
Study design: Prognostic accuracy studies where the

2 2 contingency table (ie, the number of true/false negatives and positives for prediction of poor outcome) was reported, or where those variables could be calculated from reported data, are eligible for inclusion. Unpublished studies, reviews, case reports, case series, studies including fewer than 10 patients, letters, editorials, conference abstracts, and studies published in abstract form were excluded.

Time frame: In 2015, an ILCOR evidence review1,7 identified 4 categories of predictors of neurological outcome after cardiac arrest, namely clinical examination, biomarkers, electrophysiolo- gy, and imaging. In the last 4 years, several studies have been published and new predictors have been identified, therefore the topic needs an update.

The most recent search of the previous SysRevs on neuro- prognostication was launched on May 31, 2013. We searched studies published from January 1, 2013, to December 31, 2019.

PROSPERO Registration: CRD42019141169

Consensus on Science

Neuron-Specific Enolase. The prognostic value of NSE was investigated in 12 observational studies.202,206,208,214,239,246 252 In these studies, NSE with thresholds ranging from 33 to 120 mg/L within 72hours after ROSC predicted poor neurological outcome from hospital discharge to 6 months. Specificity ranged from 75% to 100% and sensitivity ranged from 7.8% to 83.6% (certainty of evidence from moderate to very low).

In 1 study,248 NSE with a threshold of 50.2 mg/L at day 4 (after ROSC) predicted poor neurological outcome at 1 month with 100% specificity and 42.1% sensitivity (moderate certainty of evidence).

S-100B. The accuracy of S-100B protein in predicting poor outcome in patients with ROSC after cardiac arrest was investigated in 3 observational studies.251,253,254

In 2 studies,251,254 S-100B protein with threshold ranging from 3.58 to 16.6mg/L immediately after ROSC predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 2.8% to 26.9% (certainty of evidence from moderate to very low).

In 3 studies,251,253,254 S-100B protein with a threshold ranging from 0.193 to 2.59 mg/L at 24 hours after ROSC predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 10.1% to 77.6% (certainty of evidence from moderate to very low). In the same 3 studies,251,253,254 S-100B protein with a threshold ranging from 0.159 to 3.67 mg/L at 48 hours after ROSC predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 5% to 77.6% (certainty of evidence from moderate to very low). In the same 3 studies,251,253,254 S-100B protein with a threshold ranging from 0.202 to 1.83 mg/L at 72 hours after ROSC predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 5% to 61.2% (certainty of evidence from moderate to very low).

Glial Fibrillary Acidic Protein. In 1 study,252 glial fibrillary acidic protein with a threshold of 0.08 mg/L at 48 12 hours after ROSC

104 RESUSCITATION 156 (2020) A80 A119

predicted poor neurological outcome at 1 month with 100% specificity and 21.3% sensitivity (low-certainty evidence).

Serum Tau Protein. In 1 study with 667 patients,255 serum tau protein with a threshold ranging from 72.7 to 874.5 ng/L at 24 to 72 hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and sensitivity ranging from 4% to 42% (very low-certainty evidence).

Serum Neurofilament Light Chain. In 1 study,256 serum neurofila- ment light chain with a threshold ranging from 1539 to 12317 pg/mL at 24 to 72 hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and sensitivity ranging from 53.1% to 65% (moderate certainty of evidence).

In 1 study,257 serum neurofilament light chain with a threshold ranging from 252 to 405pg/mL from day 1 to day 7 after ROSC predicted poor neurological outcome (CPC 4 5) at 6 months with 100% specificity and sensitivity ranging from 55.6% to 94.4% (very low-certainty evidence).

Treatment Recommendations

We recommend that neuroprognostication always be undertaken by using a multimodal approach because no single test has sufficient specificity to eliminate false positives (strong recommendation, very low-certainty evidence).

We suggest using NSE within 72hours after ROSC, in combination with other tests, for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommen- dation, very low-certainty evidence). There is no consensus on a threshold value.

We suggest against using S-100B protein for predicting neurolog- ical outcome of adults who are comatose after cardiac arrest (weak recommendation, low-certainty evidence).

We suggest against using serum levels of glial fibrillary acidic protein, serum tau protein, or neurofilament light chain for predicting poor neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

As was noted in the information addressing this topic in the 2015 CoSTR,1,7 the task force opinion is that a multimodal approach should be used in all cases with all supplementary tests considered in the context of prognostication.

Theevidence-to-decisiontablesareincludedin Supplement Appendixes A-18, 19, and 20.

Limited evidence suggests that high concentrations of NSE predict poor neurological outcome with 100% specificity at 24 to 72 hours after cardiac arrest, but there is a wide variability of thresholds for 100% specificity across studies. Lack of blinding was a limitation in most of included studies, even if withdrawal of life sustaining therapy based only on NSE was not documented.

Although the risk of self-fulfilling prophecy for S-100B protein is lower than that observed in other predictors, the evidence is limited by the few available studies and the wide variability of thresholds for 100% specificity across studies.

The supporting evidence about the use of neurofilament light chain, glial fibrillary acidic protein, and serum tau protein for prognostication after cardiac arrest is limited to very few studies. Consistent thresholds for 100% specificity need to be identified before any of these biomarkers can be recommended for prognostication in

the clinical setting. These biomarker tests are not widely available. The methods used for measuring these biomarkers need to be more widely available, standardized, and studied.

Knowledge Gaps

Large cohort studies are desirable to identify consistent NSE and S-100B thresholds for predicting poor neurological outcome after cardiac arrest. There is very little evidence concerning the predictive value of these biomarkers when measured later than 72 hours after ROSC.

Further studies on glial fibrillary acidic protein, serum tau protein, and neurofilament light chain are needed to confirm their predictive value after cardiac arrest, to assess their reproducibility, and to identify consistent thresholds for 100% specificity.

The potential impact of TTM on prognostication remains to be determined.

Imaging for Prognostication (ALS 450, 713, 458: SysRev)

Population, Intervention, Comparator, Outcome, Study Design, and Time Frame

Population: Adults who are comatose after resuscitation from cardiac arrest in any setting (in-hospital or out-of-hospital) and regardless of target temperature

Intervention: Imaging studies assessed within 1 week after cardiac arrest

Comparator: None
Outcome: Unfavourable neurological outcome defined as CPC

3 to 5 or mRS 4 to 6 at hospital discharge, 1 month, or later
Study design: Prognostic accuracy studies where the 2 2 contingency table (ie, the number of true/false negatives and positives for prediction of poor outcome) was reported, or where those variables could be calculated from reported data, are eligible for inclusion. Unpublished studies, reviews, case reports, case series, studies including fewer than 10 patients, letters, editorials, conference abstracts, and studies published in abstract

form were excluded.
Time frame: In 2015,1,7 an ILCOR evidence review identified

4 categories of predictors of neurological outcome after cardiac arrest, namely clinical examination, biomarkers, electrophysiolo- gy, and imaging. In the last 4 years, several studies have been published and new predictors have been identified, therefore the topic needs an update.

The most recent search of the previous SysRevs on neuro- prognostication was launched on May 31, 2013. We searched studies published from January 1, 2013, to December 31, 2019.

PROSPERO Registration: CRD42019141169

Consensus on Science

Gray Matter to White Matter Ratio.
Gray Matter
to White Matter Ratio: Average. The prognostic

value of the gray matter to white matter ratio (GWR) average was investigated in 7 observational studies.203,214,258 262 In 4 stud- ies,214,260,261,263 a GWR average 1.23 or less within 6hours after ROSC predicted poor neurological outcome from hospital discharge to 6 months with 100% specificity and sensitivity ranging from 13.3% to 83.8% (certainty of evidence from low to very low).

RESUSCITATION 156 (2020) A80 A119

105

In 1 study,203 a GWR average 1.13 or less at 124.5 59.9 minutes from ROSC predicted poor neurological outcome at 1 month with 85% specificity and 29.8% sensitivity (very low- certainty evidence).

In 1 study,259 a GWR average 1.077 or less within 24 hours after ROSC predicted poor neurological outcome at hospital discharge with 100% specificity and 15.6% sensitivity (very low-certainty evidence).

In 1 study,258 a GWR average 1.14 or less within 72 hours after ROSC predicted poor neurological outcome at hospital discharge with 100% specificity and 38.1% sensitivity (very low-certainty evidence).

Gray Matter to White Matter Ratio: Basal Ganglia. The prognostic value of the GWR in the basal ganglia was investigated in 4 observational studies.199,258,261,264 In 1 study,261 GWR-basal ganglia 1.12 or less within 1hour after ROSC predicted poor neurological outcome at hospital discharge with 100% specificity and 3.3% sensitivity (very low-certainty evidence).

In 2 studies,199,264 GWR-basal ganglia 1.21 or less within 24 hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and sensitivity ranging from 41.8% to 42.1% (certainty of evidence from moderate to very low).

In 1 study,258 GWR-basal ganglia 1.12 or less within 72 hours after ROSC predicted poor neurological outcome at hospital discharge with 100% specificity and 28.6% sensitivity (very low-certainty evidence).

Gray Matter to White Matter Ratio: Putamen/Corpus Cal- losum. The prognostic value of the GWR putamen/corpus callosum was investigated in 3 observational studies.247,260,265

In 2 studies,247,260 the GWR putamen/corpus callosum 1.17 or less within 6 hours after ROSC predicted poor neurological outcome from hospital discharge to 6 months with 100% specificity and sensitivity ranging from 31.3% to 52.9% (very low-certainty evidence).

In 1 study,265 of 258 patients, the GWR putamen/corpus callosum 0.91 or less within 24 hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and 1.7% sensitivity (very low-certainty evidence).

Gray Matter to White Matter Ratio: Simplified (Putamen/ Posterior Limb of Internal Capsule). In 1 observational study, GWR- simplified258 a ratio 1.1 or less within 72 hours after ROSC predicted poor neurological outcome at hospital discharge with 100% specificity and 28.6% sensitivity (very low-certainty evidence).

Gray Matter to White Matter Ratio: Caudate Nucleus/Posterior Limb of Internal Capsule

In 2 observational studies,247,260 a GWR in the caudate nucleus/ posterior limb of the internal capsule 1.15 or less within 6 hours after ROSC predicted poor neurological outcome from hospital discharge to 6 months with 100% specificity and sensitivity ranging from 19.8% to 40.6% (very low-certainty evidence).

Gray Matter to White Matter Ratio: Cerebrum. The prognos- tic value of the GWR in the cerebrum was investigated in 2 observational studies.258,261 In 1 study,261 a GWR in the cerebrum 1.12 or less within 1hour after ROSC predicted poor neurological outcome at hospital discharge with 100% specificity and 20% sensitivity (very low-certainty evidence).

In 1 study,258 a GWR in the cerebrum 1.09 or less within 72 hours after ROSC predicted poor neurological outcome at hospital discharge with 100% specificity and 28.6% sensitivity (very low- certainty evidence).

Gray Matter to White Matter Ratio: Thalamus/Corpus Cal- losum. In 1 observational study,260 a GWR in the cerebrum thalamus/ corpus callosum 1.13 or less at a median time of 90 (IQR, 52 150) minutes after ROSC predicted poor neurological outcome at 6 months

with 100% specificity and 50% sensitivity (very low-certainty evidence).

Gray Matter to White Matter Ratio: Caudate Nucleus/ Corpus Callosum. In 1 observational study,260 the GWR in the caudate nucleus/corpus callosum 1.15 or less at median time of 90 (IQR, 52 150) minutes after ROSC predicted poor neurological outcome at 6 months with 100% specificity and 46.9% sensitivity (very low-certainty evidence).

Gray Matter to White Matter Ratio in Cardiac Versus Noncardiac Etiology. One study assessed the predictive value of GWR specifically in patients with cardiac arrest of cardiac etiology, and one other focused exclusively on cardiac arrest with noncardiac etiology.266,267 Both of these studies reported GWRs that had 100% specificity for poor neurological outcome, and sensitivity was low in all cases. Results are presented in detail in Tables 3a and 3b.

Diffusion-Weighted MRI. The prognostic value of diffusion-weighted magnetic resonance imaging (MRI) was investigated in 5 observa-

tional studies.198,214,260,268,269

In 1 study,260 high signal intensity on diffusion-weighted MRI within 6 hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and 81.3% sensitivity (very low-certainty evidence).

In 4 studies,198,214,268,269 positive findings on diffusion-weighted MRI within 5 days after ROSC predicted poor neurological outcome from hospital discharge to 6 months with specificity ranging from 55.7% to 100% and sensitivity ranging from 26.9% to 92.6% (very low- certainty evidence).

Apparent Diffusion Coefficient. The prognostic value of apparent diffusion coefficient (ADC) was investigated in 2 studies. 269a

In1study,270ameanADC726 10 6mm2/sorlessatlessthan 48 hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and 44% sensitivity (very low-certainty evidence).

Inthesamestudy,270ameanADC627 10 6mm2/sorlessat 48 hours to 7 days after ROSC predicted poor neurological outcome at 6 months with 100% specificity and 20.8% sensitivity (very low- certainty evidence).

In the same study,270 an ADC volume proportion (400 10 6 mm2/s) greater than 2.5% at less than 48 hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and 64% sensitivity (very low-certainty evidence).

In the same study,270 an ADC volume proportion (400 10 6mm2/s) greater than 1.66% at 48hours to 7 days after ROSC predicted poor neurological outcome at 6 months with 100% specificity and 79.2% sensitivity (very low-certainty evidence).

In another study,269a maximum cluster size in different cerebral regions on MRI 151.7 10 6 mm2/s or less at 46 (IQR, 37 52) hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and sensitivity ranging from 62.5% to 90% (very low- certainty evidence).

In that same study,269a the lowest mean ADC in different cerebral regions on MRI 555.7 10 6 mm2/s or less at 46 (IQR, 37 52) hours after ROSC predicted poor neurological outcome at 6 months with 100% specificity and sensitivity ranging from 50% to 72.5% (very low- certainty evidence).

In the same study,269a the lowest minimum ADC in different cerebral regions MRI 466.8 10 6 mm2/s or less at 46 (IQR, 37 52) hours after ROSC predicted poor neurological outcome at 6 months

106 RESUSCITATION 156 (2020) A80 A119

Table3a–SensitivityandSpecificityofGWRat50(IQR,26 107)MinutesFromROSCbyBrainLocationinPatients With Cardiac Arrest of Cardiac Etiology.

Study, Year GWR Location or Type Sensitivity Specificity Certainty of Evidence

Poor Neurological Outcome at Discharge

Lee, 2015266

1.13 Average
1.11 Basal ganglia
1.107 Putamen/corpus callosum
1.06 Simplified
1.094 Caudate nucleus/posterior limb of the internal capsule 1.15 Cerebrum

3.5% 100% 3.5% 100% 5.6% 100% 3.5% 100% 3.5% 100% 4.2% 100%

Very low Very low Very low Very low Very low Very low

GWR indicates gray matter-to-white matter ratio; and IQR, interquartile range.

with 100% specificity and sensitivity ranging from 42.5% to 82.5% (very low-certainty evidence).

Treatment Recommendations

We recommend that neuroprognostication always be undertaken by using a multimodal approach because no single test has sufficient specificity to eliminate false positives (strong recommendation, very low-certainty evidence).

We suggest using GWR on brain computed tomography for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence). However, no GWR threshold for 100% specificity can be recommended.

We suggest using diffusion-weighted brain MRI for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence).

We suggest using ADC on brain MRI for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence).

Justification and Evidence-to-Decision Framework Highlights

Theevidence-to-decisiontablesareincluded SupplementAppendix- es A-21, 22, and 23. As noted in the 2015 CoSTR on this topic,1,7 the task force consensus is that a multimodal approach should be used in all cases with all supplementary tests considered in the context of prognostication.

In patients who are comatose after cardiac arrest, severe brain edema predicts poor outcome with high specificity. Calculation of GWR allows a quantitative evaluation of brain edema. However, there

is a wide heterogeneity of measurement techniques (sites and calculation methods) for GWR. This may partly explain the wide variability of thresholds for 100% specificity across the identified studies. The evidence supporting use of the GWR for prognostication has very low certainty.

Assessing diffusion-weighted imaging has potential for predicting poor neurological outcome after cardiac arrest. The definition of a positive diffusion weighted magnetic resonance image after cardiac arrest was inconsistent or even absent in the identified studies. The supporting evidence had very low certainty.

Assessing ADC has a potential for predicting poor neurological outcome after cardiac arrest with high sensitivity. There is a wide heterogeneity of measurement techniques (sites and calculation methods) for ADC across studies. The supporting evidence for ADC had very low certainty.

Knowledge Gaps

A consistent GWR threshold for predicting poor neurological outcome after cardiac arrest should be identified.

A standardization of the methods for GWR calculation is warranted.

The optimal timing for prognostication using brain computed tomography after cardiac arrest is still unknown. Studies assessing serial brain computed tomography after cardiac arrest are desirable.

The criteria for defining a positive diffusion-weighted MRI after cardiac arrest need to be standardized.

Table3b–SensitivityandSpecificityofGWRat67(IQR,29 115)MinutesFromROSCbyBrainLocationinPatients With Cardiac Arrest of Noncardiac Etiology.

Study GWR Location or Type Sensitivity Specificity Certainty of Evidence

Poor Neurological Outcome at Discharge

Lee, 2016267

1.22 Average
1.17 Basal ganglia
1.2 Putamen/corpus callosum
1.12 Simplified
1.138 Caudate nucleus/posterior limb of the internal capsule 1.2 Cerebrum

28.3% 100% 26.2% 100% 43.4% 100% 9.7% 100% 20% 100% 11% 100%

Very low Very low Very low Very low Very low Very low

GWR indicates gray matter-to-white matter ratio; and IQR, interquartile range.

RESUSCITATION 156 (2020) A80 A119

107

 A consistent ADC threshold for predicting poor neurological outcome after cardiac arrest should be identified.

 Standardization of the methods for ADC calculation is needed.

 The potential impact of TTM on prognostication remains to be
determined.
ALS CoSTR Topics Not Reviewed in 2020
Post-ROSC Percutaneous Coronary Intervention
Updates to 2015 CoSTRs for acute coronary syndromes (ACS) are now part of ALS postresuscitation care because there is no longer an ACS Task Force.271,272 The topics of percutaneous coronary intervention after ROSC in patients with and without ST-segment elevation (ACS 340, ACS 885) will be addressed in the 2021 CoSTR after publication of an ongoing SysRev.
Organ Donation After Cardiac Arrest
The 2015 treatment recommendations1,7 have not been updated for 2020. An ILCOR scientific statement on organ donation after OHCA will provide a narrative summary of the world literature on the incidence and outcomes of organ donation after OHCA as well as an estimation of potential donors and published implementation strate- gies with or without extracorporeal resuscitation. The statement includes a review of the international ethical issues and provides cost effectiveness estimates. It will make summary suggestions for implementation as well as identify key knowledge gaps that need to be addressed by future research (Tables A1 and A2).
Manual Defibrillation Topics Not Reviewed in 2020

 Algorithm for transition from shockable to nonshockable rhythm and vice versa (ALS 444)

 Biphasic waveforms (ALS 470)

 Pulsed biphasic waveforms (ALS 470)

 First shock energy (ALS 470)

 Single shocks versus stacked shocks (ALS 470)

 Fixed versus escalating defibrillation energy (ALS 470)

 Cardioversion strategies with implantable cardioverter-defibrilla-
tors or pacemakers (ALS 475)
Circulatory Support Topics Not Reviewed in 2020
IABP versus manual CPR (ALS 724) Open-chest CPR (ALS 574)

Drugs for monomorphic wide complex tachycardia (ALS 464)
Drugs for undifferentiated stable wide complex tachycardia (ALS

583)
Drugs for bradycardia (ALS 465)
Atropine for cardiac arrest (ALS 491) Calcium for cardiac arrest (ALS 482)

Intra-arrest Monitoring Topics Not Reviewed in 2020

Point-of-care echocardiography for diagnosis during CPR (ALS 658)

Special Circumstances Topics Not Reviewed in 2020

Cardiac tamponade (ALS 478)
Cardiac arrest during coronary catheterization (ALS 479)
Cardiac arrest in operating room (ALS 812)
Post-op cardiothoracic surgery cardiac arrest (ALS 572)
Electrolyte disturbances (ALS 456)
Digoxin toxicity (ALS 468)
Tricyclic antidepressant toxicity (ALS 429)
Cyanide toxicity (ALS 471)
Cocaine toxicity (ALS 474)
Carbon monoxide toxicity (ALS 480)
Calcium channel blocker toxicity (ALS 481)
Beta blocker toxicity (ALS 485)
Benzodiazepine toxicity (ALS 486)
Lipid therapy for cardiac arrest secondary to drug toxicity (ALS

834)
Avalanche victims (ALS 489)
Morbid obesity (ALS 452)
Asthma and cardiac arrest (ALS 492)
Cardiac arrest caused by anaphylaxis (ALS 494)

Postresuscitation Care Topics Not Reviewed in 2020

IV fluids after cardiac arrest (ALS 577)
Mechanical circulatory support postresuscitation (ALS 447)
Glucose control after resuscitation (ALS 580)
Haemofiltration postresuscitation (ALS 453)
PercutaneouscoronaryinterventionafterROSCwithST-segment

elevation (ACS 340)
Percutaneous coronary intervention after ROSC without ST-

segment elevation (ACS 885) Organ donation (ALS 449)

Impedance threshold device (ALS 579) MechanicalCPRdevices(ALS782) Acknowledgements

Drugs During CPR Topics Not Reviewed in 2020

IV fluids during cardiac arrest (ALS 578)
Drugs for atrial fibrillation (ALS 466)
Drugs for narrow complex tachycardia (ALS 463)

The authors thank the following individuals (the Adult Advanced Life Support Collaborators) for their contributions: Issa Mahmoud, Monica E. Kleinman, Giuseppe Ristagno, Julie Arafeh, Justin L. Benoit, Maureen Chase, Bryan L. Fischberg, Gustavo E. Flores, Mark S. Link, Joseph P. Ornato, Sarah M. Perman, Comilla Sasson, and Carolyn M. Zelop.

108 RESUSCITATION 156 (2020) A80 A119

 

Disclosures
Appendix 1 Writing Group Disclosures

Writing Group Member

Employment

Research Grant

Other Speakers’ Research Bureau/ Support Honoraria

Expert Ownership Witness Interest

Consultant/ Other Advisory
Board

Katherine M. Berg

Jasmeet Soar

Lars W. Andersen BerndW.Böttiger

Sofia Cacciola Clifton W. Callaway

Keith Couper

Tobias Cronberg

Sonia D’Arrigo Charles D. Deakin

Michael W. Donnino

Ian R. Drennan

Asger Granfeldt Mary Fran Hazinski

Cornelia W.E. Hoedemaekers Mathias Johan Holmberg Cindy H. Hsu

Marlijn Kamps

Beth Israel Dea- coness Medical Center Southmead Hospi- tal North Bristol NHS Trust (United Kingdom)

Aarhus University (Denmark) University HospitalNone of Cologne

(Germany) Self-employed University of Pittsburgh Warwick Medical School, University of Warwick (United Kingdom)

Lund University, Skane University Hospital (Sweden) Catholic University (Italy)

NIHR Southampton Respiratory Bio- medical Research Unit

Beth Israel Dea- coness Medical Center

Sunnybrook Health Sciences Center (Canada)
Aarhus University (Denmark) Vanderbilt University

RadboudUMC (The Netherlands) Aarhus University (Denmark) University of Michigan

Radboud Universi- ty (The Netherlands)

None NIHy

None

None

None None

NIHy; General Electric (Investiga- tor initiated study with VO2)*; Kaneka (Investigator initiat- ed research grant with ubiquinol)* None

None None

None None

NIH (K12HL133304-01) *; AHA (AHA Stra- tegic Network – Michigan Resusci- tation Innovation and Science Enter- prise (M-RISE))* None

None None

None None

NHLBI Grant K23 HL128814 y

None

None None

None None

None None

None FomF*;Zoll*; C.R. Bard*

None None None None

None None

None None

None None None None

None None

None None

None None None None

None None None None None None

None None

None None

None None

None None None None

None None None None

None None

None None

None None None None

None None

None None

None None None None

None None None None None None

None None

None None

None None None None

None None None None

None None

None None

None None None None

None None

None None

None None

American None Heart
Associationy
None None

None None None None

None

RESUSCITATION 156 (2020) A80 A119

109

Peter T. Morley

Laurie J. Morrison

Szymon Musiol

Kevin J. Nation

Robert W. Neumar

Tonia Nicholson

Jerry P. Nolan

Brian J. O’Neil

Quentin Otto

Edison Ferreira de Paiva Michael J.A. Parr

Joshua C. Reynolds Claudio Sandroni

Barnaby R. Scholefield

Markus B. Skrifvars

University of Mel- bourne, Royal Mel- bourne Hospital (Australia)

St Michael’s Hospi- tal, University of Toronto (Canada) Core Medical Trainee, Severn Deanery, Bristol (United Kingdom) New Zealand Re- suscitation Council (New Zealand) University of Michigan

Waikato Hospital Emergency Medi- cine (New Zealand) Warwick Medical School, University of Warwick (United Kingdom)

Wayne State University

Anaesthetic Train- ee, Severn Dean- ery, Bristol (United Kingdom) University of Sao Paulo (Brazil) Liverpool Hospital, University of Neew South Wales and Macquarie Univer- sity Hospital, Mac- quarie University (Australia) Michigan State University Università Cattolica del Sacro Cuore, Policlinico Gemelli (Italy)

University of Bir- mingham (United Kingdom)

Helsinki University Hospital and Uni- versity of Helsinki (Finland)

None

None

None

None

NIH (R01
HL133129, K12 PhysioCon-

Tzong-Luen Wang

None None

None None None None

HL133304)y; AHA (19SFR- N34760762)y

None

None

SIREN Network (Clinical trial network through NHLBI)*

None

None None

None None

NIHR UK (Clinician Scientist Fellow- ship program for research into neu- roprognostication after paediatric cardiac arrest)y

COVIDIEN (Invos) (Support for study conducted in 2016 2017)*

None

trol (Equip-
ment sup-
port for
laboratory
and clinical research)*
None None

None None

None Zoll circulation*; Genentech*

None None

None None None None

None None None None

None None

None BARD Medical (Ireland)

None None

None None

None None

None None

None None None None

None None None None

None None None None

None None None None

None None None None

None None None None

None None None None

None None None None

None None None None

None None None None None None None None

None None None None None None None None

None None None Salary (NIHR UK

Fellowship Funding– Clinician Scientist (academic, non- commerci- al))y

None None None None

Stryker/ None

110 RESUSCITATION 156 (2020) A80 A119

Michelle Welsford

Wolfgang A. Wetsch

Joyce Yeung

Chang Bing Show Chwang Memorial Hospital (Taiwan)
Center for Para- None medic Education

and Research
(Canada)
University Hospital None of Cologne
(Germany)
University of War- None wick, Warwick
Medical School
(United Kingdom)

None None

None None

None None

None None None None

None None None None

None None None 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 $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. *Modest.

ySignificant.

Appendix2 ReviewerDisclosures

Reviewer Employment Research Other Grant Research

Support

Speakers’ Bureau/ Honoraria

Expert Witness

Ownership Interest

Consultant/ Other Advisory
Board

Alix Carter Henry Halperin Jonathan Jui Fred Severyn

Robert A. Swor Andrew H. Travers

Dalhousie University (Canada) Johns Hopkins University

Oregon Health and Science University
Denver Health and Hospital Au- thority and University of Colorado Campus; University of Arkansas William Beaumont Hospital Emergency Health Services, Nova Scotia (Canada)

Maritime None Heart*
Zoll Medicaly; None NIHy

None None None None

None None None None

None None None None None None None None None None None None

None None None None None None

None None None None None 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 Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10,000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10,000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.

*Modest. ySignificant.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.resuscitation.2020.09.012.

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