OPTImal Ventilation to Improve Pediatric Cardiac Arrest Outcomes (OPTI-VENT)
Phase: NA
Conditions: Cardiac Arrest (CA)
Sponsor: Children's Hospital of Philadelphia

 
Template version: January 30, 2020 
  
Title: 
OPTImal Ventilation to Improve Pediatric Cardiac Arrest 
Outcomes (OPTI-VENT) 
Short Title 
Optimal Ventilation for Cardiac Arrest 
Regulatory Sponsor: 
 
eIRB Number 
IRB 24-022623 
Protocol Date: 
October 11, 2024 
Amendment 1 Date:  
Amendment 3 Date:  
Amendment 2 Date: 
Amendment 4 Date: 
Sponsor: NIH/NICHD 
Study Principal Investigator:  Robert Michael Sutton MD MSCE 
9th Floor Main Building: Room 9NW66 
3401 Civic Center Blvd., Philadelphia, PA, 19104 
Phone 267-273-3919 
email: suttonr@chop.edu 
Site Principal Investigators:  
Ryan W. Morgan MD MTR and Amanda O’Halloran MD  
The Children’s Hospital of Philadelphia 
9th Floor:  Main Building CCM Suite 
3401 Civic Center Blvd., Philadelphia, PA, 19104 
email: morganr1@chop.edu and ohallorana@chop.edu 
 
 

  
 
 
 
 
 
 
 
ii
 
TABLE OF CONTENTS 
Table of Contents ............................................................................................................................. ii 
Abbreviations and Definitions of Terms ................................................................................. iv 
Abstract ...............................................................................................................................................v 
Protocol Synopsis ........................................................................................................................... vi 
1 
Background Information and Rationale......................................................................... 1 
1.1 
Introduction .................................................................................................................................. 1 
1.2 
Name and Description of Investigational Product or Intervention .......................... 1 
1.3 
Findings from Non-Clinical and Clinical Studies.............................................................. 1 
1.4 
Relevant Literature and Data ................................................................................................. 2 
1.5 
Compliance Statement............................................................................................................... 2 
2 
Study Objectives ...................................................................................................................... 2 
2.1 
Primary Objective (or Aim) ..................................................................................................... 3 
3 
Investigational plan .............................................................................................................. 3 
3.1 
General Schema of Study Design ........................................................................................... 3 
3.1.1 
Screening Phase ...........................................................................................................................................................3 
3.2 
Allocation to Treatment Groups and Blinding ................................................................. 3 
3.3 
Study Duration, Enrollment and Number of Sites ........................................................... 4 
3.3.1 
Duration of Subject Study Participation ..........................................................................................................4 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected ....................................................4 
3.4 
Study Population ......................................................................................................................... 4 
3.4.1 
Subject Inclusion Criteria ........................................................................................................................................4 
3.4.2 
Subject Exclusion Criteria .......................................................................................................................................4 
4 
Study Procedures .................................................................................................................... 5 
5 
Study Evaluations and Measurements ............................................................................ 5 
5.1 
Screening and Monitoring Evaluations and Measurements ....................................... 5 
5.1.1 
Medical Record Review ............................................................................................................................................5 
5.2 
Efficacy Evaluations .................................................................................................................... 6 
5.2.1 
Diagnostic Tests, Scales, Measures, etc. ...........................................................................................................6 
6 
STATISTICAL CONSIDERATIONS ......................................................................................... 7 
6.1 
Primary Endpoint ........................................................................................................................ 7 
6.2 
Secondary Endpoints ................................................................................................................. 8 
6.3 
Statistical Methods...................................................................................................................... 8 
6.4 
Sample Size and Power ............................................................................................................. 9 
6.5 
Interim Analysis........................................................................................................................ 10 

 
 
 
 
 
 
 
 
iii
7 
Study INTERVENTION .......................................................................................................... 11 
7.1 
Description ................................................................................................................................. 11 
8 
SAFETY MANAGEMENT........................................................................................................ 12 
8.1 
Clinical Adverse Events .......................................................................................................... 12 
8.2 
Adverse Event Reporting ....................................................................................................... 12 
9 
STUDY ADMINISTRATION .................................................................................................. 12 
9.1 
Treatment Assignment Methods ........................................................................................ 12 
9.1.1 
Randomization .......................................................................................................................................................... 12 
9.2 
Data Collection and Management ...................................................................................... 13 
9.3 
Confidentiality ........................................................................................................................... 14 
9.4 
Regulatory and Ethical Considerations............................................................................ 14 
9.4.1 
Data and Safety Monitoring Plan ...................................................................................................................... 14 
9.4.2 
Risk Assessment ....................................................................................................................................................... 15 
9.4.3 
Potential Benefits of Trial Participation ....................................................................................................... 15 
9.4.4 
Risk-Benefit Assessment ...................................................................................................................................... 15 
9.5 
Recruitment Strategy .............................................................................................................. 16 
9.6 
Informed Consent/Assent and HIPAA Authorization ................................................. 16 
9.6.1 
Main Study ................................................................................................................................................................... 16 
9.6.2 
Waiver of Consent .................................................................................................................................................... 16 
10 
PUBLICATION / Dissemination .................................................................................... 17 
11 
References .......................................................................................................................... 17 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
iv 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
AHA 
 
American Heart Association 
BPM 
 
Breaths per minute 
CC 
 
Chest Compression 
CPR 
 
Cardiopulmonary resuscitation 
IHCA 
 
In-hospital cardiac arrest 
ICU 
 
Intensive care unit 
PCPC 
 
Pediatric Cerebral Performance Category 
pediRES-Q 
 
Pediatric Resuscitation Quality of CPR Collaborative 
A multicenter pediatric cardiac arrest resuscitation quality 
collaborative collecting standard cardiac arrest data across 
>50 domestic/international sites. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
v
ABSTRACT 
Context:   
In 2020, the American Heart Association (AHA) increased the recommended 
cardiopulmonary resuscitation (CPR) ventilation rate from 10 breaths per minute (bpm) to a range of 
20 – 30 bpm. Unfortunately, providers do not achieve this recommended target in actual practice. In 
response, we developed an OPTImizing VENTilation (OPTI-VENT) QI bundle consisting of 
provider education and point-of-care CPR ventilation rate guidance (CPR cue cards and a ventilation 
rate metronome) that demonstrated efficacy to train providers to a specific ventilation rate with high 
compliance in a single-center investigation. 
 
Objectives:  
Our primary objective is to evaluate the effectiveness of the OPTI-VENT bundle to improve 
survival to discharge with favorable neurological outcome among children receiving at least 1 
minute of intensive care unit (ICU) CPR.  
 
Study Design:  
Parallel-stepped-wedge hybrid cluster-randomized trial 
Setting/Participants: 
Across 20 domestic academic children’s hospitals, children ≥37 weeks corrected gestational 
age and <18 years old with an invasive airway in place at the time of an ICU cardiac arrest or who 
had an airway placed during the first 5 minutes of CPR are eligible for inclusion.  
Study Interventions and Measures:  
Standard cardiac arrest data collection will be completed for cardiac arrest subjects from the 
electronic medical record, continuous bedside monitors, and other patient physiologic monitoring 
devices (e.g., near infrared spectroscopy [NIRS]) for pre-, intra-. and post-arrest time periods. 
The primary outcome is survival to hospital discharge with favorable neurologic outcome, 
defined as a Pediatric Cerebral Performance Category score of 1-2 or no change from baseline. 
Secondary outcomes will be survival to discharge, return of spontaneous circulation (ROSC) >20 
minutes, return of circulation (ROC) with extracorporeal support, substantive new morbidity among 
survivors (increase in Functional Status Scale score ≥3), intra-arrest cerebral oxygen saturation, and 
proportion of events 1) that achieve diastolic blood pressure (DBP) thresholds during CPR, and 2) 
with either hyperoxia or hypocarbia in the immediate post-arrest period. 
 

  
 
 
 
 
 
 
 
vi 
PROTOCOL SYNOPSIS 
Study Title 
OPTImal Ventilation to Improve Cardiac Arrest Outcomes 
Funder 
National Institute of Child Health and Human Development 
Clinical Phase 
NA 
Study Rationale 
In 2020, the American Heart Association (AHA) increased the 
recommended CPR ventilation rate from 10 breaths per minute (bpm) to a 
range of 20 – 30 bpm, a target associated with better outcomes. 
Unfortunately, providers do not achieve this recommended target in actual 
practice. As such, innovative training strategies to this CPR parameter are 
potential therapeutic interventions to rescue more children from cardiac 
arrest. To that end, we developed an OPTImizing VENTilation (OPTI-
VENT) bundle consisting of provider education and point-of-care CPR 
ventilation rate guidance (CPR cue cards and a ventilation rate 
metronome). Our bundle demonstrated efficacy to train providers to a 
specific ventilation rate with high compliance. In this protocol, we 
describe an adaptive, parallel-stepped-wedge hybrid cluster-randomized 
trial to determine if the OPTI-VENT bundle can improve cardiac arrest 
outcomes by training providers to the 2020 CPR ventilation rate.   
Study Objective(s) 
Primary  
• 
To evaluate the effectiveness of the OPTI-VENT bundle to improve 
survival to discharge with favorable neurological outcome (Pediatric 
Cerebral Performance Category Score 1-2 or no change from baseline) 
among children receiving at least 1 minute of CPR.  
Secondary Analytic Observational Objectives 
• 
Determine if there is an alternative ventilation rate that is associated 
with improved 1) survival outcomes and 2) intra-arrest physiology 
(e.g., blood pressure). 
• 
Determine the association between Airway Opening Index (a newly 
discovered ventilation metric) and 1) survival outcomes, and 2) intra-
arrest physiology (e.g., blood pressure and exhaled carbon dioxide) 
• 
Determine if AOI can be modified by changing airway pressures 
delivered during CPR using novel multidimensional machine learning 
algorithms. 
Test Article(s) 
(If Applicable) 
OPTI-VENT QI Bundle Description: 
Provider Education: There are two main components to the provider 
education: 1) low-intensity / high-frequency point-of-care training and 2) 
monthly integration into existing education or quality meetings. Point-of-
care training will be conducted by pediRES-Q network site quality 
physician champions. During this brief (<2 minute) bedside education, the 
educator will 1) review the AHA CPR ventilation rate target, and 2) 
ensure the provider has their rate cue card on his/her person and knows 
how to activate the CPR ventilation rate metronome described below. 
Additionally, a focus on CPR ventilation rates will be integrated into 
resuscitation education or quality meetings for all disciplines. A brief 
Microsoft PowerPoint presentation focusing on the benefits of ventilation 

 
 
 
 
 
 
 
 
 
 
vii
rate compliance will be standardized for distribution across all sites. 
“Report cards” detailing unit-level performance will be generated by the 
University of Utah Data Coordinating Center and emailed to the PIs for 
review during their monthly presentations.    
Point-of-Care Guidance: Similar to the single-center study supporting 
our multicenter trial, we will deploy a metronome to all cardiac arrests. In 
the single-center OPTI-VENT study, a smart phone application was used. 
For this multicenter trial, we will use a similar method or leverage the 
existing pediRES-Q infrastructure which already deploys CPR feedback 
defibrillators to all cardiac arrest events.   
 
Study Design 
 
Prospective hybrid cluster randomized stepped-wedge interventional 
multicenter trial 
Subject Population 
key criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1. Children ≥37 weeks corrected gestational age and <18 years of 
age  
2. Invasive airway in place at the start of CPR or airway placed 
within the first 5 minutes 
3. Received at least 1 minute of CPR. 
Exclusion Criteria 
1. Lack of commitment to aggressive ICU therapies (e.g., CPR 
performed as part of end-of-life care. 
2. Brain death determination prior to the CPR event. 
3. Out-of-hospital cardiac arrest was the reason for initial admission 
to the hospital (known poor outcomes). 
4. Supported by Veno-Arterial Extra Corporeal Membrane 
Oxygentation at the start of CPR 
Healthcare providers inclusion criteria: bedside care providers of all 
disciplines working in ICU 
Healthcare provider exclusion criteria: none 
Number Of Subjects  
 
Total Number of Subjects:  1530 
Total Number at CHOP:  200 (estimated) 
Total Number of Sites:  20 
Study Duration 
Each subject’s participation will last from the time of their cardiac arrest 
(CPR event) to their discharge from the hospital or death. Subjects alive 
30 days after the end of the 4.25-year enrollment period will have their 
final outcome data assessed at that time. 
Study Phases 
 
Cardiac arrest data (e.g., subject demographics, intra- and peri-arrest 
physiologic waveforms, outcome data) will be collected on all subjects 
meeting inclusion / exclusion criteria. There is no identifying information 
collected on the ICU care providers who work in the participating ICUs. 
 

 
 
 
 
 
 
 
 
 
 
viii
Recruitment and Informed Consent: Cardiac Arrest Subject: As this 
study is observational at the patient level, similar to other pediRES-Q 
network quality improvement interventional studies, a waiver of consent 
will be requested. This is also exactly similar to the consent process 
utilized for Dr. Sutton’s now published ICU-RESUS interventional trial 
(Journal of the American Medical Association) which implemented a 
similar training bundle to ICU providers, albeit focused on the chest 
compression aspect of CPR rather than ventilation. A waiver will be 
requested on the following factors: 1) This study poses no more than 
minimal risk (CPR training already exists at the participating hospitals and 
quality will be at least as good with OPTI-VENT implementation); 2) The 
waiver will not adversely affect the rights and welfare of the subjects (i.e., 
cardiac arrest patients undergoing CPR); 3) Obtaining informed consent 
would threaten the scientific validity of the study. The scientific validity 
of the study is dependent upon capturing all eligible events during the 
period of study, as one of the major goals is to associate ventilation data 
with survival outcomes; 4) This study involves no therapeutic intervention 
at the patient level (no drug, no technology), and there are no changes in 
accepted clinical practice; 5) Only a limited dataset will be shared with the 
University of Utah. The minimal risk of loss of privacy will be mitigated 
by the substantial data management resources of the data management 
team at CHOP and the process by which they verify that only a limited 
dataset is sent to the University of Utah for analysis. As presently accepted 
in other pediRES-Q protocols, waiver of HIPAA authorization at the 
patient level will also be requested, as again, no identifying information 
will be transmitted outside of CHOP. Healthcare Provider: 1) This study 
poses no more than minimal risk (CPR training already exists in 
ICUs and is a normal job-related responsibility and there are no 
links between the providers identify and their performance, either in 
the educational session or during actual patient care); 2) The 
research cannot be practically carried out without the waiver as it 
will be important to describe how the participating sites 
implemented the bundle.  Additionally, consenting all providers 
would place undue burden on these healthcare providers who are 
caring for critically ill children who by definition have labor 
intensive care plan; 3) There are also no identifying links between 
the care providers and their resuscitation performance; 4) The 
waiver will not adversely affect the rights and welfare of the 
subjects as CPR training already exists in ICUs and is a normal job-
related responsibility.  The minimal risk of loss of privacy will be 
mitigated by the substantial data management resources of the data 
management team at CHOP and the process by which they verify 
that only a limited dataset is sent to the University of Utah for 
analysis. As presently accepted in other pediRES-Q protocols, 
waiver of HIPAA authorization at the patient level will also be 
requested, as again, no identifying information will be transmitted 
outside of CHOP.  

  
 
 
 
 
 
 
 
ix 
 
Efficacy Evaluations 
The primary outcome is survival to hospital discharge with favorable 
neurologic outcome, defined as a PCPC score of 1-2 or no change from 
baseline.  
Pharmacokinetic 
Evaluations 
NA 
Safety Evaluations 
NA 
Statistical And 
Analytic Plan 
The analysis of survival to discharge with favorable neurological outcome 
is based on all enrolled index events excluding transition periods. For the 
primary analysis, a mixed effect logistic regression model will be fit with 
our primary outcome as the dependent variable. The primary predictor will 
be treatment group, an indicator of whether the OPTI-VENT bundle was 
fully implemented prior to the arrest. Fixed covariates will be illness 
category (e.g., medical cardiac, medical non-cardiac, surgical cardiac), 
age, first documented rhythm, and time since trial start (to prevent 
confounding due to unrelated temporal changes in outcome). Etiology and 
severity of pre-existing lung disease will be evaluated as a confounder / 
effect modifier. Unit will be included as a random effect to account for 
heterogeneity in patient outcomes across ICUs and to accommodate 
clustering of patients within ICUs. The null hypothesis will be tested using 
the standard type III test for the fixed effect, and the p-value for the two-
sided alternative will be presented. 
DATA AND SAFETY 
MONITORING PLAN 
Despite CPR training existing in ICUs as a job-related responsibility and 
this investigation being observational at the subject-level, as we did for the 
ICU-RESUS trial, we plan to assemble a DSMB in collaboration with the 
Eunice Kennedy Schriver National Institute of Child Health and Human 
Development (NICHD) for this study. The DSMB is responsible for 
monitoring subject safety, accrual of study subjects, adherence to the 
study protocol, assessments of data quality, performance of individual 
clinical centers, and review of formal interim statistical analyses of 
treatment efficacy. DSMB meetings will be scheduled as follows: full 
DSMB meeting at 1, 2, 3, and 4.25 years; chair only review at 0.5, 1.5, 
2.5, and 3.5 years. Efficacy will be formally assessed at 2, 3, and 4.25 
years. A symmetric, two-sided O’Brien-Fleming type boundary with 
overall alpha level set to 0.05 will be used as a guideline for stopping the 
study due to a difference between treatment arms. Stopping boundaries 
will be generated using symmetric monitoring boundaries, corresponding 
to alpha spending of 0.025 to detect a benefit and 0.025 to detect a harmful 
effect of treatment vs control. Lan-DeMets spending functions 
corresponding to O’Brien-Fleming type boundaries will be used. 
Monitoring boundaries will be set according to the proportion of total 
statistical information (information fraction) available in each interim 
analysis dataset. Futility monitoring will be at the discretion of the DSMB. 
Futility analyses, if they are requested, will calculate estimated conditional 
power of the trial to detect a significant treatment difference, if it 
continues, under relevant scenarios (e.g., the treatment effect being as 
postulated). 

 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Pediatric cardiac arrest is a life-threatening problem affecting >15,000 hospitalized children 
each year (1). Less than half of these children survive to hospital discharge, and neurologic 
morbidity is common among survivors. Moreover, pediatric cardiac arrest survival outcomes 
plateaued nearly ten years ago, highlighting the critical need for evidence-based and innovative 
therapeutic approaches (2).        
Our team has established that high-quality cardiopulmonary resuscitation (CPR) improves 
outcomes from pediatric cardiac arrest (3). To date, an imbalance exists with overwhelmingly more 
investigation into chest compression (CC) quality (i.e., depth, rate, and release velocity) as compared 
to the delivery of ventilations. Given that most pediatric patients have respiratory disease at the onset 
of cardiac arrest (4), the lack of rigorous investigation into optimal CPR ventilation strategies 
represents a significant roadblock to understanding how best to rescue more children from cardiac 
arrest. 
 
1.2 Name and Description of Investigational Product or Intervention 
The OPTI-VENT bundle consists of two main components: 1) provider education: physician, 
registered nurse, and respiratory therapist education (via scheduled existing educational or quality 
meetings) and 2) point-of-care ventilation guidance (CPR cue cards highlighting ventilation rate 
targets and the introduction of a ventilation rate metronome). The primary ventilation training targets 
will be: 30 breaths per minute (bpm) for infants < 1 year of age (1 breath every 2 seconds) and 20 
bpm for older children (1 breath every 3 seconds), consistent with 2020 AHA Guidelines (5) . 
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1.1 Clinical Studies in Children 
• 
In a previous NHLBI-funded multicenter study (6), we evaluated the association between 
CPR ventilation rates and survival. In this study of 47 intubated children who suffered a 
cardiac arrest, “high ventilation rates,” defined as ≥30 bpm among infants <1 year of age and 
≥25 bpm among older children, were associated with a more than 4x greater likelihood of 
survival to hospital discharge with favorable neurologic outcome (primary outcome of this 
investigation). Our data were translated by the AHA CPR Guideline committee into a target 
rate of 20 – 30 bpm. 
• 
The OPTI-VENT bundle provider education in our pilot work followed a “low-intensity / 
high frequency” (spaced learning) training paradigm. Our team has pioneered this approach 
(7), documenting its effectiveness to improve compression quality. In a single-center study, 
the OPTI-VENT bundle improved ventilation rate target compliance (absolute risk reduction 
of ventilation rates exceeding 30 bpm: 22%, [CI95 16% – 28%], p<0.001) (8).  
• 
A recent landmark study established that intrathoracic airway closure impacts CPR 
ventilation (9). In this 3-part series of investigations, end-tidal carbon dioxide (ETCO2) 
waveforms – waveforms that are part of standard clinical care in ventilated patients in ICUs 
– were used to infer the degree of airway closure during CPR. Importantly, the degree of 
airway closure could be mitigated, and the ventilation during CPR improved, by small 
increases in the amount of airway pressure delivered during CPR. By maintaining airway 
patency, the chest compression oscillations provide a tidal volume (i.e., size of the delivered 
breath) that is additive to the tidal volume provided by the rescuer during CPR. 
 

 
  
 
 
 
2
1.4 Relevant Literature and Data 
Background: Of the >15,000 US children who have a pediatric in-hospital cardiac arrest (p-IHCA) 
each year, only ~40% survive (1). Interventions to improve CPR quality can save lives, but to date, 
there is a research imbalance, with much more of a focus on optimal chest compression techniques as 
compared to ventilation strategies. Using data extrapolated from adult studies, previous iterations of 
CPR Guidelines recommended a ventilation rate of 10 bpm for both children and adults. This 
recommendation was based upon the concern that higher ventilation rates would detrimentally affect 
hemodynamics during pediatric CPR as well (i.e., decreased venous return from increased 
intrathoracic pressure)(10, 11). In contrast, our NIH-funded multicenter observational data found that 
higher ventilation rates were beneficial to children (6). As a result, in 2020, the AHA increased the 
CPR ventilation rate from 10 bpm to 20 – 30 bpm. Due to the small number of patients and 
observational nature of our preliminary work, there remains intense controversy across the seven 
international resuscitation councils (e.g., AHA, European Resuscitation Council [ERC]) regarding 
optimal pediatric CPR ventilation rates. While the AHA recommends 20 – 30 bpm, the ERC 
recommends a range of 10 – 25 bpm (25 bpm for infants down to 10 bpm for anyone over 12 years). 
All councils classify their pediatric ventilation rate recommendation as “weak,” with “very low level 
of evidence,” and list ventilation rate as a research gap that requires high priority multicenter 
evidence to inform future guidelines. 
Resuscitation Care Bundles (ICU-RESUS): We recently published findings from a large (>1000 
patients) NHLBI-funded multicenter trial evaluating physiologic-directed point-of-care CPR 
education and cardiac arrest reviews with a focus on improving chest compression quality 
(NCT02837497) in the Journal of the American Medical Association (12). In contrast to the 
ventilation-targeted intervention we propose in this investigation, the ICU-RESUS bundle focused 
specifically on the chest compression aspect of CPR with the goal to improve intra-arrest diastolic 
blood pressure (DBP). And while the ICU-RESUS trial demonstrated our ability to implement a 
bundled intervention across a diverse group of ICUs with high compliance (>90%), we did not 
observe an improvement in patient outcomes with implementation of the chest compression targeted 
intervention. Given the high incidence of respiratory disease at the onset of cardiac arrest in children, 
we suspect that not including ventilation rate-focused training (CPR ventilation rate compliance was 
<6% among ICU-RESUS subjects) was a key driver of ICU-RESUS bundle “failure,” and thus, made 
the OPTI-VENT trial the next logical step. 
1.5 
Compliance Statement 
 
The investigators will perform the study in accordance with this protocol and will report 
unanticipated problems involving risks to subjects or others in accordance with The Children’s 
Hospital of Philadelphia IRB Policies and Procedures and all federal requirements. Collection, 
recording, and reporting of data will be accurate and will ensure the privacy, health, and welfare of 
research subjects during and after the study. All episodes of noncompliance will be documented. 
2 
STUDY OBJECTIVES 
In an adaptive, parallel-stepped-wedge hybrid cluster-randomized trial, the purpose of the study 
is to determine if the OPTI-VENT bundle can improve pediatric cardiac arrest outcomes by training 
providers to the 2020 CPR ventilation rate (20-30 bpm).   

 
  
 
 
 
3
2.1 Primary Objective (or Aim) 
The primary objective of this study is to determine the effectiveness of the OPTI-VENT bundle to 
improve survival to discharge with favorable neurological outcome among children receiving at least 
1 minute of CPR. 
In embedded observational studies, the secondary objectives are to: 
• 
Determine if there is an alternative ventilation rate that is associated with improved 1) survival 
outcomes and 2) intra-arrest physiology (e.g., blood pressure). 
• 
Determine the association between Airway Opening Index and 1) survival outcomes and 2) 
intra-arrest physiology (e.g., blood pressure and exhaled carbon dioxide) 
• 
Determine if AOI can be modified by changing airway pressures delivered during CPR using 
novel multidimensional machine learning algorithms. 
 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
This study is a prospective hybrid cluster randomized stepped-wedge interventional 
multicenter trial to evaluate the effectiveness of an educational QI bundle focused on CPR 
ventilation rate to improve survival outcomes when providers are trained to existing American Heart 
Association (AHA) Guidelines (20 – 30 breaths per minute [bpm]). It is essentially a platform trial, 
leveraging the existing infrastructure and database of the pediRES-Q network. 
3.1.1 Screening Phase 
Potential subjects will be screened from all cardiac arrest subjects at participating study sites 
using this protocol’s inclusion and exclusion criteria. All subjects ≥37 weeks corrected gestational 
age and <18 years old with an invasive airway in place at the time of a cardiac arrest or who had an 
airway placed during the first 5 minutes of CPR, and who required at least 1 minute of CPR will be 
enrolled.    
Providers who work in the ICU are also potential subjects of this investigation. No identifying 
information will be collected that could be used to provide a link to their actual CPR performance. 
3.2 Allocation to Treatment Groups and Blinding 
The basis of this investigation is a hybrid between a parallel and stepped-wedge cluster-
randomized trial (13). As in a parallel design, 5 randomly selected sites will be permanently assigned 
to enroll in the control group, and 5 others will be permanently assigned to enroll in the intervention 
group. The remaining 10 sites, as in a stepped-wedge design, will initially enroll in the control group 
but will be randomly assigned a time to begin implementing the intervention. Data collection will be 
continuous for the entire 4.25-year study, but events enrolled in the 8-week transition period after the 
intervention is initiated will be excluded from analyses comparing intervention to control. In order to 
ensure roughly equal numbers of subjects in the intervention and control groups, and to ensure 
balance with respect to baseline pre-trial survival rates, the computer-generated randomization 
schedule will be selected from all possible configurations with sufficient expected balance in both 
expected enrollment and pre-trial survival rates.  

 
  
 
 
 
4
 
  Figure 1: Schematic summary of overall study design 
 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Subject Study Participation 
The study duration per subject will be from the time of their cardiac arrest through hospital discharge 
or death. Subjects alive 30 days after the end of the 4.25 year enrollment period will have their final 
outcome data assessed at that time. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at approximately 20 investigative sites in the United States. 
Recruitment will stop when approximately 1530 subjects are enrolled. As per the study design, 
enrollment will end 4.25 years from study start. 
3.4 Study Population 
3.4.1 Subject Inclusion Criteria 
All children ≥37 weeks corrected gestational age and <18 years old with an invasive airway in place 
at the time of a cardiac arrest or who had an airway placed during the first 5 minutes of CPR, and 
who required at least 1 minute of CPR. 
3.4.2 Subject Exclusion Criteria 
1) Lack of commitment to aggressive ICU therapies (e.g., CPR performed as part of end-of -life 
care as documented in the medical record) 
2) Brain death determination prior to the CPR event 
3) The admission to the hospital was secondary to an out-of-hospital CPR event (known poor 
outcomes if there is a recurrent arrest) 
4) Supported by Veno-Arterial ECMO at the start of CPR 
Healthcare provider inclusion criteria: bedside care providers of all disciplines working in ICU 
 
Exclusion criteria: none 

 
  
 
 
 
5
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of these 
criteria must be reported in accordance with IRB Policies and Procedures.   
4 
STUDY PROCEDURES 
Standard cardiac arrest data (e.g., demographics, intra- and post-arrest physiologic variables, CPR 
quality variables) will be collected on all subjects, extracted from the electronic medical record, 
continuous bedside monitors, and other patient physiologic monitoring devices (e.g., NIRS). Data 
elements to be collected from the pre-, intra-, and post-arrest periods include but are not limited to: 
Patient Characteristics: date of birth; sex; race/ethnicity; height; weight; illness category (medical 
cardiac, medical non-cardiac, surgical cardiac, surgical non-cardiac, trauma). Pre-existing 
conditions: respiratory insufficiency; hypotension; congestive heart failure; pneumonia; sepsis; 
trauma; renal insufficiency; malignancy; congenital heart disease, if yes, single ventricle; if single 
ventricle, the anatomy is specified; if surgical palliation completed, type of most recent surgical 
procedure is noted (Norwood with Sano modification, Norwood with modified BT shunt, Hybrid 
Procedure, Bi-directional Glenn, Fontan, other); vasoactive inotropic scores (2 hours preceding 
CPR); pediatric cerebral performance category (PCPC) score; functional status scale (FSS) score.  
CPR Event Characteristics: interventions at CPR start (e.g., vasoactive infusion); immediate cause of 
arrest (Y/N for hypotension, respiratory decompensation, arrhythmia, cyanosis without respiratory 
decompensation); first documented rhythm requiring CPR; time of first shockable rhythm; pre-shock 
pause (seconds); time of first defibrillation; time of first vasopressor administration for non-
shockable rhythm; drug interventions during CPR; duration of CPR (minutes). CPR mechanics 
variables: Compression depth (mm); rate (per minute); chest compression fraction; and leaning 
during relaxation phase (release velocity, if available [mm/second]). Ventilation variables: ETCO2 
(mmHg); ventilation rate (bpm); airway opening index; other ventilation variables as available (e.g., 
Peak Inspiratory Pressure [cmH2O]). Intra-arrest physiology (arterial BP (mmHg), ETCO2 (mmHg), 
and arterial/venous blood gases. 
Post-cardiac Arrest Care Variables (first 6 and >6-24 hours post-arrest with highest and lowest 
unless indicated): systolic and diastolic arterial BP (mmHg); temperature (°C); arterial PaO2 
(mmHg); PaCO2 (mmHg); pH; highest lactate (mmol/L); glucose (mg/dL); vasoactive scores (6, 12 
and 24 hours); required extracorporeal membrane oxygenation (ECMO) support (Y/N); targeted 
temperature management (TTM, Y/N); if TTM, goal max temperature; electroencephalography 
(EEG; Y/N). 
ICU Care Providers:  No identifying information will be collected from the providers working in the 
ICUs who may be targeted with the training intervention. During bedside trainings described below, 
only shift (AM [7am to 7pm], PM [7pm to 7am]), discipline (MD, RN, RT, other) and time since last 
training (<1 week, <1 month, >3 months) will be recorded. These variables are used to be able to 
describe the spread of the OPTI-VENT training.  
 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
All data elements to be collected are entered into the electronic medical record as part 
of routine clinical care. 

 
  
 
 
 
6
5.2 Cardiac Arrest Event Data:  
Data recorded during the chest compression event include but are not limited to those 
listed in Section 4.  
 
5.3 Patient Characteristics 
Patient characteristics to be collected include but are not limited to those listed in 
Section 4. The only PHI data collected will be subject name, MRN, date of birth, and date of 
the event, which will be kept confidential in accordance with Institutional policies and 
HIPAA IRB regulations. The only PHI that will be entered into REDCap database will be 
date of birth and date of arrest.   
5.4 Post-Resuscitation Phase   
Data elements to be collected include but are not limited to those outlined in Section 4.  
5.5 Efficacy Evaluations 
The primary outcome is survival to hospital discharge with favorable neurologic outcome, defined as 
a PCPC score of 1-2 or no change from baseline.  
Secondary outcomes will be: 
• 
survival to discharge 
• 
Return of spontaneous circulation (ROSC) >20 minutes 
• 
Return of circulation with ECMO support 
• 
Substantive new morbidity among survivors (increase in Functional Status Scale score ≥3) 
• 
Intra-arrest cerebral oxygen saturation (%) as measured by Near Infrared Spectroscopy 
(NIRS) monitors, as part of standard clinical care in the pedRES-Q sites. 
• 
Proportion of events 1) that achieve the DBP recommended thresholds during CPR (14), and 
2) with either hyperoxia (PaO2 >300 mmHg) or hypocarbia (PaCO2 <30 mmHg) in the 
immediate post-arrest period (15).  
5.5.1 Diagnostic Tests, Scales, Measures, etc. 
Table 1: Pediatric Cerebral Performance Category (from medical record review)(16) 

 
  
 
 
 
7
 
Table 2: Functional Status Scale Score (from medical record review)(17) 
 
 
6 
STATISTICAL CONSIDERATIONS 
6.1 Primary Endpoint 
The primary outcome is survival to hospital discharge with favorable neurologic outcome, defined as 
a PCPC score of 1-2 or no change from baseline. Baseline will be defined as the child’s pre-

 
  
 
 
 
8
admission status.  For those children hospitalized more than 90 days at the time of their CPR event, a 
new “baseline” will be assessed at least 30 days prior to the CPR event. 
6.2 Secondary Endpoints 
Secondary outcomes will be: 
• 
Survival to discharge, a binary indicator of whether or not the subject was discharged alive. 
• 
Return of spontaneous circulation (ROSC) >20 minutes, a binary indicator of whether or not the 
subject achieved adequate circulation via a native heartbeat. 
• 
Return of circulation with extracorporeal membrane oxygenation (ECMO) support, a binary 
indicator that adequate circulation could only be achieved with ECMO support (i.e., E-CPR).  
• 
Substantive new morbidity among survivors (increase in Functional Status Scale score ≥3). 
• 
Intra-arrest cerebral oxygen saturation (%) as measured by Near Infrared Spectroscopy (NIRS) 
monitors, as part of standard clinical care in the pedRES-Q sites. 
• 
Proportion of events 1) that achieve the DBP thresholds during CPR (14), and 2) with either 
hyperoxia (PaO2 >300 mmHg) or hypocarbia (PaCO2 <30 mmHg) in the post-arrest period 
(15).  
6.3 Statistical Methods 
For analysis, each CPR event will be divided into multiple 30-second epochs. An average of 
the following will be calculated: 1) ventilation rate (bpm); 2) ETCO2 (mmHg); 3) compression rate; 
4) arterial BPs; 5) chest compression fraction; 6) compression depth (mm); 7) exhaled tidal volume 
(mL); 8) minute ventilation (L/minute); 9) PIP (cm H2O); 10) PEEP (cm H2O); 11) % leak; and 12) 
cerebral oxygen saturation. An average of all epochs (event-level average) will be used in survival 
analyses. 
Primary Objective (Efficacy of OPTI-VENT bundle) 
The analysis of our primary outcome is based on all enrolled index events (first in-ICU cardiac 
arrest) excluding transition periods. For the primary analysis of the interventional trial, a mixed 
effect logistic regression model will be fit with our primary outcome as the dependent variable. The 
primary predictor will be treatment group, an indicator of whether the OPTI-VENT bundle was fully 
implemented prior to the arrest. Fixed covariates will be illness category, age, first documented 
rhythm, and time since trial start (to prevent confounding due to unrelated temporal changes in 
outcome). Etiology and severity of pre-existing lung disease will be evaluated as a confounder / 
effect modifier. Unit will be included as a random effect to account for heterogeneity in patient 
outcomes across ICUs and to accommodate clustering of patients within ICUs. The null hypothesis 
will be tested using the standard type III test for the fixed effect, and the p-value for the two-sided 
alternative will be presented. 
Brief Description of Secondary Analytic Objectives 

 
  
 
 
 
9
Ventilation Rate and Survival: We will explore the relationship between ventilation rate and survival 
using cubic splines and ROC curves. We will randomly divide our cohort into a derivation set (70%) 
and a validation set (30%). The derivation set will be used in an exploratory fashion to identify an 
optimal target using cubic splines and ROC curves in conjunction with clinical expertise. Then, the 
validation set will be used to validate the rate selected and to provide an unbiased estimate of the 
effect of achieving the target rate on outcome. Cubic splines will allow us to create a smooth curve 
of survival probability on the vertical axis against the event-level average ventilation rate on the 
horizontal axis, while controlling for potential confounders. We plan to stratify our analysis by age, 
and either adjust for / stratify by initial rhythm, immediate 
cause of arrest (e.g., respiratory deterioration, shock, 
sudden arrhythmia), severity (none, non-severe, severe) 
and etiology (none, obstructive, restrictive, mixed) of pre-
existing lung disease, chest compression depth and rate 
(AHA compliant vs. not), and clinical site. If an alternative 
ventilation rate target is identified, we will quantify its 
association with survival outcomes using logistic 
regression models. Similarly, we will also explore the 
relationship between ventilation rate and 1) arterial 
diastolic BP and 2) exhaled carbon dioxide using linear 
regression models. For this analysis, individual epoch data 
will be used. Models will be adjusted for the same 
variables as above and account for the clustering of epochs 
from within events. 
Evaluation of Airway Opening Index: The calculation of 
Airway Opening Index will be done in the manner as described in Grieco et.al. (Figure 2). As with 
other variables, an average AOI for each 30-second CPR epoch will be calculated. For each event, 
the average of all the epochs will be calculated to be used in logistic regression survival analyses. 
Epoch-level data will be used in a similar fashion as described above to evaluate the association of 
AOI with intra-arrest physiology (e.g., blood pressure and ETCO2) and delivered airway pressures 
(e.g., positive end expiratory pressure) in linear regression models, accounting for the clustering of 
epochs from within events. In addition to these standard statistical methods, this exploratory aim will 
involve the development of a multi-modal ML model. The input data will comprise both discrete 
values (e.g., demographic and clinical variables, ETCO2, I/E ratio) and high-fidelity waveform data 
(e.g., arterial BP, capnogram). To evaluate model performance, we will use metrics such as accuracy, 
F1-score, and AUC-ROC.  
 
6.4 Sample Size and Power 
Primary Objective (Efficacy of OPTI-VENT bundle) 
Figure 2: Airway Opening Index. The sum 
of the delta in ETCO2 divided by the max 
ETCO2 caused by each chest compression 
is averaged by the number of CCs. Higher 
values indicate greater airway patency.  

 
  
 
 
 
10
Based on pediRES-Q data, ~360 index CPR events are expected to occur annually. After 
excluding ~7 events/year that occur during transition periods, 1500 index events will be available for 
analysis. In our preliminary work, rates consistent with 2020 AHA Guidelines were associated with 
an improvement in survival 
with favorable neurologic 
outcome of >20 percentage 
points. Understanding that 
it is likely that the 
magnitude of the effect will 
be smaller in a multicenter 
study, we have provided 
estimated power to detect a 
12-16% improvement when 
the target rate is achieved compared to a baseline rate of survival with favorable neurologic outcome 
of 30% (data obtained from an existing pediRES-Q online real-time dashboard) when the target rate 
is not achieved. We also show the impact of the level of compliance with the target rate that we can 
achieve in the intervention group compared to a control group rate of 20%. We have assumed an 
intra-cluster correlation of 2% (based on our prior IHCA data). To ensure adequate power, we have 
included a pre-planned adaptive design. If after 12 months of enrollment, sites are enrolling ≤90% of 
expected, we will add 6 additional ICUs. If they are enrolling ≤75% of expected, we will add an 
additional 10 ICUs. As the pediRES-Q network has more than 50 active domestic / international 
sites, recruiting 10 sites is feasible. New sites if added will all begin in the control group starting at 
14 months and will randomly be assigned a transition time according to a standard stepped-wedge 
design. Start-up within 2 months is feasible due to these sites starting in control, our plan for 
continuous enrollment monitoring, and the infrastructure of the pediRES-Q network (active IRBs 
and DUAs). Our design adaptation can also be used to mitigate power issues due to unexpectedly 
high baseline compliance in the control group or inability to achieve compliance training targets in 
the interventional group. 
Secondary Analytic Objectives 
Ventilation Rate and Survival:  We conservatively estimate that ~20% of our subjects will not have 
usable ventilation data. Given the remaining cohort (~1200 patients), we will have more than 90% 
power to detect an improvement in survival from 30% to 40% if the ventilation rate is at target in 
40%-60% of subjects. Given the absolute change in survival associated with the ventilation target 
from our preliminary data was >20%, we are conservatively powered for the primary objective of 
this aim. In subgroups as small as 350, we will have >80% power to detect an improvement in 
survival probability from 30% to 45%. Additionally, our preliminary data demonstrate that >25% of 
our patients with usable ventilation data will also have usable arterial BP data. With 300 subjects, we 
have >80% power to detect an association between ventilation rate and diastolic BP (assumptions: 
standard deviation of 10 mmHg for both; slope of line -2.10 mmHg / 10 bpm; ≥seven 30-second 
epochs of data per subject; within subject correlation of 0.60; two-sided alpha = 0.05).    
Airway Opening Index:  As this objective is exploratory in nature, a power calculation is not 
provided. 
6.5 Interim Analysis 
We plan to assemble a DSMB in collaboration with the Eunice Kennedy Shriver National 
Institute of Child Health and Human Development for this study. The DSMB will be responsible for 
monitoring subject safety, accrual of study subjects, adherence to the study protocol, compliance 
with the OPTI-VENT training bundle, assessments of data quality, performance of individual clinical 

 
  
 
 
 
11
centers, and review of formal interim statistical analyses of treatment efficacy. The DSMB will be 
comprised of no less than five individuals and will include at least one independent PhD level 
statistician and one pediatric resuscitation scientist with expertise in pediatric resuscitation quality 
and interventional trials who will be proposed as the chair of the DSMB. This individual will not be 
a previous collaborator of Dr. Sutton to avoid potential conflicts of interest. DSMB meetings will be 
scheduled as follows: full DSMB meeting at 1, 2, 3, and 4.25 years; chair-only review at 0.5, 1.5, 
2.5, and 3.5 years. Efficacy will be formally assessed at 2, 3, and 4.25 years. A symmetric, two-sided 
O’Brien-Fleming type boundary with overall alpha level set to 0.05 will be used as a guideline for 
stopping the study due to a difference between treatment arms. Stopping boundaries will be 
generated using symmetric monitoring boundaries, corresponding to alpha spending of 0.025 to 
detect a benefit and 0.025 to detect a harmful effect of treatment vs control. Lan-DeMets spending 
functions corresponding to O’Brien-Fleming type boundaries will be used. Monitoring boundaries 
will be set according to the proportion of total statistical information (information fraction) available 
in each interim analysis dataset. Futility monitoring will be at the discretion of the DSMB. Futility 
analyses, if they are requested, will calculate estimated conditional power of the trial to detect a 
significant treatment difference, if it continues, under relevant scenarios (e.g., the treatment effect 
being as postulated). Adverse events will not be collected in this study as it is observational at the 
patient level (no therapeutic intervention at the patient level [no drug, no technology]). 
 
7 
STUDY INTERVENTION 
7.1 Description 
Description of the Resuscitation Bundle: The OPTI-VENT QI bundle consists of two main 
components: 1) provider education: physician, registered nurse, and respiratory therapist education 
(via scheduled existing educational or quality meetings) and 2) point-of-care ventilation guidance 
(CPR cue cards highlighting ventilation rate targets and introduction of a ventilation rate metronome 
[Figure 3]). 
Provider Education / Point-of-Care Guidance: Point-of-care training will be conducted by pediRES-
Q network site quality physician champions, leveraging their experience with high-risk patient 
identification. In short, many of these network sites are already completing bedside preparation for 
cardiac arrest resuscitation in high-risk patients (18). During this brief (<2 minute) bedside 
education, the educator will 1) review the CPR ventilation rate target, and 2) ensure the provider has 

 
  
 
 
 
12
their rate cue card on his/her person and knows how to activate the CPR ventilation rate metronome 
(Figure 3). Compliance will be defined as performance of at 
least 30 of these trainings per unit per month (~1 per day). 
Although our application focuses on ventilation rate, current 
Guidelines recommend that inflation pressures be targeted to 
“visible chest rise,” without prescribing an actual peak inflating 
or end expiratory pressure. In an attempt to standardize this 
portion of care, we will leverage these two-minute trainings to 
review the patient’s current ventilator settings as a starting point 
during CPR to ensure adequate chest rise. Post-arrest care 
ventilation and oxygenation goals (e.g., avoidance of 
hypocarbia) will also be reviewed. Additionally, an educational 
focus on CPR ventilation rates will be integrated into existing 
resuscitation education or quality meetings across all 
disciplines. A brief Microsoft PowerPoint presentation focusing 
on the benefits of CPR ventilation rate compliance will be 
developed and standardized for distribution across all sites. Past 
performance during actual cardiac arrests will also be presented 
to providers during the existing cardiac arrest debriefing 
programs that occur in all sites participating in this trial. To be 
compliant with this portion of the intervention, this must occur 
monthly. “Report cards” detailing unit-level performance will 
be generated by the University of Utah study data coordinating center and automatically emailed to 
the site PIs for review during their monthly presentations.    
8 
SAFETY MANAGEMENT 
8.1 Clinical Adverse Events 
Adverse events will not be collected in this observational study.  
8.2 Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen during the 
course of this study (including SAEs) they will be reported to the IRB in accordance with CHOP 
IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. AEs that do not meet prompt 
reporting requirements will be summarized in narrative or other format and submitted to the IRB at 
the time of continuing review (if continuing reviews are required), or will be tracked and 
documented internally by the study team but not submitted to the IRB (if continuing reviews are not 
required).  
 
9 
STUDY ADMINISTRATION 
9.1 Treatment Assignment Methods 
9.1.1 Randomization 
The basis of this investigation is a hybrid between a parallel and stepped-wedge cluster-
randomized trial. As in a parallel design, 5 randomly selected sites will be permanently assigned to 
enroll in the control group, and 5 others will be permanently assigned to enroll in the intervention 
Figure 3: Ventilation rate 
metronome on CHOP’s CPR 
Monitoring Cart (standard clinical 
practice). 

 
  
 
 
 
13
group. The remaining 10 sites, as in a stepped-wedge design, will initially enroll in the control group 
but will be randomly assigned a time to begin implementing the intervention. In order to ensure 
roughly equal numbers of subjects in the intervention and control groups, and to ensure balance with 
respect to baseline pre-trial survival rates, the computer-generated randomization schedule will be 
selected from all possible configurations with sufficient expected balance in both expected 
enrollment and pre-trial survival rates. 
9.2 Data Collection and Management 
Limited patient, event, post-cardiac arrest care, and survival outcome data will be 
entered by each site into a protected electronic database which will be managed and stored 
using the research-focused electronic web-based data capture system REDCap, under an 
agreement with the software’s development consortium, led by Vanderbilt University.  Data 
backup is performed nightly via a dedicated backup system. The backup environment is 
maintained by a dedicated staff using dedicated resources. Access to the backup 
environment is restricted to Research Information Systems staff. 
Statistical support will be provided by both the CHOP Data Science and Biostatistics 
Unit and the Data Coordinating Center (DCC) in the Department of Pediatrics at the 
University of Utah School of Medicine, which provides data coordination and management 
services for a variety of national research networks. Limited data set exports will be shared 
with the DCC & the University of Utah and may contain birth and service dates but will not 
contain names, MRNs, or similar identifying data. 
 
a. Confidentiality. Site data coordinators may keep their completed paper-based data 
collection form (case report forms) in accordance with local IRB policies. Only the 
designated, trained site data coordinators and/or site investigators will input the data 
to REDCap. The minimum necessary PHI (i.e., subject name, MRN, date of birth 
and date of cardiac arrest events) will be collected by each site.  However, the only 
patient information sent to the DCC will be date of birth and arrest (limited dataset) 
to enable proper data validation and accurate coding of data, such as the age of 
patients. The DCC will never obtain readily identifiable information from any of the 
participating sites. The DCC will protect strict confidentiality under the policy 
approved by IRB. 
b. Security.  The data is collected through a protected database portal (REDCap). The 
access is password protected. Each site investigator and/or data coordinator will have 

 
  
 
 
 
14
access to their local data only. Designated investigators at CHOP will have access only 
to the limited dataset.  
c. 
Anonymization, de-identification or destruction.  The minimum necessary PHI (subject 
name, MRN, date of birth and date of cardiac arrest events) will be collected.  
i. 
PHI will not be reused or disclosed to any other person or entity, except: as required 
by law, for authorized oversight of the research project, or for other research for which 
the use or disclosure of PHI would be permitted by HIPAA. 
9.2.1 Data sources  
REDCap will be abstracted by the University of Utah or CHOP to generate a coded 
dataset. Neither site will not have capability to identify events or patients at any study site. 
Readily identifiable information from any of the participating sites or investigators will 
never be requested. All other data are non-identifiable. 
Standard cardiac arrest data (e.g., demographics, intra- and post-arrest physiologic variables, 
CPR quality variables) will be collected on all subjects, extracted from the electronic medical record, 
continuous bedside monitors, and other patient physiologic monitoring devices (e.g., NIRS). This 
limited dataset is in accordance with definitions of HIPAA. 
9.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies of the Children’s Hospital of Philadelphia and HIPAA on subject privacy and 
the Investigator and other site personnel will not use such data and records for any purpose other 
than conducting the study.  
No identifiable data will be used for future study without first obtaining IRB approval or 
determination of exemption. Data use agreements already exist or will be obtained between 
CHOP/PI and the pediRES-Q sites / University of Utah DCC before sharing a limited dataset.  
PHI will not be reused or disclosed to any other person or entity, except: as required 
by law, for authorized oversight of the research project, or for other research for which the 
use or disclosure of PHI would be permitted by HIPAA.  
 
9.4 Regulatory and Ethical Considerations 
9.4.1 Data and Safety Monitoring Plan 
We plan to assemble a DSMB in collaboration with the Eunice Kennedy Schriver National 
Institute of Child Health and Human Development for this study. The DSMB is responsible for 
monitoring subject safety, accrual of study subjects, adherence to the study protocol, assessments of 
data quality, performance of individual clinical centers, and review of formal interim statistical 
analyses of treatment efficacy. DSMB meetings will be scheduled as follows: full DSMB meeting at 
1, 2, 3, and 4.25 years; chair only review at 0.5, 1.5, 2.5, and 3.5 years. Efficacy will be formally 
assessed at 2, 3, and 4.25 years. A symmetric, two-sided O’Brien-Fleming type boundary with 
overall alpha level set to 0.05 will be used as a guideline for stopping the study due to a difference 
between treatment arms. Stopping boundaries will be generated using symmetric monitoring 
boundaries, corresponding to alpha spending of 0.025 to detect a benefit and 0.025 to detect a 

 
  
 
 
 
15
harmful effect of treatment vs control. Lan-DeMets spending functions corresponding to O’Brien-
Fleming type boundaries will be used. Monitoring boundaries will be set according to the proportion 
of total statistical information (information fraction) available in each interim analysis dataset. 
Futility monitoring will be at the discretion of the DSMB. Futility analyses, if they are requested, 
will calculate estimated conditional power of the trial to detect a significant treatment difference, if it 
continues, under relevant scenarios (e.g., the treatment effect being as postulated). 
9.4.2 Risk Assessment 
As this study is observational at the patient level, there is no more than minimal risk from 
the proposed study. Although there is a minor risk of loss of confidentiality, the risk is mitigated by 
data security procedures at CHOP and the University of Utah. 
All data and records generated during this study will be kept confidential in 
accordance with Institutional policies and HIPAA on subject privacy.  
The risk to patient confidentiality of this study is further minimized by taking following 
steps: 
1. Only minimally necessary data will be collected at the local level (subject name, 
MRN, date of birth and cardiac arrest event) 
2. The minimally necessary PHI data to be entered into the REDCap database will be 
date of birth and date of arrest only. 
3. The data entry will only be completed by the trained site data coordinator or site PI. 
4. No individual site will have any access to another site’s data besides the aggregated 
report. As noted above, the University of Utah will have access to the limited dataset. 
5. DCC will strictly protect the limited dataset under the policy in accordance with 
HIPAA. 
6. DCC will never request any readily identifiable information from any site 
9.4.3 Potential Benefits of Trial Participation 
There is the potential for direct benefit to the human subjects enrolled in this trial (i.e., CPR 
training will improve the quality of care they receive). Additionally, even if the OPTI-VENT training 
bundle fails to improve outcomes, future cardiac arrest victims have the potential to broadly benefit 
from the findings of this study, as evidenced-based ventilation targets for pediatric CPR will improve 
the care and outcomes of these patients. Implementation of these findings into future AHA 
Emergency Cardiovascular Care guidelines will influence the care provided to millions of patients 
around the world. 
9.4.4 Risk-Benefit Assessment 
Based on the discussion above and the lack of deviation from standard clinical care in this study, the 
benefits of this study outweigh the risks.  

 
  
 
 
 
16
9.5 Recruitment Strategy 
While patients cannot be recruited for this study (i.e., a cardiac arrest has to occur to be 
considered eligible), over the first 7 years of pediRES-Q network existence, trained clinical research 
assistants, clinical research coordinators, and site primary investigators have intensively screened for 
any eligible cardiac arrests. This has included local pager notification of cardiac arrests, email 
screening logs, daily morning screening rounds, and reviews of resuscitation records.  
9.6 Informed Consent/Assent and HIPAA Authorization 
9.6.1 Main Study 
9.6.2 Waiver of Consent 
Cardiac Arrest Subject: As this study is observational at the patient level, similar to other pediRES-Q 
network quality improvement interventional studies, a waiver of consent will be requested. This is 
also exactly similar to the consent process utilized for Dr. Sutton’s now published ICU-RESUS 
interventional trial (Journal of the American Medical Association)(12) which implemented a similar 
training bundle to ICU providers, albeit focused on the chest compression aspect of CPR rather than 
assisted ventilation delivery. A waiver will be requested on the following factors: 1) This study poses 
no more than minimal risk (CPR training already exists at the participating hospitals and quality will 
be at least as good with OPTI-VENT implementation); 2) The waiver will not adversely affect the 
rights and welfare of the subjects (i.e., cardiac arrest patients undergoing CPR); 3) Obtaining 
informed consent would threaten the scientific validity of the study. The scientific validity of the 
study is dependent upon capturing all eligible events during the period of study, as one of the major 
goals is to associate ventilation data with survival outcomes; 4) This study involves no therapeutic 
intervention at the patient level (no drug, no technology), and there are no changes in accepted 
clinical practice; 5) Only a limited dataset will be shared with the University of Utah. The minimal 
risk of loss of privacy will be mitigated by the substantial data management resources of the data 
management team at CHOP and the process by which they verify that only a limited dataset is sent to 
the University of Utah for analysis. As presently accepted in other pediRES-Q protocols, waiver of 
HIPAA authorization at the patient level will also be requested, as again, no identifying information 
will be transmitted outside of CHOP.  
Healthcare Provider:  
1) This study poses no more than minimal risk (CPR training already exists in ICUs and is a 
normal job-related responsibility and there are no links between the providers identify and 
their performance, either in the educational session or during actual patient care); 2) The 
research cannot be practically carried out without the waiver as it will be important to 
describe how the participating sites implemented the bundle.  Additionally, consenting all 
providers would place undue burden on these healthcare providers who are caring for 
critically ill children who by definition have labor intensive care plan; 3) There are also no 
identifying links between the care providers and their resuscitation performance; 4) The 
waiver will not adversely affect the rights and welfare of the subjects as CPR training 
already exists in ICUs and is a normal job-related responsibility.  The minimal risk of loss of 
privacy will be mitigated by the substantial data management resources of the data 
management team at CHOP and the process by which they verify that only a limited dataset 
is sent to the University of Utah for analysis. As presently accepted in other pediRES-Q 
protocols, waiver of HIPAA authorization at the patient level will also be requested, as 
again, no identifying information will be transmitted outside of CHOP.  

 
  
 
 
 
17
 
 
10 PUBLICATION / DISSEMINATION 
As a clinical trial, this study will be governed by the NIH Policy on the Dissemination of NIH-
Funded Clinical Trial Information, including but not limited to registering the trial on 
ClinicalTrials.gov and submitting clinical trial summary results information to ClinicalTrials.gov no 
later than 1 year following the end of study enrollment. Additionally, the study findings will be 
disseminated through the presentation at scientific meetings and publications. We will leverage the 
Society of Critical Care Medicine Annual Congress and the AHA’s Resuscitation Science 
Symposium for knowledge dissemination. Only aggregate data, without individually identifiable 
information, will be published. 
 
11 REFERENCES 
1. 
Holmberg MJ, Ross CE, Fitzmaurice GM, Chan PS, Duval-Arnould J, Grossestreuer AV, et 
al. Annual Incidence of Adult and Pediatric In-Hospital Cardiac Arrest in the United States. Circ 
Cardiovasc Qual Outcomes. 2019;12(7):e005580. 
2. 
Girotra S, Nallamothu BK, Spertus JA, Li Y, Krumholz HM, Chan PS, et al. Trends in 
survival after in-hospital cardiac arrest. N Engl J Med. 2012;367(20):1912-20. 
3. 
Wolfe H, Zebuhr C, Topjian AA, Nishisaki A, Niles DE, Meaney PA, et al. Interdisciplinary 
ICU cardiac arrest debriefing improves survival outcomes*. Crit Care Med. 2014;42(7):1688-95. 
4. 
Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, et al. First 
documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. 
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Topjian AA, Raymond TT, Atkins D, Chan M, Duff JP, Joyner BL, Jr., et al. Part 4: 
Pediatric Basic and Advanced Life Support: 2020 American Heart Association Guidelines for 
Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 
2020;142(16_suppl_2):S469-S523. 
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Sutton RM, Reeder RW, Landis WP, Meert KL, Yates AR, Morgan RW, et al. Ventilation 
Rates and Pediatric In-Hospital Cardiac Arrest Survival Outcomes. Crit Care Med. 
2019;47(11):1627-36. 
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Sutton RM, Niles D, Meaney PA, Aplenc R, French B, Abella BS, et al. Low-dose, high-
frequency CPR training improves skill retention of in-hospital pediatric providers. Pediatrics. 
2011;128(1):e145-51. 
8. 
Chapman JD, Geneslaw AS, Babineau J, Sen AI. Improving Ventilation Rates During 
Pediatric Cardiopulmonary Resuscitation. Pediatrics. 2022;150(3). 
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Grieco DL, L JB, Drouet A, Telias I, Delisle S, Bronchti G, et al. Intrathoracic Airway 
Closure Impacts CO(2) Signal and Delivered Ventilation during Cardiopulmonary Resuscitation. Am 
J Respir Crit Care Med. 2019;199(6):728-37. 
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Aufderheide TP, Lurie KG. Death by hyperventilation: a common and life-threatening 
problem during cardiopulmonary resuscitation. Crit Care Med. 2004;32(9 Suppl):S345-51. 
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Aufderheide TP, Sigurdsson G, Pirrallo RG, Yannopoulos D, McKnite S, von Briesen C, et 
al. Hyperventilation-induced hypotension during cardiopulmonary resuscitation. Circulation. 
2004;109(16):1960-5. 
12. 
The ICU-RESUS and the Eunice Kennedy Shriver National Institute of Child Health and 
Human Development Collaborative Pediatric Critical Care Research Network Investigator Groups, 

 
  
 
 
 
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Sutton RM, Wolfe HA, Reeder RW, et al. Effect of Physiologic Point-of-Care Cardiopulmonary 
Resuscitation Training on Survival With Favorable Neurologic Outcome in Cardiac Arrest in 
Pediatric ICUs: A Randomized Clinical Trial. JAMA. 2022;327(10):934-45. 
13. 
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