PROSpect: Prone and Oscillation Pediatric Clinical Trial
Phase: NA
Conditions: Acute Respiratory Distress Syndrome in Children
Sponsor: University of Pennsylvania

PROSpect Protocol 
 
 
 
 
 
Curley, Kneyber, Cheifetz & Wypij  
7/11/2022 
1 
PROSpect 
PRone and OScillation PEdiatric Clinical Trial 
 
 
Martha A.Q. Curley, RN, PhD, FAAN 
Ruth M. Colket Endowed Chair in Pediatric Nursing 
Children’s Hospital of Philadelphia 
Professor, University of Pennsylvania School of Nursing 
Anesthesia and Critical Care Medicine - Perelman School of Medicine 
Claire M. Fagin Hall, Room 425 
418 Curie Boulevard  
Philadelphia, PA 19104-4217 USA 
Office Phone: 215.573.9449  
Office Fax: 215.746.2737 
curley@nursing.upenn.edu 
 
Martin C.J. Kneyber, MD, PhD, FCCM  
Chief, Division of Critical Care Medicine  
Director of Research  
Department of Pediatrics, Division of PCCM  
Beatrix Children's Hospital  
University Medical Center Groningen  
Huispost CA 80; P.O. Box 30.001  
9700 RB Groningen; The Netherlands  
Office Phone: (+)3150 - 3614215  
Office Fax: (+)3150 - 3614235  
m.c.j.kneyber@bkk.umcg.nl 
 
Ira M. Cheifetz, MD, FCCM, FAARC 
Chief, Pediatric Cardiac Critical Care 
UH Rainbow Babies and Children's Hospital 
The Congenital Heart Collaborative 
11100 Euclid Avenue, Mail Stop: 6011 
Room 381 
Cleveland, OH 44106 USA 
Office Phone: 216.286.7585 
Ira.cheifetz@UHhospitals.org 
 
David Wypij, PhD 
Director, Biostatistics and Data Coordinating Center  
Department of Cardiology  
Boston Children's Hospital 
300 Longwood Avenue  
Boston, MA 02115 USA 
Office Phone: 617.355.5123  
david.wypij@cardio.chboston.org 
 
 
 

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Table of Contents 
 
ABSTRACT ................................................................................................................................ 4 
PROTOCOL SUMMARY ............................................................................................................ 5 
ABBREVIATIONS .................................................................................................................... 10 
RESEARCH PROTOCOL ......................................................................................................... 13 
A. SPECIFIC AIMS ................................................................................................................... 13 
B. BACKGROUND AND SIGNIFICANCE ................................................................................ 14 
C. SUPPORTING DATA ........................................................................................................... 17 
C.1 Pediatric Acute Lung Injury Consensus Conference ..................................................... 17 
C.2 Pediatric Prone Trial ..................................................................................................... 17 
C.3 RESTORE HFOV Propensity Score Analysis ............................................................... 18 
C.4 Physiologic Approach to HFOV ..................................................................................... 18 
D. EXPERIMENTAL APPROACH ............................................................................................ 19 
D.1 Design and Rationale ................................................................................................... 19 
D.2 Study Population ........................................................................................................... 20 
D.3 Interventions ................................................................................................................. 22 
D.4 Primary, Secondary and Exploratory Outcome Measures ............................................. 24 
D.5 Measurement of Study Variables During Hospital Course ............................................. 27 
D.6 Study Safety ................................................................................................................. 28 
D.7 Biorepository ................................................................................................................. 28 
D.8 Follow-up Procedures ................................................................................................... 28 
E. STATISTICAL CONSIDERATIONS ..................................................................................... 30 
E.1 Study Design ................................................................................................................ 30 
E.2 Analysis Data Sets ........................................................................................................ 30 
E.3 Randomization and Randomization Update Analyses ................................................... 31 
E.4 Consideration of Early Stopping of the Trial .................................................................. 32 
E.5 Statistical Analyses ....................................................................................................... 33 
E.6 Sample Size Justification .............................................................................................. 34 
E.7 Dissemination Plan and Data Archiving ........................................................................ 35 
F. DATA MANAGEMENT AND QUALITY CONTROL ............................................................. 35 
F.1 Development of Electronic Case Report Forms (eCRFs) and Manual of Operations 
(eMOO) ......................................................................................................................... 35 
F.2 Data Management System ............................................................................................ 36 
F.3 Data Coordination ......................................................................................................... 36 
F.4 Data Entry, Editing and Audit Trails ............................................................................... 36 
F.5 Data Confidentiality, Security and Back-up .................................................................... 36 
F.6 Firewalls ........................................................................................................................ 37 
F.7 Study Monitoring ........................................................................................................... 37 
F.8 Data Management for the Follow-up Procedures .......................................................... 38 
F.9 Strategies to Optimize Enrollment and Protocol Adherence .......................................... 38 
Protection of Human Subjects ............................................................................................... 40 
Literature Cited ....................................................................................................................... 47 
Clinical Protocols – V.12/14/20 ............................................................................................... 52 
I. Ventilator Management Guidelines ........................................................................................ 52 
A.  Monitoring ...................................................................................................................... 52 
B. Oxygenation and Ventilation Goals (all groups) .............................................................. 52 
C. Strategy: Conventional Mechanical Ventilation (CMV) .................................................... 53 
1. Initiating CMV ................................................................................................................ 53 
2. Initial settings CMV ........................................................................................................ 53 
3. Ongoing CMV support ................................................................................................... 54 

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4. Escalation of Support .................................................................................................... 55 
5. Failed CMV ................................................................................................................... 56 
6. Weaning CMV – As the patient’s clinical condition improves and criteria for extubation 
readiness testing (ERT) are met, oxygenation and ventilation parameters are 
normalized, i.e., SpO2 ≤ 97% and pH ≤ 7.45 .................................................................. 57 
D. Strategy: High Frequency Oscillatory Ventilation (HFOV) ............................................... 58 
1. Initiating HFOV .............................................................................................................. 58 
2. Initial Settings HFOV ..................................................................................................... 58 
3. Ongoing HFOV support ................................................................................................. 60 
4. Escalation of Support .................................................................................................... 60 
5. Failed HFOV.................................................................................................................. 61 
6. Conversion to conventional ventilation .......................................................................... 61 
Conversion to conventional ventilation is mandated when mPaw 15-20 cm H2O and FiO2 < 
0.50.  Extubation from HFOV will be considered a protocol deviation. When converting to 
CMV manage the patient per CMV protocol matching the initial PEEP to the FiO2 per 
PEEP-FiO2 grid.  Typically, there is a downward adjustment made to the mPaw of 2-4 
cm H2O. ......................................................................................................................... 61 
II. Suctioning and Re-recruitment (all groups) ........................................................................... 62 
III. Daily Test for Patient Readiness for Extubation (all groups after 1st 24H) ............................. 63 
IV. Positional Therapy Protocol ................................................................................................. 65 
A. Both Groups .................................................................................................................... 65 
B. Supine Group .................................................................................................................. 65 
C. Prone Group ................................................................................................................... 65 
V. Prone Position Procedure ..................................................................................................... 67 
VI. Prone Positioning Check Sheet ........................................................................................... 70 
VII. Failed Management ............................................................................................................ 72 
VIII. Hemodynamic Management Guidelines (all groups) .......................................................... 73 
IX. Sedation Guidelines (all groups) .......................................................................................... 76 
X. Skin Care and Pressure Injury Guidelines (all groups) .......................................................... 77 
 
 
 

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ABSTRACT 
Although acute respiratory distress syndrome is a life-threatening and frequent problem 
experienced by thousands of children each year, little evidence supports best ventilation 
practices during their critical illness. For over 25 years, pediatric critical care clinicians have 
debated the risk-benefit ratio of supine versus prone positioning and conventional mechanical 
ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV) in the management of 
these young patients. Without pediatric-specific data, the debate of how best to care for children 
with high moderate-severe Pediatric Acute Respiratory Distress Syndrome (PARDS) will 
continue and prevent progress in the field of pediatric critical care.  
PROSpect (PRone and OScillation PEdiatric Clinical Trial) is a two-by-two factorial, response-
adaptive, randomized controlled clinical trial of supine/prone positioning and CMV/HFOV. 
Approximately 60 pediatric intensive care units (PICUs), about 2/3 U.S. and 1/3 international, 
with at least 5 years of experience with prone positioning and HFOV in the care of pediatric 
patients with high moderate-severe PARDS, that can provide back-up extracorporeal membrane 
oxygenation (ECMO) support are participating. Eligible patients with high moderate-severe 
PARDS are randomized within 48 hours of meeting eligibility criteria and within 4 days of 
endotracheal intubation to one of four groups: supine/CMV, prone/CMV, supine/HFOV or 
prone/HFOV. Subjects who fail their assigned positional and/or ventilation therapy for either 
persistent hypoxemia or hypercapnia may receive the reciprocal therapy while being considered 
for ECMO cannulation. Our primary outcome is ventilator-free days (VFD) through day 28, 
where non-survivors receive zero VFD. We hypothesize that children with high moderate-severe 
PARDS treated with either prone positioning or HFOV will demonstrate ≥2 more VFD. Our 
secondary outcome is nonpulmonary organ failure-free days. We will also explore the 
interaction effects of prone positioning with HFOV on VFD and investigate the impact of these 
interventions on 90-day in-hospital mortality and, among survivors, the duration of mechanical 
ventilation, PICU and hospital length of stay and trajectory of post-PICU functional status and 
health-related quality of life (HRQL). Up to 800 patients with high moderate-severe PARDS will 
be randomized by age group and direct/indirect lung injury. Adaptive randomization will first 
occur after 300 patients are randomized and have been followed for 28 days, and every 100 
patients thereafter. At these randomization update analyses, new allocation probabilities will be 
computed based on ongoing intention-to-treat trial results, increasing allocation to well 
performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per 
intention-to-treat for the primary analyses and per-protocol received for primary, secondary and 
exploratory analyses. 
This clinical trial will provide the definitive evidence necessary for the field to consider a major 
change in clinical practice in the care of critically ill children with high moderate-severe PARDS.  
 
 
 
 
 

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PROTOCOL SUMMARY 
Title: PROSpect: PRone and OScillation PEdiatric Clinical Trial 
Phase: This is an NIH-Defined Phase III Clinical Trial. 
Funding: 1 UG3 HL141736-01 and 1 U24 HL141723-01 
Committees: Executive Committee, Advisory Committee, Data and Safety Monitoring Board, 
CCC-DCC Operations Committee, Steering Committee, Associated Study Committee, 
Publications and Presentations Committee 
Background and significance:  
Although acute respiratory distress syndrome is a life-threatening and frequent problem 
experienced by thousands of children each year, little evidence supports best ventilation 
practices during their critical illness. For over 25 years, pediatric critical care clinicians have 
debated the risk-benefit ratio of supine versus prone positioning and conventional mechanical 
ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV) in the management of 
these young patients. Without pediatric-specific data, the debate of how best to care for children 
with high moderate-severe Pediatric Acute Respiratory Distress Syndrome (PARDS) will 
continue and prevent progress in the field of pediatric critical care.  
Study aims: In children with high moderate-severe PARDS: 
1. To compare the effects of prone positioning with supine positioning on ventilator-free 
days (VFD). 
2. To compare the effects of HFOV with CMV on VFD. 
 
Secondary: To compare the impact of these interventions on nonpulmonary organ failure-
free days (OFFD). 
 
Exploratory: To explore the interaction effects of prone positioning with HFOV on VFD and 
to investigate the impact of these interventions on 90-day in-hospital mortality and, among 
survivors, the duration of mechanical ventilation, pediatric intensive care unit (PICU) and 
hospital length of stay and trajectory of post-PICU functional status and health-related 
quality of life (HRQL). 
 
Study design:  
This is a two-by-two factorial, response-adaptive multi-center randomized controlled clinical trial 
that tests whether pediatric patients with high moderate-severe PARDS randomized to supine 
versus prone positioning and to CMV versus HFOV exhibit more VFD over a 28-day period. 
Improvement in VFD will be considered within the context of patient safety; specifically, patients 
must also exhibit a similar safety profile. 
 
 
 
 
 
 
 
 
 
 
 
 

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Study scheme:  
 
 
Study population: Critically ill pediatric patients, 2 weeks to 20 years, with high moderate-severe 
PARDS  
Treatment groups: Patients will be randomized within 48 hours of meeting eligibility criteria and 
within 4 days of endotracheal intubation to one of four groups: supine/CMV, prone/CMV, 
supine/HFOV or prone/HFOV. The Data Coordinating Center (DCC) will manage the 
randomization process centrally and will stratify enrollment by age group (<1; 1-7; 8-17; 18-20 
years) and direct/indirect lung injury. 
 
• 
Supine positioning: Patients randomized to supine positioning will remain supine.  
• 
Prone positioning: Patients randomized to receive prone positioning will be positioned 
prone ≥16 hours per day for a maximum duration of 28 days.  
• 
Conventional Mechanical Ventilation (CMV): The CMV arm will use a ventilation strategy 
consistent with Pediatric Acute Lung Injury Consensus Conference Group (PALICC) 
recommendations. The strategy includes: (1) low tidal volume to obtain expired tidal 
volume (Vte) of 5-7 ml/kg (ideal body weight [IBW]); (2) Peak Inspiratory Pressure (PIP) 
goal limited to ≤28 cm H2O (may allow up to 32 cm H2O for subjects with poor chest wall 
compliance); (3) lung recruitment maneuver to identify best PEEP then maintained per 
PEEP-FiO2 grid; and (4) use of synchronized intermittent mandatory ventilation (SIMV) 
or assist control (AC), Pressure Control Ventilation (PCV) or Pressure Regulated 
Volume Control (PRVC or equivalent).  
• 
High Frequency Oscillatory Ventilation (HFOV): The HFOV arm will use a ventilation 
strategy consistent with PALICC recommendations. For reproducibility across centers 
we will restrict the HFOV ventilator to the SensorMedics 3100A if patient weight <35 kg 
or SensorMedics 3100B if patient weight ≥35 kg. To optimize the high-frequency 
approach, high rates (≥8 Hz) will be used knowing that increased amplitudes will be 
required for adequate ventilation. Given the known attenuation of pressure amplitude 
across the endotracheal tube and along the natural airways, pressure amplitude and 
tidal volume delivery will remain within typical parameters for HFOV at the alveolar level. 
The HFOV strategy includes use of a frequency at 8-15 Hz, an amplitude (delta-P) of 60-
90, a mPaw recruitment maneuver and a weaning strategy.  
• 
Failed Management: Clinicians may consider a reciprocal therapy (supine to prone; 
prone to supine; CMV to HFOV; HFOV to CMV) in a sequence based on their clinical 
judgment while considering extracorporeal membrane oxygenation (ECMO) cannulation. 
Reciprocal treatments, when used, will be managed per PROSpect protocol. Subjects 
cannulated for ECMO will be discontinued from further study treatments and followed so 
that ventilator management can be described and for study outcomes.  
 

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Inclusion criteria:  
• 
Pediatric patients ≥2 weeks of age (≥42 weeks post gestational age) and <21 years of age  
• 
Intubated and mechanically ventilated with high moderate-severe PARDS for <48 hours per 
PALICC guidelines (chest imaging consistent with acute pulmonary parenchymal disease 
and OI ≥12 or OSI ≥10)1. We require two blood gases meeting high moderate-severe 
PARDS criteria (separated by at least 4 ± 2 hours during which time the clinical team is 
actively working to recruit lung volume and optimize the patient’s hemodynamic status per 
PALICC guidelines; specifically, incremental decremental PEEP changes to optimize lung 
volume). A second blood gas is not required for OI ≥16.  
Exclusion criteria:  
• 
Perinatal related lung disease 
• 
Congenital diaphragmatic hernia or congenital/acquired diaphragm paralysis 
• 
Respiratory failure explained by cardiac failure or fluid overload 
• 
Cyanotic heart disease 
• 
Cardiomyopathy  
• 
Unilateral lung disease 
• 
Primary pulmonary hypertension 
• 
Intubated for status asthmaticus 
• 
Obstructive airway disease (e.g., Severe airways disease without parenchymal involvement 
or disease characterized by hypercapnia with FiO2 <0.30 and/or evidence of increased 
resistance visible on the flow – time scalar and/or presence of intrinsic PEEP) 
• 
Active air leak  
• 
Bronchiolitis obliterans 
• 
Post hematopoietic stem cell transplant; specifically, patients receiving continuous 
supplemental oxygen for three or more days prior to intubation; receiving noninvasive 
ventilation for more than 24 hours prior to intubation; receiving more than one vasoactive 
medication at time of meeting inclusion criteria; spending more than four days in the PICU 
prior to intubation; supported on or with immediate plans for renal replacement therapies; 
with two or more allogeneic transplants; who relapsed after the transplant; or with diffuse 
alveolar hemorrhage 
• 
Post lung transplant 
• 
Home ventilator dependence with baseline Oxygen Saturation Index (OSI) >6 (baseline is 
defined as a stable period, prior to current illness)  
• 
Neuromuscular respiratory failure 
• 
Critical airway (e.g., post laryngotracheal surgery or new tracheostomy) or anatomical 
obstruction of the lower airway (e.g., mediastinal mass) 
• 
Facial surgery or trauma in previous 2 weeks 
• 
Head trauma (managed with hyperventilation)  
• 
Intracranial bleeding 
• 
Unstable spine, femur or pelvic fractures 
• 
Open abdomen 
• 
Currently receiving either prone positioning or any high-frequency mode of MV with current 
illness (Up to 4 hours of prone positioning and/or any mode of high-frequency mode of MV is 
allowed as long as the therapies are off for least 4 hours prior to the subject meeting 
oxygenation criteria.) 
• 
Supported on ECMO during the current admission 
• 
Family/medical team not providing full support (patient treatment considered futile) 
 
1 With SaO2 <98% 

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• 
Previously enrolled in current study 
• 
Enrolled in any other interventional clinical trial not approved for co-enrollment 
• 
Known pregnancy  
Study sample size: Up to 800 patients with high moderate-severe PARDS randomized by age 
group and direct/indirect lung injury from approximately 60 PICUs, about 2/3 U.S. and 1/3 
international.  
 
Subject participation duration: Enrolled subjects will be followed from endotracheal intubation 
(or, for ventilator dependent patients supported on invasive mechanical ventilation with baseline 
OSI ≤6, the time the patient exhibits a qualifying OI/OSI) until hospital discharge or hospital Day 
90, whichever occurs first. After PICU discharge, we will complete telephone-based family 
interviews at 1, 3, 6 and 12 months to assess the subject’s functional status and health-related 
quality of life (HRQL).  
 
Outcome measures: 
 
Primary: VFD through day 28 
Secondary: Nonpulmonary OFFD through Day 28 
Exploratory: 
• 
Interaction effects of prone positioning with HFOV on VFD  
• 
90-day in-hospital mortality 
• 
Among survivors: 
o Duration of mechanical ventilation 
o PICU and hospital length of stay  
o Post hospital discharge functional status and health-related quality of life 
Statistical issues: 
Primary hypothesis: Children with high moderate-severe PARDS treated with prone positioning 
or HFOV will demonstrate more VFD. We hypothesize that a superior treatment would improve 
VFD by at least 2 days, a clinically meaningful difference.  
Sample size: Power calculations are based on data from the RESTORE trial. Of 2,449 
RESTORE patients, 712 patients met PROSpect eligibility criteria. The mean VFD for these 712 
patients was 16.0 days with 14.2% patients assigned zero VFD (died or still intubated by day 
28). We powered for a clinically meaningful 2-day improvement in VFD by either intervention 
alone (i.e., the other intervention had no effect; Scenario 1) or a 4-day improvement (e.g., 2-day 
improvement for each intervention when both interventions showed a 2-day improvement; 
Scenario 2). Based on the full design including response-adaptive randomization and early 
stopping for a maximum total sample size of 800 patients, simulation results (based on 20,000 
simulations) estimate that we would have 81.8% power for Scenario 1 and 86.1% power for 
each intervention for Scenario 2. 
Statistical analysis plan: There are two primary outcome analyses, one for positioning strategy 
and one for ventilation strategy. For positioning strategy, analysis of the primary outcome will be 
performed on an intention-to-treat basis using a stratified Wilcoxon rank-sum test, adjusting for 
ventilation strategy. Similarly, for ventilation strategy, analysis of the primary outcome will be 
performed on an intention-to-treat basis using a stratified Wilcoxon rank-sum test, adjusting for 
positioning strategy. Differences between positioning or ventilation strategies will be considered 
statistically significant if a one-sided p-value is <0.020. This threshold was obtained by 
simulation to control Type I error at the 0.025 level, given the response-adaptive randomization 
design. Analysis of the primary outcome will also be performed on a per-protocol basis, and we 
will explore adjustment for age group (<1, 1-7, 8-17, 18-20 years) and lung injury type (direct; 

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indirect) using proportional hazards regression models. We will also explore adjusting for history 
of hematopoietic stem cell transplant (HSCT) due to potential differences in mortality in this 
group. 
Analysis of the secondary outcome, nonpulmonary organ failure-free days, will be performed on 
a per-protocol basis using stratified Wilcoxon rank-sum tests, and we will explore adjustment for 
age group, lung injury type, and history of HSCT using proportional hazards regression models. 
For analyses of exploratory outcomes, we will use logistic regression for binary outcomes, 
proportional hazards regression for time to event outcomes and linear regression for continuous 
outcomes to compare supine vs prone positioning subjects and CMV vs HFOV subjects. These 
analyses will be performed on a per-protocol basis and will control for age group and lung injury 
type. For secondary and exploratory outcomes, differences between positioning or ventilation 
strategies will be considered statistically significant if the two-sided p-value is <0.025. 
Adaptive randomization will first occur after 300 patients are randomized and have been 
followed for 28 days, and every 100 patients thereafter. At these randomization update 
analyses, new allocation probabilities will be computed based on ongoing intention-to-treat trial 
results, increasing allocation to well performing arms and decreasing allocation to poorly 
performing arms. PROSpect may close enrollment early for efficacy or futility based on pre-
specified stopping rules.  
 
 
 
 

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ABBREVIATIONS 
 
AACN 
American Association of Critical Care Nurses 
AC 
Assist Control 
ANZICS 
Australian and New Zealand Intensive Care Society 
ARDS 
Acute Respiratory Distress Syndrome 
ATS 
American Thoracic Society 
BCH 
Boston Children’s Hospital 
BMI 
Body Mass Index 
CAPD 
Cornell Assessment of Pediatric Delirium 
CCC 
Clinical Coordinating Center 
CCM 
Critical Care Medicine 
cm 
Centimeter 
cm H2O 
Centimeter of water pressure 
CMV 
Conventional Mechanical Ventilation 
CXR 
Chest X-ray 
DCC 
Data Coordinating Center 
delta-P 
HFOV amplitude 
DSMB 
Data and Safety Monitoring Board 
DTPI 
Deep Tissue Pressure Injury 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
eMOO 
Electronic Manual of Operations 
ENE 
Eligible Not Enrolled 
ERT 
Extubation Readiness Test 
ESPNIC 
European Society of Pediatric and Neonatal Intensive Care 
ETCO2 
End-tidal carbon dioxide 
ETT 
Endotracheal Tube 
FiO2 
Fraction of inspired oxygen 
FLACC 
Facial expression, Leg movement, Activity, Cry and Consolability 
FSS 
Functional Status Scale 
HALF-PINT 
Heart And Lung Failure - Pediatric INsulin Titration Trial  
HFOV 
High-Frequency Oscillatory Ventilation 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQL 
Health-Related Quality of Life 
HSCT 
Post Hematopoietic Stem Cell Transplant 
IBW 
Ideal Body Weight 
IC 
Integration Committee  
ICH-GCP 
International Conference on Harmonisation-Good Clinical Practice 
I:E 
Inspiratory-to-expiratory time 
IMV 
Intermittent Mandatory Ventilation 
iNO 
Inhaled Nitric Oxide 
INRS 
Individualized Numeric Rating Scale 
IRB 
Institutional Review Board 
ISD 
Information Services Department 
IWS 
Iatrogenic Withdrawal syndrome  
kg 
Kilograms 
LPV 
Lung Protective Ventilation 
MODS 
Multiple Organ Dysfunction Syndrome  
mPaw 
Mean airway pressure  
MPI 
Multiple Principal Investigator 

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MV 
Mechanical Ventilation 
NHLBI 
National Heart, Lung and Blood Institute 
NIH 
National Institutes of Health 
NIRS 
Near-infrared spectroscopy  
NM3 
Philips NM3 monitor 
NPUAP 
National Pressure Injury Advisory Panel  
NRS 
Numeric Rating Scale 
OFFD 
Organ Failure-Free Days 
OI 
Oxygenation Index 
OSCAR 
OSCillation for ARDS 
OSCILLATE 
OSCILLation for ARDS Treated Early  
OSI 
Oxygen Saturation Index 
PACCMAN 
Pediatric Acute and Critical Care Medicine Asian Network  
PaCO2 
Partial pressure of carbon dioxide  
PALICC 
Pediatric Acute Lung Injury Consensus Conference Group  
PALISI 
Pediatric Acute Lung Injury and Sepsis Investigator Network 
PaO2 
Partial pressure of oxygen 
PARDIE 
Pediatric ARDS Incidence and Epidemiology 
PARDS 
Pediatric Acute Respiratory Distress Syndrome  
pCAM-ICU 
Pediatric Confusion Assessment Method for the Intensive Care Unit 
PCPC 
Pediatric Cerebral Performance Category 
PCV 
Pressure Control Ventilation  
PedsQL 
Pediatric Quality of Life Inventory 
PEEP 
Positive End-Expiratory Pressure 
PELOD-2 
PEdiatric Logistic Organ Dysfunction-2 
PF ratio 
PaO2/FiO2 ratio 
pH 
Potential of hydrogen 
PICU 
Pediatric Intensive Care Unit 
PIP 
Peak Inspiratory Pressure  
POPC 
Pediatric Overall Performance Category 
Pplat 
Pressure Plateau  
PRISM IV 
Pediatric Risk of Mortality IV 
PROSEVA 
Proning Severe ARDS Patients  
PROSpect 
PRone and OScillation PEdiatric Clinical Trial 
PRVC 
Pressure Regulated Volume Control 
PS 
Pressure Support 
QC 
Quality Control 
RCT 
Randomized Controlled Trial 
RESTORE 
Randomized Evaluation of Sedation Titration for Respiratory Failure 
SAE 
Serious Adverse Event 
SBS 
State Behavioral Scale 
SC 
Steering Committee  
SIMV 
Synchronized Intermittent Mandatory Ventilation 
SOP 
Standard Operating Procedures 
SpO2 
Pulse oximeter oxygen saturation 
UOP 
Urine Output 
UP 
Unanticipated Problem 
VFD 
Ventilator-Free Days 
VILI 
Ventilator-Induced Lung Injury 
V/Q 
Ventilation Perfusion matching  

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Vt 
Tidal volume 
Vte 
Expired tidal volume  
WAT-1 
Withdrawal Assessment Tool - Version 1 
WBFPS 
Wong-Baker Faces Pain Scale 
WFPICCS 
World Federation of Pediatric Intensive and Critical Care Societies  

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RESEARCH PROTOCOL 
A. SPECIFIC AIMS 
Although acute respiratory distress syndrome is a life-threatening and frequent problem 
experienced by thousands of children each year, little evidence supports best ventilation 
practices during their critical illness.1 For over 25 years, pediatric critical care clinicians have 
debated the risk-benefit ratio of supine versus prone positioning and conventional mechanical 
ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV).2-4 This debate has been 
recently fueled by the completion of the Pediatric Acute Lung Injury Consensus Conference 
Group (PALICC) guidelines1 noting the lack of high quality evidence and the publication of three 
definitive adult-based studies with acute respiratory distress syndrome (ARDS); specifically, one 
positive prone positioning trial and two adult ARDS HFOV clinical trials -- one neutral and one 
likely harmful.5-7 Without pediatric-specific data, the debate of how best to care for children with 
high moderate-severe Pediatric Acute Respiratory Distress Syndrome (PARDS) will continue 
and prevent progress in the field.  
Unique maturational differences prevent data generated in adults to be directly applied to 
children. There are important differences in lung growth and development, immune response 
and surfactant homeostasis.3,8 The scientific premise supporting the potential benefits of prone 
positioning and HFOV are well-grounded. Prone positioning augments ventilation (V) and 
perfusion (Q) matching along the gravitational axis. Improved V/Q matching reduces the need 
for potentially toxic levels of delivered oxygen and mean airway pressure.9,10 HFOV is a mode of 
ventilation that takes advantage of hysteresis, maintaining the lung open throughout the 
respiratory cycle, and aims to prevent the injurious effects of volutrauma, atelectrauma and 
potentially biotrauma that has been linked to multiple organ dysfunction syndrome (MODS).11,12 
It is unknown whether prone positioning and/or HFOV provides a benefit in children with high 
moderate-severe PARDS as compared to supine positioning and/or a CMV strategy that 
delivers small tidal volumes.13  
The purpose of PROSpect (PRone and OScillation PEdiatric Clinical Trial) is to provide 
evidence to support best ventilation practices in critically ill children with high moderate-severe 
PARDS defined per PALICC guidelines.1,13,14 We propose a two-by-two factorial, response-
adaptive, randomized controlled clinical trial of supine/prone positioning and CMV/HFOV. 
Approximately 60 pediatric intensive care units (PICUs), about 2/3 U.S. and 1/3 international, 
with at least 5 years of experience with prone positioning and HFOV that can provide back-up 
extracorporeal membrane oxygenation (ECMO) support, will participate.2 Eligible patients with 
high moderate-severe PARDS will be randomized within 48 hours of meeting eligibility criteria 
and within 4 days of endotracheal intubation to one of four groups: supine/CMV, prone/CMV, 
supine/HFOV or prone/HFOV. Subjects who fail their assigned positional and/or ventilation 
therapy for either persistent hypoxemia or hypercapnia may receive a reciprocal therapy while 
being considered for ECMO cannulation. Our primary outcome is ventilator-free days (VFD) 
through day 28, where non-survivors receive zero VFD.3 We have powered this study to detect 
a clinically meaningful 2-day improvement in VFD.15 Up to 800 patients will be randomized, 
stratified by age group (<1; 1-7; 8-17; 18-20 years) and direct/indirect lung injury. Adaptive 
randomization will first occur after 300 patients are randomized and have been followed for 28 
days, and every 100 patients thereafter. At these randomization update analyses, new 
 
 
3 We will use an alternative strategy to calculate VFD for ventilator dependent patients supported on 
invasive mechanical ventilation; specifically, we will calculate VFDs from the time the patient exhibits a 
qualifying OI/OSI to the first time that the patient maintains our prespecified OSI criteria to initiate 
extubation readiness testing (OSI ≤6) for 24 hours. 

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allocation probabilities will be computed based on ongoing intention-to-treat trial results, 
increasing allocation to well performing arms and decreasing allocation to poorly performing 
arms. PROSpect may close enrollment early for efficacy or futility based on pre-specified 
stopping rules. Subjects will be monitored for safety and followed until hospital discharge or 
hospital Day 90, whichever occurs first, then evaluated at fixed intervals after PICU discharge 
for functional status and health-related quality of life (HRQL). Data will be analyzed per 
intention-to-treat for the primary analyses and per-protocol received for primary, secondary and 
exploratory analyses. 
Specific Aims: In children with high moderate-severe PARDS: 
1. To compare the effects of prone positioning with supine positioning on ventilator-free days. 
2. To compare the effects of HFOV with CMV on ventilator-free days. 
Hypothesis: Children with high moderate-severe PARDS treated with prone positioning or 
HFOV will demonstrate more VFD. 
Secondary: To compare the impact of these interventions on nonpulmonary organ failure-free 
days. 
Hypothesis: Children with high moderate-severe PARDS treated with prone positioning or 
HFOV will demonstrate more nonpulmonary organ failure-free days. 
Exploratory: To explore the interaction effects of prone positioning with HFOV on VFD and 
investigate the impact of these interventions on 90-day in-hospital mortality and, among 
survivors, the duration of mechanical ventilation, PICU and hospital length of stay and trajectory 
of post-PICU functional status and HRQL.  
 
B. BACKGROUND AND SIGNIFICANCE 
Pediatric acute respiratory distress syndrome (PARDS) is a manifestation of severe lung injury 
with a mortality rate of up to 35%.16-18 The disease is characterized by massive pulmonary 
inflammation, alterations in surfactant homeostasis and ventilation/perfusion mismatching 
leading to severe hypoxemia and multiple organ dysfunction.19,20 Despite the significance of 
PARDS in critically ill mechanically ventilated children, respiratory management remains largely 
supportive with no data to support one approach over another.21-25  
The maximum level of pulmonary function reached during childhood is a crucial determinant for 
respiratory function throughout life.26-29 Any event in childhood that causes lung injury and, 
thereby, reduces the level of pulmonary function may exert a negative impact in adulthood. This 
may especially be true for lung injurious events during early childhood (i.e., <8 years of age) 
when the lung is still developing. Although beneficial to many patients with PARDS, numerous 
studies have shown that mechanical ventilation (MV) induces pulmonary inflammation 
(biotrauma) that aggravates pre-existing lung injury, known as ventilator-induced lung injury 
(VILI).30-32 This inflammation is not limited to the lung as inflammatory mediators enter the 
systemic circulation to induce organ dysfunction and often failure. As a consequence, patients 
generally do not die from lung injury but rather from MODS linked to VILI.33  
Data generated in adults with acute respiratory distress syndrome (ARDS) have shown positive 
results for prone positioning7,34 and lung protective ventilation (LPV),35-37 while demonstrating 
neutral or negative results for HFOV.5,6 However, unique maturational anatomic and physiologic 
differences prevent data generated in adults to be directly applied to children. Specifically, there 
are important differences in lung parenchyma and airway growth and development, immune 
response and surfactant homeostasis.8,38 The immune system of a child <1 year of age is 
relatively immature, including broad deficits in innate and adaptive immunity. As airway 

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resistance is inversely proportional to the fourth power of airway radius, young children tend to 
have higher baseline airway resistances compared to adults. Additionally, infants and young 
children have more compliant chest walls as compared to adolescents and adults due to 
incomplete ribcage ossification. These factors predispose a young child to greater vulnerability 
of airway and lung collapse and importantly question the applicability of adult-based ARDS data 
to children.  
In the absence of definitive pediatric-specific data, the management of PARDS remains largely 
supportive.1 Critically ill children with PARDS are mechanically ventilated, sedated and often 
chemically paralyzed until their underlying pulmonary process resolves. Lung protective 
ventilation, one of the key components of the management of PARDS, comprises the delivery of 
small tidal volumes (Vt) to avoid volutrauma and positive end-expiratory pressure (PEEP) to 
prevent alveolar collapse.13,39 In patients with high moderate-severe PARDS, such a LPV 
strategy may be insufficient to provide adequate gas exchange. When this happens, pediatric 
critical care practitioners resort to unproven alterative interventions, including prone positioning 
and/or HFOV. 
Prone Positioning: Prone positioning is an intervention that improves oxygenation and outcomes 
from acute hypoxemic respiratory failure in adults and, when applied consistently, has few 
serious adverse events.40-44 Several small prospective and retrospective studies in critically ill, 
mechanically ventilated children with acute lung injury or PARDS confirmed improved 
oxygenation and a highly favorable safety profile.45-50 To date, there has been only one pediatric 
randomized controlled trial (RCT) comparing prone to supine positioning.4 This study, performed 
by members of our study group (R01 NR005336), randomized 102 patients with acute lung 
injury (PaO2/FiO2 ratio; PF <300 mmHg) to prone positioning for 20 hours each day or to supine 
positioning. Despite the significant improvement in oxygenation, the study was stopped at the 
planned interim analysis on the basis of futility. Prone positioning did not exert a beneficial effect 
on the primary outcome VFD or in the secondary end points, including the proportion of children 
alive and ventilator-free on day 28, all-cause mortality, time to recovery of lung injury, number of 
organ failure-free days and cognitive impairment or overall functional health at hospital 
discharge or on day 28. However, the major drawback of this trial was that it was not limited to 
pediatric patients with severe PARDS and the use of HFOV was mandated when the child’s 
oxygenation index (OI) was ≥15. Indications that prone positioning might be of benefit in severe 
PARDS arose from a meta-analysis of primarily adult ARDS patients, showing that the effect of 
prone positioning was the greatest in patients with severe disease, i.e., a PF <100 mmHg.34 
This conclusion was supported by the adult Proning Severe ARDS Patients (PROSEVA) trial, 
identifying a 50% reduction in all-cause mortality at 28 days (the primary outcome of the trial) as 
compared to those who remained in the supine position in patients with severe ARDS defined 
as PF <150 mmHg.7 As such, PALICC strongly suggested further investigation of the effects of 
prone positioning in severe PARDS.51  

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Scientific Premise: PROSpect will replicate PROSEVA methodology and enroll patients with 
high moderate-severe PARDS while controlling the mode of mechanical ventilation. Prone 
positioning reduces ventral-to-dorsal transpulmonary pressure differences, making ventilation 
more homogeneous along the vertical axis, decreasing ventral alveolar overinflation and dorsal 
alveolar collapse, limiting VILI.10  
High-Frequency Oscillatory Ventilation: From a theoretical perspective, HFOV is an ideal LPV 
mode given its very small tidal volumes and change in pressure at the alveolar level.2 With 
HFOV, a continuous distending pressure is generated to maintain adequate lung volume, with 
superimposed small oscillations in a frequency range of 5-15 Hz allowing for gas exchange. In 
an international cross-sectional study of pediatric acute lung injury, ranging from mild to severe, 
16% of patients were managed with HFOV.52 To date, there has been only one pediatric RCT 
comparing HFOV to conventional mechanical ventilation (CMV) in 70 children with diffuse 
alveolar disease and/or air leak syndrome.53 This study showed that HFOV using an aggressive 
volume recruitment strategy resulted in a significant improvement in oxygenation and a 
decreased requirement for supplemental oxygen at 30 days. However, 30-day mortality was not 
changed and the control group did not utilize a lung protective approach to ventilation. A meta-
analysis of all six pediatric and adult clinical trials demonstrated improved mortality in patients 
randomized to HFOV.54 However, two large randomized studies in adults with moderate to 
severe early ARDS launched the recent discussion on HFOV in PARDS.5,6 Whereas in the 
OSCillation for ARDS (OSCAR) trial no difference in 30-day mortality was observed, the 
OSCILLation for ARDS Treated Early (OSCILLATE) trial was prematurely stopped (after the 500 
patient analysis) because of higher in-hospital (47% versus 35%) and 60-day mortality (47% 
versus 38%) in the HFOV group. It should be noted that approximately half of the subjects 
enrolled in the OSCILLATE trial were septic requiring vasoactive agent support. Such a 
population would be anticipated to do poorly when exposed to the high mean airway pressures 
(mPaw) as directed by the protocol. The “one size fits all” approach of OSCILLATE did not allow 
for ventilator management to be titrated according to a patient’s unique pathophysiology, a 
conclusion also noted by Malhorta and Drazen in their editorial entitled “High-frequency 
oscillatory ventilation on shaky ground.”55 Furthermore, a post-hoc data analysis of pediatric 
patients enrolled in a protocolized sedation trial performed by members of our study group 
(Randomized Evaluation of Sedation Titration for Respiratory Failure, RESTORE, U01 
HL086622)56 showed similar mortality rates but prolonged duration of MV among patients 
managed with HFOV compared to CMV after adjusting for risk category. The current 
management of pediatric patients with HFOV may not be superior than that with CMV, 
supporting PALICC’s call for a pediatric RCT to examine the role of HFOV in PARDS.57  

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Scientific Premise: PROSpect will use a more physiologic-based approach to HFOV with 
individualized mPaw titration and higher frequencies to maximize lung volume and deliver the 
smallest tidal volume. HFOV maintains the recruited and stabilized alveoli due to the delivery of 
a constant mPaw.2,58-60 Data from our team show that such an approach is safe in terms of 
hemodynamics and feasible in terms of oxygenation and ventilation. Furthermore, this approach 
is very different from the approach to HFOV in the two adult trials. Both OSCAR and 
OSCILLATE employed low frequencies (thereby delivering larger tidal volumes) and used a 
protocolized “one size fits all” mPaw titration, which led to the application of high pressures and 
subsequent hemodynamic compromise. 
C. SUPPORTING DATA 
C.1 Pediatric Acute Lung Injury Consensus Conference 
A panel of 27 international pediatric experts met over two years to develop a taxonomy to define 
PARDS and make recommendations regarding treatment and research priorities.1 The experts 
developed and voted on recommendations addressing: 1) Definition, prevalence and 
epidemiology; 2) Pathophysiology, comorbidities and severity; 3) Ventilator support; 4) 
Pulmonary-specific ancillary treatment; 5) Non-pulmonary treatment; 6) Monitoring; 7) 
Noninvasive support; 8) ECMO support; and 9) Morbidity and long-term outcomes. Additional 
data recently supported the PALICC PARDS definition noting that severe PARDS was 
associated with high mortality (37%), particularly if present 24 hours after diagnosis.61 
C.2 Pediatric Prone Trial 
From 2001 to 2004, we conducted a multi-center, randomized, controlled clinical trial, testing the 
hypothesis that at the end of 28 days children with acute lung injury (PF <300 mmHg) treated 
with prone positioning would have more VFD than those treated with supine positioning.4 We 
enrolled 102 pediatric patients, aged 2 weeks to 18 years, from 7 U.S. PICUs. Patients were 
randomized to either supine or prone positioning within 48 hours of meeting acute lung injury 
criteria, with those patients in the prone group being positioned within 4 hours of randomization 
and remaining prone for 20 hours each day during the acute phase of their illness for a 

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maximum of 7 days, after which they were positioned supine. Both groups were managed using 
a low tidal volume/PEEP strategy, extubation readiness testing and sedation, hemodynamic, 
nutrition and skin care guidelines. The use of HFOV was mandated when a subject’s OI was 
≥15. Ninety percent of the patients randomized to the prone arm showed improved oxygenation 
(PF ≥20 mmHg or OI ≥10% decrease). The trial was stopped at the planned interim analysis on 
the basis of the pre-specified futility stopping rule. There were no differences in the number of 
VFD between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, 
−0.2 days; 95% CI, −3.6 to 3.2; P=0.91). After controlling for age, Pediatric Risk of Mortality III 
score, direct vs indirect acute lung injury and mode of mechanical ventilation at enrollment, the 
adjusted difference in ventilator-free days was 0.3 days (95% CI, −3.0 to 3.5; P=0.87). Prone 
positioning did not significantly reduce VFD or improve other clinical outcomes in pediatric 
patients with acute lung injury. 
C.3 RESTORE HFOV Propensity Score Analysis 
In the absence of pediatric trials, we conducted a propensity score analysis of data from the 
RESTORE study to compare the outcomes of patients with acute respiratory failure managed 
with HFOV within 24-48 hours of endotracheal intubation with those receiving CMV and/or late 
HFOV.57 Among 2,449 patients enrolled in RESTORE, 353 patients (14%) were ever supported 
on HFOV, of which 210 (59%) had HFOV initiated within 24-48 hours of intubation. The 
propensity score model predicting the probability of receiving early HFOV included 1,064 
patients (181 early HFOV vs 883 CMV/late HFOV) with significant hypoxemia (OI ≥8.0). The 
degree of hypoxemia was the most significant contributor to the propensity score model. After 
adjusting for risk category, early HFOV use was associated with a longer duration of mechanical 
ventilation (hazard ratio, 0.75; 95% CI, 0.64–0.89; P=0.001) but not with mortality (odds ratio, 
1.28; 95% CI, 0.92–1.79; P=0.15) compared with CMV/late HFOV. These analyses make 
supporting the current approach to HFOV less convincing.62 
C.4 Physiologic Approach to HFOV 
We will use an individualized mPaw titration algorithm and higher frequencies than traditionally 
practiced, thereby maximizing lung volume while delivering the smallest tidal volume. Data from 
our team show that such an approach is safe in terms of hemodynamics and feasible in terms of 
oxygenation and ventilation. Between 2014 and 2016, 115 non-cardiac patients with acute 
hypoxemic respiratory failure, of whom 53% met the criteria for PARDS (40% severe PARDS) 
were oscillated. Indications for HFOV included Peak Inspiratory Pressure (PIP)/Pressure 
Plateau (Pplat) >28 cm H2O, PEEP >8 cm H2O, FiO2 >0.60 and increase in oxygenation index 
on three consecutive measurements one hour apart from each other. All patients underwent a 
staircase incremental-decremental mPaw titration. An open-lung strategy was employed, 
targeting frequency >9 Hz and amplitude 70-90 cm H2O. Analysis within three age groups (<12 
CDP: continuous distending 
pressure

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months, 13-60 months and >60 months) showed that this approach was feasible irrespective of 
age. Also, there were no significant negative effects on heart rate or blood pressure, indicating 
that the open-lung strategy did not result in hemodynamic instability. Also, both oxygenation and 
ventilation were feasible; the pH was always >7.15 without severe or refractory hypercapnia.  
D. EXPERIMENTAL APPROACH 
D.1 Design and Rationale 
This is a two-by-two factorial, response-adaptive multi-center randomized controlled clinical trial 
that tests whether pediatric patients with high moderate-severe PARDS randomized to supine 
versus prone positioning and to conventional mechanical ventilation versus high-frequency 
oscillatory ventilation exhibit more ventilator-free days over a 28-day period. Our primary 
research hypothesis is that children with high moderate-severe PARDS randomized to either 
prone positioning or HFOV will demonstrate more ventilator-free days. We hypothesize that a 
superior treatment would improve VFD by at least 2 days, a clinically meaningful difference.15 
Our secondary research hypothesis is that these two interventions will demonstrate more 
nonpulmonary organ failure-free days. The rationale for our research hypotheses is that prone 
positioning and HFOV will provide better support for the failing lung without causing harm as 
evidenced by a more rapid recovery and return to unsupported breathing or, for children with 
chronic respiratory disease, baseline respiratory support status. Improvement in VFD will be 
considered within the context of patient safety; specifically, patients must also exhibit a similar 
safety profile.  
Up to 800 patients will be randomized. Randomization will be stratified by age group (<1; 1-7; 8-
17; 18-20 years) and direct/indirect lung injury. Adaptive randomization will first occur after 300 
patients are randomized and have been followed for 28 days, and every 100 patients thereafter. 
At these randomization update analyses, new allocation probabilities will be computed based on 
ongoing intention-to-treat trial results, increasing allocation to well performing arms and 
decreasing allocation to poorly performing arms. PROSpect may close enrollment early for 
efficacy or futility based on pre-specified stopping rules. 
Enrolled subjects will be followed from endotracheal intubation (or, for ventilator dependent 
patients supported on invasive mechanical ventilation with baseline OSI ≤6, the time the patient 
exhibits a qualifying OI/OSI) until hospital discharge or hospital Day 90, whichever occurs first. 
After PICU discharge, we will complete telephone-based family interviews at 1, 3, 6 and 12 
months to assess the subject’s functional status and health-related quality of life (HRQL). Data 
will be analyzed per intention-to-treat for the primary analyses and per-protocol received for 
primary, secondary and exploratory analyses.  
Study Scheme: 
 

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Rationale: 
Two-by-two factorial study design. This study will address two major research questions with 
one clinical trial, saving time and resources. In addition, pediatric practice commonly uses prone 
and supine positioning with both ventilation strategies (CMV and HFOV), and though we are not 
anticipating significant interaction effects between positioning and ventilation strategies, this 
study will allow an evaluation of potential synergistic effects. 
Response-adaptive randomization. This design will improve trial efficiency. Data generated 
during the course of the trial will be used to modify randomization allocation, thereby randomly 
assigning more subjects to a more efficacious intervention(s).  
Randomization stratification by age group and lung injury type. We are stratifying by age group 
(<1; 1-7; 8-17; 18-20 years) because in infancy, chest wall compliance is nearly three-times that 
of the lung. By the second year of life, the increase in chest wall stiffness is such that the chest 
wall and lung have similar compliance as in adults. By eight years of age, the height of the chest 
wall is similar to that of an adult. It is possible that the increased chest wall compliance and the 
consequent increase in alveolar excursion for the same transpulmonary pressure may place the 
infant at greater risk for ventilator associated lung injury. It is also possible that chest wall 
stiffening relative to the lung may improve the infant's ability to maintain adequate end-
expiratory lung volume, an important determinate of lung unit patency in dependent lung 
regions. When evaluating the impact of age on prone positioning we will search for nonlinear 
relationships; specifically, does the effect of prone positioning vary in different age groups.  
We are also stratifying by direct/indirect lung injury because there may be a differential lung 
recruitment response to prone positioning and HFOV; specifically, prone positioning may be 
more effective in patients with indirect lung injury whereas HFOV may be more effective in direct 
lung injury. Direct lung injury is operationally defined as lung injury originating from pulmonary 
disease (e.g., pneumonia) and indirect lung injury originating from non-pulmonary disease (e.g., 
sepsis).63  
D.2 Study Population  
Participating Centers: Approximately 60 PICUs with at least 5 years of experience with prone 
positioning and HFOV that can provide back-up ECMO support have been recruited to 
participate.4 Consistent with the PROSEVA study, experienced centers are those with at least a 
 
 

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5-year history of using the therapies.7 Our rationale for including experienced centers diminishes 
the need for fundamental training in study interventions and will allow our team to focus training 
on the PROSpect protocols. Requiring ECMO backup optimizes patient safety since all enrolled 
subjects will have high moderate-severe PARDS and would not easily tolerate an inter-hospital 
transport for ECMO if study interventions failed.5  
We modeled our anticipated enrollment rate based on our experience with the RESTORE trial; 
specifically, 761 PROSpect-eligible RESTORE patients (31% of 2449 RESTORE patients) were 
enrolled over a total of 1309 months from 31 U.S. PICUs (of varying size with unequal start/stop 
times) at a rate of 0.58 patients per site per month. Assuming that the PROSpect consent rate 
will be approximately 60% (lower than the RESTORE intervention group consent rate of 72%; 
yet higher than the 50% rate in HALF-PINT), the enrollment rate becomes 0.58×(60%/72%) = 
0.58×83% = 0.48 patients per site per month.56,64 
To ensure that PROSpect ends fully enrolled and on-time with results that can be generalized 
throughout the field, we have designed PROSpect to include one-third international sites.52 
PICUs in Asia, Australia/New Zealand and Western Europe have volunteered, augmenting 
existing U.S. resources. All PICUs are active in pediatric critical care research, members of their 
national research societies and engaged in each other’s work through the World Federation of 
Pediatric Intensive and Critical Care Societies (WFPICCS). The clinical practices of the 
international PICUs are known by the Principal Investigators and all are English-competent.  
All PICUs provided letters of support outlining their organizational, leadership and 
interprofessional team support for PROSpect. All have reviewed and agreed to follow our 
research protocols (http://www.prospect-network.org). All have equipoise on the topic, can enroll 
a minimum of 6 subjects/year and are aware of the expectation that at least a quarter of our 
sites must be ready to enroll in our UG3 year. In addition, all domestic sites have agreed to 
engage in a reliance agreement with the University of Pennsylvania and international sites will 
complete local human subjects review processes. We used external data from either the 
RESTORE database and/or the Pediatric ARDS Incidence and Epidemiology (PARDIE; 
http://pardie.palisi.org) database to validate each PICU’s reported available population.  
Patient Eligibility and Recruitment: Site co-investigators or their designee will screen their 
PICUs daily for eligible patients. Screening logs will be used to facilitate the screening process 
and provide an auditable record of potentially eligible patients. Patient eligibility criteria focus on 
pediatric patients with high moderate-severe PARDS occurring within 4 days of endotracheal 
intubation. Enrolling subjects within 48 hours of meeting criteria for high moderate-severe 
PARDS occurring within 4 days of endotracheal intubation allows us to enroll a more 
homogenous group of subjects with potentially recruitable lung disease. 
Inclusion Criteria: Pediatric patients (≥2 weeks of age and ≥42 weeks post gestational age and 
<21 years of age) intubated and mechanically ventilated with high moderate-severe PARDS 
for <48 hours per PALICC guidelines, that is, chest imaging consistent with acute 
pulmonary parenchymal disease and OI ≥ 12 or, if an arterial specimen is not available, 
oxygen saturation index (OSI) ≥ 10 (OI: [FIO2 × mPaw]/PaO2 × 100; OSI: [FIO2 × mPaw]/SpO2 
× 100). We will require two blood gases meeting high moderate-severe PARDS criteria 
separated by at least 4 ± 2 hours. Requiring two blood gases avoids enrolling transiently 
hypoxemic patients who are responsive to conventional measures to improve hypoxemia. A 
second blood gas is not required for OI ≥16.  
 
 

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Exclusion Criteria: Exclusion criteria focus on patients in whom prone positioning or HFOV is 
contraindicated. Patients will be excluded if they are/have any of the following at the start of 
mechanical ventilation:  
• 
Perinatal related lung disease 
• 
Congenital diaphragmatic hernia or congenital/acquired diaphragm paralysis 
• 
Respiratory failure explained by cardiac failure or fluid overload 
• 
Cyanotic heart disease 
• 
Cardiomyopathy 
• 
Unilateral lung disease 
• 
Primary pulmonary hypertension 
• 
Intubated for status asthmaticus 
• 
Obstructive airway disease (e.g., severe airways disease without parenchymal 
involvement or disease characterized by hypercapnia with FiO2 <0.30 and/or evidence of 
increased resistance visible on the flow – time scalar and/or presence of intrinsic PEEP) 
• 
Active air leak  
• 
Bronchiolitis obliterans 
• 
Post hematopoietic stem cell transplant; ; specifically, patients receiving continuous 
supplemental oxygen for three or more days prior to intubation; receiving noninvasive 
ventilation for more than 24 hours prior to intubation; receiving more than one vasoactive 
medication at time of meeting inclusion criteria; spending more than four days in the 
PICU prior to intubation; supported on or with immediate plans for renal replacement 
therapies; with two or more allogeneic transplants; who relapsed after the transplant; or 
with diffuse alveolar hemorrhage 
• 
Home ventilator dependence with baseline Oxygen Saturation Index (OSI6) >6 (baseline 
is defined as a stable period, prior to current illness)  
• 
Neuromuscular respiratory failure 
• 
Critical airway (e.g., post laryngotracheal surgery or new tracheostomy) or anatomical 
obstruction of the lower airway (e.g., mediastinal mass) 
• 
Facial surgery or trauma in previous 2 weeks 
• 
Head trauma (managed with hyperventilation) 
• 
Intracranial bleeding  
• 
Unstable spine, femur or pelvic fractures 
• 
Open abdomen 
• 
Currently receiving either prone positioning or any high-frequency mode of MV with 
current illness (Up to 4 hours of prone positioning and/or any mode of high-frequency 
mode of MV is allowed as long as the therapies are off for least 4 hours prior to the 
subject meeting oxygenation criteria.) 
• 
Supported on ECMO during the current admission 
• 
Family/medical team not providing full support (patient treatment considered futile) 
• 
Previously enrolled in current study 
• 
Enrolled in any other interventional clinical trial not approved for co-enrollment 
• 
Known pregnancy  
D.3 Interventions  
Once randomized, subjects will be transitioned to their allocated intervention(s) within 4 hours. 
Receiving the allocated intervention(s) after this time will be considered a protocol violation. 
 
6 Calculation to determine mPaw from ventilator settings are included in Appendix 3.  

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Protocol highlights are as follows (full protocol with pre-specified modifications for subjects 
with home ventilator dependence at baseline are included in the Appendix):  
All groups:  
• 
During the acute phase (OI ≥8), the goal is adequate oxygenation and ventilation: 
Oxygenation: Pulse oximeter oxygen saturation (SpO2) 88-92%  
Ventilation: pH 7.15-7.30 (irrespective of PaCO2)  
• 
Monitoring will include an arterial line. 
• 
Continuous neuromuscular blockade administered for first 24 hours, then as clinically 
indicated. 
• 
Subjects will be placed in their allocated position (supine or prone) first, then converted to 
their allocated ventilation strategy (CMV or HFOV). This will avoid multiple consecutive 
recruitment maneuvers. 
Supine Positioning: Patients randomized to supine positioning will remain supine. Supine 
repositioning includes a Q2H rotation from full supine to right lateral/supine to full supine to left 
lateral/supine to full supine. 
Prone Positioning: Patients randomized to receive prone positioning will be positioned prone 
≥16 hours/day for a maximum of 28 days. Prone repositioning includes a Q2H rotation from full 
prone to right lateral/prone to full prone to left lateral/prone to full prone. For safety, clinicians 
will use the positioning checklist and Standard Operating Procedure (SOP) for all turns. Failure 
to do so will be considered a protocol violation.  
Criteria for stopping prone positioning includes (1) improved lung function consistent with 
resolving PARDS; specifically, spontaneous breathing and OI <8 (OSI <7.5) in the supine 
position for at least 4 hours after the end of a prone session or (2) pattern of no effect where the 
subject demonstrates a three-day pattern of decreased PF ratio of at least 20% or an increase 
in OI of at least 10% post supine-to-prone positioning. 
Prone positioning is immediately interrupted in an emergency: e.g., non-scheduled extubation, 
main-stem bronchus intubation, ETT obstruction, hemoptysis, cardiac arrest, bradycardia or 
hypotension for more than 5 minutes and any other life-threatening event. Evolving clinical 
situations that may also preclude daily prone positioning, that is, Stage 3 pressure injuries that 
cannot be managed in the prone position.  
Conventional Mechanical Ventilation (CMV): The CMV arm will use a lung-protective 
ventilation strategy consistent with PALICC recommendations. This includes: (1) low tidal 
volume to obtain exhaled Vt (Vte) of 5-7 ml/kg (ideal body weight [IBW]); (2) PIP goal limited to 
≤28 cm H2O (may allow up to 32 cm H2O for subjects with poor chest wall compliance); (3) lung 
recruitment maneuver to identify best PEEP then maintained per PEEP-FiO2 grid; and (4) use of 
synchronized intermittent mandatory ventilation (SIMV) or assist control (AC), Pressure Control 
Ventilation (PCV) or Pressure Regulated Volume Control (PRVC or equivalent). The protocols 
delineate ongoing CMV support, escalation of support and weaning of support. Monitoring will 
include Vte and percent ETT air leak measured at the airway. Criteria for failed CMV include a 2-
hour pattern of either persistent hypoxemia (SpO2 <85%) with FiO2 1.0 and max PEEP per grid 
or persistent hypoventilation (pH <7.15) with PIP >32 cm H2O and a respiratory rate that does 
not cause intrinsic PEEP.  
High-Frequency Oscillatory Ventilation (HFOV): The HFOV arm will use a lung-protective 
ventilation strategy consistent with PALICC recommendations. HFOV management is based on 
physiologic principles of gas delivery. To optimize the high-frequency approach, high rates (≥8 
Hz) will be used knowing that increased amplitudes will be required for adequate ventilation. 
Given the known attenuation of pressure amplitude across the endotracheal tube and along the 
natural airways, pressure amplitude and tidal volume delivery will remain within typical 

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parameters for HFOV at the alveolar level. The HFOV strategy includes use of a frequency at 8-
15 Hz, an amplitude (delta-P) 60-90, a mPaw recruitment maneuver and a weaning strategy. 
The protocols delineate ongoing HFOV support, escalation of support, weaning of support and 
conversion to CMV. Criteria for failed HFOV include a 2-hour pattern of either persistent 
hypoxemia (SpO2 <85%) at FiO2 1.0 and mPaw >35 cm H2O or persistent hypoventilation (pH 
<7.15) with max power/amplitude at a frequency <8 Hz. 
For reproducibility across centers we will restrict the HFOV ventilator to the SensorMedics 
3100A (patient <35 kg) or 3100B (patient ≥35 kg). The SensorMedics, compared to other HFOV 
ventilators, allows manipulation of the inspiratory-to-expiratory time ratio, provides an active 
exhalation phase, can be used across the enrolling age groups, is FDA-approved for this 
application and is available in each of the proposed clinical sites. 
Failed Management: Clinicians may consider a reciprocal therapy (supine to prone; prone to 
supine; CMV to HFOV; HFOV to CMV) in a sequence based on their clinical judgment while 
considering ECMO cannulation. Reciprocal treatments, when used, will be managed per 
PROSpect protocols. Subjects cannulated for ECMO will be discontinued from further study 
treatments and followed so that ventilator management can be described and for study 
outcomes.  
Co-Interventions (all groups), managed per PALICC recommendations.13,51,65  
• 
Artificial airway (AA) suctioning: Performed with an unexplained, rapid increase in PaCO2 
and/or decrease in chest movement. Aside from Q12H AA patency check, routine suctioning 
is not recommended.  
• 
Hemodynamic management guidelines: Subjects will be managed using a fluid 
conservative strategy based on the subject’s mean arterial blood pressure percentile for 
age, net fluid balance and urine output.66 
• 
Sedation guidelines: The care team will prescribe a target comfort level each day. 
Adjustment of sedatives to achieve target comfort levels will be guided by a nurse-
implemented goal-directed sedation protocol.  
• 
Enteral nutrition: Monitoring, advancement and maintenance managed by a goal-directed 
protocol that is collaboratively established by the interprofessional team. The 2017 ASPEN 
nutrition guidelines recommend that critically ill pediatric patients receive a minimal protein 
intake of 1.5 gm/kg/day to achieve positive nitrogen balance.67 
• 
Skin care and pressure injuries guidelines: A skin assessment will be recorded daily. 
Pressure injuries will be staged and managed according to National Pressure Injury 
Advisory Panel (NPUAP) guidelines.68 
• 
Extubation Readiness Test (ERT): This standardized test will be implemented once daily 
at 07:00 ± 2H in subjects who are spontaneously breathing with an OI/OSI <6 and in whom 
there has there been a decrease and/or plateau in ventilator support over the previous 12 
hours.  The ERT is repeated at 16:00 ± 2H in subjects who fail the morning test for 
oversedation.69 Since our primary outcome is VFD, failure to complete an ERT on an eligible 
subject will result in a protocol deviation.56 
• 
The use of inhaled nitric oxide (iNO) and systemic steroids will be monitored but not 
protocolized. Per the PALICC guidelines, iNO should only be used for patients with 
documented pulmonary hypertension and/or right ventricular failure, and there are no data 
supporting the routine use of systemic steroids. 
D.4 Primary, Secondary and Exploratory Outcome Measures  
Primary Outcome: Ventilator-free days (VFD) through Day 28. VFD is defined as the 
number of days within 28 days that a subject is alive and free of mechanical ventilation.70 It is 
the inverse equivalent of the 28-day hospital mortality-adjusted duration of mechanical 

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ventilation. While mortality is an ideal primary outcome, the cause of death in PARDS is 
multifactorial. Mortality-adjusted duration of mechanical ventilation is a well-accepted alternative 
way to evaluate outcomes of treatments for PARDS.71 VFD appropriately reflect both improved 
survival and shorter duration of ventilation and avoid potential biases caused by shorter duration 
of ventilation as a result of early mortality. In computing VFD, we will consider day 0 as the time 
of endotracheal intubation or, in subjects with tracheostomies, the time of initiation of pressure 
supported breathing (BiPAP, CPAP ≥5 cm H2O, or HHFNC ≥5 L/min) or in ventilator dependent 
patients supported on invasive mechanical ventilation with baseline OSI ≤6, the time the patient 
exhibits a qualifying OI/OSI. Duration of mechanical ventilation continues until the first time the 
endotracheal tube is continuously absent for at least 24 hours or, in subjects with 
tracheostomies, the first time positive pressure is <5 cm H2O (continuous or bi-level) for at least 
24 hours or in ventilator dependent patients supported on invasive mechanical ventilation with 
baseline OSI ≤6, the first time that the patient maintains our prespecified OSI criteria to initiate 
extubation readiness testing (OSI ≤6) for 24 hours.  
Subjects will be assigned zero VFD if they remained intubated or died prior to day 28 without 
remaining extubated for more than 24 hours. For intubated subjects who are transferred to 
another hospital, we will attempt to obtain date/time of extubation from the outside hospital so 
that VFD can be calculated. In the event that this data cannot be obtained, these subjects will 
be assigned the worst possible outcome of zero VFD. 
To accommodate the use of noninvasive ventilation (BiPAP, CPAP ≥5 cm H2O, or HFNC ≥5 
L/min), as a separate outcome, we will also compute the total duration of assisted breathing to 
include the use of noninvasive ventilation pre-intubation and post-extubation. 
Secondary Outcome: Nonpulmonary organ failure-free days (OFFD) through Day 28. 
Nonpulmonary OFFD is defined as the number of days within 28 days that a subject is alive and 
free of clinically significant non-pulmonary organ failure. Nonpulmonary organ failure-free days 
will be calculated for the clinically important nonpulmonary organ systems (neurologic, 
cardiovascular, renal and hematologic) using nonpulmonary PEdiatric Logistic Organ 
Dysfunction-2 (PELOD-2) scores to Day 28.72 Slutsky and Tremblay postulate that ventilator-
induced lung injury (VILI) may play a pivotal role in the initiation and/or propagation of a 
systemic inflammatory response leading to multisystem organ failure.30,73,74 In animal models, 
the strategy of mechanical ventilation influences the local release of inflammatory mediators 
from the lung and preventing volutrauma and atelectrauma reduces the release of these 
mediators. Effective lung protection strategies that limit VILI may lead to a modification of the 
systemic inflammatory response and development of MODS. Thus, nonpulmonary OFFD is a 
relevant secondary outcome of interventions posited to limit the inflammatory milieu in the lung. 
Exploratory Outcome: Interaction effects between the positioning and ventilation 
strategies. We will evaluate possible interaction effects of prone positioning with HFOV on 
VFD, which will allow us to probe for potential differential effects when these two interventions 
are used concurrently.  
Exploratory Outcome: 90-day in-hospital mortality. 90-day in-hospital mortality is a critical 
measure of treatment safety and considers death beyond 28 days. Deaths from all causes will 
be monitored through hospital discharge or day 90 (whichever occurs first). The primary and 
secondary causes of death (as specified on the death certificate) will be recorded to allow us to 
probe the cause of death in PARDS. 
Exploratory Outcome: Duration of mechanical ventilation (among survivors). Duration of 
mechanical ventilation provides a prospective evaluation of ventilator support independent of 
mortality. As above, duration of mechanical ventilation is defined as the time from day 0 to the 
first time the endotracheal tube is continuously absent for at least 24 hours or, in ventilator 

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dependent patients supported on invasive mechanical ventilation with baseline OSI ≤6, the first 
time that the patient maintains our prespecified OSI criteria to initiate extubation readiness 
testing (OSI ≤6) for 24 hours. For subjects with tracheostomies, duration of mechanical 
ventilation is defined as the time of initiation of pressure supported breathing (BiPAP, CPAP ≥5 
cm H2O, or HHFNC ≥5 L/min) to the first time positive pressure is <5 cm H2O (continuous or bi-
level) for at least 24 hours. Duration of mechanical ventilation will be considered to be 28 days 
for subjects still intubated on day 28, and will be calculated for subjects who survive to hospital 
discharge or day 90 (whichever occurs first). 
Exploratory Outcome: PICU and hospital length of stay (among survivors). PICU and 
hospital length of stay (LOS) provide proxy measures of resource utilization. PICU LOS is 
defined as the time from day 0 to the time of PICU discharge, while hospital LOS is defined as 
the time from day 0 to the time of hospital discharge. PICU and hospital LOS will be considered 
to be 90 days for subjects still in the PICU/hospital on day 90, and will be calculated for subjects 
who survive to hospital discharge or day 90 (whichever occurs first). 
Exploratory Outcome: Post hospital discharge functional status and HRQL. Not all 
pediatric patients who survive PARDS return to their previous level of health. These outcomes 
will allow us to explore the trajectory and quality of patient survival. Functional status will be 
assessed using the Pediatric Cerebral Performance (PCPC), Pediatric Overall Performance 
Category (POPC),75 and Functional Status Scale (FSS) score76. HRQL will be assessed using 
the chronological age-appropriate Pediatric Quality of Life Inventory (PedsQLTM; Version 4.0 
Generic Core Scales for subjects 2-21 years; Infant Scales for subjects <2 years; 
http://www.pedsql.org) with associated modules (see table).77,78 See section D.8 for information 
on the timing of assessments. 
Measure 
Domain*  
Age 
Group 
Number of Items / 
Time Required 
Child 
 
 
 
PedsQL™ 4.0 Generic Core or Infant Scales 
(Acute version – per age) 
1. Young adult (18-25 y) self-report, parent-
report 
2. Teen (13-18 y) self-report, parent-report  
3. Child (8-12 y) self-report, parent-report 
4. Young child (5-7 y) parent-report 
5. Toddler (2-4 y) parent-report 
6. Infant (13-24 m) parent-report 
7. Infant (1-12 m) parent-report 
Physical, 
Cognitive, 
Emotional, 
Social 
1 m-21 y 
 
 
23 items / <5 min 
 
23 items 
23 items 
23 items 
21 items 
45 items / <10 min 
36 items / <7min 
PedsQL™ Multi-dimensional Fatigue Scale V3 
(Acute version – per age) 
1. Young adult (18-25 y) self-report, parent-
report 
2. Teen (13-18 y) self-report, parent-report  
3. Child (8-12 y) self-report, parent-report 
4. Young child (5-7 y) parent-report 
5. Toddler (2-4 y) parent-report 
Physical, 
Cognitive 
2-21 y 
18 items / <4 min 
PedsQL™ Cognitive Functioning Scale 
1. Young adult (18-25 y) self-report, parent-
report 
2. Teen (13-18 y) self-report, parent-report  
3. Child (8-12 y) self-report, parent-report 
Cognitive 
2-21 y 
6 items / <2 minutes 

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4. Young child (5-7 y) parent-report 
5. Toddler (2-4 y) parent-report 
PedsQL Pediatric Pain Questionnaire, self-report 
Physical 
8-21 y 
1 item / <1 min 
Functional Status Scale (FSS), parent-report 
Physical 
1 m-21 y 
6 items / 2-5 min 
Pediatric Overall Performance Category (POPC), 
parent-report 
Physical 
1 m-21 y 
1 item / 1 min 
Pediatric Cerebral Performance Category (PCPC), 
parent-report 
Cognitive 
1 m-21 y 
1 item / 1 min 
Parent  
 
 
 
PedsQL™ Family Impact Module 2.0 (acute version) 
Physical, 
Cognitive, 
Emotional, 
Social 
- 
36 items / 5 min 
D.5 Measurement of Study Variables During Hospital Course 
Methods of Data Collection: Site co-investigators will be trained in data collection methods by 
the DCC Project and Data Managers prior to enrolling subjects. 
Baseline assessments will be completed on all subjects to allow group comparison. This 
includes demographic and socioeconomic data, medical history information, primary cause for 
acute respiratory failure, pre-enrollment chest X-ray (CXR; de-identified digitized file), baseline 
PCPC, POPC,75 FSS,76,79 PedsQL,77,78 (clinician and parent-report) and the PRISM IV score.80,81 
Schedule of clinical and laboratory evaluations:  
 
Data Collection Schedule  
 
Screening 
Baseline 
Daily PICU  
to Day 28* 
PICU 
Discharge 
 
Demographic data 
X 
X 
 
 
Past and present medical history, pre-
enrollment CXR  
X 
X 
 
 
PCPC, POPC, FSS score  
 
X 
 
X 
Preadmission PedsQL – parent report 
 
X 
 
 
Admission PRISM IV score 
 
X 
 
 
Vital signs, vasopressor use 
 
X 
X 
 
Ventilator parameters; arterial blood gases 
 
X 
X 
 
If CMV: ETCO2 (NM3) dead 
space/volumetric capnography evaluation 
 
X 
X 
 
NMB, iNO, systemic steroids 
 
X 
X 
 
Comfort status/agents 
 
X 
X 
 
Skin assessment 
 
X 
X 
 
PELOD-2  
 
X 
X 
 
Pre-specified and unanticipated adverse 
events  
 
X 
X 
 
Daily data, extracted from existing documentation at 10:00±2H.  
* Daily measurements will be assessed in both CMV/HFOV groups when the subject is supine. 
Comfort status includes pain, sedation, delirium and iatrogenic withdrawal syndrome (IWS) 
scores. Exposure to sedative medications includes total dose and length of exposure.56 

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D.6 Study Safety 
Subjects will be prospectively monitored daily for the occurrence of pre-specified adverse 
events. Potential risks associated with the positioning protocols include unplanned extubation, 
vascular line/invasive tube removal, plugging/obstruction of the endotracheal tube with 
secretions and/or blood, main-stem bronchus intubation, transient hemodynamic instability, 
cardiac dysrhythmias, clinically significant agitation (State Behavioral Scale; SBS +1/+2 for 2 
consecutive hours), facial and eyelid edema, pressure injuries (any dependent surface) and 
corneal abrasions. Potential risks associated with the ventilation protocols include hemodynamic 
instability, air leak (e.g., pneumothorax, pneumomediastinum), cardiac dysrhythmias related to 
increased mPaw, mucous plugging/airway obstruction, clinically significant agitation and 
pressure injuries (occipital/auricular). Most specified events should be tracked in the PICU only 
and not the Ward, with the exception of clinically significant iatrogenic withdrawal (IWS) for 
subjects receiving ≥5 days of opioids or benzodiazepines, ventilator-associated pneumonia 
through 24 hours after ETT extubation, and catheter-associated bloodstream infection (if the line 
was inserted in the PICU) through 24 hours after PICU discharge. If an adverse event overlaps 
the positioning and ventilation protocols (e.g., agitation), attribution will be assigned based on 
the clinical judgment of the bedside team. See also section F.7 for information about event 
severity and relatedness classifications and reporting procedures. 
D.7 Biorepository 
With parental/legal guardian permission, we will collect blood and endotracheal aspirate 
samples for future studies of genomics, proteomics and metabolomics of PARDS. The sample 
collection will allow the investigative team to probe the biological basis for potentially disparate 
outcomes between PROSpect treatment groups and allow the study of the trajectory of PARDS 
illness and recovery. Fiduciary oversight of the biorepository rests with the Biorepository 
Governance Committee as outlined in PROSpect Policy for the Use of PROSpect 
Biospecimens. The governance committee will consider and approve the use of biorepository 
samples and subsequent data sharing for studies of high scientific merit that support the study 
of children with severe respiratory failure. Such studies will provide objective measures of 
PARDS, intermediate outcomes for clinical trials and allow for early interventions and prevention 
of PARDS. PROSpect provides a unique opportunity to collect biomarker samples in 
conjunction with a wealth of clinical data for further study. Blood sampling will be based on the 
child’s weight and when enrollment occurs with relationship to the day of high moderate-severe 
PARDS, ensuring that blood removal is maintained under the cap of 3 mL/kg. At maximum, 
blood samples will be obtained on high moderate-severe PARDS Day 0, 1, 2, 3, 5, 7, 10, 14, 21 
and 28, processed locally, then shipped to Children’s Hospital of Philadelphia (CHOP) for bio-
banking. The collection of blood samples will be an optional component of this study as 
parents/legal guardians can choose to participate during informed consent.  ETA samples will 
be obtained using discarded endotracheal secretions on high moderate-severe PARDS Day 0, 
3, and 28 or End of Study (whichever occurs first), again processed locally, then shipped to 
Children’s Hospital of Philadelphia for bio-banking. For purposes of Biorepository sampling, 
EOS is defined as extubation. 
D.8 Follow-up Procedures 
We base these procedures on our experience with the RESTORE and RESTORE-cognition 
(R01 HD074757) studies. Prior to hospital discharge, all U.S. parents/legal guardians will be 
assisted in entering their full contact information plus two alternative contacts into a Qualtrics 
database that is separate from the PROSpect clinical database. Parents/legal guardians will 
provide contact information for young adults.  Following the consent process for young adults 
the information will be updated or confirmed.  Contact information for young adults who decline 

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participation will be destroyed.  All emails and telephone numbers will be verified by the CCC so 
that data entry errors can be identified and rectified prior to hospital discharge. Parents/legal 
guardians will also be given a refrigerator magnet to remind them to contact the CCC if their 
contact information changes.  
Before hospital discharge, the CCC will call or email parents/legal guardians/young adults and 
confirm their preferred method of communication for follow-up. Options include phone interview 
plus completion of instruments online or by mail. Contacting the family at this time will provide 
us another contact point with families. A trained Spanish-speaking interviewer will contact 
Spanish-only speaking families. If the parent/guardian/young adult are unable to be reached we 
will contact the participating site to see if any further contact occurred (e.g., readmission or clinic 
visit) and attempt to locate families using people-finding software (LexisNexisTM) and/or social 
media before considering the family lost to follow-up. 
At 1, 3, 6 and 12 months post-PICU discharge, we will contact parents/legal guardians/young 
adults based on their stated preference. If a participant is still hospitalized or re-hospitalized 
during the data collection period, all data collection may proceed or be held until the patient 
returns home per parent’s/participant’s discretion. If held, we will resume data collection per 
schedule based upon the PICU discharge date. If re-hospitalized, parents/legal guardian/young 
adult will be asked to obtain or give permission to allow the PENN team to obtain a copy of the 
child/young adult’s discharge summary, so the readmission can be generally described.  
We will reassess functional status using the PCPC, POPC75 and FSS76 and assess HRQL using 
the chronological age-appropriate Pediatric Quality of Life Inventory (PedsQL™; Version 4.0 
Generic Core Scales for subjects 2-21 years; Infant Scales for subjects <2 years; 
http://www.pedsql.org) with associated modules.77,78 The surveys will take 7 to 20 minutes to 
complete, depending on the age of the subject. In addition to the parents/legal guardians/adult 
participant, children 8-20 years who are cognitively capable (PICU discharge PCPC ≤3) will be 
asked to self-report their HRQL. We will also ask parents and young adults who live outside 
their parent’s home to complete a brief survey about their ongoing resource use and healthcare 
needs. Parent/legal guardian of young adults will provide a parent-report if the participant 
resides in the same household.   
At the end of follow-up period, will compensate each family $50 for their participation. We are 
interviewing families over time to better understand the trajectory of their recovery. We will not 
follow our international subjects because of potential language barriers, time-zone differences, 
inability to systematically locate subjects lost to follow-up and the questionable validity of our 
instruments in all countries enrolling in PROSpect.  
We will implement tools for maximizing patient cohort retention for longitudinal long-term 
outcomes research studies.82-84 Establishing a rapport with families enhances successful follow-
up as well as 1) collection of extensive and verified family contact information, 2) telephone 
contacts at regular intervals not greater than Q3 months (considered to be positive encounters 
by families), 3) regular contact with families by mail and email (if desired by family), 4) managing 
follow-up in one location (CCC), 5) flexibility in accommodating family schedules. We will also 
assist families in obtaining referrals for medical and psychiatric services if requested. We will 
develop a public study website and a study Facebook page to enhance study enthusiasm. The 
website will include study information, a private portal for subjects to update their contact 
information, provide contact preferences, schedule telephone interviews and links to internet 
resources for parents. 

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E. STATISTICAL CONSIDERATIONS 
The overall objective of this study is to identify the best positional and/or ventilation practice that 
leads to improved patient outcomes in critically ill children with high moderate-severe PARDS. 
The study design is a two-by-two factorial, response-adaptive, randomized controlled clinical 
trial of supine positioning vs. prone positioning and conventional mechanical ventilation vs. high-
frequency oscillatory ventilation. The primary outcome for this study is ventilator-free days 
(VFD) through day 28. The Biostatistics and Data Coordinating Center in the Department of 
Cardiology at Boston Children’s Hospital, led by DCC PI Wypij, will function as the independent 
PROSpect Data Coordinating Center (DCC). The DCC PI and Biostatistician will be responsible 
for all statistical analyses, including the analysis of post-discharge outcomes, and will 
collaborate with Berry Consultants for the response-adaptive randomization. 
E.1 Study Design 
The design evaluates four arms in a two-by-two factorial structure, crossing supine positioning 
vs. prone positioning and conventional mechanical ventilation (CMV) vs. high-frequency 
oscillatory ventilation (HFOV). Eligible children will be randomly assigned to one of the four 
possible treatment options. Thus this study will address two major research questions with one 
clinical trial. The sample size selected (up to 800 patients in total; see section E.6) provides high 
power to detect a clinically meaningful two-day difference in our primary outcome (VFD) 
between groups to address both of our research questions. In addition, pediatric practice 
commonly uses supine and prone positioning with both ventilation strategies, and though we are 
not anticipating significant interaction effects between positioning and ventilation strategies, this 
study will allow an evaluation of potential synergistic or antagonistic effects. 
The design utilizes response-adaptive randomization, which will improve trial efficiency. Data 
generated during the course of the trial will be used to modify randomization allocation, thereby 
randomly assigning more patients to a more efficacious arm(s). 
E.2 Analysis Data Sets 
Data sets for DSMB reports, randomization update analyses and final data analyses consist 
only of data for which all queries have been resolved. In addition to the data management steps 
described in section F to reduce error in data acquisition and entry, a biostatistical cleaning will 
focus on inconsistencies, missing data and outliers in variables related to the derivation of key 
outcomes. These activities will be ongoing throughout the study and will involve the DCC Data 
Managers and Biostatistician. Preplanned construction of new variables will be conducted in 
accordance with the study hypotheses and analysis plans. Variable transformations may be 
required for interpretive and statistical purposes. 
Intention-to-Treat Analysis Data Set: The intention-to-treat data set consists of all randomized 
subjects. Subjects will be classified according to the treatment randomized regardless of actual 
treatment received. The ITT data set will be used for analysis of the primary outcome, including 
DSMB reports, randomization update analyses and final data analyses (see sections E.3 and 
E.5). Missing data during the hospital stay is expected to be minimal, as patients have severe 
respiratory disease, and we expect minimal parental withdrawal during patient hospital stays. If 
the primary outcome is not known, the worst possible outcome (i.e., zero ventilator-free days) 
will be assigned. 
Per-Protocol Analysis Data Set: The per-protocol data set consists of all randomized subjects, 
except subjects who never received the intervention, subjects withdrawn from the protocol 
during the first 24 hours post-randomization by a clinician or parent/legal guardian and subjects 
whose parent/legal guardian withdrew full consent for the protocol and data collection. The per-

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protocol dataset will be used for analysis of all primary, secondary and exploratory outcomes, 
including DSMB reports and final data analyses.  
E.3 Randomization and Randomization Update Analyses 
After verifying the patient's eligibility status with the potential subject’s attending physician, the 
parent or legal guardian will be introduced to the site co-investigator or their designee by a 
member of the clinical team. The site co-investigator or their designee will provide information 
about the study and alternatives to participating in the study. Based on our previous studies, we 
have found that these introductions respect the primacy of the bedside team and acknowledge 
local support for the clinical trial.85,86 
After informed consent is obtained and the subject has been stabilized from a hemodynamic 
perspective, patients will be randomized to one of four groups: supine/CMV, prone/CMV, 
supine/HFOV or prone/HFOV. The DCC will manage the randomization process centrally, as 
centralized randomization is necessary for the adaptive randomization.  
For the first 300 randomized subjects (intention-to-treat population), allocation will be 1:1:1:1 
among the four treatment arms, stratifying by age (<1; 1-7; 8-17; 18-20 years) and by 
direct/indirect lung injury (8 strata in total). Stratification by age and type of lung injury will allow 
us to balance potentially important subgroups among the four intervention groups (see also 
section D.1). Randomization will occur in permuted blocks with random block sizes of 4 and 8.  
Randomization Update Analyses: Randomization update analyses will first occur after 300 
patients are randomized and have been followed for 28 days, and every 100 patients thereafter. 
At these randomization update analyses, new allocation probabilities are computed based on 
ongoing intention-to-treat trial results, increasing allocation to well performing arms and 
decreasing allocation to poorly performing arms. 
Each of the four strategies has a probability of death 𝜋𝜋𝑗𝑗. The four 𝜋𝜋𝑗𝑗’s are assigned independent 
Beta(0.5, 0.5) priors, which is the standard Jeffreys prior. Using Supine/CMV as the base 
strategy, we define 𝜃𝜃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃, 𝜃𝜃𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 and 𝜃𝜃𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 as the effects of the positioning and ventilation 
strategies on duration of mechanical ventilation among those who do not experience death 
within 28 days, comparing these three strategies to Supine/CMV. For these Supine/CMV 
patients, we model the duration of mechanical ventilation as follows as Gamma(𝛼𝛼, 𝛽𝛽) with any 
values larger than 28 truncated to 28. The distribution of duration of mechanical ventilation for 
these patients for the other three strategies is defined similarly; we assume they all use the 
same shape parameter 𝛼𝛼 but different rate parameters as follows:  
 
• 
Supine/CMV: rate parameter 𝛽𝛽 
• 
Prone/CMV: rate parameter 𝛽𝛽× 𝜃𝜃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 
• 
Supine/HFOV: rate parameter 𝛽𝛽× 𝜃𝜃𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 
• 
Prone/HFOV: rate parameter 𝛽𝛽× 𝜃𝜃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃× 𝜃𝜃𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻× 𝜃𝜃𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼. 
We place gamma priors on 𝜃𝜃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃, 𝜃𝜃𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 and 𝜃𝜃𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼, each with prior mean 1. The gamma 
shape parameters are 3 for 𝜃𝜃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 and 𝜃𝜃𝐻𝐻𝐻𝐻𝐻𝐻𝐻𝐻 and 10 for 𝜃𝜃𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼. Since the prior distribution 
for 𝜃𝜃𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 is more tightly concentrated around 1, the model encourages additivity unless it is 
clearly contradicted in the data. Here, α has a prior density proportional to α-1.5 on [1,100] and β 
has an exponential prior distribution with mean 1/15. 
After fitting this model we obtain posterior distributions for all the parameters, which induces a 
joint distribution over the median duration of mechanical ventilation for each strategy. Define: 
MX/Y = Pr(strategyX/Y has the lowest median duration of mechanical ventilation). 

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We construct new allocation probabilities beginning with defining: 
𝑟𝑟X/Y = ඥ𝑀𝑀X/Y𝑆𝑆𝑆𝑆(𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀X/Y)
𝑁𝑁X/Y
. 
These 𝑟𝑟X/Y values are normalized to sum to 1. If, after renormalization, any value is under 5%, 
those values will be truncated to 0 and the remaining 𝑟𝑟X/Y values renormalized. This process 
results in the new allocation probabilities pSupine/CMV, pProne/CMV, pSupine/HFOV and pProne/HFOV that will 
be used until the next randomization update analysis. For example, if pSupine/CMV=0, pProne/CMV=0, 
pSupine/HFOV=0.4 and pProne/HFOV=0.6, this would indicate that the CMV arms have been temporarily 
eliminated from consideration for poor performance (allocation is 0), and that all subjects until 
the next randomization update analysis would be allocated with a probability of 40% for 
Supine/HFOV and 60% for Prone/HFOV. Balance among the age and lung injury strata will be 
maintained in the response-adaptive randomization phase by the method in Saville and Berry.87 
This formula is driven by the probability that each strategy has the lowest median duration of 
mechanical ventilation. The square root results in moving the probability closer to equal 
randomization to limit the aggressiveness of the response-adaptive randomization, and the 
standard error component acts to avoid strong imbalances in the data. This response-adaptive 
randomization is hence quite conservative compared to others in the literature, maintaining 
closer to equal randomization unless the data strongly prefer one positioning strategy or one 
ventilation strategy. 
E.4 Consideration of Early Stopping of the Trial 
The DSMB may elect to stop the trial if there are concerns regarding safety, low patient accrual, 
protocol performance/compliance and data quality. Early stopping rules for futility and efficacy 
are described below. 
Stopping Early for Futility: Early stopping for futility will be considered at the time of 
randomization update analyses, after 300 patients are randomized and have been followed for 
28 days, and every 100 patients thereafter. At these times, in an intention-to-treat analysis of 
the primary outcome variable, we will calculate four Bayesian predictive probabilities at the 
maximum sample size, namely that prone is declared superior to supine, that supine is declared 
superior to prone, that HFOV is declared superior to CMV and that CMV is declared superior to 
HFOV. If at any of these times, all four of these predictive probabilities are <10%, then we would 
stop the trial for futility. Effectively, even with the maximum number of subjects, there would be 
little possibility that any arm is identified as better than any other arm. 
Stopping Early for Efficacy: Early stopping for efficacy will be considered at the time of 
randomization update analyses, after 300 patients are randomized and have been followed for 
28 days, and every 100 patients thereafter. At these times, in an intention-to-treat analysis of 
the primary outcome variable, we will calculate these same four Bayesian predictive 
probabilities but at the current sample size. If at any of these times, any of these predictive 
probabilities are >95%, then we would consider stopping some or all of the arms for efficacy. If 
the Bayesian predictive probability that prone is declared superior to supine (or else the reverse) 
is >95%, then we would declare prone (or else supine) as the better positioning strategy and 
stop randomizing prone vs. supine. However, it would still be important to evaluate comparisons 
between HFOV and CMV. If the other Bayesian predictive probabilities (that HFOV is declared 
superior to CMV, or else the reverse) are both <50% and do not increase by more than 10% 
from the current sample size to the maximum sample size, we would stop study accrual for 
efficacy of prone (or else supine) positioning but for futility of HFOV vs. CMV strategies, follow 
all previously randomized subjects for their outcomes and then stop. Otherwise, we would 
continue to randomize patients to HFOV vs. CMV using the better positioning strategy. An 

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analogous plan would be implemented if the Bayesian predictive probability that HFOV is 
declared superior to CMV (or else the reverse) is >95%. 
E.5 Statistical Analyses 
Analysis of the Primary Outcome: The primary outcome for this study is ventilator-free days 
(VFD) through day 28, which is the inverse equivalent of the 28-day hospital mortality-adjusted 
duration of mechanical ventilation. In practice, we will model this inverse equivalent (e.g., 28 – 
VFD). There are two primary outcome analyses, one for positioning strategy and one for 
ventilation strategy. For positioning strategy, analysis of the primary outcome will be performed 
on an intention-to-treat basis using a stratified Wilcoxon rank-sum test, adjusting for ventilation 
strategy. Similarly, for ventilation strategy, analysis of the primary outcome will be performed on 
an intention-to-treat basis using a stratified Wilcoxon rank-sum test, adjusting for positioning 
strategy. Differences between positioning or ventilation strategies will be considered statistically 
significant if a one-sided p-value is <0.020. This threshold was obtained by simulation to control 
Type I error at the 0.025 level, given the response-adaptive randomization design. 
We will also evaluate possible interaction effects between the positioning and ventilation 
strategies, which will allow us to probe for potential differential effects when these two strategies 
are used concurrently. Although we may have low power to detect possible effect modification 
between positioning and ventilation strategies, we will explore for them using the statistical 
model in section E.3. If a significant interaction is found, a separate analysis will be conducted 
comparing all four combination strategies separately. 
Analysis of the primary outcome will also be performed on a per-protocol basis. In addition, we 
will explore adjustment for age group (<1; 1-7; 8-17; 18-20 years) and lung injury type (direct; 
indirect) using proportional hazards regression models. We will also explore adjusting for history 
of hematopoietic stem cell transplant (HSCT) due to potential differences in mortality in this 
group. We will also make graphical comparisons using boxplots and Kaplan-Meier survival 
curves. 
Analysis of the Secondary Outcome: Similar to the analysis of the primary outcome, analysis 
of the secondary outcome, nonpulmonary organ failure-free days, will also use stratified 
Wilcoxon rank-sum tests. Differences between positioning or ventilation strategies will be 
considered statistically significant if the two-sided p-value is <0.025. This analysis will be 
performed on a per-protocol basis. In addition, we will explore adjustment for age group, lung 
injury type, and history of HSCT using proportional hazards regression models. 
Analysis of the Exploratory Outcomes: Analyses of exploratory outcomes will use logistic 
regression for binary outcomes (90-day in-hospital mortality), proportional hazards regression 
for time to event outcomes (durations of mechanical ventilation, PICU stay and hospital stay 
among survivors) and linear regression for continuous outcomes. For non-normal continuous 
outcomes, data transformations or nonparametric methods will be considered, as appropriate. 
These analyses will be performed on a per-protocol basis and will control for age group and 
lung injury type. Differences between positioning or ventilation strategies will be considered 
statistically significant if the two-sided p-value is <0.025. Careful assessment of the results from 
exploratory analyses will be made, though no formal multiple comparisons procedures are 
planned. 
We will use appropriate methods for longitudinal outcomes, including random effects models or 
generalized estimating equations, to model repeated measures outcomes from the follow-up 
study, including PCPC, POPC, FSS and PedsQL scores. 

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Descriptive statistics will be calculated, including means, standard deviations, medians, 
interquartile ranges and ranges for continuous variables and frequency counts and percentages 
for categorical variables. Data will be examined for skewness, outliers and systematic missing 
data. Throughout, residual analyses and model fit assessments will be performed to assess the 
appropriateness of modeling assumptions and check for outlying or overly influential 
observations. 
Data analyses will be performed using SAS® (Version 9.4, SAS Institute, Inc., Cary, NC), R 
(Version 3.5.1, R Foundation for Statistical Computing, Vienna, Austria) or similar statistical 
packages. 
Additional Analyses: PARDS is a complex disease having many causes and, among PARDS 
patients, responses to any intervention may be heterogeneous. The net benefit for an individual 
patient likely depends on the amount of potentially recruitable lung. Thus, we will perform a 
post-hoc analysis of responders, defined as patients who exhibit an increase in PaO2/FiO2 ratio 
of at least 20 or a decrease in oxygenation index [OI = (FiO2 × mean airway pressure × 
100)/PaO2] of at least 10% within 24 hours of starting an intervention. In addition, we will 
tabulate the number of subjects who switch to the reciprocal therapy (i.e., treatment failures), 
We will also examine for time trends on outcome measures or treatment group effects (due to 
seasonal variation or learning effects) for primary and secondary outcome measures. If 
necessary, we will adjust for time in regression models. We do not expect effects of sex/gender 
or racial/ethnic group on outcome variables or treatment group differences, but we will carefully 
examine for them. We will perform stratified analyses in subgroups and assess statistical 
interactions in the total sample. As necessary, we will present sex- and/or race-specific results. 
We will assess whether adjustment for site through the use of mixed effects or generalized 
estimating equations models or for region (e.g., North America, Europe, Australia, southeast 
Asia) through the use of fixed effects affects study inferences. We will also assess whether 
varying levels of protocol compliance result in varying levels of intervention effects using 
regression methods.  
E.6 Sample Size Justification 
We base our sample size calculations on patient data from the RESTORE trial. Of 2,449 
RESTORE patients, 712 patients had severe PARDS with bilateral disease by the fourth day of 
intubation, were not intubated for asthma/reactive airways disease or bronchopulmonary 
dysplasia and were not supported on extracorporeal membrane oxygenation. The mean VFD for 
these 712 patients was 16.0 days with 14.2% patients assigned zero VFD (died or still intubated 
by day 28). We powered for a clinically meaningful 2-day improvement in VFD15 by either 
intervention alone (i.e., the other intervention had no effect; Scenario 1) or a 4-day improvement 
(e.g., 2-day improvement for each intervention when both interventions showed a 2-day 
improvement; Scenario 2). 
We performed simulations based on these data, assuming that, for the least effective arm(s) in 
each simulation scenario, 10% of patients die, a further 4.2% of patients survive but accumulate 
zero VFD, and mean VFDs are 16 days including patients with zero VFD. We considered two 
main scenarios for sample size justification: in Scenario 1, there is a 2-day improvement in VFD 
by one intervention alone (e.g., prone) while the other intervention has no effect (e.g., HFOV). In 
Scenario 2, there is a 2-day improvement in VFD by each intervention, so the most efficacious 
treatment is 4 VFDs better than the least efficacious treatment. 
Based on the full design including response-adaptive randomization and early stopping for a 
maximum total sample size of 800 patients, simulation results (based on 20,000 simulations) 
estimate that we would have 81.8% power for Scenario 1 and 86.1% power for each 

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intervention for Scenario 2. In addition, response-adaptive randomization allocates more study 
patients to the superior intervention (or interventions). For example, for Scenario 1, 
approximately 64% of patients would be assigned to the more efficacious treatment 
(approximately 378 out of 587 on average). 
E.7 Dissemination Plan and Data Archiving 
The results of this clinical trial will be critically important to disseminate to critical care clinicians, 
both pediatric and adult. The PROSpect Publications and Presentations Committee will develop 
a strategic plan for the comprehensive dissemination of the study findings. Together, the 
Principal Investigators will work expeditiously to submit the primary paper within 6 months of the 
last subject providing primary outcome data. Major secondary papers will also be completed 
within the following 2 years. Abstracts, papers for presentation and podcasts will be targeted for 
the annual meetings of American Thoracic Society (ATS), Critical Care Medicine (CCM) and the 
American Association of Critical Care Nurses (AACN) and the biennial meeting of the World 
Federation of Pediatric Intensive and Critical Care Societies (WFPICCS). Members of the 
PROSpect Integration Committee will provide the Pediatric Acute Lung Injury and Sepsis 
Investigator (PALISI) network, the Australian and New Zealand Intensive Care Society 
(ANZICS), the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) and the 
Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) updates on the clinical 
trial yearly to maintain disciplinary interest in the study. It is anticipated that the results of this 
study will impact the professional training of numerous disciplines and will inform clinicians on 
the long-term outcomes of high moderate-severe PARDS survivors. In addition to several 
primary publications targeted for simultaneous presentation and publication in high impact 
journals, we anticipate numerous secondary publications as well.  
Per NHLBI policy, we will provide a deidentified dataset and all the data-related documentation 
necessary to utilize the study data (dictionary, calculated variables and standard operating 
procedures) to the NHLBI no later than 3 years after the final follow-up interview or 2 years after 
the primary paper has been published, whichever comes first. We will submit this dataset to the 
NHLBI Data Repository managed by the BioLINCC (Biologic Specimen and Data Repository 
Information Coordinating Center). In addition, analyses of the primary, secondary and pre-
specified exploratory outcomes will be reported on ClinicalTrials.gov. 
F. DATA MANAGEMENT AND QUALITY CONTROL 
The PROSpect DCC and will manage all data for the study, including post-discharge data. 
F.1 Development of Electronic Case Report Forms (eCRFs) and Manual of Operations 
(eMOO) 
The PROSpect DCC will collaborate with the CCC in electronic case report form (eCRF) and 
manual of operations (eMOO) development to ensure the highest possible data quality. Forms 
design features include the selection of valid, reliable measurements that are least burdensome, 
pre-testing of forms, formatting of forms to ensure clarity (standard conventions for coding 
close-ended questions, minimal use of open-ended questions) and smooth flow in question 
patterns to reduce missing data. The detailed eMOO will ensure efficient and accurate data 
collection and ease of communication and its web-based format will allow updating as needed. 
Members of the Executive Committee will sign off on eCRFs and the eMOO before 
implementation. 

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F.2 Data Management System 
The DCC will develop a web-based data management system (DMS) for PROSpect using the 
REDCap (version 8/10/18 or higher, Vanderbilt University, Nashville, TN) and InFormTM 
electronic data capture system (Version 5.5 or higher, Oracle Health Sciences, Redwood 
Shores, CA) with access via a secure website at www.prospect-network.org. According to 
programmed workflow logic, the DMS will generate eCRFs as needed for each patient (e.g., 
daily forms, study discharge form). The DMS will accommodate use of both US and non-US 
measurement units (e.g., glucose values could be entered in mg/dL or mmol/L). The DMS 
allows for the data to be viewed in real-time by the DCC staff and certified data entry personnel 
at the clinical sites. Many logic and range checks and cross-form validations will be 
programmed to ensure data quality. Automated queries will be generated as data are entered 
and the DCC Data Managers and Biostatistician will also generate queries as they review data. 
The system supports source data verification and maintains a complete audit trail of 
transactions to ensure data integrity and regulatory compliance. Furthermore, the DMS provides 
staff with a variety of reports to assist project management and study data may be readily 
exported for use in Microsoft Excel®, SAS® or other software. 
The DCC will be supported by the Boston Children’s Hospital Clinical Research Information 
Technology team, who have supported more than 25 clinical trials that used InFormTM and who 
will help the DCC with database releases, upgrades and troubleshooting. 
F.3 Data Coordination 
The InFormTM DMS includes standard reports about enrollment and queries and custom reports 
can be easily programmed. The DCC will provide weekly reports to the PIs about enrollment, 
consent rates and adverse events. The DCC will also provide monthly reports to site co-
investigators regarding data entry accuracy and timeliness and query resolution. The DCC will 
have two full-time Data Managers available to assist site personnel on all DMS-related issues 
during the data collection phase. 
F.4 Data Entry, Editing and Audit Trails 
All clinical data will be entered into the InFormTM DMS by certified clinical site personnel to 
ensure accurate record keeping. The DMS data capture screens closely resemble the 
appearance of a paper CRF. The DMS allows data entry personnel to easily view which eCRFs 
are complete, incomplete with missing required fields highlighted or incomplete with open 
queries. Context-specific help and logic and range checks reduce the number of errors and 
assist the data entry process. As data are being entered, the DMS generates queries about out-
of-range or illogical values. The query may give the range of valid responses or reference 
responses to other related questions that make the current entry invalid. In addition, the Data 
Managers or Biostatistician may issue queries as they review data. In response to a query, the 
system user may confirm an out-of-range value, correct a data entry error or temporarily bypass 
the error and continue with data entry. The DMS contains a complete audit trail of all original 
values and all edits. 
F.5 Data Confidentiality, Security and Back-up 
To ensure data safety and reliability, server back-up procedures will be executed daily to back 
up all electronic study-related materials, which include the database, Word® documents, 
statistical programs and files. Access to the DMS requires user authentication. Authorized users 
include the DCC staff and certified data entry personnel at each site. Identifiable patient data, 
such as contact information and medical record numbers, will not be tracked in the DMS. A 
Patient Study ID paper log containing the Patient Study ID Number, patient initials and the last 3 

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digits of the Medical Record Number (MRN) will be stored separately and securely at the clinical 
sites and will not be shared with the DCC. 
F.6 Firewalls 
All DCC application software and data are hosted securely on the BCH network. The BCH 
network is protected by several firewalls and security is monitored and audited regularly by the 
BCH Information Services Department (ISD). All application and database software will enforce 
access rules through user authentication and authorization schemes established by the DCC 
and ISD. The DCC will ensure that no data are compromised or shared inappropriately by 
maintaining strict security procedures between personnel, data and all other study investigators. 
For example, Drs. Curley, Cheifetz and Kneyber and their research staffs will have limited 
access to status reports within the database and they will be unable to view or change any of 
the study participant data, except at their own study sites (for Drs. Cheifetz and Kneyber). 
F.7 Study Monitoring 
Remote Site Monitoring: The DCC will coordinate the remote site monitoring process, and the 
CCC advanced practice pediatric critical care nurse will serve as the study monitor. If an 
international site’s medical record system is in a foreign language, a bilingual registered nurse 
not affiliated with the study will be recruited to serve as an unbiased assistant to the study 
monitor. Remote site monitoring sessions will commence after a site enrolls their third subject 
and will occur at least yearly or more frequently if performance thresholds are of concern to 
either the Executive Committee or DSMB. Specific triggers for additional site monitoring may 
include variation in site performance metrics, variation in reporting of PROSpect-specified 
events or the occurrence of an unanticipated problem. In addition, international sites will 
demonstrate competence in the International Conference on Harmonisation’s Guideline for 
Good Clinical Practice (ICH-GCP) standards by remote site monitoring. 
Prior to a remote site monitoring session, study sites will complete a Site Self-Assessment 
Checklist, which includes verifying the accuracy, completeness and security of regulatory 
documents, study logs and informed consent documents. Next, the study monitor will conduct 
the remote monitoring process using a data-encrypted web conferencing system to review 
patient-specific data. The monitor will compare the source documentation to a printout of 
patient-specific data downloaded from the InForm database by the DCC. Via remote monitoring, 
the primary outcome will be 100% source verified on all subjects. A random selection of data 
elements on a subset of subjects will also be also source verified, including inclusion/exclusion 
criteria, secondary and exploratory outcomes and adverse events. An attempt will be made to 
schedule remote site monitoring sessions for when a PROSpect subject is on study so that the 
study monitor can audit, in real-time, positional and ventilation practices/protocol adherence. 
A report is generated after completion of the remote monitoring review. Members of the Steering 
Committee will review these reports. The site co-investigators are responsible for correcting 
deficiencies, if any, to the satisfaction of the Steering Committee.  
Support for Study Safety Monitoring: Subjects will be monitored daily for the occurrence of 
events defined as any undesirable experience or unanticipated benefit. A description of all 
adverse events will be recorded in the study database. The relationship of the PROSpect 
protocol to the event will be classified as not, remotely, possibly, probably or highly probably 
related by the bedside team. The severity of an adverse event will be classified as mild, 
moderate or severe by the bedside team.  
Within 8 hours of an event, site co-investigators will enter all serious, protocol-related (probably 
or highly probably related) adverse events and/or unanticipated problems that are fatal/life-

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threatening into the study database. The DCC will run a SAE/UP report twice daily and 
immediately notify the MPI on-call of all newly reported events. The CCC and DCC will work 
with the site co-investigator to prepare a detailed description of the SAE/UP, an explanation of 
the basis for determining that the event represents a SAE/UP, and a description of any 
corrective actions that are proposed in response to the SAE/UP. Within 48 hours of the event, 
the DCC will send a full narrative report of the event to the DSMB Chair, NHLBI Executive 
Secretaries, and NHLBI Clinical Trials Specialist. The DSMB Chair will confirm receipt and e-
mail the DCC and NHLBI with recommendations, if any. The CCC Administrative Project 
Manager will report the event to the University of Pennsylvania IRB within 3 days and to each 
international clinical center for submission to their local ethics committee. Recommended 
protocol modifications will be implemented immediately. 
Within 12 hours of an event, site co-investigators will enter all serious, protocol-related (probably 
or highly probably related) adverse events and/or unanticipated problems that are non-fatal/life-
threatening into the study database. The DCC will run a SAE/UP report twice daily and 
immediately notify the MPI on-call of all newly reported events. The CCC and DCC will work 
with the site co-investigator to prepare a detailed description of the SAE/UP, an explanation of 
the basis for determining that the event represents a SAE/UP, and a description of any 
corrective actions that are proposed in response to the SAE/UP. Within 96 hours of the event, 
the DCC will send a full narrative report of the SAE/UP to the DSMB Chair, NHLBI Executive 
Secretaries, and NHLBI Clinical Trials Specialist. The DSMB Chair will confirm receipt and e-
mail the DCC and NHLBI with recommendations, if any. The CCC Administrative Project 
Manager will report the SAE/UP to the University of Pennsylvania IRB within 10 days and to 
each international clinical center for submission to their local ethics committee. Recommended 
protocol modifications will be implemented as specified. 
Non-protocol-related SAE/UP and all other safety events will be tabulated and reported at each 
DSMB meeting. 
F.8 Data Management for the Follow-up Procedures 
For the follow-up procedures, the DCC will assist the CCC in developing two web-based 
databases that are separate from the InForm clinical database. These databases will be housed 
at the University of Pennsylvania-based CCC. The first database, built in Qualtrics, will be used 
to collect contact information for subjects and their families. Once contact information data 
collection and entry has started, the DCC will no longer have access to this database. The 
second database, built in REDCap, will be used to collect follow-up data on functional status 
and health-related quality of life. The DCC will continue to be able to access this database and 
will monitor and analyze these follow-up data. 
The DCC will closely monitor follow-up rates. The Data Manager will generate monthly reports 
to track the number of contact attempts and follow-up interviews and will create data-driven 
benchmarks to identify monthly follow-up goals and progress towards reaching these goals. 
Also on a monthly basis, the DCC will clean the follow-up data and issue queries to the CCC. 
Upon the completion of follow-up data collection, the DCC Biostatistician will export necessary 
follow-up data to address specific needs of the proposed analyses. These data will be merged 
with the main study data as needed to perform any additional analyses. 
F.9 Strategies to Optimize Enrollment and Protocol Adherence 
We will implement the following activities to optimize enrollment and protocol adherence: 
1. Understanding local practices and structure: Site co-investigators will complete an 
Organizational Assessment yearly to identify all research team members and PROSpect 
Champions and delineate their roles and responsibilities, levels of expertise, communication 

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expectations and readiness for training. Sections include information on the hospital, unit, 
medical staff, nursing staff, respiratory therapy staff, unit-based practices, routine 
competency testing and quality metrics.  
2. Training tool-box: The CCC will take the lead in developing a tool-box of training materials 
that will include discipline-specific voice-over slide sets, positioning and ventilation videos, 
self-learning packets, post-tests, pocket cards and bedside research binders. All study tools 
will contain the PROSpect Logo but accommodate local individualization to facilitate unit-
based adoption. 
3. Train-the-trainer methodology and certification: All site co-investigators will be required to 
undergo a competency-based training program and certification process. The site co-
investigators will then train all clinicians (physicians, nurses, respiratory therapists [if 
utilized]) involved in the clinical management of intubated, mechanically ventilated patients. 
In addition to the core physician-nurse-RT team, each PICU will identify additional 
multidisciplinary “Champions” to serve as unit-based resources on PROSpect protocols. 
This Champion team will allow clinical staff access to a PROSpect expert 24/7 and will also 
accommodate the monthly training schedules of new staff/orientees. Prior to caring for a 
study patient, clinical staff must complete a self-learning packet by passing a scenario-
based post-test. Any subject cared for by a non-certified clinician will be considered a 
protocol deviation. If this occurs, an improvement plan will be required prior to enrolling a 
subsequent subject.  
4. Project management training: Training will be coordinated with the DCC who will be 
responsible for certifying all research assistants in study-related activities that include 
screening and data management. The Principal Investigators will train site co-investigators 
in best-practices in obtaining informed consent.85,88 
5. Web-based electronic manual of operations (eMOO): The CCC and DCC will develop and 
maintain an eMOO that will include all study materials: study protocols, Standard Operating 
Procedures (SOP) for screening, consenting, enrolling subjects, electronic Case Report 
Forms (eCRFs), form completion guidelines, training materials, Q&A bank, quality control 
(QC) tools and reports.  
6. Virtual start-up/Go-live meetings: Prior to enrolling subjects, all sites will participate in a 
virtual call with the CCC-DCC teams to verify the completion of all regulatory, training and 
study coverage requirements. 
7. Monthly Steering Committee (SC) calls: These monthly calls will be held to review clinical 
and administrative issues and study metrics. 
8. Audit and feedback (study metrics): 
• 
We will prospectively monitor treatment fidelity by embedding an auditing function into 
eCRFs and implementing daily PROSpect walk rounds. During the PROSpect walk 
rounds the site co-investigator or PROSpect Champion will provide bedside clinicians 
with real-time protocol support and log the extent to which PROSpect protocols are 
implemented as designed (if not implemented, capturing the rationale: e.g., training 
issue, concerns about patient safety). These data will be summarized monthly and these 
reports will constitute a standing agenda item on our SC calls. We will pair high and low 
adherent sites to allow cross-PICU learning. We will also implement random remote site 
monitoring when subjects are on study to audit, in real time, protocol adherence. 
• 
Our weekly enrollment reports (site and total) will include: (1) screening and enrollment; 
(2) enrollment rate; (3) summary of reasons eligible patients were not enrolled (ENE); (4) 
parent/legal guardian consent rate; (5) language involved in failure to consent issues; (6) 
hours the parent/legal guardian were unavailable (physically or emotionally) to consent; 
(7) enrollment graph plotting number of subjects enrolled over our 4-year enrollment 
period. 

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• 
Our weekly safety reports will include (1) pre-specified events; (2) tracer events (e.g., 
documented episodes of FiO2 1.0); (3) unanticipated events; and (4) protocol deviations. 
• 
Monthly data quality reports will include timely data entry, accurate data entry (per form 
completion guidelines), open queries, time to resolution of open queries and usable 
subjects. 
• 
We will conduct dashboard calls with each enrolling PICU after 3 subjects are enrolled 
and once/year thereafter. The calls will review all site metrics identifying strengths and 
opportunities for improvement.  
Protection of Human Subjects  
This is an NIH-Defined Phase III Clinical Trial. 
1. Risks to Human Subjects  
a. Human Subjects Involvement and Characteristics, and Design  
PROSpect (PRone and OScillation PEdiatric Clinical Trial) is a two-by-two factorial, response-
adaptive, randomized controlled clinical trial of supine positioning/prone positioning and 
conventional mechanical ventilation (CMV)/high-frequency oscillatory ventilation (HFOV) in 
children with high moderate-severe Pediatric Acute Respiratory Distress Syndrome (PARDS). 
Our primary outcome is ventilator-free days (VFD), where non-survivors receive zero VFD. We 
hypothesize that children with high moderate-severe PARDS treated with either prone 
positioning or HFOV will demonstrate ≥2 more VFD. Improvement in VFD will be considered 
within the context of patient safety; specifically, patients must also exhibit a similar safety profile. 
Our secondary outcome is nonpulmonary organ failure-free days. We will also explore the 
interaction effects of prone positioning with HFOV on VFD and also investigate the impact of 
these interventions on 90-day in-hospital mortality and, among survivors, the duration of 
mechanical ventilation, PICU and hospital length of stay and post-PICU functional status and 
health-related quality of life (HRQL). 
Approximately 60 pediatric intensive care units (PICUs), about 2/3 U.S. and 1/3 international, 
with at least 5 years of experience with prone positioning and HFOV in the care of pediatric 
patients with high moderate-severe PARDS, that can provide back-up extracorporeal membrane 
oxygenation (ECMO) support will participate.7 Approximately 60 PICUs will enroll up to 800 
pediatric patients (≥2 weeks of age and ≥42 weeks post gestational age and <21 years of age) 
intubated and mechanically ventilated with high moderate-severe PARDS for <48 hours per 
Pediatric Acute Lung Injury Consensus Conference Group (PALICC) guidelines, that is, chest 
imaging consistent with acute pulmonary parenchymal disease and oxygenation index (OI) ≥12 
or oxygenation saturation index (OSI) ≥10. We will require two blood gases meeting high 
moderate-severe PARDS criteria (separated by at least 4 hours during which time the clinical 
team is working to recruit lung volume and optimize the patient’s hemodynamic status per 
PALICC guidelines). A second blood gas is not required for OI ≥16. Exclusion criteria focus on 
patients in whom the length of mechanical ventilation is unlikely to be altered by positional or 
ventilation management and in those for whom prone positioning or HFOV is contraindicated. 
The clinical sites are all PICUs who normally manage patients with PARDS within this age 
group and are specifically trained in the clinical, including ventilatory, management of critically ill 
children, 2 weeks to 20 years of age, who are typically cared for in Pediatric ICUs.  
Eligible patients with high moderate-severe PARDS will be randomized within 48 hours of 
meeting eligibility criteria and within 4 days of endotracheal intubation to one of four groups: 
supine/CMV, prone/CMV, supine/HFOV or prone/HFOV. Subjects who fail their assigned 
 
 

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positional and/or ventilation therapy for either persistent hypoxemia or hypercapnia may receive 
the reciprocal therapy while being considered for ECMO cannulation. Randomization will be 
stratified by age group (<1; 1-8; 8-17; 18-20 years) and direct/indirect lung injury. Adaptive 
randomization will first occur after 300 patients are randomized and have been followed for 28 
days, and every 100 patients thereafter. At these randomization update analyses, new 
allocation probabilities will be computed based on ongoing intention-to-treat trial results, 
increasing allocation to well performing arms and decreasing allocation to poorly performing 
arms. PROSpect may close enrollment early for efficacy or futility based on pre-specified 
stopping rules. Data will be analyzed per intention-to-treat for the primary analyses and per-
protocol received for primary, secondary and exploratory analyses. 
Enrolled subjects will be followed from endotracheal intubation (or, for ventilator dependent 
patients supported on invasive mechanical ventilation with baseline OSI ≤6, the time the patient 
exhibits a second qualifying OSI of ≥10) until hospital discharge or hospital Day 90, whichever 
occurs first. Approximately two weeks post-PICU discharge, the Clinical Coordinating Center 
(CCC) will call or email the family/participant and confirm their preferred method of 
communication for their follow-up contacts. Options include phone interview plus completion of 
instruments online or by paper mail. At 1, 3, 6 and 12 months after PICU discharge, we will 
contact the family/participant to complete the follow-up interview, scheduled at their 
convenience, to assess the subject’s functional status and HRQL. All U.S. parents/legal 
guardians/adult participants will be invited to participate as well as cognitively capable (Pediatric 
Cerebral Performance Category ≤3) subjects 8-20 years of age. All interviews will be 
coordinated and conducted by trained personnel from the CCC at the University of 
Pennsylvania.  
b. Sources of Materials  
Sources of research material will include: (1) subject's medical record, (2) arterial blood samples 
for blood gas analysis, (3) blood samples for bio-banking, (4) family contact information and (5) 
follow-up interviews with parents/legal guardians and with cognitively capable children ≥8 years 
of age to assess functional status and HRQL.  
Site co-investigators (or their designee) will be trained by the Data Coordinating Center (DCC) 
to collect data using electronic study case report forms (eCRF). A web-based electronic Manual 
of Operations (eMOO) describing Standard Operating Procedures (SOP) for data collection will 
be prepared to ensure consistent decision-making across centers. 
Each site will maintain an enrollment log that will link each patient to a unique study number. All 
data collection forms will contain this unique study number. Enrollment logs will be maintained 
by the site in a locked filing cabinet in a locked office accessible to study staff only. All data 
received at the DCC in Boston will be de-identified. All family contact data received at the CCC 
in Philadelphia for subject follow-up will be entered into a Qualtrics database that is separate 
from the DCC database. Only Dr. Curley and her CCC team will have access to individually 
identifiable private information about human subjects.  
The follow-up data will only be collected with parental/legal guardian consent and, if applicable, 
subject assent and consent from subjects turning 18 after PICU hospitalization. All subject data 
will be maintained with strict privacy measures. Online surveys and surveys completed over the 
telephone will be entered directly into a REDCap database. Paper surveys will be returned via a 
dedicated secure fax machine or by certified U.S. Mail. All data will be secured for the purpose 
of confidentiality, and these data will only be used for research purposes.  
c. Potential Risks  

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Potential risks associated with prone positioning include unplanned extubation, vascular 
line/invasive tube removal, plugging/obstruction of the endotracheal tube with secretions and/or 
blood, main-stem bronchus intubation, transient hemodynamic instability cardiac dysrhythmias, 
clinically significant agitation (SBS +1/+2 for 2 consecutive hours), facial and eyelid edema, 
pressure injury (any dependent surface) or corneal abrasions. 
Potential risks associated with the ventilation protocols include hemodynamic instability related 
to increased mean airway pressure, air leak (e.g., pneumothorax, pneumomediastinum), cardiac 
dysrhythmias related to increased mean airway pressure, mucous plugging/airway obstruction, 
clinically significant agitation (SBS +1/+2 for 2 consecutive hours), and pressure injuries 
(occipital/auricular). 
In all groups, potential subject risk also includes blood loss associated with the blood draws. 
There are no expected risks associated with the follow-up study aside from the time burden and 
potential psychological stress imposed on the subjects and their families by the questionnaires 
and the structured telephone interviews. We anticipate that each interview will be completed in 
approximately 20 minutes. The other important risks associated are related to potential loss or 
release of confidential information. Each consenting parent/legal guardian will provide 
identifying and contact information, allow review of his/her child’s hospital records and provide 
information about his/her child’s health status, functional status and health-related quality of life. 
These risks, and the steps enacted to protect against these risks, will be specified in the 
parental/legal guardian consent forms, all of which will be HIPAA-compliant.  
2. Adequacy of Protection Against Risks  
a. Recruitment and Informed Consent 
Site co-investigators or their designee will screen their PICUs for potential subjects each day 
using the patient screening logs without identifying data. After verification that a patient meets 
eligibility criteria, the patient’s gender and ethnic background recorded in the medical record will 
be entered into the electronic screening form. This Health Insurance Portability and 
Accountability Act (HIPAA)-compliant database will also provide the registry of potentially 
eligible patients to determine whether a representative number of minorities and females have 
been enrolled in the study. Patients who meet study criteria but who do not consent to 
participate will be noted. Patient eligibility for enrollment will be determined after a complete 
review of the patient's demographic and clinical information. We will maintain a log of all non-
enrolled patients (without identifying information) with rationale for non-enrollment (exclusion 
criteria, physician denial, etc.). 
After verifying the patient's eligibility status with the patient’s attending physician, the parent or 
legal guardian will be introduced to the site co-investigator or their designee by a member of the 
clinical team. The site co-investigator will provide information about the study and alternatives to 
participating in the study. Parents and legal guardians will be given ample opportunity to 
carefully consider study participation and read the informed consent document. 
Given the criticality of the potential subject’s condition, the investigator will work closely with the 
clinical care team to approach the parents or legal guardian(s) at a time that would not 
significantly overburden them. All consents will be obtained in writing. If a parent/legal guardian 
refuses consent, their management will be provided at the discretion of the bedside team. All 
subjects will be intubated, mechanically ventilated and sedated so will be unable to provide 
assent while acutely ill. Permission for participation of adult patients, ages 18-20, will be 
obtained in the same manner via parental/LAR permission.  Prior to hospital discharge, children 
≥8 years of age who are cognitive capable will be asked to provide assent for follow-up using 
age-appropriate assent/consent forms (8-12 years; 13-17 years; 18+ after hospital discharge). 

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Adult participants will be consented as soon as they are medically and cognitively available 
(e.g., without sedative medication for > 72 hours and not intubated/ventilated).  If this is not 
possible during hospitalization the consent process will be conducted remotely by the CCC 
team and electronic signatures will be obtained via DocuSign.  If children do not assent or a 
young adult declines further participation in the study, they will not participate in follow-up. 
Subjects and their parents have a right to discontinue their participation in the study at any time 
and for any reason. 
The decision to withdraw a subject from the study may be made for a variety of reasons 
including the request of the care team, patient or family, events related to or not related to the 
study or continued deterioration of the subject’s clinical condition. The site co-investigator will 
record the primary reason for withdrawal. Every attempt will be made to continue data collection 
through Day 90 providing that the family/patient concurs with continued data collection.  
All sites will undergo rigorous training in the administration of informed consent prior to 
enrollment. Site co-investigators and their designees will complete competency assessments in 
study procedures, randomization and human subject protections. International sites will 
demonstrate competence in ICH-GCP standards by remote site monitoring.  
b. Protections Against Risk 
Risks associated with prone positioning will be minimized by strict adherence to the research 
protocol that is based on our previous prone positioning study. Risks associated with ventilation 
management will be minimized by strict adherence to the research protocol which is based on 
the PALICC guidelines.  
We require that each enrolling site have at least 5 years of experience with both prone 
positioning and HFOV and have back-up extracorporeal membrane oxygenation (ECMO) 
support.8 Including only experienced centers augments patient safety. Requiring PICUs to have 
ECMO backup optimizes patient safety since all enrolled subjects will have high moderate-
severe PARDS and would not easily tolerate an inter-hospital transport for ECMO if study 
interventions failed.9  
Adaptive randomization will first occur after 300 patients are randomized and have been 
followed for 28 days, and every 100 patients thereafter. At these randomization update 
analyses, new allocation probabilities will be computed based on ongoing intention-to-treat trial 
results, increasing allocation to well performing arms and decreasing allocation to poorly 
performing arms. With response-adaptive randomization we expect to allocate more study 
patients to the superior intervention or interventions. 
The total blood loss from all clinical and research-related activities will be monitored and kept 
below age/size dependent thresholds. All blood specimens will be obtained through existing 
vascular catheters or from wasted blood specimens. Endotracheal tube aspirates will be 
obtained from discarded samples.    
Coding all subject data with a unique identification number will minimize risk to loss of subject 
confidentiality. Each site’s enrollment log, linking Study ID Number to patient identity, will remain 
with the site co-investigators in a locked file in a locked office, accessible to study staff only. The 
eCRFs will contain limited personal identifying information (i.e. date and time of intubation). 
Web-based data collection will be protected by stringent authentication and authorization 
procedures. Users must have valid login credentials (authentication), database access 
privileges and specific permissions within the database (authorization). Authentication and 
 
 
 

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authorization can only be granted and revoked by authorized system administrators within the 
DCC. All components within the system are tested on a regular basis by Boston Children’s 
Hospital Information Services Department. Transaction logs are backed up daily and full back 
ups are performed weekly on all databases.  
The CCC employs procedures to protect against the risk of unwanted loss or release of 
confidential follow-up information. Subject-specific data and completed mailed and telephone 
questionnaire data will be made available only to Dr. Curley and the CCC research staff. The 
only dataset with subject identifier information will be the subject tracking system used to follow-
up and contact families. All other datasets will label subject records with a unique study number; 
specifically, clinical data will not reside with identifying data. Questionnaire data will be kept in 
locked files and/or password-protected data files.  
We will prospectively monitor all specified events and the Principal Investigators will review their 
occurrence rates to determine whether there are any trends. Clinical aspects of care related to 
the prevention of iatrogenic injury, when identified, will immediately inform the care provided to 
patients enrolled into the study. 
At the end of the telephone interview, parents/legal guardians/adult participants will be 
specifically asked if they would like to have further conversations with their child’s or their 
primary intensive care physician. If they would, then they will be provided with the phone 
number of the ICU physician’s office, and CCC staff will also notify the site co-investigator 
directly that a subject or subject’s family member desires additional contact. Risks associated 
with the study will be monitored by the Executive Committee, Steering Committee and Data and 
Safety Monitoring Board. Any publication arising from this study will maintain the anonymity of 
study participants.  
3. Potential Benefits of the Proposed Research to Human Subjects and Others  
Potential benefits to the critically ill subjects with high moderate-severe PARDS include an 
improvement in ventilator-free days and/or nonpulmonary organ failure-free days. We anticipate 
no direct benefits to most subjects and their families who participate in the follow-up study, 
although some may benefit from the contact provided during telephone interviews. Ventilator 
dependent children are included for enrollment because they also develop PARDS, and 
represent an important at-risk patient population. Enrolling this cohort would improve the 
generalizability of PROSpect study results to a wider, more inclusive population. 
Society in general and future critically ill children and their families will benefit, however, from 
the study’s results, which will provide a better understanding of how positional and ventilation 
strategies can best be administered to critically ill children with high moderate-severe PARDS. 
Potential benefits may outweigh potential risks. 
4. Importance of the Knowledge to be Gained  
Critical illness among children is a significant health problem because of a generally long life 
expectancy, any impairment in a child can have consequences that last for decades. These 
consequences are extremely important for the individual. However, the consequences may also 
impact society at large in terms of cost to provide prolonged medical services and lost work 
productivity. 
This study will help provide a definite answer to the role of prone positioning and HFOV for 
children with high moderate-severe PARDS. First, this would be the first large-scale, multi-
center, multi-national randomized controlled trial of interventions designed to improve clinical 
outcomes for high moderate-severe PARDS. The global nature of this investigation will improve 
international implementation of the outcomes. Second, the protocol is physiology-based in terms 

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of the use of prone positioning as well as the management of HFOV. Testing these interventions 
will establish a standard of care that will influence the care of the vast majority of pediatric 
patients supported on mechanical ventilation, future studies evaluating new or different 
combinations of sedative agents and clinican education. 
5. Data and Safety Monitoring Plan  
The CCC and DCC will work with the NHLBI to appoint an independent data and safety 
monitoring board (DSMB). The DSMB will be responsible for monitoring subject safety, 
implementation of the study protocol and reviewing the quality of study data. The DSMB will 
review, make recommendations and approve the final protocol and informed consent 
documents prior to implementation. The DSMB will review the progress of the trial, including 
assessments of participant risk versus benefit, data quality and timeliness, participant 
recruitment, accrual and retention, site performance and other factors that can affect study 
outcome. The DSMB chair will receive reports of all serious adverse events throughout the 
conduct of the study. If the DSMB recommends a study change for patient safety or ethical 
reasons, the Principal Investigators will be responsible for implementing the recommendations 
as expeditiously as possible, according to standard NIH policies.  
The DSMB may recommend that the trial be stopped if: 
• 
The intervention is associated with an increased dependency on mechanical ventilation, 
increased mortality or increased adverse events. 
• 
Compliance to the study protocol and/or recruitment is well below acceptable goals and 
the ability of the study to achieve its goals is seriously compromised. 
• 
Evidence external to the study renders it unethical to continue the study. 
All specified adverse events will be prospectively monitored and recorded on study eCRFs. All 
specified events will be reviewed monthly for trends by the Operations Committee then the 
Executive Committee. Clinical aspects of care related to the prevention of iatrogenic injury, 
when identified, will inform the care provided all patients via the Steering Committee. The 
reporting of each event will include a description of the event, required interventions, patient’s 
condition after the event, an estimate of the extent of injury and prevention strategies. The 
relationship of the study protocol to the event will be classified by the bedside clinicians as 
follows:  
• 
Not related: The event is clearly related to factors such as the subject’s clinical state, not 
with therapeutic interventions associated with the study protocol. 
• 
Remote: The event was most likely related to factors such as the subject’s clinical state, 
not with therapeutic interventions associated with the study protocol.  
• 
Possible: The event follows a reasonable temporal sequence from the implementation of 
study treatments and/or is consistent with known events related to the study treatments 
but is possibly related to factors such as the subject’s clinical state. 
• 
Probable: The event follows a reasonable temporal sequence from the implementation 
of study treatments and/or is consistent with known events related to the study 
treatments and cannot be reasonably explained by factors such as the subject’s clinical 
state. 
• 
Highly Probable: The event follows a reasonable temporal sequence from the 
implementation of study treatments and/or is consistent with known events related to the 
study treatments and cannot be reasonably explained by factors such as the subject’s 

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clinical state. In addition, the event occurs immediately following the titration of study 
treatments, or improves on changing study treatments, or reappears on repeat initiation 
of study treatments. 
The severity of an adverse event is defined as a qualitative assessment of the degree of 
intensity of an adverse event as determined by the bedside clinicians as follows:  
• 
Mild: Does not impact (in any way) the patient’s course of illness. 
• 
Moderate: Impacts the subject’s course of illness but is not life-threatening or 
incapacitating. 
• 
Severe: Fatal, life threatening, permanently disabling; severely incapacitating; 
requires/prolongs inpatient hospitalization.  
 
 
 

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48. Casado-Flores J, Martinez de Azagra A, Ruiz-Lopez MJ, Ruiz M, Serrano A. Pediatric 
ARDS: effect of supine-prone postural changes on oxygenation. Intensive Care Med 
2002;28:1792-6. 
49. Relvas MS, Silver PC, Sagy M. Prone positioning of pediatric patients with ARDS results in 
improvement in oxygenation if maintained > 12 h daily. Chest 2003;124:269-74. 
50. Fineman LD, LaBrecque MA, Shih MC, Curley MA. Prone positioning can be safely 
performed in critically ill infants and children. Pediatr Crit Care Med 2006;7:413-22. 
51. Tamburro RF, Kneyber MC, Pediatric Acute Lung Injury Consensus Conference Group. 
Pulmonary specific ancillary treatment for pediatric acute respiratory distress syndrome: 
proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care 
Med 2015;16:S61-72. 
52. Santschi M, Jouvet P, Leclerc F, et al. Acute lung injury in children: therapeutic practice and 
feasibility of international clinical trials. Pediatr Crit Care Med 2010;11:681-9. 
53. Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez J, Berens RJ, Anglin DL. Prospective, 
randomized comparison of high-frequency oscillatory ventilation and conventional 
mechanical ventilation in pediatric respiratory failure. Crit Care Med 1994;22:1530-9. 
54. Sud S, Sud M, Friedrich JO, et al. High frequency oscillation in patients with acute lung 
injury and acute respiratory distress syndrome (ARDS): systematic review and meta-
analysis. BMJ 2010;340:c2327. 
55. Malhotra A, Drazen JM. High-frequency oscillatory ventilation on shaky ground. N Engl J 
Med 2013;368:863-5. 
56. Curley MA, Wypij D, Watson RS, et al. Protocolized sedation vs usual care in pediatric 
patients mechanically ventilated for acute respiratory failure: a randomized clinical trial. 
JAMA 2015;313:379-89. 
57. Bateman ST, Borasino S, Asaro LA, et al. Early high-frequency oscillatory ventilation in 
pediatric acute respiratory failure. A propensity score analysis. Am J Respir Crit Care Med 
2016;193:495-503. 
58. Lai-Fook SJ, Rodarte JR. Pleural pressure distribution and its relationship to lung volume 
and interstitial pressure. J Appl Physiol (1985) 1991;70:967-78. 
59. Cornejo RA, Diaz JC, Tobar EA, et al. Effects of prone positioning on lung protection in 
patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2013;188:440-
8. 
60. Gattinoni L, Carlesso E, Taccone P, Polli F, Guerin C, Mancebo J. Prone positioning 
improves survival in severe ARDS: a pathophysiologic review and individual patient meta-
analysis. Minerva Anestesiol 2010;76:448-54. 

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61. Parvathaneni K, Belani S, Leung D, Newth CJ, Khemani RG. Evaluating the performance of 
the Pediatric Acute Lung Injury Consensus Conference definition of acute respiratory 
distress syndrome. Pediatr Crit Care Med 2017;18:17-25. 
62. Kneyber MC, Markhorst DG. Do we really know how to use high-frequency oscillatory 
ventilation in critically ill children? Am J Respir Crit Care Med 2016;193:1067-8. 
63. Pelosi P, D'Onofrio D, Chiumello D, et al. Pulmonary and extrapulmonary acute respiratory 
distress syndrome are different. Eur Respir J Suppl 2003;42:48s-56s. 
64. Agus MS, Wypij D, Hirshberg EL, et al. Tight glycemic control in critically ill children. N Engl 
J Med 2017;376:729-41. 
65. Valentine SL, Nadkarni VM, Curley MA, Pediatric Acute Lung Injury Consensus Conference 
Group. Nonpulmonary treatments for pediatric acute respiratory distress syndrome: 
proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care 
Med 2015;16:S73-85. 
66. Valentine SL, Sapru A, Higgerson RA, et al. Fluid balance in critically ill children with acute 
lung injury. Crit Care Med 2012;40:2883-9. 
67. Mehta NM, Skillman HE, Irving SY, et al. Guidelines for the provision and assessment of 
nutrition support therapy in the pediatric critically ill patient: Society of Critical Care Medicine 
and American Society for Parenteral and Enteral Nutrition. JPEN J Parenter Enteral Nutr 
2017;41:706-42. 
68. Baharestani MM, Ratliff CR. Pressure ulcers in neonates and children: an NPUAP white 
paper. Adv Skin Wound Care 2007;20:208, 10, 12, 14, 16, 18-20. 
69. Faustino EV, Gedeit R, Schwarz AJ, et al. Accuracy of an extubation readiness test in 
predicting successful extubation in children with acute respiratory failure from lower 
respiratory tract disease. Crit Care Med 2017;45:94-102. 
70. Schoenfeld DA, Bernard GR, ARDS Network. Statistical evaluation of ventilator-free days as 
an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. 
Crit Care Med 2002;30:1772-7. 
71. Yehya N, Thomas NJ. Relevant outcomes in pediatric acute respiratory distress syndrome 
studies. Front Pediatr 2016;4:51. 
72. Leclerc F, Duhamel A, Deken V, et al. Nonrespiratory pediatric logistic organ dysfunction-2 
score is a good predictor of mortality in children with acute respiratory failure. Pediatr Crit 
Care Med 2014;15:590-3. 
73. Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a 
contributing factor? Am J Respir Crit Care Med 1998;157:1721-5. 
74. Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma. Proc 
Assoc Am Physicians 1998;110:482-8. 
75. Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr 1992;121:68-74. 
76. Pollack MM, Holubkov R, Glass P, et al. Functional Status Scale: new pediatric outcome 
measure. Pediatrics 2009;124:e18-28. 
77. Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 
2001;39:800-12. 
78. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of 
life inventory. Med Care 1999;37:126-39. 
79. Pollack MM, Holubkov R, Funai T, et al. Relationship between the functional status scale 
and the pediatric overall performance category and pediatric cerebral performance category 
scales. JAMA Pediatr 2014;168:671-6. 
80. Pollack MM, Dean JM, Butler J, et al. The ideal time interval for critical care severity-of-
illness assessment. Pediatr Crit Care Med 2013;14:448-53. 
81. Pollack MM, Holubkov R, Funai T, et al. The Pediatric Risk of Mortality Score: Update 2015. 
Pediatr Crit Care Med 2016;17:2-9. 

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82. Abshire M, Dinglas VD, Cajita MI, Eakin MN, Needham DM, Himmelfarb CD. Participant 
retention practices in longitudinal clinical research studies with high retention rates. BMC 
Med Res Methodol 2017;17:30. 
83. Robinson KA, Dinglas VD, Sukrithan V, et al. Updated systematic review identifies 
substantial number of retention strategies: using more strategies retains more study 
participants. J Clin Epidemiol 2015;68:1481-7. 
84. Turnbull AE, O'Connor CL, Lau B, Halpern SD, Needham DM. Allowing physicians to 
choose the value of compensation for participation in a web-based survey: randomized 
controlled trial. J Med Internet Res 2015;17:e189. 
85. Lebet R, Fineman LD, Faustino EV, Curley MA. Asking for parents' permission to enroll their 
child into a clinical trial: best practices. Am J Crit Care 2013;22:351-6. 
86. Menon K, Ward RE, Gaboury I, et al. Factors affecting consent in pediatric critical care 
research. Intensive Care Med 2012;38:153-9. 
87. Saville BR, Berry SM. Balanced covariates with response adaptive randomization. Pharm 
Stat 2017;16:210-7. 
88. Natale JE, Lebet R, Joseph JG, et al. Racial and ethnic disparities in parental refusal of 
consent in a large, multisite pediatric critical care clinical trial. J Pediatr 2017;184:204-8 e1. 
 
 
 
 
 
 
 

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Clinical Protocols – V.12/14/20 
I. Ventilator Management Guidelines  
A.  Monitoring  
1. All subjects require an arterial line and pulse oximeter (SpO2) monitoring. Subjects 
supported on CMV also require ETCO2 monitoring. Noninvasive data are recorded at 
least Q6H.  
 
2. PICUs may continue using near-infrared spectroscopy (NIRS), transcutaneous gas 
monitoring, and volumetric capnography (CMV groups) if considered usual care.    
B. Oxygenation and Ventilation Goals (all groups) 
1. During the acute phase (OI ≥ 8; OSI ≥ 7.5), the goal is adequate oxygenation and 
ventilation:   
a. Oxygenation: SpO2: 88-92%10 
b. Ventilation: pH ≥ 7.15 and ≤ 7.30 (irrespective of PaCO2)11,12 
 
2. As the patient’s clinical condition improves (titration phase; OI < 8; OSI < 7.5), 
oxygenation and ventilation parameters are normalized, i.e., SpO2 ≤ 97% and pH ≤ 7.45.  
   
3. Arterial blood gases and chest radiographs (CXR) are obtained per the discretion of the 
clinical team. If lung overinflation is present on CXR (i.e., diaphragms flat and/or 
depressed below the 10th posterior rib) consider decreasing mean airway pressure by 2 
cm H2O. 
 
4. Neuromuscular blockade (NMB) is administered continuously for the first 24H post 
enrollment.13  After the first 24H, NMB is administered per the discretion of the clinical 
team.  
 
5. Ventilator disconnects: lung volume is re-established after all ventilator disconnects that 
result in a decrease in SpO2 based on the mode of mechanical ventilation as described 
below (i.e., PEEP or mPaw recruitment).   
 
 
 
10 When SpO2 is used to assess arterial oxygenation, the following measures will be taken to improve 
accuracy: SpO2 sensor will be checked to ensure optimal position, cleanliness, and consistent readings 
with satisfactory waveforms; no position changes or endobronchial suctioning for ≥ 10 minutes; no 
invasive procedures or ventilator changes for ≥ 30 minutes. SpO2 will be observed for a minimum of 1 
minute, and a representative value will be recorded on the appropriate source-document flowsheet. 
11 Use of cuffed/uncuffed artificial airways will be documented. 
12 Per PALICC guidelines, the routine use of NaHCO3 administration is not recommended.  
13 Medication and mode (continuous or intermittent) per care team’s discretion. 

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C. Strategy: Conventional Mechanical Ventilation (CMV) 
 
Goal:  Lung protective ventilation using ventilatory parameters and approaches consistent with 
those recommended by the Pediatric Acute Lung Injury Consensus Conference (PALICC).   
 
1. Initiating CMV  
a. Ventilator modes include synchronized intermittent mandatory ventilation [SIMV] 
or assist control [AC]); Pressure Control Ventilation (PCV) or Pressure Regulated 
Volume Control (PRVC or equivalent)   
b. Monitor exhaled Vt (Vte) and percent leak at the artificial airway (AA).14  
c. Suction the patient.  
d. Administer neuromuscular blockade (required for the first 24 hours).   
e. Positioning – ventilation sequence: Position the patient before initiating HFOV 
 
2. Initial settings CMV   
a. Tidal volume (Vt) or Peak Inspiratory Pressure (PIP):  
1) Set to obtain Vte15 5-7 ml/kg (ideal body weight [IBW]16) 
2) Goal PIP ≤ 28 cm H2O (may allow up to 32 cm H2O for patients with poor 
chest wall compliance) 
b. Inspiratory Time:  Set based on patient age17 and disease condition. 
1) Rate adjusted to maintain pH with the target range. Assess flow-time scalar 
to assess for appropriate inspiratory time.   
2) I:E ratio: maximum 1:118 
c. Rate:  Titrate based on age and respiratory condition to maintain pH within 
prescribed goals.   
d. Pressure Support (PS):   
1) Pressure support set to maintain spontaneous Vte 5-7 mL/kg IBW 
2) Minimal PS (calculated to overcome endotracheal tube [ETT] resistance): 10 
cm H2O for ETT 3-3.5 mm, 8 cm H2O for ETT 4-4.5 mm, and 6 cm H2O for 
ETT ≥ 5 mm 
e. Fraction of inspired oxygen (FiO2): As necessary19 to achieve SpO2 88-92% 
 
 
 
14 Use a proximal airway sensor or Philips NM3 monitor (or equivalent) at the ETT. 
15 Exhaled Vt is continuously monitored and documented every 6 hours.  
16 IBW (as predicted from height): See chart for <178 cm males and <164 females; If male height is >178 
cm than IBW (kg) = 50 + 2.3(height in inches - 60); If females height is >164 cm than IBW (kg) = 45.5 + 
2.3(height in inches - 60). [To convert inches to centimeters multiply inches times 2.54; to convert 
centimeters to inches multiply centimeters times 0.4.] 
17 0-1 year:  0.4-0.65 sec; 1-2 years:  0.5-0.7 sec; 2-8 years:  0.6-0.9 sec; >8 years: 0.7-1.2 sec  
18 Inverse ratio ventilation not accepted.  
19 Minimum FiO2 should not be set below baseline FiO2 requirements. 

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f. Positive End-expiratory Pressure (PEEP): PEEP recruitment maneuver (to 
determine optimal PEEP):   
 
Step 1: Record start PEEP (PEEPstart), then increase PEEP by 2 cm H2O 
every 5 minutes20 while observing SpO2 and dynamic compliance 
(Cdyn)21 
Step 2: Record PEEP at which SpO2 starts to increase (PEEPrecruitment) 
Step 3: PEEP should be increased until no further improvement in SpO2 or 
Cdyn is noted or systolic blood pressure decreases (PEEPhyperinflation).22  
If during recruitment, SpO2 > 97%, then reduce FiO2 and continue 
recruitment.   
Step 4: Once PEEPhyperinflation is noted, decrease PEEP by 2 cm H2O every 10 
minutes23 until SpO2 decreases by more than 2 percentage points 
(PEEPderecruitment)24.  At this point, stop decreasing PEEP.   
Step 5: Re-recruit: Increase PEEP to PEEPhyperinflation for 1-2 minutes (as 
clinically tolerated).  
Step 6: Set PEEP at 2 cm H2O above PEEPderecruitment. 
 
 
3. Ongoing CMV support   
 
a. Reassess the patient and fine-tune ventilator settings at least every 6 
hours: If measured Vt, SpO2, and/or pH are not within the target range, then 
ventilator adjustments are made and the patient is reassessed within 30 minutes. 
Changes in more than one ventilator setting may be performed simultaneously. 
 
b. Titrate Vte and PIP: Maintain Vte 5-7 ml/kg IBW.  Exhaled Vt as low as 3 ml/kg 
for severe PARDS (OI ≥ 16 or OSI ≥ 13) is allowed to maintain PIP ≤ 28 cm H2O 
(may allow up to 32 cm H2O for patients with poor chest wall compliance).   
 
c. Titrate Respiratory Rate: Goal is to achieve alveolar ventilation (based on pH 
goal) using Vt within goal range at the lowest respiratory rate.   
 
 
 
 
20 Q5 minute step increases in PEEP are recommended. Clinicians may deviate from this 
recommendation based on their clinical judgment of the subject’s evolving state. 
21 Peak pressures should also be titrated to maintain the delta-P necessary to deliver Vt in the 5-7 mL 
range. Though determined on a case-by-case basis, care should be taken to avoid excessively high peak 
pressures (e.g., > 35 cm H2O). 
22 SBP decreases of approximately 10% are clinically reasonable; note that inotropes or other vasoactive 
medications should not be titrated during these maneuvers as they may obscure patient response. 
23 Q10 minute step decreases in PEEP are recommended. Clinicians may deviate from this 
recommendation based on their clinical judgment of the subject’s evolving state. 
24 For children with chronic invasive mechanical ventilation, PEEP should NOT be reduced lower than 
baseline PEEP setting. 

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d. PEEP/FiO2 table 
If a patient's PEEP/FiO2 is not compatible with the PEEP/FiO2 table (e.g., 
immediately after enrollment or after urgent changes in FiO2 or PEEP in 
response to desaturation, hypotension, etc.), either PEEP or FiO2 (or both) are 
adjusted at 5-15 minute intervals until the PEEP/FiO2 is compatible with the grid.  
 
Titrate per PEEP-FiO2 grid – Performed every 12 hours  
FiO2 
.30 
.40 
.40 
.40 
.50 
.50 
.60 
PEEP 
5 
5 
8 
10 
10 
12 
12 
 
 
 
 
 
 
 
 
FiO2 
.60 
.70 
.70 
.80 
.80 
PEEP 
14 
14 
16 
16 
16*-18 
*PEEP of 16 cm H2O in subjects <1 year of age 
 
Decrease the FiO2 level to maintain SpO2 88-92% then assess if patient is on 
PEEP level that corresponds with that FiO2. If not, increase/decrease PEEP to 
keep patient on the grid (vertical pair).  
 
For subjects with chronic invasive ventilatory support, PEEP and FiO2 should 
NOT be weaned below their baseline settings. This may result in deviation from 
the grid to wean each setting individually back to their baseline settings. 
 
 
4. Escalation of Support   
 
a. Brief periods (≤10 min) of SpO2 < 85% or > 92%, may be tolerated without 
making changes in PEEP or FiO2.  FiO2 = 1.0 may be used for brief intervals (≤ 
10 min) of transient desaturation or to prevent desaturation during treatments, 
such as suctioning or position changes. 
 
b. OXYGENATION:  If SpO2 < 85% for more than 10 minutes, then: 
 
1. In the event of any abrupt clinical changes, assess for pneumothorax and 
obstructed/dislodged ETT.   
 
2. Increase FiO2 in increments of 0.2 until SpO2 85-92%.   
 
3. Once SpO2 stabilizes at 85-92% for 5 minutes irrespective of FiO2 or when 
FiO2 reaches 1.0 perform a PEEP titration maneuver as per the next step. 
 
 

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4. Recruit lung by performing a PEEP recruitment maneuver 
Step 1: Record start PEEP (PEEPstart), then increase PEEP by 2 cm H2O 
every 5 minutes10 while observing SpO2 and dynamic compliance 
(Cdyn)11 
Step 2: Record PEEP at which SpO2 starts to increase (PEEPrecruitment) 
Step 3: PEEP should be increased until no further improvement in SpO2 or 
Cdyn is noted or systolic blood pressure decreases (PEEPhyperinflation).  
If during recruitment, SpO2 > 97%, then reduce FiO2 and continue 
recruitment.   
Step 4: Once PEEPhyperinflation is noted, decrease PEEP by 2 cm H2O every 10 
minutes12 until SpO2 decreases by more than 2 percentage points 
(PEEPderecruitment)25.  At this point, stop decreasing PEEP.   
Step 5: Re-recruit: Increase PEEP to PEEPhyperinflation for 1-2 minutes (as 
clinically tolerated).  
Step 6: Set PEEP at 2 cm H2O above PEEPderecruitment. 
 
3.  If Vte < 5-7 mL/kg and PIP ≤ 28 cm H2O, increase Vte to 5-7 mL/kg. 
 
4.  If Vte within range and/or PIP > 28 cm H2O, assess for overdistension (e.g., 
increase in PaCO2 with a patent airway).  If present, perform PEEP titration as 
described above starting at Step 5 (use current PEEP as PEEPhyperinflation).   
 
c. VENTILATION: If primary respiratory acidemia (pH < 7.15) is present:  
Step 1:  Increase ventilator rate in increments of 2-4 bpm until pH > 7.15 unless 
 
evidence exists for air trapping based on airway graphics.  Do not exceed 
 
I:E 1:1. Ensure inspiratory time within range indicated in Table.   
Step 2:  If Vt < 8 mL/kg, then increase Vt incrementally to 8 mL/kg (while 
maintaining pressure limitation).   
 
5. Failed CMV  
Two-hour pattern of either:   
a. Persistent hypoxemia (SpO2<85%) with FiO2 1.0 and max PEEP per grid (16 cm 
H2O for < 1 year of age; 18 cm H2O for ≥ 1 year of age).   
b. Persistent hypoventilation (pH < 7.15) with PIP > 32 cm H2O and a respiratory 
rate that does not cause intrinsic PEEP (i.e., air trapping)26  
 
 
 
 
25 For children with chronic invasive mechanical ventilation, PEEP should NOT be reduced lower than 
baseline PEEP setting. 
26 Document total PEEP by performing an expiratory hold maneuver so that auto-PEEP can be 
calculated. 

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6. Weaning CMV – As the patient’s clinical condition improves and criteria for extubation 
readiness testing (ERT) are met, oxygenation and ventilation parameters are 
normalized, i.e., SpO2 ≤ 97% and pH ≤ 7.45 
a. Decrease ventilator settings as clinically indicated  
b. If SpO2 > 92% and Vte 4-7 mL/kg: Decrease set PEEP and/or FiO2 in tandem  
using the PEEP/FiO2 grid, while maintaining Vte = 4-7 mL/Kg and ≤ 28 cm H2O. 
c. If over ventilating such that pH ≥ 7.3027   
Step 1: If Vte = 4-7 mL/kg: Incrementally decrease ventilator rate by 2-4 bpm 
while maintaining spontaneous respiratory rate within physiologic 
range.28,29 
Step 2: If Vte = 4-7 mL/kg and good spontaneous effort: may consider Pressure 
Support Ventilation to maintain spontaneous Vte at 4-7 mL/kg. (Minimal 
PS per ETT size30).  
d. If at any time PIP above range, attempt to wean while maintaining Vte 4-7 mL/kg 
and pH > 7.30.   
 
Subjects on chronic invasive mechanical ventilation will not receive an ERT. End of 
ventilation will be identified as the first time that the patient maintains our prespecified 
OSI criteria to initiate extubation readiness testing (OSI ≤6) for 24 hours.  
 
 
27 Note that oxygenation and ventilation are not independent.  If at any time decreasing ventilator 
pressure results in decreased oxygenation, maintain the same PIP or Vt and decrease the rate 
incrementally to achieve increase in PaCO2.  
28 Spontaneous RR goal: <6 months 20-60; 6 mo-2 yrs 15-45; 2-5 yrs 15-40; >5 yrs 10-35.  
29 Increased RR can be from anxiety. May need to increase sedation or if anxiety appears to be from 
excessive work of breathing, then increase PS 2 cm H2O (if Vt <6 mL/kg) or increase the ventilator rate 
until RR is within range. If RR is below range and if the patient is over sedated, then decrease 
sedation/analgesia. 
30 Minimal PS (calculated to overcome the resistance of the ETT): 10 cm H2O if 3-3.5 mm ETT; 8 cm H2O 
if 4-4.5 mm ETT; and 6 cm H2O if ≥ 5 mm ETT. 

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D. Strategy: High Frequency Oscillatory Ventilation (HFOV)   
 
Goal:  The HFOV strategy is based on physiologic principles of gas delivery. To optimize the 
high-frequency approach, high rates (> 8 Hz) will be used knowing that increased amplitudes 
will be required for adequate ventilation. Given the known attenuation of pressure amplitude 
across the endotracheal tube and along the natural airways, pressure amplitude and tidal 
volume delivery will remain within typical parameters for HFOV at the alveolar level.   
 
1. Initiating HFOV  
a. Ventilator: 3100A if subject weight < 35 kg, 3100B if subject weight ≥ 35 kg31  
Alternate devices with similar gas exchange mechanisms (e.g., active exhalation) 
may be used once approved by the CCC.   
b. If part of usual care, correlate transcutaneous CO2 monitoring with an arterial 
blood gas.   
c. Suction the patient. 
d. Administer neuromuscular blockade (required for the first 24 hours).   
e. Consider a fluid bolus (5 mL/kg) if concerned about hemodynamic instability.  
f. Positioning – ventilation sequence: Position the patient before initiating HFOV 
 
2. Initial Settings HFOV 
a. FiO2: As necessary to achieve SpO2 88-92% 
b. Frequency at 8-12 Hz.  
c. Amplitude (delta-P) 60-9032   
 
 
 
31 While the 3100A is limited to patients < 35 kg, the 3100B can be used for patients < 35 kg. 
32 Increased amplitude is required to provide adequate tidal volume for ventilation given the high starting 
frequencies.   

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d. Mean Airway Pressure (mPaw) 
1) Set the initial mPaw 5-6 cm H2O above the current CMV monitored value. 
May use a smaller mPaw increase if air leak is present.   
2) Perform a mPaw recruitment maneuver: 
Step 1: Record start mPaw (mPawstart) 
Step 2: Increase mPaw by 2 cm H2O every 5 minutes33 and observe SpO234 
Step 3: Record mPaw at which SpO2 starts to increase (mPawrecruitment) 
Step 4: Continue to increase mPaw until SpO2 no longer increases or systolic 
blood pressure starts to decrease (record as mPawhyperinflation).35 If 
during recruitment SpO2 > 97%, then first reduce the FiO2 and 
continue recruitment.  
Step 5: Once mPawhyperinflation is determined, decrease mPaw by 2 cm H2O 
every 10 minutes36 and observe SpO237 
Step 6: Record the mPaw at which the SpO2 starts to decrease by more than 
2 percentage points (mPawderecruitment)38.  At this point, stop 
decreasing mPaw. 
Step 7: Increase mPaw to mPawhyperinflation for 1-2 minutes, then decrease 
mPaw to 2 cm H2O above mPawderecruitment39 
3) Maintain mPaw at this setting until FiO2 is weaned to ≤ 0.60 – wean FiO2 
when at goal SpO2 for > 2 hours40 
e. Inspiratory Time 
1) Initially set at 33% 
2) When amplitude is maximized and frequency is minimized (8 Hz), increase 
inspiratory time to 40% (and then 50%, if needed)    
f. Bias Flow 
1) Initial settings per patient age: 
< 1 year of age: 15-25 L/min  
1 -8 years of age: 15-30 L/min 
≥ 8 years of age: 25-40 L/min  
2) Consider increasing bias flow if frequency is minimized at 8 Hz, mPaw is set 
at maximum, and/or patient has significant spontaneous respiratory effort.   
 
33 Q5 minute step increases in mPaw are recommended. Clinicians may deviate from this 
recommendation based on their clinical judgment of the subject’s evolving state. 
34 If during the recruitment maneuver SpO2 does not increase despite approximately 5 mPaw increments, 
the patient should be considered a non-responder.  If so, proceed to step 5 (anticipate that the optimal 
mPaw would be 2-4 cm H20 lower than the pressure at which the decision was made that the patient is a 
non-responder).   
35 Consider 5 mL/kg fluid bolus if transient and gentle pressure on the liver bed improves saturation. 
36 Q10 minute step decreases in mPaw are recommended. Clinicians may deviate from this 
recommendation based on their clinical judgment of the subject’s evolving state. 
37 For those who do not respond to a recruitment maneuver with an improvement in SpO2, the optimal 
mPaw should generally be set approximately 2-4 cm H2O lower than the pressure at which the decision 
was made that the patient is a non-responder.   
38 For children with chronic invasive mechanical ventilation, the lowest mPaw should not be below the 
baseline mPaw. 
39 mPaw optimal should not be set below the mPaw on conventional ventilation; The clinical team may – 
based on the clinical condition of the patient - decide to set the optimal mPaw higher than recommended 
in Step 7. 
40 If the patient desaturates within approximately 60 minutes of a MAP titration maneuver (i.e., consistent 
with lung decrecruitment), consider repeating a recruitment maneuver with a longer equilibration time per 
step on the deflation limb. 

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3. Ongoing HFOV support 
a. Reassess patient and fine-tune ventilator settings at least every 6 hours. If 
measured SpO2 and/or pH are not within the target range, then ventilator 
adjustments are made and the patient is reassessed within 30 minutes. Changes 
in more than one ventilator setting may be performed simultaneously.  
  
b. Titrating mPaw - If starting FiO2 is < 0.70 start with a decrease in mPaw 
(described below) if FiO2 ≥ 0.70 perform a recruitment maneuver (described on 
previous page) 
 
mPaw titration maneuver – Performed every 12 hours41  
Step 1: Record the start mPaw (mPawstart) 
Step 2: Decrease mPaw by 2 cm H2O every 10 minutes23 and observe SpO2 
Step 3: Record the mPaw at which the SpO2 starts to decrease by more than 2 
percentage points (this point is called mPawderecruitment)42.  At this point, 
stop decreasing mPaw. 
Step 4: Increase mPaw to either mPawstart or by 5-8 cm H2O (whichever is 
greater) for 2 minutes 
Step 5: Decrease mPaw to 2 cm H2O above mPawderecruitment 
Step 6: 1 hour after titration, obtain ABG and titrate Frequency/Power (see 
below)43 
 
Between mPaw maneuvers, FiO2 may be gradually weaned to a minimum of 0.40 
and/or mPaw may be decreased by 2 cm H2O to maintain SpO2 at goal. 
 
c. Titrating FiO2 
If SpO2 ≥ 92% and FiO2 > 0.60, reduce FiO2 by 0.10 until FiO2 0.40 
 
d. Titrating Frequency and Power  
Goal is highest frequency that achieves adequate alveolar ventilation.  
a) Titration is performed, at least, every 6 hours 
b) If the pH is too high (> 7.30) 
Step 1: Increase the frequency by 0.5-1 Hz (max 15 Hz) 
Step 2: If the frequency is 12-15 Hz, decrease the power by 10% 
 
e. If difficulty ventilating, consider deflating ETT cuff (while maintaining current 
mPaw) to augment expiratory gas flow. 
 
4. Escalation of Support  
 
a. Brief periods (≤10 min) of SpO2 < 85% or > 92% may be tolerated without making 
changes in mPaw or FiO2.  FiO2 = 1.0 may be used for brief intervals (≤ 10 min) 
 
41 If the patient was randomized to HFOV prone, perform the mPaw titration when the patient is in the 
prone position. 
42 For children with chronic invasive mechanical ventilation, the lowest mPaw should not be below the 
baseline mPaw. 
43 If the patient desaturates within approximately 60 minutes of a MAP titration maneuver (i.e., consistent 
with lung decrecruitment), consider repeating a recruitment maneuver with a longer equilibration time per 
step on the deflation limb. 

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of transient desaturation or to prevent desaturation during treatments, such as 
tracheobronchial suctioning or position changes. 
 
b. OXYGENATION: If SpO2 < 85% for more than 10 minutes 
1. Assess for occluded or dislodged ETT. 
2. Assess for overdistension (e.g., increase in PaCO2 with a patent airway). If 
present, perform mPaw titration maneuver as described above; e.g., start 
with a decrease in mPaw. 
3. Increase FiO2 in increments of 0.2 until SpO2 85-92%.   
4. Once SpO2 stabilizes at 85-92% for 5 minutes irrespective of FiO2 or when 
FiO2 reaches 1.0 perform a mPaw recruitment maneuver; e.g., start with an 
increase in mPaw.     
 
c. VENTILATION: If primary respiratory acidemia (pH < 7.15) is present:44 
 
Step 1. If the power is not at 10.0, increase the power by 10%.45 
Step 2. Decrease the frequency by 0.5-1 Hz (minimum frequency of 8 Hz). 
Step 3. If the frequency is 8 Hz, increase the bias flow per patient age then 
inspiratory time to 40-50%.   
 
5. Failed HFOV   
Two-hour pattern of either:  
a. Persistent hypoxemia (SpO2<85%) at FiO2 1.0 and mPaw > 35 cm H2O 
b. Persistent hypoventilation (pH <7.15) with max power/amplitude at a 
frequency < 8 Hz  
 
6. Conversion to conventional ventilation 
Conversion to conventional ventilation is mandated when mPaw 15-20 cm H2O and 
FiO2 < 0.50.  Extubation from HFOV will be considered a protocol deviation. When 
converting to CMV manage the patient per CMV protocol matching the initial PEEP 
to the FiO2 per PEEP-FiO2 grid.  Typically, there is a downward adjustment made to 
the mPaw of 2-4 cm H2O.     
  
 
 
 
44 The protocol allows for permissive hypercarbia if the pH is within range.  If the clinical team feels that 
increased CO2 elimination is needed, the following may be performed.  
1. If the power is not at 10.0, increase the power by 10%. (Additional power increases may be done 
as clinically indicated along with the following options.) 
2. Decrease the frequency by 0.5-1 Hz (minimum frequency of 8 Hz). 
3. If the frequency is 8 Hz, increase the bias flow per patient age, then consider increasing the 
inspiratory time to 40-50%.  
4. In conjunction with the above measures based on clinical judgement, the AA cuff may be deflated 
as long as the optimal mean airway pressure can be maintained.  One must keep in mind that the 
associated air leak around the AA to promote CO2 elimination may vary with changes in patient 
position.  Repeat mean airway pressure titration may be required with significant changes in AA 
air leak. 
45 May increase further per clinical discretion. 

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II. Suctioning and Re-recruitment (all groups) 
 
A. For safety, the patency of the AA is assessed Q12H by AA suctioning.46   
 
B. Routine suctioning is not recommended.   
 
C. Consider suctioning with unexplained, rapid increases in PaCO247 and/or decrease in chest 
movement or, for example, when there is an apparent “saw” pattern visible on the flow – 
time scalar when on CMV.48  
 
D. Care must be taken to maintain lung volumes during suctioning. Significant reductions in 
SpO2 <85% after suctioning are managed with re-establishing lung volume per mode of 
mechanical ventilation utilized (e.g., recruitment maneuver during HFOV).   
 
 
 
 
46 Perform prior to recruitment maneuver. 
47 Increase in ETCO2 (CMV) or TCO2M (HFOV). 
48 There are no data to support specific recommendations on tracheobronchial suctioning technique. No 
attempt will be made to standardize suctioning practices across study sites, although closed suctioning 
is recommended per PALICC guidelines.  Saline or no saline instillation can be used per study unit 
routine.  

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III. Daily Test for Patient Readiness for Extubation (all groups after 1st 24H) 
 
A. Every day at 07:00 ± 2H49-50 the patient is assessed for the following while in the supine 
position: 
• 
Spontaneous breathing 
• 
Oxygenation Index/Oxygen Saturation Index < 6 
• 
Decrease and/or plateau in ventilator support over the previous 12 hours 
If these criteria are present, then the patient is tested for readiness for extubation. 
 
B. Daily Test  
1. Hold enteral feedings  
2. If FiO2 is not set at 0.5, set FiO2 at 0.551  
3. If PEEP is not set at 5 cm H2O, set PEEP at 5 cm H2O 
4. Evaluate SpO2 after the above changes 
a. If SpO2 ≥ 95%, change mode to PSV with set PS min based on size of ETT  
1. 10 cm H2O if ETT 3-3.5 mm  
2. 8 cm H2O if ETT 4-4.5 mm 
3. 6 cm H2O if ETT ≥ 5 mm 
b. Monitor SpO2, exhaled Vt, and RR 
 
C. Ready for extubation 
1. The patient is potentially ready for extubation (from a pulmonary perspective) if all 3 of 
the following are present for ≥ 2 hours: 
a. SpO2 ≥ 95% with FiO2 ≤ 0.5 and PEEP ≤ 5 cm H2O 
b. Exhaled Vt ≥ 5 mL/kg 
c. Respiratory rate within respiratory rate goal of age:  
i. <6 months 20-60; 6 mo to 2 yrs 15-45; 2 to 5 yrs 15-40; >5 yrs 10-35 
2. If the patient does not meet the above criteria because of excessive sedation, the care 
team may elect to wean the patient’s sedation (per the sedation protocol) and retest the 
patient after the wean. If the patient does not meet the criteria at 16:00 ± 2H, they are 
returned to their pre-test ventilator settings and re-tested the following morning.  
3. If they meet the above criteria, then the medical team is notified that the patient is ready 
(from a pulmonary perspective) for unassisted breathing.   
4. Extubation is expected to be performed within 6 hours of passing the ERT; however, it 
may be delayed for the following non-pulmonary reasons:52 
• 
Neurological unresponsiveness and inability to protect one’s airway 
• 
Inaudible leak around an uncuffed/deflated cuff ETT53  
• 
Scheduled test/procedure that requires deep sedation/anesthesia  
 
D. Extubation Guidelines 
1. May extubate to FiO2 higher than on ventilator, then wean FiO2 every two hours to room 
air to maintain SpO2 >92%. 
 
49 If a patient procedure, test, or other extenuating circumstance prevents assessment for these criteria 
between 07:00 ± 2H then the test can be delayed up to 4 hours.  
50 For prone positioned patients, the one hour post-supine ABG is used for OI calculation.  
51 Stop feeding per institutional standard 
52 Should extubation be delayed, the reason for the delay will be recorded on data sheet. 
53 In this case, the care team by elect to prescribe dexamethasone for 24-48 hours. 

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2. If patient develops respiratory distress after extubation and if stridor is present may 
consider dexamethasone IV. ± racemic epinephrine treatment Q15 minutes x 2 (1-2 
years 0.25 mL or >2 years 0.5 mL). 
3. If stridor is not present, may consider noninvasive ventilation or high-flow nasal cannula  
if patient is alert, cooperative and able to protect their airway.   
4. Should reintubation be required within 24H, cause and date/time is recorded on data 
sheet. 
 
E. Patient management if reintubation is required:    
• 
For patients extubated to, but not liberated from, noninvasive ventilation (BiPAP, CPAP 
≥5 cm H2O, or HFNC ≥5 L/min), patients should be managed per their allocated 
intervention.  
• 
For patients extubated to pressure support <5 cm H2O and reintubated within 24 hours 
of extubation, patients should be managed per their allocated intervention.   
• 
For patients extubated to pressure support <5 cm H2O and reintubated more than 24 
hours after extubation, patients are preferably but not required to be managed per their 
allocated intervention. 
 

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IV. Positional Therapy Protocol 
A. Both Groups 
 
1. Positioning – ventilation sequence: Enrolled subjects will be placed in their randomized 
position first then transitioned to their randomized mode of mechanical ventilation. 
2. Standard beds, per PICU’s routine, will be used.  
3. The head of the bed will be elevated at least 30 degrees.  
4. When supine, positioning includes a cyclic rotation from full supine to right lateral/supine 
to full supine to left lateral/supine to full supine. If the care team believes that a subject 
cannot tolerate full turns then half turns (listing)54 will be made every 2 hours to prevent 
the development of pressure injuries.  
5. When supine, a draw sheet will be placed under the patient to facilitate patient turns 
every two hours. The patient's occiput will be cushioned using pressure-redistribution 
materials (pillow, gel pillow, or similar). The patient's heels are elevated off the bed using 
an appropriate size pillow placed under the patient’s lower legs. Side positioning will be 
maintained using a soft wedge. Only pressure redistribution material will be placed under 
the patient (no rolled blankets, densely filled stuffed animals, etc.). The integrity of the 
patient’s ear is verified whenever they are positioned on their side. 
B. Supine Group 
 
1. Patients assigned to the supine group will remain supine. 
2. If hypoxemia (SpO2<85%) is persistent, may want to consider performing a maneuver to 
re-establishing lung volume (per ventilation mode) to increase the amount of aerated 
lung.  
3. Failed Supine: Two-hour pattern of persistent hypoxemia (SpO2<85%)  
a. CMV: with FiO2 1.0 and max PEEP per grid (16 cm H2O for < 1 year of age; 18 
cm H2O for ≥ 1 year of age). 
b. HFOV: with FiO2 1.0 and mPaw > 35 cm H2O 
C. Prone Group 
 
1. Patients assigned to prone positioning will be positioned prone within 4 hours of 
randomization and will remain prone for at least 16 consecutive hours/day.55  When 
supine, patients may be returned prone position ≤ 8H if the SpO2 decreases to <85% for 
more than 5 minutes. 
2. To assure that each group is assessed at the same time each day (10:00 ± 2 hours), the 
prone positioned group will be returned supine after the morning assessment.56 The 
subject’s SpO2 will be assessed immediately before and two hours after each supine-to-
prone turn each prone-to-supine turn. 
3. When subjects less than 8 years of age are prone positioned, the patient’s head, upper 
chest, and pelvis are elevated to allow the abdomen to be unrestrained from the bed. 
4. Prone positioning will be accomplished per associated procedure.57  
 
54 Listing is defined as half turns in a patient's position for the purpose of shifting pressure points. 
55 We selected a continuous 16-hour period of prone positioning to remain consistent with the PROSEVA 
trial.  
56 Thus patients may not be positioned prone for 16 consecutive hours on their first day. 
57 Units using the Rotoprone bed as a standard of care in adolescents may continue to use the bed.   

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a. Depending on the size of the patient, each turn procedure (supine to prone; prone to 
supine) will involve 2-4 individuals including the patient’s nurse and respiratory 
therapist.58 During the turn procedure, one person (usually the respiratory therapist) 
will be delegated the primary responsibility of ETT protection. 
b. When prone, the subject's head is turned to the side; arms are flexed up; and the 
lower limbs are cushioned so that the patient’s toes are off the bed. The subject’s 
abdomen will not be supported; specifically, rolls will not be used to the elevate the 
subject’s upper chest, and pelvis to allow the abdomen to be unrestrained from the 
bed.   
c. Prone repositioning includes a cyclic rotation from full prone to right lateral/prone to 
full prone to left lateral/prone to full prone. When tilted into a lateral prone position, 
the patient’s dependent arm is repositioned against their torso and the non-
dependent arm is flexed at the elbow and positioned up towards the patient's head. If 
the care team believes that the patient cannot tolerate full turns than half turns 
(listing) will be made every 2 hours to prevent the development of pressure injuries.  
5. Unless a change in management is anticipated, procedures that require anterior access 
to the patient will be accomplished during the 8-hour supine time period.59 If the care 
team decides to reposition a patient supine for a procedure during the subject's 16-hour 
prone period, the site co-investigator must be consulted. The care team and site co-
investigator may elect to return the patient prone to complete their daily protocol after an 
evaluation of the clinical situation. 
6. Failed Prone:  Two-hour pattern of persistent hypoxemia (SpO2<85%)  
a. CMV: with FiO2 1.0 and max PEEP per grid (16 cm H2O for < 1 year of age; 18 
cm H2O for ≥ 1 year of age). 
b. HFOV: with FiO2 1.0 and mPaw > 35 cm H2O 
7. Criteria for stopping prone positioning  
a. Improving lung function consistent with resolving PARDS and the subject is close to 
meeting criteria to be tested for extubation readiness; Specifically, spontaneous 
breathing and OI < 8 (OSI < 7.5) in the supine position for at least 4 hours after the 
end of the last prone session. After 28 days of prone positioning, all patients who are 
still intubated can be positioned per the discretion of their care team. 
b. Pattern of no effect where the subject demonstrates a three-day pattern of 
decreased PF ratio of at least 20%, or an increase in OI of at least 10% post supine-
to-prone positioning.  If available, documentation of an increase in dead space 
reflecting a decrease volume of perfused lung after a supine-to-prone turn will be 
obtained.   
8. Prone positioning will be immediately discontinued in an emergency: for example, 
non-scheduled extubation, main-stem bronchus intubation, ETT obstruction, hemoptysis, 
cardiac arrest, bradycardia or hypotension for more than 5 minutes, and any other life-
threatening event. 
9. Evolving clinical situations that may also preclude daily prone positioning, that is, Stage 
III pressure injury that cannot be managed in the prone positioning. 
 
 
 
58 Two individuals can safely turn an infant, three individuals can safely turn a toddler and young school-
aged child, four individuals can safely turn an older school-aged child,adolescent, and young adult. 
More individuals may be required for an obese patient at the discretion of the clinical team.  
59 Chest films may be obtained in the prone position. 

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V. Prone Position Procedure 
 
A. Preparation for Prone Positioning 
1. If < 8 years of age: (Note: No cushioning is required if ≥ 8 years of age.) 
• 
Create individually sized head, chest, pelvic, distal femoral, and lower limb 
cushions60 using egg crate material (Eggcrate; Span American Medical Systems, 
Greenville, SC) or its equivalent to allow the patient’s abdomen to be unrestrained 
from the patient’s bed and to provide skin protection.   
1. The chest cushion should measure: slightly less than the right-to-left greater 
tubercle of the upper arm; equal the subject's anterior-posterior width; and wide 
enough to cover the subject's sternum when compressed.61 
2. The pelvic cushion should measure slightly smaller than the right-to-left iliac crest 
and be slightly smaller than the subject's anterior-posterior width. 
3. The head pillow should allow the subject's head to be slightly higher than their 
chest. 
4. A small cushion should be placed under the distal femur to elevate the subject's 
knees off the bed. 
5. The lower limb cushion should elevate the subject's toes off the bed. 
2. On supine AP CXR, assure that the tip of the ETT is deeper than 1/3 of the thoracic 
trachea.62 
3. Assess the security of the endotracheal tube (ETT), vascular lines, and SpO2 probe (by 
applying gentle traction) and reinforce as necessary. If necessary, re-tape the ETT to the 
upper lip.63 Place a protective layer of plastic tape over the white adhesive tape holding 
the ETT.64  
4. If the patient is receiving neuromuscular blockade, provide eye protection. Specifically, 
cleanse, lubricate, then covered both eyes with plastic wrap or unit standard.  
5. If the patient is supported on high frequency oscillatory ventilation, apply a transparent 
film dressing over the anterior surface bony prominences to protect the skin against a 
friction injury. 
6. Move EKG electrodes to the lateral aspects of the upper arms and hips. 
7. Remove clothing surrounding thorax and abdomen. 
8. Coil then secure bladder catheter to inner thigh.  
9. Suction the patient’s oropharynx. 
10. Temporarily cap nonessential vascular lines and the patient’s nasogastric tube. Review 
the start and end point of all that is left attached to the patient. Arrange the remaining 
vascular lines and bladder catheter tubing to prevent excessive tension. 
11. May provide pre-procedural sedation at the discretion of the nurse caring for the patient. 
 
B. Prone Positioning  
1. The bedside nurse(s)/respiratory therapist team will coordinate the turn. 
2. Preplan who will be responsible for what patient aspect (e.g., head/ETT - respiratory 
therapist; chest/arms – Nurse 1; hips/legs – Nurse 2). 
 
60 Roll loosely and/or cut to appropriate compressed size. Tape along edges to retain shape. Cover egg 
crate material with pillowcases so that they can easily slide under the patient. 
61 Avoid hyperextension of the patient's shoulder girdle - shoulders should fold into cushion. 
62 Marcano et al. Cephalad movement of tracheal tubes due to PP of pediatric patients with ARDS. CCM 
2000; 28(12supp); A31. 
63 To prevent pressure injury, the ETT should not be positioned at the corner of the mouth. 
64 Draining oral secretions will loosen the white adhesive tape.  
 

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3. Review technique: 
a. Infants/toddlers: levitate up, turn 45 degrees, pause/reassess, turn prone, levitate up 
to place cushions under the subject.  
b. Children <8 years: using all the bed linens under the subject - slide patient to the 
edge of the bed away from the ventilator, place new draw sheet over patient; position 
chest and pelvic cushions over new draw sheet; place new full sheet over entire 
patient; create a mummy effect by tucking the edges of the full sheet under patient; 
turn patient 45 degrees toward ventilator, pause/reassess, position patient prone on 
new linen and cushions/remove old linen.  
c. Children ≥8 years: using all the bed linens under the subject - slide patient to the 
edge of the bed away from the ventilator, place new draw sheet over patient; place 
new full sheet over entire patient; create a mummy effect by tucking the edges of the 
full sheet under patient; turn patient 45 degrees toward ventilator, pause/reassess, 
position patient prone on new linen and remove old linen.  
4. During the turn keep the patient's head in alignment with their body – avoid 
hyperextension; contain the patient's arms next to their torso; support the patient's legs 
so that the toes of the upper leg point in the direction of the turn.  
5. Patients are turned toward the ventilator without disconnecting the patient from the 
ventilator.65 If the patient must be disconnected from the ventilator consider clamping the 
ETT using a smooth clamp to avoid the loss of lung volume.  If the patient requires ETT 
suctioning, turning is delayed until the patient is suctioned and has returned to pre-
suctioning ventilator settings.66  
6. Ventilator management: If deemed necessary by the care team, the FiO2 may be 
manipulated to maintain the target SpO2 during repositioning. After study blood gases 
are obtained ventilator settings can be adjusted to achieve target blood gases.67  
7. Talk the patient through the turn. 
 
C. Immediately after Prone Positioning  
1. Reassess the security and patency of all tubes/lines.  
2. Reassess SpO2, blood pressure cardiac rhythm, breath sounds. 
3. Reassess ETT/Tracheostomy air leak; may readjust cuff volume, head position, or 
delivered Vt to assure adequate ventilation.  
4. Uncap/reattach capped off lines/nasogastric tube.  
5. Position the patient: 
a. Turn head to side and cushion head and ear with pressure relieving material. Place 
an absorbent diaper under the patient's mouth to catch draining naso/oropharyngeal 
secretions. 
b. If < 8 years, avoiding excessive flexion/extension of the spine, cushion the upper 
chest, and pelvis using either a rolled eggcrate or foam pad - allowing the abdomen 
to protrude. In adolescent and young adult females, check that the breasts/nipples 
are not pinched. In males, check that the penis and scrotum are unrestrained. 
c. Flex arms up. 
d. Position knees and feet off bed using a roll under the distal femur and lower leg. 
 
65 Prevent a loss of lung volume. If patient is disconnected from ventilator than re-recruitment maneuvers 
may be used to reestablish lung volume. 
66 Extremely important in vulnerable patients who decompensate with multiple procedures. 
67 If the patient is supported on HFOV the care team should anticipate the need to increase the 
oscillator’s power to maintain the same PaCO2 while in the prone position.  
 

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e. Check that everything attached to the patient is not pressing against their skin (e.g., 
ETT balloon port) and that the patient’s skin in not pinched in any way (e.g., peri-
umbilical area). 
 
D. Supine Repositioning  
1. The bedside nurse/respiratory therapist team will coordinate the turn.  
2. The precautions and techniques described above apply with the following changes. 
3. Consider performing the patient's daily suctioning procedure at hour 14.68 
4. Patients are turned away from the ventilator without disconnecting the patient from the 
ventilator.69  
5. Position the patient: 
a. Cushion head using pressure-relieving materials (pillow, jell pillow). 
b. Elevate the patient's heels off the bed using an appropriate size pillow. 
 
 
68 Bronchial drainage may be enhanced while in the prone position. 
69 Prevent a loss of lung volume. If patient is disconnected from ventilator than re-recruitment maneuvers 
may be used to reestablish lung volume. 

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VI. Prone Positioning Check Sheet 
 
Preparation (Prior to getting help into room) 
  If < 8 years of age:  Create cushions using egg crate material (head, chest, pelvic, distal 
femoral, & lower limb). No cushions necessary if ≥ 8 years of age.  
  Check ETT on CXR - tip should be in the lower 1/3 of the thoracic trachea. 
  
 
 
Assess the security of the ETT, vascular lines, SpO2 probe and reinforce as necessary.  
o Retape the ETT to the upper lip on the side of the mouth. 
o Place a protective layer of plastic tape over the white adhesive tape holding the 
ETT. 
  Protect eyes if chemically paralyzed &/or open (cleanse, lubricate, cover with plastic 
wrap). 
  If HFOV, apply plastic film dressing over anterior bony prominences to avoid friction 
injury. 
  Move EKG electrodes to the lateral aspects of the upper arms and hips. 
  Remove clothing surrounding thorax and abdomen. 
  Coil then secure bladder catheter to inner thigh. 
  Suction the patient’s oropharynx.  
(If ETT suctioned, postpone turn until unit patient returned to pre-suctioning ventilator 
settings). 
  Temporarily cap nonessential vascular lines and the patient’s NGT/JT.  
  
 
Final Check - Review the start and end point of all that is left attached to the patient. 
Arrange the remaining vascular lines and Foley catheter tubing to prevent excessive 
tension. 
  Premed with comfort medications at the discretion of the bedside nurse. 
Turning (Bedside nurse/RT team.) 
  Call for RT and at least one other nurse. 
  Preplan responsibility: RT - Head/ETT; Nurse 1 - chest/arms; Nurse 2 - hips/legs. 
  
 
 
 
Review technique: 
o Infants/toddlers: Levitate = levitate up, turn 45 degrees, pause/reassess, turn 
prone,  to place cushions under the subject.  
o Children: Mummy = using all bed linens - slide patient to the edge of the bed 
away from the ventilator, place new draw sheet over patient; (If < 8 years: position 
chest and pelvic cushions over draw sheet); place full sheet over entire patient; 
create a mummy effect by tucking the edges of the full sheet under patient; turn 
patient 45 degrees toward ventilator, pause/reassess, position patient prone on 
new linen and cushions/remove old linen.  
 
Keep head in alignment with body, avoid hyperextension, keep arms next to torso, point 
toes of the upper leg in the direction of turn. 
 
Turn toward the ventilator without disconnecting. (FiO2 may be manipulated to maintain 
target SpO2. All other ventilator settings remain constant until 1-hour post turn ABG 
obtained.) 
 
Talk the patient through the turn. 

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Immediately after the Turn 
 
 Reassess the security and patency of all tubes/lines.  
 
 Reassess SpO2, blood pressure, cardiac rhythm, & breath sounds. 
 
 Reassess ETT/Trach leak (May adjust cuff volume, head position, delivered Vt to assure 
adequate ventilation.)  
 
 Uncap/reattach capped off lines/NGT/NJT. 
 
 
 
 
 
 
 
 
 
Position the patient: 
o Turn head to side & cushion head and ear with pressure relieving material.  
o Place an absorbent diaper under the patient's mouth. 
o If < 8 years: Avoid excessive flexion/extension of the spine. In adolescent and 
young adult females, check that the breasts/nipples are not pinched. In males, 
check that the penis and scrotum are unrestrained. 
o Flex arms up. 
o Position knees and feet off bed using a roll under the distal femur and lower leg. 
o Check that everything attached to the patient is not pressing against their skin 
(ETT balloon port) and that the patient’s skin in not pinched in any way (peri-
umbilical area). 
Return to Supine 
 
 Precautions & techniques described above apply. 
 
 Consider performing the patient's daily suctioning procedure at hour 14 (2 hours before 
turn) 
 
 Patients are turned away from the ventilator without disconnecting.  
 
 
 
 
Position the patient: 
o Cushion head using pressure-relieving materials (pillow, jell pillow). 
o Elevate the patient's heels off the bed using an appropriate size pillow. 

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VII. Failed Management 
Clinicians may consider a reciprocal therapy (supine to prone; prone to supine; CMV to 
HFOV; HFOV to CMV) in a sequence based on their clinical judgment while considering 
ECMO cannulation. Reciprocal treatments, when used, will be managed per PROSpect 
protocols. Subjects cannulated for ECMO will be followed so that ventilator management 
can be described and for study outcomes.  
 
 
 

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VIII. Hemodynamic Management Guidelines (all groups) 
 
A. Patients will be managed using a fluid conservative strategy, as outlined below.70 
B. The goal is adequate cardiac output to meet the metabolic needs of the patient, 
specifically, an acceptable blood pressure for age,71 brisk capillary refill, and adequate 
peripheral perfusion to achieve adequate end organ perfusion. 
C. The care team will delineate daily mean arterial BP goals.72 
D. Hypotension, as defined by American Heart Association PALS guidelines,73 is managed 
per the shock protocol for resuscitation. 
E. If hypotension is not present (may be on dopamine ≤ 5 mcg/kg/min, or epinephrine ≤ 
0.03 mcg/kg/min, or any dose of milrinone), determine the appropriate column by 
evaluating the effectiveness of the circulation. Locate the appropriate instruction box by 
determining fluid balance (hourly input and urine output).   
F. Fluid management in subjects with concurrent acute renal failure are managed at the 
discretion of the care team.  
G. Hemodynamic assessments will be documented at least every four hours. These 
measurements include systolic blood pressure, urine output/kg/hr, clinical assessment of 
the effectiveness of the arterial circulation, and central venous pressure (if available). 
Standard methods for assessing the effectiveness of arterial circulation, that is, capillary 
refill time, cutaneous “mottling” of the extremities, and core-extremity temperature 
differences will be used. 
H. Fluid Management 
1. Maintenance fluids are calculated per standard pediatric practice.74 
2. The care team will determine the type of fluid (colloids, crystalloids) administered.  
3. All fluids, including IV continuous infusions, IV intermittent medications, blood 
products, IV and enteral nutrition, will contribute to the patient’s hourly total. 
Medications should be administered using the least amount of fluid possible. 
4. Of note, routine pRBC transfusion for a hemoglobin >7 g/dl, without evidence of 
severe hypoxemia, poor tissue perfusion, active bleeding, or hemodynamic 
instability, is not recommended.  
5. In choosing fluids, ensure normoglycemia. 
I. Furosemide is used to achieve desired fluid balance. 
1. Consider withholding if: 
a. vasopressor or a fluid bolus given in the last 24 hours OR  
b. renal failure present (dialysis dependence) OR oliguria with creatinine 2x upper 
limit of normal for age OR oliguria with creatinine <2x upper limit of normal for 
age and urinary studies indicative of acute renal failure. 
2. Begin continuous IV infusion of 0.05 mg/kg/hr (consider 0.5 mg/kg initial bolus) OR 
bolus 0.5-2 mg/kg/dose IV (single suggested max bolus: 20 mg) every 6-12 hours 
OR last known effective dose.  
3. Double continuous infusion hourly, after the first 6 hours, until urine output >0.5 
 
70 Sections of this protocol were modified from that provided by Stacey Valentine, MD; University of 
Massachusetts   
71 Blood pressure that is associated with normal lactate, urine output, delta skin-core < 2 degrees C and 
normal capillary refill.  
72 The use of a central venous catheter is not mandated. CVP includes internal jugular, subclavian or long 
femoral line in the absence of abdominal pathology.  Consider with reproducible waveforms.   
73 Hypotension is defined as a systolic blood pressure <70 mmHg + 2x age in years. 
74 Maintenance fluids universal standard: 100 ml/kg first 10 kg + 50 ml/kg second 10 kg + 25 ml/kg third 
plus kg.  

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74
ml/kg/hour OR maximum infusion of 0.5 mg/kg/hr or maximum total daily dose of 8 
mg/kg (not to exceed -600 mg/day).   
a. Discontinue if:  
1) no response to maximum dose after 1 hour OR 
2) intravascular pressure declines to a cell not requiring furosemide therapy. 
4. May repeat diuretic trial q 24 hours. 
5. The care team may elect to add a second diuretic to achieve the above stated 
clinical outcomes. 
 
Fluid balance algorithm  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 NET fluid balance = total measured fluids administered to the patient from admission to study 
randomization (including all nutrition, medications, blood products and intravenous fluids) – total 
of fluids removed or excreted from the patient (in milliliters) divided by body weight (in kilograms). 
2 UOP = urine output as measured in ml/kg/hour.  If a Foley catheter is not in place, average each 
void over the period that elapsed since the previous void. 
3 Hourly input = total fluids being given including all continuous infusions, nutrition, intermittent 
medications and/or blood products. 
4 Fluid overload percentage = [(Total intake (L) – Total output (L)) /weight (kg)] x 100% 
5 Fluid challenge = 5-10 ml/kg given via push/pull technique with bedside monitoring of HR and BP.  
If no improvement in HR, consider start of diuresis to augment urine output. 
 
J. Fluid Bolus may be required to reestablish adequate tissue perfusion. 
1. Use 10-15 ml/kg (ideal body weight) normal saline, Ringer’s lactate, pRBCs, or 
albumin. Administer as rapidly as possible then reassess patient. Repeat up to 3 
times daily if indicated by protocol.  
NET fluid balance1 is < 0  
NET fluid balance is > 0 
  
UOP2  < 0.5ml/kg/hr 
  
UOP < hourly input3 
  
UOP < 0.5 ml/kg/hr 
  
UOP < hourly input 
If >10% FO4,  
consider diuresis 
If ≤10% FO, consider 
fluid challenge5 
Start or increase 
diuresis with a goal 
of UOP > hourly 
input 
SBP ≥ 70 mmHg +2x age in years* 
(*on dopamine ≤ 5 mcg/kg/min, or epinephrine ≤ 0.03 
mcg/kg/min, or any dose of milrinone) 
10 ml/kg fluid 
bolus & assess 
response 
Consider diuresis 
with a goal of  
UOP = hourly 
input 

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2. Fluid bolus may be withheld if bolus was given within 24 hours and such bolus did 
not result in a sustained increase in filling pressure. 
 
K. Inotropes may be necessary to maintain adequate tissue perfusion.  Choice at the 
discretion of the clinical care team.  
1. Dopamine 
a. Start at 5 mcg/kg/min and increase by 5 mcg/kg/min in increments at ~15-minute 
intervals until ineffective circulation reversed or maximum dose of 20 mcg/kg/min 
is reached. 
b. Wean by 1-2 mcg/kg/min every 1-2 hours as tolerated, beginning 4 hours after 
signs of ineffective circulation are reversed. 
2. Epinephrine:  
a.  Start at 0.03 mcg/kg/min and increase by 0.02 mcg/kg/min in increments at 
~15-minute intervals until ineffective circulation reversed or maximum dose of 
0.1 mcg/kg/min is reached.   
b. Wean by 0.01-0.02 mcg/kg/min every 1-2 hours as tolerated, beginning 4 
hours after signs of ineffective circulation are reversed.   
3. Milrinone: 
a. Milrinone is administered with a loading dose (optional) followed by a continuous 
infusion. Volume expanders should be made available to counteract both 
vasodilator and decreases in filling pressures. 
b. Loading Dose (optional): 50 mcg/kg IV x 1 administered slowly over 20 minutes. 
c. Maintenance Dose: Continuous infusion 0.25-0.75 mcg/kg/min. 
4. Dobutamine 
c. Start at 5 mcg/kg/min and increase by 5 mcg/kg/min in increments at ~15-minute 
intervals until ineffective circulation reversed or maximum dose of 20 mcg/kg/min 
is reached. 
d. Wean by 1-2 mcg/kg/min every 1-2 hours as tolerated, beginning 4 hours after 
signs of ineffective circulation are reversed. 
 
L. Shock Guidelines 
 
1. Fluid Bolus: Use 20 ml/kg (ideal body weight) normal saline or Ringers Lactate. 
Administer as rapidly as possible then reassess patient. Repeat bolus at least up to 6 
times daily if indicated by protocol. 
2. Vasopressor Therapy: Choice of any single agent or any combination of the following 
to re-establish and maintain normal blood pressure for age: 
a. Dopamine 5 mcg/kg/min, increase in 2 mcg/kg/min steps q 3-5 min to 
maximum of 20 mcg/kg/min. (Note: Dopamine <3 mcg/kg/min is not 
considered a vasopressor.) 
b. Norepinephrine at 0.05 mcg/kg/min, increase in 0.05 mcg/kg/min steps q 3-5 
min to maximum of 1 mcg/kg/min.  
c. Epinephrine at 0.05 mcg/kg/min, increase in 0.05 mcg/kg/min steps q 3-5 min 
to maximum of 0.3 mcg/kg/min.  
d. Phenylephrine at 0.1 mcg/kg/min, increase in 0.1 mcg steps q 3-5 min to 
maximum of 1.5 mcg/kg/min 
 
 

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IX. Sedation Guidelines (all groups) 
 
A. The goals of comfort therapy include analgesia, amnesia, anxiolysis, and compliance 
with routine care.  
 
B. The patient’s level of comfort is assessed per phase of illness and criticality: 
1. Sedation levels will be scored using a valid and reliable pediatric sedation 
assessment instrument; e.g., the State Behavioral Scale (SBS) or the COMFORT 
Behavioral Scale at least every 4 hours while intubated.  
2. Pain levels will be scored using an age-appropriate pain scale at least every 4 hours 
while in the PICU. The pain scale used depends on the patient’s age and 
verbal/cognitive capacity: e.g., the Face, Legs, Activity, Cry, Consolability (FLACC) 
scale in nonverbal children 0 to 6 years of age, the individualized numeric rating 
scale (INRS) in nonverbal cognitively impaired children age 6 and older, and the 
Wong-Baker Faces Pain Scale (WBFPS) in verbal children age 3 and older. All pain 
scales range 0-10 with higher scores indicating more pain. 
3. In patients receiving neuromuscular blockade, pain/agitation is judged to be present 
by the bedside nurse when a patient demonstrates a ≥20% increase in heart rate or 
blood pressure when stimulated. 
4. Delirium screening using either the Cornell Assessment of Pediatric Delirium (CAPD) 
or the Pediatric or Preschool Confusion Assessment Method for the Intensive Care 
Unit (pCAM-ICU/psCAM-ICU) will be accomplished at least daily while in the PICU. 
5. Patients weaning from ≥5 days of sedation are monitored for Iatrogenic withdrawal 
syndrome (IWS) using the Withdrawal Assessment Tool-1 (WAT-1). The WAT-1 
scale ranges 0-12 with higher scores indicating more withdrawal symptoms at least 
Q12 hours. 
 
C. The patient’s care team will prescribe a level of sedation/analgesia on daily rounds. 
Oversedation will be avoided. Nurses will use a sedation protocol to maintain the 
patient’s level of comfort in the prescribed range.75 Developmentally appropriate adjunct 
measures should be utilized whenever possible to help minimize the risks of excessive 
pharmacological intervention. 
 
D. Patients will receive pre-procedural comfort medications at the discretion of their care 
team.  
 
75 See Curley, M.A.Q., Wypij, D., Watson, R.S., Grant, MJ.C., Asaro, L.A., Cheifetz, I.M., Dodson, B.L., 
Franck, L.S., Gedeit, R.G., Angus, D.C., Matthay, M.A., for the RESTORE Study Investigators and the 
Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. (2015). Protocolized Sedation 
versus Usual Care in Pediatric Patients Mechanically Ventilated for Acute Respiratory Failure: A 
Randomized Clinical Trial.  JAMA, 313(4):379-389. (PMID: 25602358; PMC4955566) 

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           77 
X. Skin Care and Pressure Injury Guidelines (all groups) 
 
A. The goal of therapy is to maintain skin integrity. 
 
B. A daily skin assessment will be performed and recorded on every patient during the 
acute treatment phase. A Braden QD will be obtained three times per week on Monday, 
Wednesday and Fridays.  After the acute treatment phase, the Braden QD performed 
and recorded every Wednesday until PICU discharge. Pressure injuries will be staged 
and managed according to National Pressure Injury Advisory Panel (NPUAP) 
guidelines.76 
 
C. Pressure injuries will be prevented by applying universally accepted prevention 
strategies. Specifically, patients will be turned (listed; offloaded) every two hours. Turn 
schedules will be documented. Specific patient padding will be delineated in the eMOO. 
All offloading and pressure injury prevention surfaces will consist of pressure 
redistribution material. Foam dressings may be placed on bony prominences and 
labeled with a “P” for prevention. Preventative foam dressings may be worn for 7 days 
and peeled back per standard to examine the skin beneath. 
 
D. Pressure injuries will require an evaluation by a Skin Care Specialist as soon as possible 
after identification. In addition to continuing aggressive prevention strategies: 
• 
Stage 1 pressure injuries may be treated by the application of a transparent film 
dressing or a sting-free barrier film dressing. Sting-free barrier film dressings applied 
daily or twice daily to bony prominences are also ideal to protect from friction-shear 
injury during supine/prone positioning. Sting-free barrier film also protects skin from 
medical adhesive-related skin injury (also called epidermal stripping or skin tears). 
 
• 
Stage 2 pressure injuries will be treated by the application of an absorbent foam 
dressing. Foam dressings that are applied over Stage 2 wounds should be labeled 
with a “2” to correspond with the Stage so providers know what is beneath. Foam 
dressings on Stage 2 pressure injuries should be worn for 5 days and peeled back 
per standard to examine the skin beneath. Open blisters also benefit from an 
absorbent foam dressing. 
  
• 
Stage 3 and 4 pressure injuries will be treated according to a dry or moist wound 
bed. A dry Stage 3 or 4 will be treated with NSS moistened gauze dressing. A moist 
Stage 3 or 4 will be treated with a calcium alginate dressing. Label a secondary 
dressing with a “3” or “4” to correspond with the Stage so providers know what is 
beneath. 
 
76 Classify as Stage 1 or 2 or 3 or 4, based on the deepest tissue type exposed. Stage 1 pressure injuries 
include reversible non-blanchable erythema of intact skin; Stage 2 pressure injuries include partial 
thickness skin loss involving epidermis and/or dermis; Stage 3 pressure injuries include full thickness 
skin loss involving damage and necrosis of subcutaneous tissue that may extend down to, but not 
though, underlying fascia; and Stage 4 include full thickness skin loss with extensive destruction, tissue 
necrosis or damage to muscle, bone, or supporting structures. If the wound base cannot be evaluated, 
classify as: Deep Tissue Pressure Injury (DTPI) when the skin is intact with deep red, purple or maroon 
discoloration or blood blister(s) or as Unstageable when the base is obscured by slough or eschar. If on 
a mucosal membrane, document, but do not stage. National Pressure Ulcer Advisory Panel NPUAP 
Pressure Ulcer Stages http://www.npuap.org/resources/educational-and-clinical-resources/npuap-
pressure-injury-stages/, Accessed May 1, 2019. 

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• 
Unstageable pressure injuries may be treated with an active Leptospermum 
honey/hydrocolloid product.  
 
• 
Deep Tissue Pressure Injuries (DTPI) should be protected with offloading. No 
dressing is needed. 
 
• 
Mucosal pressure injuries require removing the source of pressure (e.g., changing 
the side or location of a medical device). 
 
 

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Appendix 1: Ideal Body Weight (kg) by Length (cm), Gender and Age Weight-for-
Recumbent-Length: 2 Weeks to 36 Months 
 
Recumbent 
Length 
(cm) 
Weight (kg) 
 
Recumbent 
Length 
(cm) 
Weight (kg) 
Male 
Female 
Male 
Female 
45 
2.29 
2.31 
 
74.5 
9.51 
9.34 
45.5 
2.39 
2.40 
 
75.5 
9.74 
9.57 
46.5 
2.59 
2.61 
 
76.5 
9.97 
9.79 
47.5 
2.80 
2.82 
 
77.5 
10.21 
10.02 
48.5 
3.02 
3.04 
 
78.5 
10.43 
10.24 
49.5 
3.25 
3.26 
 
79.5 
10.66 
10.47 
50.5 
3.48 
3.49 
 
80.5 
10.89 
10.69 
51.5 
3.72 
3.72 
 
81.5 
11.12 
10.91 
52.5 
3.96 
3.96 
 
82.5 
11.34 
11.13 
53.5 
4.21 
4.20 
 
83.5 
11.57 
11.35 
54.5 
4.47 
4.45 
 
84.5 
11.79 
11.57 
55.5 
4.72 
4.69 
 
85.5 
12.02 
11.80 
56.5 
4.98 
4.94 
 
86.5 
12.24 
12.02 
57.5 
5.24 
5.19 
 
87.5 
12.47 
12.24 
58.5 
5.50 
5.44 
 
88.5 
12.70 
12.46 
59.5 
5.76 
5.70 
 
89.5 
12.92 
12.69 
60.5 
6.02 
5.95 
 
90.5 
13.16 
12.91 
61.5 
6.28 
6.20 
 
91.5 
13.39 
13.14 
62.5 
6.54 
6.45 
 
92.5 
13.62 
13.37 
63.5 
6.79 
6.70 
 
93.5 
13.86 
13.61 
64.5 
7.05 
6.95 
 
94.5 
14.10 
13.84 
65.5 
7.30 
7.20 
 
95.5 
14.34 
14.08 
66.5 
7.56 
7.44 
 
96.5 
14.59 
14.33 
67.5 
7.81 
7.69 
 
97.5 
14.84 
14.58 
68.5 
8.06 
7.93 
 
98.5 
15.10 
14.83 
69.5 
8.30 
8.17 
 
99.5 
15.35 
15.09 
70.5 
8.55 
8.41 
 
100.5 
15.62 
15.36 
71.5 
8.79 
8.64 
 
101.5 
15.89 
15.63 
72.5 
9.03 
8.88 
 
102.5 
16.16 
15.91 
73.5 
9.27 
9.11 
 
103.5 
16.43 
16.19 
 
This chart is an example from the National Center for Health Statistics. Charts used 
locally should match the norms of the enrolled subject. 
 
 
 
 
 
 
 
 

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Appendix 2: Ideal Body Weight (kg) by Length (cm), Gender and Age Weight-for-
Recumbent-Length: 3-21 Years 
 
Recumbent 
Length 
(cm) 
Weight (kg) 
 
Recumbent 
Length 
(cm) 
Weight (kg) 
Males 
Females 
 
Males 
Females 
77-80 
10.53 
10.34 
 
 
 
 
80-82 
11.19 
10.98 
 
 
 
 
82-84 
12.09 
11.86 
 
130-132 
27.4 
26.8 
86-88 
12.54 
12.31 
 
132-134 
28.4 
28.0 
88-90 
13.2 
12.9 
 
134-136 
29.8 
29.4 
90-92 
13.6 
13.3 
 
136-138 
31.2 
31.0 
92-94 
14.0 
13.8 
 
138-140 
32.7 
32.4  
94-96 
14.4 
13.8 
 
140-142 
34.3 
34.1 
96-98 
14.9 
14.20 
 
142-144 
35.7 
35.6  
98-100 
15.5 
14.90 
 
144-146 
37.5 
37.0 
100-102 
16.0 
15.40 
 
146-148 
39.1 
38.1 
102-104 
16.7 
16.0 
 
148-150 
40.7 
39.2 
104-106 
17.2 
16.6 
 
150-152 
42.3 
40.7 
106-108 
17.9 
17.3 
 
152-154 
43.6 
41.8 
108-110 
18.7 
17.8 
 
154-156 
45.4 
43.3 
110-112 
19.2 
18.6 
 
156-158 
46.7 
44.7 
112-114 
20.0 
19.2 
 
158-160 
48.1 
46.0 
114-116 
20.8 
19.7 
 
160-162 
49.4 
48.1 
116-118 
21.4 
20.5 
 
162-164 
50.8 
51.4 
118-120 
22.2 
21.2 
 
164-166 
63.8 
59.3 
120-122 
23.0 
22.0 
 
166-168 
65.64 
61.14 
122-124 
23.8 
22.9 
 
168-170 
67.48 
62.98 
124-126 
24.6 
23.6 
 
170-172 
69.32 
64.82 
126-128 
25.5 
24.5 
 
172-174 
71.6 
66.66 
128-130 
26.4 
25.5 
 
174-176 
73 
68.5 
 
 
 
 
176-178 
74.84 
70.34 
 
 
 
 
178-180 
76.68 
72.18 
 
This chart is an example from the National Center for Health Statistics. Charts used 
locally should match the norms of the enrolled subject. 
• If male height is >178 cm, then IBW (kg) = 50 + 2.3[(height in cm * 0.3937) – 60] 
• If female height is >164 cm, then IBW (kg) = 45.5 + 2.3[(height in cm * 0.3937) – 60] 
 
 
 
 
 
 
 
 
 

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Appendix 3: Calculation of Mean Airway Pressure for OSI Calculation by 
Ventilator Mode Type 
 
Mean airway pressure (mPaw) of a breath is a factor of the total pressure for the breath, 
the amount of time devoted to inspiration compared to the total breath time and amount 
of pressure remaining during exhalation. Most current invasive and non-invasive 
ventilation machines measure mean airway pressure. The following calculations can be 
used to estimate mean airway pressure from stable ventilator settings, if the 
measurement is not known.  
 
Triangular Waveform: 
Triangular pressure waveform is the result of true volume controlled ventilation or a flow 
targeted mode of ventilation. Adaptive modes of ventilation are NOT true volume 
controlled modes even though a tidal volume, and not a pressure, is set for each breath. 
These modes are pressure modes of ventilation, and the triangle waveform calculation 
should be used. 
 
mPaw = (0.5 x (PIP-PEEP) x (Inspiratory Time/ (frequency/60) )) + PEEP77 
 
Rectangular (square) Waveform: 
Rectangular or square pressure waveforms are commonly seen during pressure modes 
of ventilation. These include adaptive modes of ventilation where a tidal volume is set 
but the breath is delivered with pressure targeting and volume is measured. 
 
mPaw = ((PIP-PEEP) x (Inspiratory Time/ (frequency/60) )) + PEEP78 
 
 
 
 
77 Volume mode (triangular waveform): use measured PIP of a mandatory breath; use set PEEP 
78 Pressure mode (rectangular/square waveform): use set PIP or use measured PIP of a mandatory 
breath in an adaptive mode; use set PEEP