Identifying and Preventing Ventilator Induced Diaphragm Dysfunction in Children
Phase: NA
Conditions: Ventilation Therapy; Complications, Diaphragm Disease, Pediatric Respiratory Diseases
Sponsor: Children's Hospital Los Angeles

Title: Identifying and Preventing Ventilator Induced Diaphragm Dysfunction in Children 
NCT Number: NCT03266016 
Date of Document: 7/14/2024 
PI: Robinder Khemani, MD. Email: rkhemani@chla.usc.edu, Children’s Hospital Los Angeles  
 

Table of Contents 
 
Item 
Page 
REDvent Initial IRB approved protocol 
2 
REDvent most current IRB approved protocol (final protocol) 
56 
Summary of Major Protocol amendments/changes and dates 
131 
REDvent Initial Statistical Analysis Plan 
132 
REDvent Final Statistical Analysis Plan including changes and rationale 
140 
Summary of REDvent Statistical Analysis Plan changes and dates 
153 
 
 
 

REDvent Study Protocol 
PI: Khemani 
June 29, 2017 
 
 
 
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REDVENT 
(Real-time Effort Driven VENTilator management) 
 
NIH/NHLBI R01HL124666 
 
 
Robinder G. Khemani MD, MsCI 
Associate Professor of Pediatrics 
University of Southern California 
Attending Physician, Critical Care Medicine 
Children’s Hospital Los Angeles 
4650 Sunset Blvd MS 12 
Los Angeles, CA 90027 
rkhemani@chla.usc.edu 
Phone: 323.361.2376 
Fax: 323.361.1001 
Cell: 206.619.6968 
 
Martha A.Q. Curley, RN, PhD, FAAN 
Ellen and Robert Kapito Professor in Nursing Science 
School of Nursing/Anesthesia and Critical Care Medicine 
University of Pennsylvania 
School of Nursing 
Claire M. Fagin Hall  
418 Curie Boulevard, Room 424  
Philadelphia, PA 19104-4217 USA 
Office Phone: 215.573.9449 
Cell: 617.803.6996 
Office Fax: 215.746.2737 
curley@nursing.upenn.edu 
 
Christopher JL Newth MD, FRCPC 
Professor of Pediatrics 
University of Southern California 
Attending Physician, Critical Care Medicine 
Children’s Hospital Los Angeles 
4650 Sunset Blvd MS 12 
Los Angeles, CA 90027 
cnewth@chla.usc.edu 
Phone: 323.361.2117 
Fax: 323.361.1001 
Cell: 818.952.5340 

REDvent Study Protocol 
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June 29, 2017 
 
 
 
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TABLE OF CONTENTS 
A 
INTRODUCTION ............................................................................................................................... 4 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PROTOCOL SUMMARY ................................................................................................................... 5 
A3 
PRIMARY HYPOTHESIS AND SPECIFIC AIMS ................................................................................... 9 
B 
BACKGROUND ................................................................................................................................ 10 
B1 
PRIOR LITERATURE AND STUDIES ................................................................................................ 10 
B2 
RATIONALE FOR THIS STUDY ....................................................................................................... 10 
B3 
PRELIMINARY DATA .................................................................................................................... 12 
C 
STUDY OBJECTIVES ..................................................................................................................... 17 
C1 
PRIMARY AIM .............................................................................................................................. 17 
C2 
SECONDARY AIMS ....................................................................................................................... 17 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ......................................................... 17 
D 
STUDY DESIGN ............................................................................................................................... 20 
D1 
OVERVIEW OR DESIGN SUMMARY ............................................................................................... 20 
D2 
SUBJECT SELECTION  ................................................................................................................... 20 
D.2.1 Inclusion Criteria…………………………………………………………………………………… 20 
D.2.2 Exclusion Criteria ................................................................................................................ 20 
D.2.3 Screening and Eligibility ...................................................................................................... 21 
D3 
STUDY INTERVENTIONS ............................................................................................................... 21 
D.3.1 Acute Phase Description ...................................................................................................... 21 
D.3.2 Intervention Arm Acute (REDvent-acute) ............................................................................ 21 
D.3.3 Control Arm…………………………………………………………………………………………...22 
D.3.4 Acute Phase Respiratory Monitoring ................................................................................... 22 
D.3.5 Spontaneous Breathing Trials success/failure ..................................................................... 23 
D.3.6 Weaning Phase Description ................................................................................................. 23 
D.3.7 Intervention Arm Weaning Phase (REDvent-weaning) ........................................................ 23 
D.3.8 Control Arm Weaning .......................................................................................................... 24 
D.3.9 Weaning Phase Respiratory Monitoring .............................................................................. 24 
D.3.10 Post-extubation Management ............................................................................................. 24 
D.3.11 Suspension of Weaning Phase ............................................................................................ 24 
D.3.12 Failure of Weaning Phase .................................................................................................. 24 
D.3.13 Termination of Study Intervention at day 28 ...................................................................... 25 
D.3.14 Post Enrollment Exclusion Criteria ................................................................................... 25 
D4 
MEASUREMENT OF STUDY VARIABLES ........................................................................................ 26 
D.4.1 Serial Respiratory Measurements ........................................................................................ 26 
D.4.2 Airway Occlusion Measurements ......................................................................................... 26 
D.4.3 SBT measurements ............................................................................................................... 26 
D.4.4 Rationale for measurements ................................................................................................. 27 
D5 
CO-INTERVENTIONS ..................................................................................................................... 27 
D6 
STATISTICAL CONSIDERATIONS ................................................................................................... 28 
D.6.1 Randomization Strategy and Blinding .................................................................................. 28 
D.6.2 Rationale for Randomization Strategy ................................................................................. 27 
D.6.3 Dataset Preparation ............................................................................................................. 28 
D.6.4 Statistical Analysis Plan and Sample Size ............................................................................ 28 
D.6.5 Dissemination Plan and Data Archiving .............................................................................. 33 
D7 
DATA AND INSTRUMENT MANAGEMENT ...................................................................................... 33 
D8 
DATA QUALITY CONTROL  ........................................................................................................... 34 

REDvent Study Protocol 
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D.8.1 Training ................................................................................................................................ 34 
D.8.2 Case Report Forms .............................................................................................................. 34 
D9 
ANTICIPATED PROBLEMS AND SOLUTIONS .................................................................................. 34 
D10 
MILESTONE ACCRUAL PLAN ........................................................................................................ 35 
 
E 
HUMAN SUBJECTS CONSIDERATIONS ................................................................................... 36 
E1 
ETHICAL CONSIDERATIONS ......................................................................................................... 36 
E2 
RECRUITMENT AND CONSENT ...................................................................................................... 36 
E3 
RISKS AND BENEFITS ................................................................................................................... 37 
E4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................. 38 
F 
DATA SAFETY MONITORING PLAN AND BOARD ................................................................ 38 
G 
REFERENCES .................................................................................................................................. 39 
H 
DETAILED VENTILATION PROTOCOLS FOR INTERVENTION GROUP ........................ 44 
 

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A Introduction 
 
A1 Study Abstract 
 
Nearly half of mechanically ventilated (MV), critically ill adults develop 
ventilator-induced respiratory muscle weakness (particularly of the diaphragm), which 
impairs successful weaning from MV, often leads to re-intubation, and is associated with 
higher post-ICU mortality. Respiratory muscle weakness is associated with extubation 
failure in critically ill children. However, we lack crucial information on the mechanisms 
and timing of this weakness, its importance for ventilator weaning, and its potential 
prevention through promoting more physiologic levels of patient effort of breathing 
during MV.   
 
This study is a Phase II controlled clinical trial that will obtain comprehensive, 
serial assessments of respiratory muscle strength and architecture to understand the 
evolution of ventilator-induced respiratory muscle weakness in critically ill children, and 
test whether a novel computer-based approach (Real-time Effort Driven ventilator 
management (REDvent)) can preserve respiratory muscle strength and reduce time on 
MV.  REDvent offers systematic recommendations to reduce controlled ventilation 
during the acute phase of MV, and uses real-time measures from esophageal manometry 
to adjust supported ventilator pressures such that patient effort of breathing remains in a 
normal range during the ventilator weaning phase.   This phase II clinical trial is 
expected to enroll 300 children with pulmonary parenchymal disease, anticipated to be 
ventilated > 48 hrs. Patients will be randomized to REDvent-acute vs. usual care for the 
acute phase of MV (interval from intubation to first spontaneous breathing trial (SBT)).  
Patients in either group who fail their first Spontaneous Breathing Trial (SBT), will also 
be randomized to REDvent-weaning vs. usual care for the weaning phase of MV (interval 
from first SBT to passing SBT). The primary clinical outcome is length of weaning (time 
from first SBT until successful passage of an SBT or extubation (whichever comes first)).  
Mechanistic outcomes surround multi-modal serial measures of respiratory muscle 
capacity (PiMax), load (resistance, compliance), effort (esophageal manometry), and 
architecture (ultrasound) throughout the course of MV.   Upon completion, this study 
will provide important information on the pathogenesis and timing of respiratory muscle 
weakness during MV in children and whether this weakness can be mitigated by 
promoting more normal patient effort during MV via the use of REDvent. This will form 
the basis for a larger, Phase III multi-center study, powered for key clinical outcomes 
such as 28-day Ventilator Free Days.  

REDvent Study Protocol 
PI: Khemani 
June 29, 2017 
 
 
 
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A2 Protocol Summary 
Title: Real-time Effort Driven Ventilator Management (REDvent) 
 
Phase: Phase II 
 
Funding: NIH/NHLBI R01HL124666 
 
Committees: Steering Committee, Institutional Data and Safety Monitoring Board 
 
Background and Significance: Nearly half of critically ill patients on MV develop 
respiratory muscle weakness, particularly of the diaphragm. In adults, this weakness 
leads to the inability to resume unassisted ventilation after the acute illness has resolved, 
prolongs the weaning phase of MV, and contributes to extubation failure. 1-11 However, in 
critically ill children, we lack crucial information about the importance of ventilator-
induced respiratory muscle weakness during weaning, the means to prevent it, and 
whether it is influenced by maturational changes in respiratory mechanics and 
diaphragm histology that occur throughout infancy and childhood.12    
 
Consistent with the pediatric literature,4 our preliminary data has shown that  usual care 
ventilation  in children is associated with minimal patient effort of breathing; 13, 14 known 
to be a major risk factor for ventilator-induced diaphragm weakness in adults.5  To 
reduce this weakness, we developed a computer-based approach (Real-time Effort 
Driven ventilator management (REDvent)), which recommends systematic reductions in 
controlled ventilation during the acute phase of MV and uses real-time measures to 
adjust supported ventilator pressures to maintain patient effort of breathing during the 
weaning phase.  Through a Phase I trial, we demonstrated that patients managed with 
REDvent spent fewer days on MV than historical controls, and bedside providers could 
easily implement REDvent.  Our central hypothesis is that REDvent use will reduce 
ventilator-induced respiratory muscle weakness, leading to shorter time on MV by 
enhancing the patient’s capacity for effective, unsupported ventilation and by facilitating 
MV weaning.     
 
Study Aims: 
SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the 
duration of weaning from MV (Primary outcome).   
SA2: To determine if changes to direct measures of respiratory muscle strength, load, 
effort, and architecture throughout the duration of MV are related to weaning outcomes.  
SA3: To determine if patient effort of breathing during both acute and weaning phases of 
MV is independently associated with the development of respiratory muscle weakness.   
Study Design: Single-center randomized controlled trial (150 children per arm) using 
REDvent (intervention arm) as compared with usual care ventilator management 
including a standardized daily SBT (control arm). Acute phase randomization will occur 
upon study enrollment, and patients who fail the first SBT will undergo a weaning phase 
randomization. We will obtain serial measurements of respiratory system capacity, load, 
effort of breathing, and diaphragm architecture throughout the course of MV.  
 
Inclusion Criteria:  
1. Children > 1 month (>44 weeks CGA) and ≤ 18 years of age AND 

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2. Supported on mechanical ventilation with pulmonary parenchymal disease (i.e., 
pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome 
(PARDS)) with Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥) 
AND 
3. Who are within 48 hours of initiation of invasive mechanical ventilation  (allow 
for up to 72 hours for those transferred from another institution)   
Exclusion Criteria:  
1. Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding, 
nasal encephalocele, transphenoidal surgery) OR 
2. Contraindications to use of  RIP bands (i.e. omphalocele, chest immobilizer or 
cast) OR 
3. Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall 
defects, pregnancy) OR 
4. Conditions on enrollment that preclude conventional methods of weaning (i.e., 
status asthmaticus, severe lower airway obstruction, critical airway, intracranial 
hypertension, Extra Corporeal Life Support (ECLS), intubation for UAO, 
tracheostomy, DNR, severe chronic respiratory failure, spinal cord injury above 
lumbar region, cyanotic heart disease (unrepaired or palliated)) OR 
5. Primary Attending physician refuses (will be cleared with primary attending 
before approaching the patient).  
 
A high level overview is presented in Figure 1. 
 
Acute Phase: The acute phase is defined as the time 
from intubation until the patient meets weaning 
criteria,15, 
16 passes the initial oxygenation test 
(decrease PEEP to 5 cmH2O and FiO2 to 0.5, 
maintains 
SpO2 
> 
90%), 
and 
undergoes 
a 
Spontaneous Breathing Trial (SBT).   
1. Intervention Arm (REDvent-acute): Patients will 
be managed with pressure control plus pressure 
support ventilation using a computerized decision 
support tool that will recommend changes to 
ventilator settings approximately every 4 hr (with 
or without a new blood gas). If the patient is 
spontaneously breathing, it will incorporate real-
time measures of effort of breathing (esophageal 
manometry) to keep it in a target range.   
2. Control 
Arm 
(Control-acute): 
Ventilator 
management will be per usual care until the 
patient meets weaning criteria and passes the 
oxygenation test.    
 
Weaning Phase: The weaning phase is defined as the time from the first Spontaneous 
Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated 
(whichever comes first). Patients who pass the initial SBT at the end of the acute phase 
will not undergo weaning phase randomization.  
1. Intervention Arm (REDvent-weaning): Patients will be managed in a pressure 
support/CPAP mode of ventilation with assessments or changes to the level of 
Figure 1: Study Schematic 

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June 29, 2017 
 
 
 
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pressure support every 4 hours, targeting maintaining effort of breathing (esophageal 
manometry) in a normal range.   An SBT will be conducted daily, and the weaning 
phase will continue until the patient passes the SBT.   
2. Control Arm (Control-weaning): Ventilator management will be per usual care.   An 
SBT will be conducted daily, and the weaning phase will continue until the patient 
passes the SBT.   
 
Endpoints:  
Primary:  
• 
Duration of Weaning (Time from first attempted SBT until SBT passage or 
extubation  [whichever comes first]) 
Secondary 
• 
Ventilator Free Days 
• 
Extubation Failure 
• 
Pre-specified and Unanticipated Adverse Events 
• 
ICU, Hospital, and 90 Day Mortality 
• 
Esophageal Manometry: Maximal Inspiratory Pressure During Airway 
Occlusion (ePiMax) 
• 
Airway Pressure: Maximal Inspiratory Pressure During Airway Occlusion 
(aPiMax) 
• 
Diaphragm Ultrasound: Change in diaphragm thickness on Exhalation (Dte) 
• 
Respiratory Inductance Plethysmography: Phase angle (PA) 
 
Analysis Plan and Sample Size Justification: 
 
Aim 1: The primary outcome is weaning duration. Sample size has been determined to 
adequately power 3 separate comparative analyses: (a) REDvent-acute versus Acute 
Phase control (b) REDvent-weaning phase versus Weaning Phase control (c) REDvent 
both phases versus control both phases.    Power is based on 2 planned methods for 
analysis: cox proportional hazard ratios for multivariable analysis and univariate 
analysis with an independent t-test using log transformation (as needed) to account for 
the expected distribution of weaning duration.  For all three of the planned comparisons 
above, with the proposed sample size we would be adequately powered (>0.8) to detect a 
difference in weaning duration of ≥ 1 day, or a hazard ratio of ≥ 1.4 between groups.  The 
secondary outcomes are ventilator free days and extubation failure.  Directly comparing 
control only patients to REDvent only patients, with an expected standard deviation for 
VFDs between 5 to 9 days, we will be able to detect a 2-day change in VFDs between 
groups with a power between 0.35 and 0.82.  Re-intubation rates are expected to be 10%, 
allowing us to confirm that REDvent is not inferior to usual care in regards to re-
intubation with a non-inferiority margin of 0.10 with a power of 0.8 and alpha of 0.05.     
 
Aim 2: The primary outcome of this aim is weaning duration.  For respiratory muscle 
strength we will compare the first measured aPiMax (after resolution of the acute phase, 
before the first SBT), the trajectory and value of the daily aPiMax during the weaning 
phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the 
day of extubation against weaning duration.  For analysis, aPiMax will be dichotomized 
at 30 cmH2O, and weaning duration  will be compared between patients with aPiMax > 
30 versus ≤ 30 cmH2O using a t-test with or without log-transformation, or Mann-
Whitney U test, depending on the distribution.  From our preliminary data, we anticipate 
at least 35% of patients (n=84) will have aPiMax ≤ 30 cmH2O.    Based on a similar 
power analysis as presented above, this would allow us to determine whether low aPiMax 

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is associated with a ≥ 1-day increase in weaning duration, with an alpha of 0.05 and 
power of 0.8.    We will perform identical analysis for ePiMax.  Diaphragm Thickness 
analysis will compound daily ultrasound measures to detect the relative change in 
diaphragm thickness from study day 1 until passage of an SBT.  We will compare the 
change in thickness after resolution of the acute phase (on the day of the first SBT) 
against weaning duration, in a similar manner as proposed above for aPiMax.  In 
addition to weaning duration, we will also examine whether the respiratory measures 
taken just prior to or during each SBT are associated with the patient passing the SBT. 
For example with aPiMax and ePiMax, we will examine if there is a dose response 
relationship between PiMax measured just before the SBT and the rate of passage of the 
subsequent SBT.   
 
Aim 3: The primary outcome of this aim is aPiMax < 30 cmH2O.The analysis will focus 
on determining whether the degree of patient effort of breathing is independently 
associated with the development of respiratory muscle weakness.  For the acute phase, 
we will generate a time-weighted average PRP during the acute phase and graph it 
against aPiMax at the first SBT.  We will subsequently dichotomize aPiMax at the first 
SBT and compare mean time weighted average PRP in the acute phase between aPiMax 
groups (> 30 vs. ≤ 30 cmH2O).  For the weaning phase, we will graph the changes in 
aPiMax throughout the weaning phase (from first failed SBT until successful SBT) 
against time-weighted average PRP, with the anticipation that low PRP will be associated 
with either further reductions in aPiMax, or no improvement, while PRP in the 
physiologic range of 150-400 will be associated with improvement in aPiMax.  We will 
subsequently dichotomize aPiMax (at 30 cm H2O) at the time of successful passage of an 
SBT and compare time-weighted average PRP in the weaning phase between aPiMax 
groups. Subsequently, we will build a multivariable logistic regression model on the 
outcome of aPiMax ≤ 30 cmH2O to determine if time-weighted PRP in the acute phase, 
weaning phase or both have an independent association with preserving aPiMax, after 
controlling for confounding variables. 
 
Monitoring: The study will one planned interim analysis at 150 patients, with no rules 
planned for early stopping, given the low risk nature of this study and the high degree of 
physiologic data collected.  In addition, there will be an early safety check after 
approximately 50 patients are enrolled, to review rates of adverse events between 
groups. There will be review of adverse events by the DSMB during scheduled meetings 
twice a year, or as requested.   

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A3 Primary Hypothesis and Specific Aims 
Our central hypothesis is that REDvent use will reduce ventilator-induced respiratory 
muscle weakness, leading to shorter time on MV by enhancing the patient’s capacity for 
effective, unsupported ventilation and by facilitating MV weaning.    This will be 
specifically tested with 3 complementary specific aims: 
 
SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the 
duration of weaning from MV (Primary outcome).  We expect that patients randomized 
to receive REDvent-acute will either pass their first SBT or experience a shorter duration 
of weaning when compared to usual care. In addition, patients randomized to receive 
REDvent-weaning will experience a shorter duration of weaning compared to usual care. 
Secondary outcomes include 28-day Ventilator Free Days and extubation failure.     
SA2: To determine if changes to direct measures of respiratory muscle strength, load, 
effort, and architecture throughout the duration of MV are related to weaning outcomes. 
We expect that diminished respiratory muscle strength (low PiMax), and diaphragm 
atrophy (ultrasound) will be prevalent after resolution of the acute phase of MV, and the 
combination of high respiratory load (or effort) with low PiMax will be a major factor 
leading to prolonged weaning and weaning failure (failure of SBT).   
SA3: To determine if patient effort of breathing during both acute and weaning phases of 
MV is independently associated with the development of respiratory muscle weakness.  
We expect that after controlling for confounding variables like age, diagnosis, sedation, 
use of neuromuscular blockade, and other risk factors for neuromuscular weakness, 
children who maintain normal effort of breathing in the acute or weaning phases will 
have higher respiratory muscle capacity as measured by PiMax.  

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B Background 
 
B1 Prior Literature and Studies 
 
 
Children supported by mechanical ventilators in intensive care units contribute 
to over $5 billion dollars a year in US healthcare costs.17, 18  Efficient methods to optimize 
ventilator support in children are lacking, resulting in some children being on ventilators 
longer than necessary.16 Each additional day of ventilation leads to added health risks 
such as exposure to medications that may harm the developing brain, higher risk of 
infection, and critical illness acquired weakness leading to long-term impairment in 
patient quality of life.17, 19-25  Mechanical ventilation (MV) of critically ill adults frequently 
leads to acquired respiratory muscle weakness, particularly of the diaphragm, which is a 
major factor contributing to extra days on MV.1, 2 Mechanisms responsible for ventilator-
induced diaphragm weakness relate to the underlying disease status of the patient, the 
severity of inflammation, the use of therapies like neuromuscular blockade and 
corticosteroids, the degree of protein catabolism, and the degree of diaphragm 
contraction during MV.1, 5, 6, 8-10, 26    Accumulating data indicate that > 50 % of critically 
ill adults who are on MV > 72 hours have thinning of the diaphragm (based on 
ultrasound) within the first few days of MV, 5  and there is a dose response relationship 
between diaphragm atrophy and increasing ventilator driving pressure.5   Moreover, low 
diaphragm contractile activity leads to atrophy, while diaphragm thickness is preserved 
when contractile activity during MV is normal (i.e., patient maintains normal work of 
breathing).27    
 
Many adult studies have demonstrated architectural changes to the diaphragm 
which occur throughout the course of mechanical ventilation, but these changes may not 
directly translate into weakness.5, 7 Respiratory muscle weakness can be objectively 
measured as the inability to generate sufficient changes in airway or esophageal pressure 
with maximal diaphragm contraction (PiMax), either voluntarily or through external 
stimulation of the phrenic nerve.  However, there are limited data quantifying the time 
frame and degree to which these direct measures of respiratory muscle weakness 
(PiMax) become impaired during MV, although evidence suggests that low PiMax at 
extubation is associated with longer lengths of MV and higher mortality in adults.8, 28   
Single direct measures of respiratory muscle strength may be misleading.  Experts in the 
field of pulmonary function testing of the respiratory muscles recommend serial 
measurements, combining multiple techniques to obtain the most comprehensive view 
of the respiratory muscles.   This approach has been used when investigating other 
causes of diaphragm dysfunction, 29  but such a systematic, multi-modal approach has 
not been applied to study ventilator induced diaphragm dysfunction in critically ill 
patients. 
 
 
  
B2 Rationale for this Study 
 
 
Few data are available regarding the prevalence of ventilator induced diaphragm 
weakness and the risk factors for its development in children, although the respiratory 
muscles of the infant and newborn are more susceptible to weakness and fatigue than 

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those of older children because of crucial differences in diaphragm histology.12, 30 
However, the pathophysiology of ventilator-induced diaphragm weakness supports in 
children, as in adults, that ventilator management in both acute and weaning phases of 
MV contribute to diaphragm weakness.4, 11  During the acute phase of MV, the goals are 
to maintain safe gas exchange, reduce excessive patient work of breathing, and prevent 
ventilator-induced lung injury through lung protective ventilation.  While prolonged 
periods of high effort of breathing should be avoided because they worsen gas exchange, 
compromise oxygen delivery and potentiate ventilator induced lung injury,  MV is often 
too highly controlled, resulting in minimal to no patient effort of breathing4 and minimal 
changes of the ventilator settings.   Consistent with other investigations 31, we have found 
that practitioners do not make changes to promote lung protective ventilation 32, 33 and 
do not reduce high ventilator settings over 50% of the time when managing MV without 
an explicit protocol, even in circumstances of respiratory alkalosis and over-ventilation.33  
Ventilator driving pressures are often higher than necessary and respiratory alkalosis 
prevents meaningful patient effort during the acute phase of MV.  This strategy results in 
high rates of fully controlled mechanical ventilation and directly leads to diaphragm 
weakness. 34 35-38 
 
When critical illness has stabilized, weaning towards extubation in current 
practice involves slow, gradual reductions of ventilator pressures until spontaneous 
breathing trials (SBTs) are performed,16, 39 although routine SBTs are only performed in 
< 25% of MV children. 33, 39  While practitioners frequently have the patient initiate 
ventilator breaths (spontaneous breathing) during weaning, the ventilator performs 
most of the required work of breathing. In general, during usual care ventilator 
management, patient breathing effort during both acute and weaning phases of MV is 
well below the normal physiologic range that would be expected if their lungs were 
healthy and off a ventilator. 4, 5 This sub-physiologic patient effort potentiates diaphragm 
weakness. 
 
We hypothesize that maintaining patient effort of breathing closer to a normal, 
physiologic range will protect against diaphragm weakness. In pediatrics, there has been 
little work developing methods to promote early return to more natural breathing in this 
physiologic range. For adults, there are a few commercially available closed-loop 
ventilation weaning systems that provide an estimate of effort of breathing, and 
concurrently reduce ventilator support during weaning.  Such systems have been shown 
to reduce length of MV by 20-40% over conventional weaning, 40 with supportive pilot 
data in older children. 41 Unfortunately, current closed-loop weaning tools are not 
available for most children, and these strategies are not initiated until the weaning phase 
of MV, allowing respiratory muscle weakness to develop during the acute phase of 
illness. 5, 42  New methods to continuously measure effort or work of breathing to guide 
ventilator management in young children are needed. 
 
Through the use of technology systems developed specifically for children, we 
seek to determine whether a physiology-based ventilator management approach can 
prevent acquired respiratory muscle weakness in children, thus facilitating MV weaning 
and earlier recovery from critical illness. 43 The approach promotes the safe reduction in 
controlled ventilation during the acute phase of MV and early return to spontaneous 
breathing with maintenance of normal patient effort of breathing in the weaning phase 
(Real-time Effort Driven ventilator management (REDvent)).  Through this study, we 
seek to understand the importance of respiratory muscle weakness in both the acute and 
weaning phases of MV in children, quantify the importance of patient effort of breathing 
for the development of respiratory muscle weakness, and determine whether REDvent 
can shorten ventilator weaning time.  This study will improve our understanding of the 
pathogenesis of ventilator-induced diaphragm weakness in children and determine 

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whether computer-driven management prevents this weakness and leads to improved 
patient outcomes.  
 
B3 Preliminary Data 
 
B.3.1 Patient effort of breathing is generally very low with usual care 
ventilation: Dr. Khemani led a study of 409 mechanically ventilated children (77% 
consent rate) in which respiratory parameters were measured using esophageal 
manometry and respiratory inductance plethysmography 44 near extubation (K23 
HL103785, PI Khemani).  From secondary analysis of that data, we found that Pressure 
Rate Product (PRP, a direct measure of patient effort of breathing derived from 
esophageal manometry) on the day of extubation under what is considered minimal 
respiratory support (PS of 10/5 cmH20) was nearly 2.5 fold lower (median 90 (50, 140)) 
than PRP post-extubation (median 220 (120, 320)).13, 14,39  Other pediatric investigators 
have demonstrated frequent periods of no detectable diaphragm effort during 
conventional ventilation, with electrical activity of the diaphragm 3 times lower during 
MV  than it was at ICU discharge. 4  Thus, current ventilator strategies do not maintain 
normal patient effort and may contribute to respiratory muscle weakness. We have also 
shown that there is a normal range for effort of breathing that can be maintained by 
adjusting ventilator support.  75% of patients from our cohort who did well after 
extubation (i.e., no re-intubation, no need for post-extubation noninvasive ventilation) 
had a PRP from 150 to 400.   These cut points appear to work across the entire pediatric 
age spectrum (neonate to 18 years), and form the basis for the “optimal range” that will 
be used for titration in this application.   
 
B.3.2 REDvent management protocol:  The computerized decision support (CDS) 
tool used by REDvent-acute is an electronic protocol that makes recommendations at 
user-set time intervals to adjust both ventilation (ventilator pressure or tidal volume and 
ventilator rate) and oxygenation (Positive End Expiratory Pressure and FiO2) to promote 
lung protective ventilation during the acute phase of MV. It implements a pediatric 
modification of the Acute Respiratory Distress Syndrome Network protocol,45 
(R21HD061870, PI Newth).  We have demonstrated that pediatric critical care 
practitioners agree on the recommendations generated by the modified protocol.46, 47  
The CDS tool has been extensively tested in our ICU to provide explicit 
recommendations, and has built-in reporting features to measure protocol adherence.  
REDvent-weaning recommends adjusting supported ventilator pressures based on real-
time direct measures of effort of breathing using RESPivice. RESPivice is an open-loop 
patient monitor that incorporates an esophageal manometry catheter and Respiratory 
Inductance Plethysmography Bands (RIP Bands) connected to a hardware box that  
passes signals to a laptop computer. 48, 49 The esophageal manometry catheter (which has 
an integrated feeding tube) is used for continuous effort of breathing calculations and 
RIP bands allow for measurement of  phase angle (a measure of thoraco-abdominal 
asynchrony), and can be calibrated to measure flow or volume after extubation. 49  
 
B.3.3 Phase I trial using REDvent protocols: To test the feasibility of REDvent in 
MV children, Dr. Khemani led an open label, intervention only Phase I study enrolling 
20 children <18 yr of age with pulmonary parenchymal disease and an anticipated 
intubation of > 48 hours (83% consent rate).  Details of the REDvent management 
protocol are summarized in Figure 2. The acute phase of ventilator management was 

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controlled by the CDS tool with a ventilator recommendation generated every 4 hr, or 
with a new blood gas value.  If a blood gas was not available at the 4 hr interval, then 
non-invasive parameters (pulse oximetry and end-tidal CO2) were used to provide 
estimates for the adequacy of oxygenation and ventilation based on prediction models we 
have previously validated. 50   When patients met weaning criteria (no increase in 
ventilator support for 24 hr, spontaneous breathing, PEEP ≤ 10 cmH2O, FiO2 ≤ 60%), 
they had an oxygenation test (decease PEEP to 5, Fio2 ≤ 0.5, maintain SpO2 > 88%). If 
they passed the oxygenation test, they were then given a SBT on CPAP of 5 cmH2O and 
then extubated (i.e. both clinical and effort of breathing criteria were met).  If they failed 
the SBT, they were initiated on the effort of breathing part of the study and pressure 
support was added to PEEP to maintain PRP in the target range.  After patient 15, we 
modified the weaning protocol to allow 3 ranges for adjustment (Figure 2) to better fit 
with clinical practice and improve adherence.  Every 4 hr, a recommendation was given 
to adjust pressure support by 2 cmH2O to keep PRP in the target range (200-400) .  The 
SBT and extubation evaluation were performed every 24 hr. 
 
B.3.4 The protocol has the potential to shorten duration of ventilation: We 
have completed the Phase I study described above.  During the acute phase, 698/966 
recommendations were accepted (73% adherence). During the weaning phase 136/187 
(73%) recommendations were accepted. However, after the protocol modification for the 
weaning phase, 96% of the recommendations were followed.   Over 40 bedside 
respiratory therapists have used the acute and weaning protocols.  A study respiratory 
therapist has been providing initial training of the bedside RT.  In addition the study RT 
or PI has been available during the day and as needed by phone at night. Specific 
training sheets have been developed, overnight support by research personnel was 
generally minimal, and no safety concerns were identified.  MV is generally weaned 
steadily in both acute and weaning phases.   As the Phase I study did not have a control 
group, we used matched historical controls that were similar with respect to age and 
 
Figure 2: Details of REDvent protocol for both acute and weaning phases.    
 

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Figure 3: Re-intubation rates increase in a dose response fashion as a 
function of low  aPiMax.    
initial hypoxemia severity, with a similar percentage of immune compromise, sepsis and 
pneumonia 
patients 
between groups. Patients 
treated 
with 
REDvent 
had larger changes in 
Peak 
Inspiratory 
Pressure and Ventilator 
Rate per day in the acute 
phase as compared with 
historical 
controls.  
REDvent was associated 
with 
approximately 
2 
fewer days on MV (25% 
reduction) compared to 
historical 
controls 
(p=0.36, Table 1). While not statistically significant due to the small sample size, 
REDvent appears to lead to faster MV weaning.   
 
B.3.5 Ventilator-induced respiratory muscle weakness is common in 
children, leading to failed extubation: Accurate quantification of the severity of 
diaphragm dysfunction is understudied, particularly in pediatrics.  While diaphragm 
ultrasound can provide corroborative data about architectural changes, ultrasound does 
not directly measure strength. 3, 5, 7, 51, 52  Single measures of respiratory muscle strength 
(airway or esophageal PiMax) measured with maximal voluntary efforts during airway 
occlusion are regarded as the most appropriate tests in adults.29 To specifically examine 
diaphragm strength (isolated from the intercostal muscles), two simultaneous pressure 
transducers (one in the esophagus and one in the stomach) can be used to calculate 
trans-diaphragmatic pressure. 29, 53  When patients are intubated, there is divergence in 
the literature as to whether maximal voluntary efforts can be guaranteed,26, 29, 54-57  
prompting 
investigators 
to 
use twitch stimulation of the 
phrenic 
nerve 
through 
electrical or magnetic coils 
with resultant measures of 
airway 
or 
esophageal 
pressure,29, 58 . Although this 
technique has been applied in 
a very limited capacity in 
young children, it has high 
variability 
and 
limited 
reproducibility. 59-64   
 
An analysis of the 409 
patients 
enrolled 
in 
our 
previous study suggested that low PiMax (both airway (aPiMax) and esophageal 
(ePiMax)) measured during airway occlusion while the child is breathing spontaneously, 
was associated with re-intubation. 65 A trained provider (research respiratory therapist 
or study PI) performed airway occlusion maneuvers to measure both aPiMax and 
ePiMax, ensuring that the child was at end-exhalation and that the airway remained 
occluded for at minimum 3 consecutive breaths, but most of the time at least 5,57 just 
before extubation.  Measures of respiratory system capacity were obtained prior to 
extubation during airway occlusion, and measures of respiratory effort were obtained 
Table 1: Comparison between REDvent and 
historical controls 
REDvent 
(n=19) 
Matched Controls 
(n=90) 
Matching Variables   
Age (years) 
9.2 (3.2,12.3) 
7.0 (0.9,14.2) 
Oxygen Saturation Index (OSI) 
15.9 (10.6,16.2) 
14.1 (9.6,19.4) 
High Frequency Oscillator (HFO) 
17% 
17% 
Immune Compromised 
39% 
32% 
Pneumonia 
50% 
58% 
Sepsis 
38% 
39% 
Outcomes  
Daily Change PIP Acute Phase 
4 (2,5) 
1.5 (1,3) 
Daily Change Vent Rate Acute Phase 
3 (0,4) 
1 (0,2) 
        Length of MV (days) 
6.5 (4.9,8.7) 
8.4 (4.5,13.9) 

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both before and after extubation.   Of the 409 patients, 34 were re-intubated within 48 
hours (8.3%).   Prior to extubation, re-intubation risk factors included lower aPiMax, and 
longer length of ventilation.  After extubation, post-extubation upper airway obstruction 
(UAO), high respiratory effort or load (Pressure Rate Product (PRP), Pressure Time 
Product (PTP), Tension Time Index (TTI)) and high Phase Angle (PA) were associated 
with re-intubation.  Because patients in this study had already passed SBTs, they 
generally had near normal compliance (low load), so pre-extubation respiratory effort 
was not associated with re-intubation. When looking specifically at measures of 
respiratory muscle capacity prior to extubation, there was a dose response relationship 
between lower aPiMax and re-intubation risk (Figure 3).  Children with aPiMax ≤ 30 
cmH20 accounted for 33% of all extubated patients, but were responsible for 56% of all 
failed extubations (19/34).  Thus, aPiMax alone is a marker of re-intubation risk (AUC 
0.66 (0.57, 0.75).   
Nevertheless, 
combining 
aPiMax 
with 
measures 
of 
respiratory 
effort 
(after 
extubation) such as PRP better 
predicted 
re-intubation 
risk 
(AUC 0.77).   For children with 
diminished respiratory muscle 
capacity (aPiMax ≤ 30 cmH2O), 
re-intubation rates were always 
higher 
than 
the 
population 
average, 
and 
they 
became 
accelerated as effort increased 
(PRP>500). 
Children 
with 
maintained respiratory muscle 
capacity (aPiMax >30 cmH2O) could tolerate moderate to high levels of load after 
extubation (PRP 500-1000), and re-intubation rates did not exceed the population 
average unless effort was very high (PRP > 1000).  Post-extubation subglottic UAO was 
the most common reason for high respiratory muscle load after extubation, and when 
children with diminished respiratory muscle capacity (aPiMax ≤ 30 cmH2O) had 
subglottic UAO after extubation, their re-intubation rates were 5.7 times higher than the 
population average (47.5% vs. 8.3%, Figure 4).  The rate of aPiMax ≤ 30 cmH2O was 
slightly higher for neonates (47%) compared to the other age groups, although this was 
not statistically significant (p=0.12; 30% infants (1-24 months), 30 % child age (2-11 
years) and 34% adolescents (11-18 years)).  Multivariable risk factors for re-intubation 
include primary intubation for neurologic disease, lower aPiMax, UAO post-extubation, 
higher PEEP before extubation, higher PRP after extubation, and lower height (AUC 
0.823).  This demonstrates that respiratory muscle weakness contributes to 
extubation failure, and maintaining respiratory muscle strength will likely reduce re-
intubation rates even when respiratory load after extubation is high.  These data further 
support the hypothesis that children with respiratory muscle weakness will 
have more trouble weaning from MV when respiratory load (compliance, 
resistance) may still be high.  
 
B.3.6 Summary of Preliminary Data: We have demonstrated that 35% of MV 
children have respiratory muscle weakness at the time of extubation, making them 3 
times more likely to be re-intubated, and nearly 6 times more likely to fail when 
respiratory load is high.65, 66 We have also shown that current ventilator management in 
children likely exacerbates the development of respiratory weakness by lowering patient 
 
Figure 4: When children with low aPiMax develop high respiratory 
load (such as from post extubation UAO), they have very high re-
intubation rates. Solid line is population average.    

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effort of breathing well below normal physiologic values.13, 14  To promote maintaining 
patient effort of breathing in a normal range we have developed and demonstrated the 
feasibility of having bedside providers use a computer-based ventilator management 
system throughout the entire course of MV.  Patients managed with this system 
experienced a median 2 day reduction in the length of MV compared to historical 
controls.  Together these data justify the next phase of this program of research, to test 
whether this ventilator management approach can lead to improved clinical outcomes in 
a robust randomized clinical trial, and to characterize the mechanisms underlying this 
improvement through detailed, serial assessments of the respiratory muscles.   
 
 

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C Study Objectives 
 
C1 Primary Aim 
SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the 
duration of weaning from MV.  We expect that patients randomized to receive REDvent-
acute will either pass their first SBT or experience a shorter duration of weaning when 
compared to usual care. In addition, patients randomized to receive REDvent-weaning 
will experience a shorter duration of weaning compared to usual care. Secondary 
outcomes include 28-day Ventilator Free Days and extubation failure.     
C2 Secondary Aims 
 
SA2: To determine if changes to direct measures of respiratory muscle strength, load, 
effort, and architecture throughout the duration of MV are related to weaning outcomes. 
We expect that diminished respiratory muscle strength (low PiMax), and diaphragm 
atrophy (ultrasound) will be prevalent after resolution of the acute phase of MV, and the 
combination of high respiratory load (or effort) with low PiMax will be a major factor 
leading to prolonged weaning and weaning failure (failure of SBT).   
SA3: To determine if patient effort of breathing during both acute and weaning phases of 
MV is independently associated with the development of respiratory muscle weakness.  
We expect that after controlling for confounding variables like age, diagnosis, sedation, 
use of neuromuscular blockade, and other risk factors for neuromuscular weakness, 
children who maintain normal effort of breathing in the acute or weaning phases will 
have higher respiratory muscle capacity as measured by PiMax.  
C3 Rationale for the Selection of Outcome Measures 
 
C.3.1. Clinical outcome measures:  
 
1. Primary Outcome – Weaning Duration  
Weaning duration is defined as the time from the first spontaneous breathing 
trial (SBT) until successful passage of an SBT or successful extubation (whichever 
comes first).  Successful extubation is defined as removal of the endotracheal 
tube without re-intubation for at least 24 hours.  SBT passage will be based on 
objective criteria, based on previous publications.   
 
a.  Criteria for SBT passage: SBTs will be performed when weaning criteria are 
met, and the patient passes the oxygenation test (maintenance of SpO2 > 
90% with FiO2 ≤ 0.5 and PEEP ≤ 5 cmH20).  SBTs will be performed on 
CPAP ≤ 5 cmH2O, for 2 hours duration.  The following criteria represent rules 
for study defined SBT failure at any time point during the 2 hour SBT.   
 
Variable 
Failure within 2 hours 
pH (arterial or capillary) 
< 7.32  
End tidal CO2 
10 mmHg from baseline 
Oxygenation  
FiO2 >0.5 and SpO2 <90% on PEEP 

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=5 cmH20 
HR 
 > 40 BPM over baseline 
Rapid Shallow Breathing Pattern 
(RSBI) (bpm/ml/kg) 
≥ 12 
Pressure.Rate.Product (PRP) 
>500 
Retractions 
Moderate or Severe 
 
 
b. Rationale for passing SBTs vs. extubation in defining weaning duration: SBTs 
systematically assess the patient’s readiness to resume unassisted ventilation, 
while extubation can be delayed after SBT passage (due to respiratory 
secretions, procedures, etc.).  For this reason, SBT passage or successful 
extubation (whichever comes first) will define the end of the weaning phase.  
If a patient passes an SBT but is not extubated within 6 hr, ventilator 
management until extubation will continue as per the group to which the 
patient has been randomized for the current phase of ventilation.  However 
the length of weaning for the primary outcome measure will be calculated as 
the time the patient passed the SBT.   If a patient does not pass the SBT, but 
the clinical team elects to extubate the child (or the child has an unplanned 
extubation), and the child is not re-intubated within 24 hours, then the length 
of weaning for the primary outcome measure will be calculated as the time 
the patient was extubated.   
     
2. Duration of Invasive Mechanical Ventilation (IMV)- Secondary Outcome 
Duration of invasive ventilation is the number of days and hours that the patient 
is intubated (from insertion to removal), censored 60 days after study 
enrollment. For calculations, removal of the ETT will be calculated as the first 
time the tube is continuously absent for at least 24 hours.  Re-intubation after 24 
hours and subsequent periods of invasive mechanical ventilation within 60 days 
of study enrollment will be summed together to represent total duration of IMV. 
 
3. Duration of Non-Invasive Mechanical Ventilation (NIV) after extubation– 
Secondary Outcome  
Duration of non-invasive ventilation after extubation is defined as the number of 
days and hours that the patient is on oro-nasal mask CPAP with minimal 
pressure of 5 cmH20, or Bi-Level ventilation (at any pressure) after extubation, 
censored 60 days after study enrollment. For calculations, the end of Non-
Invasive Ventilation will be calculated as oro-nasal mask CPAP (minimal 5 
cmH2o) or BIPAP as continuously absent for at least 24 hours.  Resumption of 
NIV after 24 hours and subsequent periods of non- invasive mechanical 
ventilation within 60 days of study enrollment will be summed together to 
represent total duration of NIV after extubation. 
 
4. Duration of Non-Invasive Mechanical Ventilation (NIV) before intubation– 
Secondary Outcome  
Duration of non-invasive ventilation before intubation is defined as the number 
of days and hours that the patient is on oro-nasal mask CPAP with minimal 
pressure of 5 cmH20, or Bi-Level ventilation (at any pressure) prior to 
intubation.  This is necessary to correctly compute ventilator free days.  For 
calculations, the patient must have been on Non-Invasive Ventilation in the 24 
hours prior to intubation.   
 

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5. Duration of Non-Invasive Respiratory Support (NRS) after extubation- 
Secondary Outcome 
Non-invasive respiratory support includes: High Flow Nasal Cannula (HFNC) or 
nasal-only modes of non-invasive ventilation (CPAP or Nasal IMV or BiPAP). It 
does not include oxygen therapy via face mask, nasal cannula, oxygen hood, or 
blow by oxygen alone.    Duration of NRS after extubation is defined as the 
number of days and hours that the patient is on NRS after extubation, censored 
at 60 days after study enrollment. For calculations, the end of NRS will be 
calculated as NRS being continuously absent for at least 24 hours.  Resumption 
of NRS after 24 hours and subsequent periods of NRS within 60 days of study 
enrollment will be summed together to represent total duration of NRS after 
extubation. 
 
6. Re-intubation within 48 hours of extubation- Secondary Outcome  
Re-intubation will be defined as re-insertion of the endotracheal tube within 48 
hours of the initial extubation. 
 
7. Re-intubation within 7 days of extubation- Secondary Outcome 
Re-intubation will be defined as re-insertion of the endotracheal tube within 7 
days of the initial extubation. 
 
8. Ventilator Free Days- Secondary Outcome  
Because the acute phase of ventilation is often long and less predictable, weaning 
duration was chosen as the primary outcome because there is more variability in 
Ventilator Free Days (VFDs) than in weaning duration.   However VFDs is a 
secondary outcome.   VFDs will be calculated at 28 and 60 days, defined as total 
number of days after initiation of MV in which the patient is alive and not on 
ventilation.  The components of length of mechanical ventilation used for VFD 
calculations include length of IMV (2 above), length of NIV after extubation (3 
above) and length of NIV prior to intubation (4) above.  Patients who die within 
the 28 or 60 days will have 0 28 or 60 Day VFDs respectively.   
 
9. Use and duration of rescue therapies - Secondary Outcomes 
We will track daily whether the patient received any of the following “rescue 
therapies” which are frequently used for ARDS management: inhaled nitric oxide, 
High Frequency Oscillatory Ventilation, Prone Positioning, Extra Corporeal Life 
Support, Corticosteroids for lung disease/ARDS, Continuous Neuromuscular 
Blockade, Airway Pressure Release Ventilation.      
 
C.3.2 Physiologic outcome measures: Our primary physiologic outcome surrounds 
respiratory muscle weakness.  Previous research has highlighted the importance of using 
multiple assessments of respiratory muscles, as single tests may be misleading. 67  We 
will use esophageal manometry, airway pressure, and diaphragm ultrasound to evaluate 
direct and indirect measures of respiratory muscle strength. 
 
1. Respiratory Muscle Strength (aPiMax- Primary Outcome; ePiMax – Secondary 
Outcome):  
a. Physiologic measures of strength include airway and esophageal pressure during 
airway occlusion (aPiMax and ePiMax, respectively).   Primary analysis is 
planned using aPimax (calculated as maximal change in airway pressure at end 
exhalation during airway occlusion for 3-5 breaths).   Secondary analysis will use 

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ePimax (calculated as maximal change in esophageal pressure at end exhalation 
during airway occlusion for 3-5 breaths).  Measurements will be obtained daily 
after the patient passes the oxygenation test.   
b. Rationale:  We found aPiMax better predicted re-intubation than ePiMax in our 
preliminary data. We believe that this is due to more artifacts in the esophageal 
pressure signal during airway occlusion, which are not present with airway 
pressure.  To isolate diaphragm weakness, a second balloon catheter would be 
necessary to calculate trans-diaphragm pressure.  However, this is not practical 
for repeated use in children and no double-balloon catheters are commercially 
available for infants. A second catheter in an already small esophagus may alter 
the signals further, and impede clinical care if the catheter is left in place. While 
we will measure both airway and esophageal PiMax, we plan to use aPiMax as the 
primary marker of respiratory system capacity.  Our previous study evaluated 
PiMax parameters only at extubation, but we are confident the technique can be 
applied earlier (i.e., just prior to SBTs), and have obtained them successfully as 
part of our pilot study.   Early in the course of MV, patients may be more sedated 
than they are at the time of extubation (but are still breathing spontaneously), 
but we have successfully measured both airway and esophageal PiMax in  
patients who are considerably more sedated, and in deeply sedated rhesus 
monkeys.48  Sedated patients still produce reliable PiMax measurements when 
using our methodology, particularly when 5 occluded breaths are used.  We will 
also calculate P0.1 (change in airway or esophageal pressure in the first 0.1 
seconds of a breath attempt) which can be used to identify if sedation is affecting 
the results of the PiMax measurements.    All PiMax procedures will be recorded 
for post-processing analysis.  
 
2. Diaphragm Architecture:  Serial measurements from diaphragm ultrasound will be 
performed daily to assess changes in diaphragm thickness during exhalation (Dte) 
during both acute and weaning phases. 3, 5-8, 26, 52, 68-73 For the acute phase, the main 
diaphragm ultrasound outcome is: change in diaphragm thickness from study 
initiation until the end of the acute phase.  For the weaning phase it is: change in 
diaphragm thickness from the end of the acute phase until the end of the weaning 
phase.  Because diaphragm ultrasound is non-invasive, it has advantages although it 
has not been validated against direct measures of respiratory muscle strength or 
weaning outcomes. We will attempt such a validation with this study, but have not 
selected it as the primary physiologic endpoint for that reason.   
 
D Study Design  
 
D1 Overview or Design Summary 
We propose a single-center randomized controlled trial (150 children per arm) using 
REDvent (intervention arm) as compared with usual care ventilator management 
including a standardized daily SBT (control arm). Acute phase randomization will occur 
upon study enrollment, and patients who fail the first SBT will undergo a weaning phase 
randomization. We will obtain serial measurements of respiratory system capacity, load, 
effort of breathing, and diaphragm architecture throughout the course of MV. 

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D2 Subject Selection  
D.2.1 Inclusion Criteria  
1. Children > 1 month (at least 44 weeks Corrected Gestational Age) and ≤ 18 years 
of age AND 
2. Supported on mechanical ventilation for pulmonary parenchymal disease (i.e., 
pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome 
(PARDS)) with Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥4 
74 AND 
3. Who are within 48 hours of initiation of invasive mechanical ventilation (allow 
for up to 72 hours for those transferred from another institution)   
 
D.2.2 Exclusion Criteria  
1. Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding, 
nasal encephalocele, transphenoidal surgery) OR 
2. Contraindications to use of  RIP bands (i.e. omphalocele, chest immobilizer or 
cast) OR 
3. Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall 
defects, pregnancy) OR 
4. Conditions precluding conventional methods of weaning (i.e., status asthmaticus, 
severe lower airway obstruction, critical airway, intracranial hypertension, Extra 
Corporeal Life Support (ECLS), intubation for UAO, tracheostomy, DNR, severe 
chronic respiratory failure, spinal cord injury above lumbar region, cyanotic heart 
disease (unrepaired or palliated)) OR 
5. Primary Attending physician refuses (will be cleared with primary attending 
before approaching the patient).  
D2.3 Screening and Eligibility  
Screening will occur daily to identify eligible patients.  An automated report has been 
generated to facilitate screening which calculates the oxygen saturation index, 
oxygenation index, PF ratio, and SF ratio for all patients on mechanical ventilation in the 
ICU.  Patients who have had qualifying hypoxemia (OSI >5 or OI >4) in the previous 24 
hours will have their chart reviewed to determine complete eligibility based on meeting 
all inclusion criteria and no exclusion criteria.   
D3 Study Interventions  
The study intervention includes both acute and weaning phase components.  A high level 
view of the study is summarized in figure 5 below.     
 
D.3.1 Acute Phase: The acute phase is defined as the time from intubation until the 
patient meets weaning criteria,15, 16 and passes the initial oxygenation test (decrease 
PEEP to 5 cmH2O and FiO2 to 0.5, Figure 6).   
 
D.3.2 Acute Phase, Intervention Arm (REDvent-acute): Patients will be 
managed with pressure control plus pressure support ventilation with the CDS tool that 
will recommend changes to ventilator settings every 4 hr or with a new blood gas. The 
computerized decision support (CDS) tool used by REDvent-acute is an electronic 

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protocol that makes recommendations at to adjust both ventilation (ventilator pressure 
or tidal volume and ventilator rate) and oxygenation (Positive End Expiratory Pressure 
and FiO2) to promote lung protective ventilation during the acute phase of MV.  Details 
of the rules behind the actual protocols are in section I.  PEEP/FiO2 is based on a 
PEEP/FiO2 table adapted from the Acute Respiratory Distress Syndrome Network 
protocol,45 (R21HD061870, PI Newth).  Ventilation is changed based on pH range, Peak  
Inspiratory Pressure, and Ventilator Rate.  
When the patient is breathing spontaneously 
during 
the 
acute 
phase, 
the 
Pressure.Rate.Product (PRP) is incorporated 
into 
the 
algorithm. 
The 
pH 
based 
recommendations are followed if increasing 
support is recommended. If the pH based 
recommendation is to decrease support, it 
will only do so if the PRP is below 200.  If the 
PRP 
is 
between 
200-400, 
support 
is 
maintained.  If the PRP is above 400, the 
protocol will recommend increasing driving 
pressure (Delta P) by 2 cm H20, to a max of 
35 cmH20.  The use of High Frequency 
Oscillatory (HFO) Ventilation as a rescue 
therapy will be left to the bedside clinicians, 
but HFO management will continue to be 
protocolized using the HFOV CDS tool 
(expected use: 10-15% in this cohort).   This 
protocol has a MAP/FiO2 table, and also 
recommends alterations in Amplitude and 
Hertz based on pH.  Details of the rules of the 
protocols are in section I.   
 
D.3.3 Acute Phase, Control Arm: Ventilator management will be per usual care 
until the patient meets weaning criteria and passes the oxygenation test (Figure 6).    
 
Figure 5: High level view of study interventions for 
both arms, during acute and weaning phases 

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D.3.4 Acute Phase Monitoring, both arms: Patients will be fitted with an 
esophageal manometry catheter, will undergo diaphragm ultrasound measurements, and 
will be connected to RIP bands during SBTs.  Once the patient passes the oxygenation 
test, an airway occlusion maneuver will be performed to measure neuromuscular 
strength, followed by a SBT.  Daily SBTs are required and will be performed between 9 
and 11 AM on CPAP of 5 cmH2O.     The primary study outcome (length of the weaning 
phase) is defined as the time from initiation of the first SBT until successful passing of an 
SBT (or extubation, whichever comes first). We will use validated objective criteria to 
define successful passing of the SBT, and track delays in extubation (> 6 hr between SBT 
passing and extubation).  These criteria are based on our previous publications and are 
detailed in the description of the primary outcome above, and again below. 16, 75  Patients 
who fail the initial SBT will move on to the weaning phase, and will undergo the weaning 
phase randomization to allocate treatment or control arms for weaning management.  
 
D.3.5 Spontaneous Breathing Trials and success/failure 
 
Variable 
Failure within 2 hours 
pH (arterial or capillary) 
< 7.32  
End tidal CO2 
10 mmHg from baseline 
Oxygenation  
FiO2 >0.5 and SpO2 <90% on PEEP = 
5 cmH20 
HR 
 > 40 BPM over baseline 
Rapid Shallow Breathing Pattern 
(RSBI) (bpm/ml/kg) 
≥ 12 
Pressure.Rate.Product (PRP) 
>500 
Retractions 
Moderate or Severe Retractions 
 
 
Figure 6: Acute Phase schematic, both arms 

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For the outcome of SBT passage, if any of the above criteria are met during the 2 hour 
SBT, the patient will be labeled as failing the SBT for study purposes. Once any of these 
failure criteria are met, the respiratory therapist will alert the clinical team.  The clinical 
team may choose to stop the SBT, in which case the patient will be returned to the 
previous ventilator settings, and weaning phase randomization will occur.  If the patient 
is randomized to REDvent-weaning, they will be placed in PS/CPAP mode and pressure 
support will be titrated to achieve PRP between 200-400 (to max of 20). PEEP may be 
adjusted between 5 and 10 cmH20.     The clinical team may alternatively choose to 
continue the SBT or to extubate the patient. If the patient is extubated, post-extubation 
management (and subsequent re-intubation management) will be usual care.  If the 
patient is not extubated but the SBT is terminated by the clinical team, then weaning 
phase randomization will occur at that point.    
 
Monitoring during the SBT will include placement of Respiratory Inductance 
Plethysmography (RIP) bands and a spirometer.  Vital signs, physiologic measurements, 
and data from RIP and esophageal manometry will be recorded every 30 minutes during 
the SBT. A study ultrasound to measure diaphragm contractile activity will occur 
approximately 15 minutes into the SBT.   
 
If the patient successfully passes the SBT, extubation readiness criteria will be confirmed 
(i.e. cough, gag, handling secretions, no procedures planned). If the patient meets 
extubation readiness criteria, the recommendation will be for extubation to the clinical 
team.  If the patient does not meet extubation readiness criteria, they return to acute 
phase management (to whichever group they were randomized), and another SBT will be 
repeated 24 hours later.  If a recommendation for extubation was given but actual 
extubation is delayed beyond 6 hours, the reasons will be recorded on the case report 
forms, and the acute phase intervention will be resumed.  If the patient is extubated as 
recommended, the esophageal catheter and RIP bands will remain in place for 1 hour 
after extubation to monitor post-extubation effort of breathing.   
 
If the patient fails the SBT, they will go on to the weaning phase randomization. 
 
D.3.6 Weaning Phase: The weaning phase is defined as the time from the first SBT 
until the patient successfully passes an SBT.  
 
D.3.7 Weaning Phase, Intervention Arm (REDvent-weaning): The weaning 
phase in the intervention arm uses esophageal manometry and a custom built hardware 
and software package for effort of breathing guided management.  The patient will be 
placed in a pressure support mode of ventilation and PRP will be monitored 
continuously, adjusting pressure support (to a max of 20 cmH20) every 4 hr to maintain 
PRP in the target range (Figure 7).  Effort of Breathing guided management will continue 
until the patient passes a SBT.  The esophageal balloon is inflated to a daily prescribed 
volume every 4 hours prior to assessment, based on an optimal filling volume algorithm. 
The median PRP over 10-20 breaths during calm periods of breathing (i.e. not agitated, 
not recently suctioned etc) is inputted into the computer decision support tool, which 
subsequently generates the recommendation regarding changing the level of pressure 
support. 
 

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D.3.8 Weaning Phase, Control Arm: 
Ventilator management will be per usual care 
until the patient passes a SBT.      
 
D.3.9 Weaning Phase, Monitoring both 
groups: In both groups, a daily airway 
occlusion 
maneuver 
and 
SBT 
will 
be 
performed, with the same rules above in 
section D.3.5 regarding SBT passage and 
monitoring.   
 
D.3.10 
Post-extubation 
Management: 
The decision to use non-invasive ventilation 
and other post-extubation management will 
not be protocolized, regardless of study arm.   
Patients who are re-intubated after a planned 
extubation (regardless of study arm) will 
subsequently receive usual care ventilation.  
The esophageal catheter and RIP bands will be 
removed 1 hour after extubation. 
 
D.3.11 Suspension of Weaning Phase: 
Suspension of the weaning phase is permitted for up to 12 hours for situations such as 
procedures, increased need for sedation preventing adequate spontaneous breathing, 
transient increase in ventilator support etc.  As soon as the patient appropriately meets 
weaning criteria (based on weaning criteria screen Figure 6), the weaning phase 
intervention is resumed.   
 
D.3.12 Failure of the Weaning Phase: If the weaning phase is suspended for > 12 
hours and the patient no longer meets weaning criteria at the 12 hour mark (Figure 6), 
then the acute phase of management and monitoring is resumed.  The patient will be 
managed as per their pre-assigned acute phase group (i.e. REDvent-acute or usual care).  
Once weaning criteria are met, an SBT will again be performed. If the patient fails the 
SBT, then the weaning phase intervention to which they were previously randomized 
(REDvent-weaning or usual care) is resumed.  The frequency with which weaning failure 
occurs in both arms will be tracked as an adverse event.   
 
D.3.13 Termination of study interventions at 28 days: If the patient has not 
passed the SBT by day 28 after enrollment, study interventions and daily measurements 
will be terminated.  All ventilator management will be as per usual care.  Clinical 
outcomes will continue to be followed.   
 
D.3.14 Post Enrollment exclusion criteria: Patients who develop exclusion criteria 
after study enrollment that preclude continuation of the study interventions (i.e. use of 
ECLS, new condition requiring removal of esophageal catheter) will have the study 
protocol and measurements terminated, but clinical outcomes will continue to be 
followed and analysis will be as per intention to treat.  For patients who are made allow 
natural death status during the study, parents will be given the option to either continue 
the study protocol, or withdraw from the study.   Clinical outcomes will continue to be 
followed.  Patients who develop a condition which may preclude calculation of secondary 
 
Figure 7: Weaning Phase schematic, both arms 

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outcomes (i.e. diaphragm ultrasound or RIP bands) will continue to receive study 
interventions, and all planned study measurements which can reasonably be obtained.   
D4 Measurement of Study Variables 
Demographics, clinical variables, and outcomes will be measured as detailed in the table 
below (data collection timeline). To ensure the adequacy of randomization and 
understand the risk factors that may contribute to neuromuscular weakness and weaning 
failure, we will gather detailed, serial data for variables that may be related to weaning 
duration and development of neuromuscular weakness.1, 5, 6, 8-10, 26 These variables are 
based upon our recent consensus-based guidelines for clinical trials in children with 
pediatric ARDS. 76     Identical measurements of respiratory parameters will occur for all 
patients enrolled in the study (regardless of study arm) (1) serially during both acute and 
weaning phases, (2) during airway occlusion prior to SBTs, and (3) during SBTs (Table 
below).    
 
D.4.1 Serial respiratory measurements during acute and weaning phases: 
We will measure patient effort of breathing twice daily with esophageal manometry 
(using Pressure Rate Product [PRP] and Pressure Time Product [PTP]) and once daily 
using diaphragm ultrasound (using Diaphragm Contractile Activity [DCA]), during the 
acute and weaning phases in both arms.  DCA is obtained by measuring the thickness of 
the right hemi-diaphragm and calculating the percent difference between diaphragm 
thickness on inspiration and exhalation. Diaphragm ultrasound measurements will be 
performed independently by 2 practitioners, one of whom is specifically trained in acute 
care ultrasound.  We will also use ultrasound to measure diaphragm thickness on 
exhalation and monitor how this changes serially over time as a measure of the 
architecture of the diaphragm. Finally, we will measure respiratory load (resistance, 
compliance) daily using spirometry.  The clinical team will remain blinded to the results 
of these measurements in both arms.  
 
D.4.2. Spontaneous Breathing trial respiratory measurements during 
Airway Occlusion: Prior to each SBT, we will perform a standardized airway occlusion 
maneuver to measure neuromuscular capacity with aPiMax (airway) and ePiMax 
(esophageal), as described in the Preliminary Data.    In addition, during airway 
occlusion we will measure DCA (as above)  5, 7, 51, 52, to provide complementary data to 
PiMax. The clinical team will remain blinded to the results of these measurements in 
both arms.  
 
D.4.3 Weaning trial measurements during SBTs: During SBTs, respiratory effort 
and capacity will be measured with PRP, PTP, inspiratory pressure from esophageal 
manometry (Pi), Pi/ePiMax, Tension Time Index (TTI), Phase angle (PA), and DCA. 
Patients will be monitored continuously during the SBT, and all of these measures will be 
recorded at the beginning of the SBT, and then every 30 minutes (for 5 minute periods) 
to monitor respiratory muscle endurance over time.   The PRP measurements will be 
shared with the clinical team in both arms because they will be used to help define 
passage of SBTs (as above).  Clinical providers will remain blinded to the results of the 
other measurements in both arms.   
 
 
 

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Data Collection timeline  
Enroll-
ment 
Acute 
(Daily) 
Weaning 
(Daily) 
SBT 
Post-
Extubation 
Demographics (age, race, gender, past medical history, 
primary diagnoses, comorbidities, PRISM-III-12 severity of 
illness scores, height, weight) 
 
 
 
 
 
Clinical Variables ( total dose of sedatives, analgesics, 
highest/lowest/modal sedation scores, pain scores, 
corticosteroids, aminoglycosides, fluid balance,  caloric and 
protein intake, hypoxemia markers, dead space markers, 
ventilator type and settings (q6h), blood gasses (all), 
inotropes/vasopressors, organ failure scores (PELOD), 
procedures) 
 
 
 
 
 
Effort of Breathing and Respiratory Load 
Esophageal Manometry: PRP, PTP, TTI, Pi 
 
 
 
 
 
Respiratory Inductance Plethysmography 44: Phase 
Angle (PA) 
 
 
 
 
 
Ultrasound: Diaphragm Contractile Activity (DCA) 
 
 
 
 
 
Spirometry: Resistance, Dynamic and Static 
Compliance 
 
 
 
 
 
Respiratory Muscle  Strength (during airway occlusion) 
Esophageal Manometry: Esophageal PiMax (ePiMax) 
 
 
 
 
 
Airway Pressure: Airway PiMax (aPiMax) 
 
 
 
 
 
Ultrasound: DCA during airway occlusion 
 
 
 
 
 
Diaphragm Architecture (Thickness on Exhalation) 
 
 
 
 
 
Outcomes (Weaning Duration, VFDs and components, re-
intubation, Non-Invasive Ventilation use and duration, ICU, 
Hospital, 90-day mortality)  
 
 
 
 
 
 
D.4.4 Rationale for respiratory measures:  Previous research has highlighted the 
importance of using multiple assessments of respiratory muscles, as single tests may be 
misleading. 67  We will use four classes of respiratory monitoring: esophageal 
manometry, diaphragm ultrasound, RIP, and ventilator/clinical data.    Our primary 
interest is respiratory muscle strength, which is best characterized during airway 
occlusion with PiMax.  PiMax measurements will be done as soon as the acute phase has 
resolved, and daily during the weaning phase, because PiMax is not feasible to measure 
during the acute phase of MV because patients may be too unstable to tolerate airway 
occlusion. Serial measurements from diaphragm ultrasound can and will be performed 
daily to assess changes in diaphragm architecture during both acute and weaning phases 
3, 5-8, 26, 52, 68-73.   Because diaphragm ultrasound is non-invasive, it has advantages 
although it has not been validated against direct measures of respiratory muscle strength 
or weaning outcomes. We will attempt such a validation with this study.  We anticipate 
DCA and PRP will provide complementary information regarding patient effort. To 
isolate diaphragm weakness, a second balloon catheter would be necessary to calculate 
trans-diaphragm pressure.  However, this is not practical for repeated use in children 
and no double-balloon catheters are commercially available for infants. A second 
catheter in an already small esophagus may alter the signals further, and impede clinical 
care if the catheter is left in place. While this leaves open the possibility of intercostal 
muscles contributing to the weakness, we will complement these data with architectural 
changes to the diaphragm on ultrasound. 

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D5 Co-Interventions 
Sedation: Sedation management will be controlled in both arms targeting a State 
Behavioral Scale, based on the sedation protocol used in the NHLBI funded RESTORE 
clinical trial. 75  This scale is being implemented for routine use in the Pediatric Intensive 
Care unit. Each day the clinical team will select an SBS target on morning rounds, based 
on the status of the patient.  The level of sedation and SBS score will be monitored every 
4 hours in each group.  Generally acceptable SBS targets range from -2 to 0.  For the 
acute phase management, the suggested SBS target is -2, and for the weaning phase of 
ventilation the SBS target is -1.  A nurse guided protocol is not currently in place for 
automatic adjustment of sedation to meet the SBS target, but the nurse will administer 
as needed medications to meet the SBS target if it is above target, and will consult with 
the MD to decrease sedation if the SBS is below target.   
 
Inhaled Nitric Oxide: Inhaled Nitric Oxide is frequently used for clinical care in our 
intensive care unit for children with ARDS. Like High Frequency Oscillatory Ventilation 
and other rescue therapies, the decision to begin inhaled nitric oxide will be left to the 
discretion of the clinical team.  However, for patients in REDvent Acute, inhaled nitric 
oxide is built into the computerized protocol management of PEEP/FiO2.  Consistent 
with the ICU protocol for nitric oxide weaning, once FiO2 is reduced to 0.6, if 
oxygenation is adequate or high, weaning of nitric oxide will be recommended (see 
section I for details).   
 
Quadriceps Ultrasound: Critically ill patients lose strength and muscle mass when in 
the intensive care unit, which may contribute to long term functional impairment. While 
functional assessment and strength testing is most accurate, they are difficult to do in 
children, or on sedated, non-cooperative patients.  Ultrasound can measure muscle 
thickness and echogenicity, and can document  progression of muscle atrophy.3 The 
quadriceps femoris muscle group is most commonly measured, with a demonstrated 
relationship between strength and quadriceps femoris muscle thickness.  Adult studies 
have documented that the quadriceps muscle thickness and cross sectional area 
decreases through the ICU course, correlates with length of stay and muscle strength 
and, less consistently, function at discharge. In most studies, ultrasound has high 
accuracy and inter-rater reliability. In children, the literature on quadriceps muscle 
thickness measurement by ultrasound is limited to comparing normal children to those 
with neuromuscular disease. While the proposed REDvent intervention is specifically 
targeting prevention of diaphragm atrophy, critical illness itself can lead to atrophy of 
other muscles. As such, in addition to measuring the change in diaphragm thickness 
daily, we will also measure the change in quadriceps muscle thickness daily, to help 
understand whether REDvent can modulate quadriceps muscle atrophy, of if the degree 
of quadriceps muscle atrophy has an interaction with the potential benefit of REDvent 
on diaphragm atrophy or strength.    In each patient while supine with their feet pointing 
up, we will measure quadriceps muscle thickness at two points, in the midsaggital plane 
for each thigh.  Like diaphragm ultrasound measurements, multiple providers will obtain 
measurements daily, to ensure reproducibility and inter rater reliability.  
 
D6 Statistical Considerations 
 
D.6.1. Randomization Strategy and Blinding 

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Consenting subjects will be block randomized to intervention or control arms for the 
acute phase based on age group: infant (30 days -365 days), child (366 days to ≤8 years), 
and older child/ adolescent (9-18 years); and immune suppression.  For study purposes 
immune suppressed patients will be defined as: patients with congenital or acquired 
conditions (including medications) which result in marked inability to respond to 
antigenic stimuli.  Examples of immune suppression include: oncologic disease with 
recent chemotherapy or radiation, congenital immunodeficiency, HIV, rheumatologic 
condition on chemotherapy, allogeneic or autologous stem cell transplant, solid organ 
transplant, or any other condition in which immunosuppressive medications are 
prescribed.   Block randomization will be based on random block sizes of 4, 6 and 8 
within the strata above, and loaded into opaque envelopes by the statistician for the 
study team to determine treatment arm at the time of randomization. Weaning phase 
randomization will be block randomized by REDvent-acute phase group, age, and 
immunosuppressed status using the same methodology. Although blinding is not 
possible given the open label nature of the intervention, analysis will be blinded to 
treatment groups, and performed by an independent statistician. 
 
D.6.2 Rationale for Randomization Strategy: Age stratified randomization is 
necessary because age is an important biological variable likely to confound the 
relationship between respiratory muscle weakness and length of weaning.  This will 
ensure an equal age distribution amongst treatment groups.  Age groups are based upon 
accepted pediatric definitions, and have been used in numerous other pediatric RCTs. 
Neonates (< 1 month) have been excluded because they are often managed with different 
ventilator strategies and because normal values for PiMax are lower in neonates 63, 64.   
Immunosuppression is a known risk factor which affects duration of ventilation and 
weaning, and an imbalance in immunosuppression between groups has been shown to 
significantly confound previous pediatric mechanical ventilation studies.   The additional 
weaning phase randomization is necessary because we anticipate an imbalance of the 
number of patients who will be extubated after the acute phase between REDvent-acute 
and control groups. Acute phase management may have a sustained effect on 
neuromuscular strength that will affect the duration of weaning.   To understand 
whether the REDvent strategy during the weaning phase can prevent prolonged 
weaning, risk factors for prolonged weaning (which may be different based on acute 
phase management) need to be rebalanced with a second randomization.  Ultimately, 
this will allow us to determine the independent utility of REDvent-acute and REDvent-
weaning components. 
 
D.6.3 Preparation of the Analysis Data Set  
 
Datasets for analyses consist only of data for which all queries have been resolved. In 
addition to data management steps 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 both the data management team and the biostatistics team. 
 
Preplanned construction of new variables will be conducted in accordance with the study 
hypotheses and analysis plans. Variable transformation may be required for interpretive 
and statistical purposes.  With respect to the primary outcome of weaning duration, 
patients who do not progress to the weaning phase within 28 days (i.e. death, prolonged 
severe illness) will not be included in analysis of the primary outcome, but will be 
considered for secondary outcomes.   

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D.6.4 Statistical Analysis Plan 
 
For all variables, descriptive statistics will be calculated, including means, standard 
deviations, medians, and interquartile ranges for continuous variables and frequency 
counts and percentages for categorical variables. Data will be examined for skewness, 
outliers, and systematic missing data. Transformations will be undertaken as needed. 
Comparisons of demographic and baseline variables will be obtained by treatment group. 
 
D.6.4.1 SA 1 Analysis Plan: To determine if REDvent acute and/or weaning phase 
protocols can shorten the duration of weaning from MV (Primary outcome).   
Primary analysis and sample size: The primary outcome for this aim is weaning 
duration. Because we seek to understand 
whether REDvent-acute and/or REDvent 
weaning have an independent effect on 
length of weaning, we propose a sample size 
to adequately power 3 separate comparative 
analyses: (a) REDvent-acute versus Acute 
Phase control (b) REDvent-weaning phase 
versus Weaning Phase control (c) REDvent 
both phases versus control both phases.    
We expect up to 13% mortality before the 
first SBT based on our Preliminary Data. 
These patients will not be included in the 
analysis for the primary outcome.  From our 
pilot data (REDvent in both acute and 
weaning phases), the duration of the weaning phase in the intervention arm was 2.2 
days, compared to 4 days in historical controls with a standard deviation of 2.1 days in 
the intervention arm and 2.8 days in the historical controls.  
Comparison (a) REDvent-acute versus control: A 1-day reduction in length of weaning is 
considered clinically significant (less sedative exposure, fewer nosocomial infections, 
lower healthcare costs).  With a sample size of 300 patients (150 per arm), up to 13% 
mortality and 7% attrition or incorrect randomization, a minimum of 240 patients (120  
per arm) will be available for analysis of the acute phase.  Power is based on 2 planned 
methods for analysis: cox proportional hazard ratios for multivariable analysis and 
univariate analysis with an independent t-test using log transformation (as needed) to 
account for the expected distribution of weaning duration.  For univariate analysis using 
the assumptions above, we would be able to detect a ≥ 1-day reduction in weaning 
duration with an alpha of 0.05 and power of 0.9 (Figure 7).  For the cox proportional 
hazard model, we would be able to detect a relative hazard ratio of 1.5 (ratio between 
control/intervention group) with a power of 0.9 or a hazard ratio of 1.4 with a power of 
0.8.  
Comparison (b) REDvent-weaning versus control:  Patients who fail the initial SBT will 
undergo the weaning phase randomization.  From our pilot data, approximately 25% of 
patients exposed to the intervention passed the initial SBT, corroborating previous 
studies. 15   Thus, at least 180 patients (90 per arm) will receive weaning phase 
interventions.  Using the same assumptions as above, we will be able to detect a ≥ 1 day 
reduction in the length of the weaning phase (Figure 8), or a hazard ratio of 1.5 with an 
alpha of 0.05 and power of 0.8.  Patients who do not pass the SBT by 28 days post the 
 
Figure 8: Power curve for a 1 day reduction in weaning    

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weaning phase randomization will be censored for analysis, as study interventions and 
daily monitoring will end on day 29.          
Comparison (c) REDvent versus control both phases: We will get an assessment of the 
cumulative effect of the intervention by comparing patients who received both REDvent-
acute and REDvent weaning to patients who received only usual care in both phases.  
Because the rates of passage of the first SBT will differ between groups, there will not be 
an equal number of patients exposed to REDvent only as control only. Based on the 
assumptions above, we anticipate that of the 240 patients included in the analysis of 
weaning duration, 78 will be REDvent only, 72 will be control only, and 90 will be mixed.  
As such, the expected sample size comparing REDvent only to control only would allow 
us to detect a ≥ 1.1- day reduction in weaning duration with a hazard ratio of 1.6 with a 
power of 0.8 and alpha of 0.05; or a ≥ 1.3- day reduction in weaning duration with a 
hazard ratio of 1.6 with a power of 0.9.    
All patients will be analyzed in the groups to which they were randomized for weaning 
duration, following intention to treat principles (allow for up to 7% incorrect allocation 
or attrition).   Clinical variables (data collection table) will be tracked and compared 
between intervention and control groups for all 3 of the planned analyses (a-c).    If there 
is an imbalance in any variable that may confound the relationship between weaning 
duration and REDvent, we will build a multivariable cox proportional hazard model to 
ensure that the measured treatment effect on weaning duration is retained after 
multivariable adjustment.   
Secondary Outcomes for SA 1: The 28 and 60 Day Ventilator Free Days (28D VFD, 
60D VFD) will be secondary outcomes of this aim.  Groups for VFD analysis will be 
based on any exposure to the intervention (acute or weaning) because some patients will 
never undergo a weaning phase randomization (i.e. died or were extubated right after the 
acute phase).    If patients who died as well as those who dropped out are included in the 
VFD analysis, with the assumptions above regarding expected passing rate of SBTs, the 
estimated distribution of patients in 3 distinct groups will be:  (a) REDvent only 
(n=108); (b) REDvent and control (n=90); (c) control only (n=102). We anticipate 
children in the REDvent only arm will have the most 28 D VFDs (anticipation 22), and 
those in the control only arm the least (anticipation 20).  Directly comparing control only 
patients to REDvent only patients, with an expected standard deviation for VFDs 
between 5 to 9 days, we will be able to detect a 2-day change in VFDs between groups 
with a power between 0.35 and 0.82.  Re-intubation rates are expected to be 10%, 
allowing us to confirm that REDvent is not inferior to usual care in regards to re-
intubation with a non-inferiority margin of 0.10 with a power of 0.8 and alpha of 0.05.  
Finally, to ensure that REDvent is promoting greater patient effort of breathing and that 
the intervention does not alter clinical practice in the usual care arm, we will compare 
time weighted average values for direct measures of patient effort of breathing (PRP, 
PTP, Diaphragm Contractile Activity), and ventilator settings between intervention and 
control groups, and monitor the separation between groups over the time of the study.    
 
D.6.4.2 SA2 Analysis Plan:  To determine if changes to direct measures of 
respiratory muscle strength, load, effort, and architecture throughout the duration of MV 
are related to weaning outcomes. 
Analysis and Sample Size: The primary outcome of this aim is weaning duration (as 
defined above).  For this analysis, we will compare how each respiratory measure 
detailed in the data collection table relates to weaning duration.  For respiratory muscle 
strength we will compare the first measured aPiMax (after resolution of the acute phase, 
before the first SBT), the trajectory and value of the daily aPiMax during the weaning 

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phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the 
day of extubation against weaning duration.  For analysis, aPiMax will be dichotomized 
at 30 cmH2O (based on our preliminary data), and weaning duration  will be compared 
between patients with aPiMax > 30 versus ≤ 30 cmH2O using a t-test with or without 
log-transformation, or Mann-Whitney U test, depending on the distribution.  From our 
preliminary data, we anticipate at least 35% of patients (n=84) will have aPiMax ≤ 30 
cmH2O.    Based on a similar power analysis as presented above, this would allow us to 
determine whether low aPiMax is associated with a ≥ 1-day increase in weaning 
duration, with an alpha of 0.05 and power of 0.8.    We will perform identical analysis for 
ePiMax. 
Diaphragm Thickness analysis will compound daily ultrasound measures to detect the 
relative change in diaphragm thickness from study day 1 until passage of an SBT.  We 
will compare the change in thickness after resolution of the acute phase (on the day of 
the first SBT) against weaning duration, in a similar manner as proposed above for 
aPiMax.  For analysis, diaphragm thickness will be tested as a continuous variable (with 
Spearman’s or Pearson’s Correlation), but also categorized into 3 groups (loss of > 10% 
in thickness, maintenance of thickness (-10% to +10%), and increase in size of > 10%) to 
account for the potential ill effects of diaphragm hypertrophy (expected in about 10% of 
patients), using Analysis of Variance (ANOVA) to compare weaning duration between 
groups.  We will characterize how diaphragm thickness changes daily during the weaning 
phase compared to the thickness on study day 1, as well as the daily thickness compared 
to that on the day of the first SBT.   This will be used to determine whether patients 
whose trajectory of diaphragm atrophy continues during the weaning phase have a 
longer weaning duration compared to those who maintain diaphragm thickness or have 
increased thickness during the weaning phase.   We anticipate high correlation between 
aPiMax and diaphragm atrophy, such that the proportion of patients with > 10% loss in 
diaphragm thickness will be similar to the proportion of those with aPiMax ≤ 30 
cmH2O, resulting in the same sample size that yield adequate power, as above.   
Respiratory load (resistance and compliance), effort (PRP, PTP) and combination 
measures of capacity, load or effort (TTI, Diaphragm Contractile Activity, Phase Angle) 
will be measured daily during or just before SBTs, as detailed in the data collection table.  
Analysis of each of these measures against the primary outcome will mimic what is 
presented above for aPiMax and Diaphragm thickness, with correlation for continuous 
variables, as well as categorization into distinct ranges for ANOVA.   
Secondary Outcomes, SBT failure: In addition to weaning duration, we will also 
examine whether the respiratory measures in the data collection table taken just prior to 
or during each SBT are associated with the patient passing the SBT. For example with 
aPiMax and ePiMax, we will examine if there is a dose response relationship between 
PiMax measured just before the SBT and the rate of passage of the subsequent SBT (e.g., 
similar to Figure 3).  In addition, we will compare mean or median values for aPiMax 
between patients who pass versus fail the SBT using a t-test or MWU test.  Finally, we 
will examine aPiMax as a continuous variable to determine its ability to discriminate 
passage of the subsequent SBT using the Area Under the Curve (AUC) of the Receiver 
operating Characteristic Plot (ROC).  Similar analysis will be done for all other 
respiratory measures in Table 2, and we will compare the AUCs (using a Chi-squared 
test) for each individual respiratory parameter against the others to identify which of 
these tests have the highest sensitivity, specificity, and overall discrimination of SBT 
failure.     We will subsequently generate multivariate logistic regression models to 
identify which combination of these measures of capacity, architecture, load, and effort 
retain an independent association with SBT failure. Because SBTs will be repeated daily, 
we will use a hierarchical logistic regression model to control for repeated measures from 

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each patient as well as controlling for the other potential confounding variables detailed 
in the data collection table. We anticipate that 240 patients will undergo SBT testing, 
and 90% of these patients will pass the SBT within 28 days of the weaning phase 
randomization.  As such, we would be able to include at least 20 variables in a 
multivariable hierarchical logistic regression model.    Finally, we will determine whether 
common “phenotypes” for weaning failure can be determined. We anticipate four 
possible phenotypes by combining information from all available measures of capacity, 
load, effort, and architecture. Based on our preliminary data, we anticipate that patients 
with high load will be more likely to fail weaning, but that this effect will be more 
pronounced if they have diminished respiratory muscle capacity.  We hypothesize that 
the rates of passage of the SBT will increase incrementally from phenotype 1 to 4:   (1) 
Diminished capacity, high load and effort; (2) Normal capacity, high load and effort; (3) 
Diminished capacity, low load and effort; (4) Normal capacity, low load and effort.  
These phenotypes are exploratory; thus, no power analysis is provided.   
 
D.6.4.3 SA3 Analysis Plan: To determine if patient effort of breathing during both 
acute and weaning phases of MV is independently associated with the development of 
respiratory muscle weakness.   
Analysis and Sample Size: The primary outcome of this aim is aPiMax < 30 
cmH2O.The analysis will focus on determining whether the degree of patient effort of 
breathing is independently associated with the development of respiratory muscle 
weakness. PRP will be the primary measure of effort of breathing, and will be measured 
twice daily in both acute and weaning phases. Secondary measures of effort of breathing 
include DCA and PTP.  For the acute phase, we will generate a time- weighted average 
PRP during the acute phase and graph it against aPiMax at the first SBT, anticipating a 
positive correlation (higher average PRP values associated with higher aPiMax).  We will 
subsequently dichotomize aPiMax at the first SBT and compare mean time weighted 
average PRP in the acute phase between aPiMax groups (> 30 vs. ≤ 30 cmH2O).  For the 
weaning phase, we will graph the changes in aPiMax throughout the weaning phase 
(from first failed SBT until successful SBT) against time-weighted average PRP, with the 
anticipation that low PRP will be associated with either further reductions in aPiMax, or 
no improvement, while PRP in the physiologic range of 150-400 will be associated with 
improvement in aPiMax.  We will subsequently dichotomize aPiMax (at 30 cm H2O) at 
the time of successful passage of an SBT and compare time-weighted average PRP in the 
weaning phase between aPiMax groups. Subsequently, we will build a multivariable 
logistic regression model on the outcome of aPiMax ≤ 30 cmH2O to determine if time-
weighted PRP in the acute phase, weaning phase or both have an independent 
association with preserving aPiMax, after controlling for confounding variables (data 
collection table).  We anticipate that 35% of patients (at least 80) will have aPiMax ≤ 30 
cmH2O, allowing for inclusion of at least 9 variables in the multivariable model. 
Secondary goals are to characterize other variables that retain an independent 
association with low aPiMax, which are likely to include age group, use and dose of 
neuromuscular blockade, driving pressure during the acute phase of ventilation, sepsis, 
corticosteroids and use of aminoglycoside antibiotics.   
 
D.6.5 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. In the final two years of the study the Steering 
Committee will develop the strategic plan for the comprehensive presentation and 

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publication of the study findings. The biostatistician will assist Dr. Khemani and Steering 
Committee members to prepare abstracts and papers for presentation at the annual 
meetings of American Thoracic Society (ATS), Society of Critical Care Medicine (SCCM), 
the European Society of Pediatric and Neonatal Intensive Care (ESPNIC). Dr. Khemani 
will provide the mechanical ventilation subgroup of the Pediatric Acute Lung Injury and 
Sepsis Investigator (PALISI) network an update on the clinical trial twice yearly to 
maintain disciplinary interest in the study. In addition to primary publication targeted at 
high priority journals, we anticipate numerous secondary publications in critical care, 
physiology, and respiratory journals. Final data sets and statistical analyses will be 
archived and a public use dataset will be made available as per NIH recommendations. 
 
D7 Data and Instrument Management 
 
A significant portion of the data management infrastructure and protocols have been 
developed with previous studies, and we will capitalize on this by modifying existing 
protocols to be relevant to this study.  The devices and software have been used 
extensively, and we will follow existing protocols to maintain calibration, quality control, 
and accuracy of all study devices.  A vast majority of the data (ventilator settings, blood 
gas values, and many of the variables in the data collection table) will be collected 
through automated electronic feeds.  A trained study data collector will use data extracts 
from the electronic feeds in conjunction with data in the electronic health care record to 
populate study specific case report forms.  Data collection will occur in real-time, to 
enable primary source verification. Respiratory measurements will be entered into web-
based case report forms at the time of study measurements. In addition, raw data from 
esophageal manometry and RIP will be recorded during each measurement for a 
minimum of 5 minutes, and the calculations will be post-processed by trained research 
personnel to verify the real-time data entry.  Ultrasound images will be interpreted in 
real-time and calculations entered into the web-based case report form.  In addition, all 
ultrasound images will be uploaded to a secure server for source data verification and 
can be de-identified.  We will develop a series of algorithms to confirm the validity of 
entered data, and will perform detailed queries of entered data monthly.     
 
To ensure data safety and reliability, server back-up procedures will be executed daily to 
back up all electronic study related materials, which include database, Word documents, 
statistical programs, and files. Access to the data management system is strictly 
prohibited and requires user authentication. Authorized users include data-entry 
personnel, research coordinators, the PI, the database programmer, and biostatisticians. 
Any hard copies of eCRFs with subject ID codes will be stored in locked file cabinets, 
accessible by authorized staff only. Identifiable subject data, such as contact information 
and medical record numbers, will be stored separately and securely, and will not be 
entered into the electronic database. 
All application software will be hosted securely on the Children’s Hospital Los Angeles 
Network, which is protected by several firewalls and security is monitored and audited 
regularly.     
D8 Quality Control Procedures 
D.8.1 Training 
Training materials detailing study protocols have been created and used for the Phase I 
study, and an order set has been created in our electronic health-care record system.   

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Research respiratory therapists and data collectors will be directly trained by the PI and 
the Lead Research Respiratory Therapist (J. Hotz).  Detailed training of all bedside staff 
will occur before beginning the study, as well as in real-time with each patient 
enrollment, using a similar model as the Phase I study.     
 
D.8.2. Development of Case Report Forms 
Case report forms will be modified from successfully implemented CRFs we have used 
for the pilot study, as well as a large observational study on Pediatric Acute Respiratory 
Distress Syndrome (PARDIE study).  Form design features include the selection of valid, 
reliable measurements, development and testing of reliability measures, pre-testing of 
forms, formatting of forms to ensure clarity (standard conventions for coding close-
ended questions, minimal use of open ended questions), smooth flow (clear skip 
patterns) to reduce missing data. Members of the Steering Committee will sign off on 
eCRFs before implementation.  
 
D9 Anticipated Problems and Solutions 
D.9.1 What if enrollment is slow? We are confident we can meet enrollment targets 
at CHLA alone and will monitor this with targeted and actual enrollment graphs.  If 
enrollment is slower than anticipated, we will add UCLA Children’s Hospital as a satellite 
ICU.  This is another PICU 15 miles away with at least 100 eligible patients per year.  
Through previous funding from the Collaborative Pediatric Critical Care Research 
Network, we share research infrastructure and resources, and have combined efforts 
(functioning as one site) for over 30 different clinical studies. 77-83      
 
D.9.2 What if aPiMax is not associated with weaning duration? We believe that 
a real strength of this application relies on the multitude of direct and indirect measures 
of respiratory system capacity, load, and effort, which we will associate with highly 
clinically relevant weaning outcomes.   While we anticipate aPiMax will be the best 
measure of strength, the multitude of other measurements concomitantly made will 
allow using alternative measures to aPiMax to assess strength (such as ePiMax, 
diaphragm contractile activity during occlusion, diaphragm thickness, or phase angle). 
Our analysis will allow us to determine which of these parameters has the strongest 
association with clinical outcomes.  
 
D.9.3 Non-compliance with the intervention study protocol? We are confident 
we will maintain high protocol compliance, as we have demonstrated in the pilot study.  
We have iteratively refined the protocol such that adherence to weaning phase 
recommendations exceeds 90%.  The acute phase recommendations generally exceed 
75%, which we view as acceptable.  The protocol is intended to provide a framework for 
ventilator decisions and is not intended to replace clinician’s judgment. For this reason it 
has been implemented as open loop.  The degree of protocol adherence will be tracked 
electronically, as part of the CDS tool itself.  If adherence is lower than anticipated, then 
detailed analysis of the reasons for protocol rejection (tracked with every 
recommendation) will be reviewed, and a protocol modification will be considered.   
 
D.9.4.  Changes in clinical practice in the ICU during this time period?  The 
impact of changes in pediatric critical care management is expected to affect both groups 
equally so should not bias treatment group comparisons. 

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D10 Study Timeline and Milestone accrual Policy  
 
 
The Milestone Accrual figure above details targeted enrollment over the course of the 
study. The Yellow, Amber, and Red zone each have corrective action associated with it, as 
part a separate milestone accrual plan with NHLBI.   

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E Human Subjects Considerations 
 
 
E1 Ethical Considerations  
 
The human subjects for this study are infants and children who are intubated and 
mechanically ventilated in intensive care unit. It is anticipated that 300 endotracheally 
intubated children will be enrolled in the study.  The age of children will range from one 
month (≥ 44 weeks Post Conceptual Age) to 18 years.  All participants enrolled in the 
study will be critically ill, requiring mechanical ventilation through an endotracheal tube. 
The main risk of participation in this study is the placement of an esophageal catheter for 
measurements of esophageal pressure.  While esophageal catheters (or nasogastric 
feeding tubes) are routinely used in children who are mechanically ventilated (it is the 
norm for all endotracheally intubated children to have a feeding tube, either nasogastric, 
orogastric, gastric, or jejunal), because this additional catheter is part of the research 
protocol, it is likely to be considered greater than minimal risk.  However the study does 
provide potential for significant benefit for the patient, and as such the benefits generally 
outweigh the risks.  Use of this catheter has been approved on multiple occasions with 
appropriate informed consent.  The ultrasound measurements and RIP bands are non-
invasive and pose minimal risk to the patient.   
 
The hardware (device) is minimal risk and has been used on a variety of studies.  All 
sensors (esophageal catheter, RIP, and spirometry) have appropriate clearance through 
FDA approval or 510K equivalence for use in children, and have been used in our 
previous investigations.  The two pieces of the software (tool to help interpret raw signals 
from the sensors), and the CDS ventilator management protocol have both previously 
been deemed non-significant risk because they are primarily implemented in an open-
loop application, incorporate current evidence based guidelines (computer CDS 
protocol), or have been iteratively tested against FDA approved post-processing 
programs as part of our previous investigations.  Moreover, clinicians are free to reject 
protocol recommendations, and to that end this data is to be used simply as an adjunct 
to clinical assessment, rather than a replacement.  
E2 Subject Recruitment Plans and Consent Process 
The subjects of this study are critically ill infants and children who will not be able to 
consent for their own participation in this study.  One or both parents will be informed 
about the study and given an opportunity to voluntarily give their consent/permission 
for their child to participate.  Assent of child subjects will not be possible because they 
are critically ill, intubated on a ventilator, and sedated.  Thus, assent will be waived.  
Families or guardians of any endotracheally intubated and mechanically ventilated child 
who meet inclusion and do not meet exclusion criteria will be approached for consent.  
Consent will be attained by the study investigator, co-investigator, or research nurse.  
Consent will be documented on a consent form, and stored in a study binder, identified 
by patient number.  This binder will be stored in a locked cabinet in the office of the site 
principal investigator.   
 

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E3 Risks and Benefits 
 
E.3.1 Risks:  
1. Placement of the esophageal catheter. While this procedure is very well tolerated, 
there is a very small risk for bleeding, incorrect placement into the lungs or other 
body cavities, or damage to the esophagus, stomach, or nasal or oral mucosa.  
Patients at high risk of bleeding (thrombocytopenia, coagulopathy, mucositis), will 
not be included in the study.   
2. Small amount of discomfort when placing the esophageal catheter, although nearly 
all patients will be receiving analgesia and sedation as part of mechanical ventilation.  
Intermittent doses of already prescribed sedative or analgesia medications may be 
administered to minimize pain during placement. 
3. A particular computer generated recommendation may not be correct for the patient 
at that time, and the clinicians may choose not to follow them. 
4. There is potential of accidental release of confidential information. 
5. There is a possibility of transient fall in oxygen levels during airway occlusion 
maneuvers, although patients will be pre-oxygenated as per ICU standard practices 
prior to measurement, and patients must pass the oxygenation test prior to 
performing these measurements.   
 
E.3.2 Potential Benefits to Subjects 
There is the prospect of direct benefit to subjects in both arms.  For the intervention arm, 
using the intervention tool has the potential to significantly shorten length of assisted 
breathing, lower re-intubation rates, increase Ventilator Free Days (VFDs), shorten ICU 
and hospital length of stay, and reduce exposure to sedatives and analgesics.  Patients in 
the control arm also have potential to benefit as enrollment in the study will prompt 
more consistent use of evidence based weaning guidelines including a daily Spontaneous 
Breathing Trial.  This may also result in more days free of ventilators compared to those 
not enrolled in the study.   
 
E.3.4 Importance of the Knowledge to Be Gained 
Completion of this study will elucidate important information on the pathogenesis and 
timing of respiratory muscle weakness during MV in children, and whether this 
weakness can be mitigated by promoting more normal patient effort during MV.  These 
data can lead to immediate change in practice by implementing mechanical ventilation 
strategies that promote more patient effort of breathing.  They will also form the basis to 
determine whether a larger, Phase III multi-center study of REDvent is indicated, which 
would focus on key clinical outcomes such as 28-day Ventilator Free Days.  Given that 
the risks to the study participants are small, the information gathered will shape the 
design of future trials and will improve our understanding of diaphragm weakness in 
mechanically ventilated children in the ICU.  
 
E.3.5 Procedures to minimize risk 
All patients will be extensively monitored in the intensive care unit throughout the 
duration of the study.  This will include close monitoring of cardio-respiratory 
parameters including heart rate, temperature, blood pressure, oxygen saturation, 
respiratory rate, and work of breathing.  Intensive care unit physicians, nurses, and 
respiratory therapists will be present during the entire study, and will intervene as 
necessary should any treatment be indicated.  In addition, to protect confidentiality of 
data, study forms will only be labeled with a unique number identifier, which can only be 

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linked to identifiable information only through a key with access restricted to the PI or 
research coordinator. 
E4 Early Withdrawal of Subjects  
The subject may be withdrawn from the study by the (1) study investigator or (2) the 
parent or legal guardian at any time after consent.  The primary attending physician can 
also request that the principal investigator consider withdrawal of the patient from the 
study if they believe the study is no longer in the best interest of the patient.   
E.4.1 When and How to Withdraw Subjects  
Subjects can be withdrawn by the parents at any time, simply by requesting that the 
principal investigator withdraw the patient.  The study investigator may withdraw the 
patient from the study if he or she believes that this is necessary to protect the health of 
the child, if the condition of the child changes such that continuation in the study poses 
additional risks, or if the child experiences an adverse event which changes the risk 
benefit profile of continuing in the study.  
 
E.4.2 Data Collection and Follow-up for Withdrawn Subjects  
If consent is withdrawn for participation in the research by the parent/guardian, then 
data collection will cease.  Parents will be asked if we can keep existing data and follow 
clinical outcomes for intention to treat analysis.  However, if they wish, existing data will 
be destroyed.  If the study investigator withdraws the patient, then existing data will be 
preserved, and clinical outcome data detailed in section C.3.1. will continue to be 
collected to enable intention to treat analysis.   
 
F Data Safety Monitoring Plan and Board 
 
Please see separate Data Safety and Monitoring Plan and Data Safety and Monitoring 
Board Charter.  An institutional DSMB has been created for this study.   
 
The Data Safety Monitoring Plan details expected adverse events, with expected rates of 
occurrence.   
 

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Measures (abstract). C27 News from the NICU and PICU: American Thoracic 
Society, 2016:7300. 

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67. 
Steier J, Kaul S, Seymour J, et al. The value of multiple tests of respiratory 
muscle strength. Thorax 2007; 62:975-80. 
68. 
Scott CB, Nickerson BG, Sargent CW, Dennies PC, Platzker AC, Keens TG. 
Diaphragm strength in near-miss sudden infant death syndrome. Pediatrics 1982; 
69:782-4. 
69. 
Zambon M, Cabrini L, Beccaria P, Zangrillo A, Colombo S. Ultrasound in critically 
ill patients: focus on diaphragm. Intensive Care Medicine 2013; 39:986. 
70. 
Rehan VK, Laiprasert J, Nakashima JM, Wallach M, McCool FD. Effects of 
continuous positive airway pressure on diaphragm dimensions in preterm infants. 
Journal of Perinatology 2001; 21:521-4. 
71. 
Rehan VK, Laiprasert J, Wallach M, Rubin LP, McCool FD. Diaphragm 
dimensions of the healthy preterm infant. Pediatrics 2001; 108:E91. 
72. 
Rehan VK, McCool FD. Diaphragm dimensions of the healthy term infant. Acta 
Paediatrica 2003; 92:1062-7. 
73. 
Rehan VK, Nakashima JM, Gutman A, Rubin LP, McCool FD. Effects of the 
supine and prone position on diaphragm thickness in healthy term infants. 
Archives of Disease in Childhood 2000; 83:234-8. 
74. 
Khemani RG, Smith LS, Zimmerman JJ, Erickson S, Group ftPALICC. Pediatric 
Acute Respiratory Distress Syndrome: Definition, Incidence, and Epidemiology: 
Proceedings From the Pediatric Acute Lung Injury Consensus Conference. 
Pediatric Critical Care Medicine 2015; 16:S23-S40. 
75. 
Curley MA, Wypij D, Watson RS, et al. Protocolized Sedation vs. Usual Care in 
Pediatric Patients Mechanically Ventialted for Acute Respiratory Failure. JAMA 
2015; 313:379-389. 
76. 
Valentine SL, Nadkarni VM, Curley MA, Pediatric Acute Lung Injury Consensus 
Conference G. Nonpulmonary treatments for pediatric acute respiratory distress 
syndrome: proceedings from the Pediatric Acute Lung Injury Consensus 
Conference. Pediatric Critical Care Medicine 2015; 16:S73-85. 
77. 
Carcillo JA, Dean JM, Holubkov R, et al. The randomized comparative pediatric 
critical illness stress-induced immune suppression (CRISIS) prevention trial. 
Pediatric Critical Care Medicine 2012; 13:165-73. 
78. 
Newth CJ, Meert KL, Clark AE, et al. Fatal and near-fatal asthma in children: the 
critical care perspective. Journal of Pediatrics 2012; 161:214-21.e3. 
79. 
Berger JT, Carcillo JA, Shanley TP, et al. Critical pertussis illness in children: a 
multicenter prospective cohort study. Pediatric Critical Care Medicine 2013; 
14:356-65. 
80. 
Moler FW, Silverstein FS, Meert KL, et al. Rationale, timeline, study design, and 
protocol overview of the therapeutic hypothermia after pediatric cardiac arrest 
trials. Pediatric Critical Care Medicine 2013; 14:e304-15. 
81. 
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 Pediatrics 2014; 168:671-6. 
82. 
Dalton HJ, Garcia-Filion P, Holubkov R, et al. Association of bleeding and 
thrombosis with outcome in extracorporeal life support. Pediatric Critical Care 
Medicine 2015; 16:167-74. 
83. 
Moler FW, Silverstein FS, Holubkov R, et al. Therapeutic hypothermia after out-
of-hospital cardiac arrest in children. New England Journal of Medicine 2015; 
372:1898-908. 
 

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H  Ventilation Protocols (Intervention group) 
 
 
Acute phase management is based on SIMV pressure control/pressure support mode of 
ventilation. Oxygenation targets are 88-93% during the acute phase, and PEEP and FiO2 
are managed as per the PEEP/FiO2 tables on the subsequent pages.  If inhaled nitric 
oxide is used by the clinical team, then rules for weaning nitic oxide have been built into 
the protocol, as detailed below.  Ventilation management during the acute phase uses 
pH, ventilator rate, and PIP to suggest changes to embrace permissive hypercapnia. 
When the patient is breathing spontaneously, rules regarding Pressure Rate Product are 
also implemented, to keep work of breathing in a physiologic range.    
 
 
If High frequency oscillatory ventilation is used for patients randomized to RED-vent 
Acute, then HFOV rules have been created. There is no requirement to transition to 
HFOV, but it will be permitted for rescue therapy.  Similar to the conventional 
ventilation, Oxygenation is managed with a MAP/FiO2 table, with rules for inhaled nitric 
oxide if used.  Ventilation adjusts Hz, Amp based on pH. There are no PRP based rules 
during HFOV, since most patients are not spontaneously breathing.  There are 
recommendations for minimal therapy with HFOV, when conversion back to 
conventional ventilation should be considered, although the clinical team will ultimately 
make the decision regarding conversion back to conventional ventilation.   
 
 
Details of the protocols are summarized on the following pages.

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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Weaning Phase Protocol 
 
 
 
 
• 
During weaning phase, PEEP ≤ 10 cmH20, FiO2 ≤ 0.6, PS ≤ 20 cmH20.   PEEP and FiO2 management can be changed within 
PEEP range of 5-10 cmH20 and FiO2 from 0.21-0.6 by the clinical team.   
• 
Suspension of the weaning phase is permitted for up to 12 hours for situations such as procedures, increased need for sedation 
preventing adequate spontaneous breathing, or other circumstances requiring transient need for increase in ventilator 
support etc.  As soon as the patient appropriately meets weaning criteria (spontaneous breathing, pH 7.32-7.47, PEEP ≤ 10 
cmH20, FiO2 ≤ 0.6 ), the weaning phase intervention is resumed.   
• 
If the weaning phase is suspended for > 12 hours and the patient no longer meets weaning criteria, the acute phase 
intervention will be resumed, until the patient again meets weaning criteria.  This will be labeled weaning failure, and tracked 
in both arms. 

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REDVENT 
(Real-time Effort Driven VENTilator management) 
 
NIH/NHLBI R01HL134666 and NIH/NHLBI 1R01HL164397 - 01A1 
(Asynchrony Secondary Analysis) 
 
Robinder G. Khemani MD, MsCI 
Professor of Pediatrics 
University of Southern California 
Attending Physician, Critical Care Medicine 
Children’s Hospital Los Angeles 
4650 Sunset Blvd MS 12 
Los Angeles, CA 90027 
rkhemani@chla.usc.edu 
Phone: 323.361.2376 
Fax: 323.361.1001 
Cell: 206.619.6968 
 
Martha A.Q. Curley, RN, PhD, FAAN 
Ellen and Robert Kapito Professor in Nursing Science 
School of Nursing/Anesthesia and Critical Care Medicine 
University of Pennsylvania 
School of Nursing 
Claire M. Fagin Hall  
418 Curie Boulevard, Room 424  
Philadelphia, PA 19104-4217 USA 
Office Phone: 215.573.9449 
Cell: 617.803.6996 
Office Fax: 215.746.2737 
curley@nursing.upenn.edu 
 
Christopher JL Newth MD, FRCPC 
Professor of Pediatrics 
University of Southern California 
Attending Physician, Critical Care Medicine 
Children’s Hospital Los Angeles 
4650 Sunset Blvd MS 12 
Los Angeles, CA 90027 
cnewth@chla.usc.edu 
Phone: 323.361.2117 
Fax: 323.361.1001 
Cell: 818.952.5340 

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TABLE OF CONTENTS 
A 
INTRODUCTION ............................................................................................................................... 4 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PROTOCOL SUMMARY ................................................................................................................... 5 
A3 
PRIMARY HYPOTHESIS AND SPECIFIC AIMS ................................................................................... 9 
B 
BACKGROUND ................................................................................................................................ 10 
B1 
PRIOR LITERATURE AND STUDIES ................................................................................................ 10 
B2 
RATIONALE FOR THIS STUDY ....................................................................................................... 10 
B3 
PRELIMINARY DATA .................................................................................................................... 12 
C 
STUDY OBJECTIVES ..................................................................................................................... 17 
C1 
PRIMARY AIM .............................................................................................................................. 17 
C2 
SECONDARY AIMS ....................................................................................................................... 17 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ......................................................... 17 
D 
STUDY DESIGN ............................................................................................................................... 20 
D1 
OVERVIEW OR DESIGN SUMMARY ............................................................................................... 20 
D2 
SUBJECT SELECTION  ................................................................................................................... 20 
D.2.1 Inclusion Criteria…………………………………………………………………………………… 20 
D.2.2 Exclusion Criteria ................................................................................................................ 20 
D.2.3 Screening and Eligibility ...................................................................................................... 21 
D3 
STUDY INTERVENTIONS ............................................................................................................... 21 
D.3.1 Acute Phase Description ...................................................................................................... 21 
D.3.2 Intervention Arm Acute (REDvent-acute) ............................................................................ 21 
D.3.3 Control Arm…………………………………………………………………………………………...22 
D.3.4 Acute Phase Respiratory Monitoring ................................................................................... 22 
D.3.5 Spontaneous Breathing Trials success/failure ..................................................................... 23 
D.3.6 Weaning Phase Description ................................................................................................. 23 
D.3.7 Intervention Arm Weaning Phase (REDvent-weaning) ........................................................ 23 
D.3.8 Control Arm Weaning .......................................................................................................... 24 
D.3.9 Weaning Phase Respiratory Monitoring .............................................................................. 24 
D.3.10 Post-extubation Management ............................................................................................. 24 
D.3.11 Suspension of Weaning Phase ............................................................................................ 24 
D.3.12 Failure of Weaning Phase .................................................................................................. 24 
D.3.13 Termination of Study Intervention at day 28 ...................................................................... 25 
D.3.14 Post Enrollment Exclusion Criteria ................................................................................... 25 
D4 
MEASUREMENT OF STUDY VARIABLES ........................................................................................ 26 
D.4.1 Serial Respiratory Measurements ........................................................................................ 26 
D.4.2 Airway Occlusion Measurements ......................................................................................... 26 
D.4.3 SBT measurements ............................................................................................................... 26 
D.4.4 Rationale for measurements ................................................................................................. 27 
D5 
CO-INTERVENTIONS ..................................................................................................................... 27 
D6 
STATISTICAL CONSIDERATIONS ................................................................................................... 28 
D.6.1 Randomization Strategy and Blinding .................................................................................. 28 
D.6.2 Rationale for Randomization Strategy ................................................................................. 27 
D.6.3 Dataset Preparation ............................................................................................................. 28 
D.6.4 Statistical Analysis Plan and Sample Size ............................................................................ 28 
D.6.5 Dissemination Plan and Data Archiving .............................................................................. 33 
D7 
DATA AND INSTRUMENT MANAGEMENT ...................................................................................... 33 
D8 
DATA QUALITY CONTROL  ........................................................................................................... 34 

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D.8.1 Training ................................................................................................................................ 34 
D.8.2 Case Report Forms .............................................................................................................. 34 
D9 
ANTICIPATED PROBLEMS AND SOLUTIONS .................................................................................. 34 
D10 
MILESTONE ACCRUAL PLAN ........................................................................................................ 35 
 
E 
HUMAN SUBJECTS CONSIDERATIONS ................................................................................... 36 
E1 
ETHICAL CONSIDERATIONS ......................................................................................................... 36 
E2 
RECRUITMENT AND CONSENT ...................................................................................................... 36 
E3 
RISKS AND BENEFITS ................................................................................................................... 37 
E4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................. 38 
F 
DATA SAFETY MONITORING PLAN AND BOARD ................................................................ 38 
G 
REFERENCES .................................................................................................................................. 39 
H 
ASYNCHRONY SECONDARY ANALYISIS……………………………………………………. 46  
I 
DETAILED VENTILATION PROTOCOLS FOR INTERVENTION GROUP ........................ 65 
 

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A Introduction 
 
A1 Study Abstract 
 
Nearly half of mechanically ventilated (MV), critically ill adults develop 
ventilator-induced respiratory muscle weakness (particularly of the diaphragm), which 
impairs successful weaning from MV, often leads to re-intubation, and is associated with 
higher post-ICU mortality. Respiratory muscle weakness is associated with extubation 
failure in critically ill children. However, we lack crucial information on the mechanisms 
and timing of this weakness, its importance for ventilator weaning, and its potential 
prevention through promoting more physiologic levels of patient effort of breathing 
during MV.   
 
This study is a Phase II controlled clinical trial that will obtain comprehensive, 
serial assessments of respiratory muscle strength and architecture to understand the 
evolution of ventilator-induced respiratory muscle weakness in critically ill children, and 
test whether a novel computer-based approach (Real-time Effort Driven ventilator 
management (REDvent)) can preserve respiratory muscle strength and reduce time on 
MV.  REDvent offers systematic recommendations to reduce controlled ventilation 
during the acute phase of MV, and uses real-time measures from esophageal manometry 
to adjust supported ventilator pressures such that patient effort of breathing remains in a 
normal range during the ventilator weaning phase.   This phase II clinical trial is 
expected to enroll 276 children with pulmonary parenchymal disease, anticipated to be 
ventilated > 48 hrs. Patients will be randomized to REDvent-acute vs. usual care for the 
acute phase of MV (interval from intubation to first spontaneous breathing trial (SBT)).  
Patients in either group who fail their first Spontaneous Breathing Trial (SBT), will also 
be randomized to REDvent-weaning vs. usual care for the weaning phase of MV (interval 
from first SBT to passing SBT). The primary clinical outcome is length of weaning (time 
from first SBT until successful passage of an SBT or extubation (whichever comes first)).  
Mechanistic outcomes surround multi-modal serial measures of respiratory muscle 
capacity (PiMax), load (resistance, compliance), effort (esophageal manometry), and 
architecture (ultrasound) throughout the course of MV.   Upon completion, this study 
will provide important information on the pathogenesis and timing of respiratory muscle 
weakness during MV in children and whether this weakness can be mitigated by 
promoting more normal patient effort during MV via the use of REDvent. This will form 
the basis for a larger, Phase III multi-center study, powered for key clinical outcomes 
such as 28-day Ventilator Free Days.  

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A2 Protocol Summary 
Title: Real-time Effort Driven Ventilator Management (REDvent) 
 
Phase: Phase II 
 
Funding: NIH/NHLBI R01HL124666 
 
Committees: Steering Committee, Institutional Data and Safety Monitoring Board 
 
Background and Significance: Nearly half of critically ill patients on MV develop 
respiratory muscle weakness, particularly of the diaphragm. In adults, this weakness 
leads to the inability to resume unassisted ventilation after the acute illness has resolved, 
prolongs the weaning phase of MV, and contributes to extubation failure. 1-11 However, in 
critically ill children, we lack crucial information about the importance of ventilator-
induced respiratory muscle weakness during weaning, the means to prevent it, and 
whether it is influenced by maturational changes in respiratory mechanics and 
diaphragm histology that occur throughout infancy and childhood.12    
 
Consistent with the pediatric literature,4 our preliminary data has shown that  usual care 
ventilation  in children is associated with minimal patient effort of breathing; 13, 14 known 
to be a major risk factor for ventilator-induced diaphragm weakness in adults.5  To 
reduce this weakness, we developed a computer-based approach (Real-time Effort 
Driven ventilator management (REDvent)), which recommends systematic reductions in 
controlled ventilation during the acute phase of MV and uses real-time measures to 
adjust supported ventilator pressures to maintain patient effort of breathing during the 
weaning phase.  Through a Phase I trial, we demonstrated that patients managed with 
REDvent spent fewer days on MV than historical controls, and bedside providers could 
easily implement REDvent.  Our central hypothesis is that REDvent use will reduce 
ventilator-induced respiratory muscle weakness, leading to shorter time on MV by 
enhancing the patient’s capacity for effective, unsupported ventilation and by facilitating 
MV weaning.     
 
Study Aims: 
SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the 
duration of weaning from MV (Primary outcome).   
SA2: To determine if changes to direct measures of respiratory muscle strength, load, 
effort, and architecture throughout the duration of MV are related to weaning outcomes.  
SA3: To determine if patient effort of breathing during both acute and weaning phases of 
MV is independently associated with the development of respiratory muscle weakness.   
Study Design: Single-center randomized controlled trial (138 children per arm) using 
REDvent (intervention arm) as compared with usual care ventilator management 
including a standardized daily SBT (control arm). Acute phase randomization will occur 
upon study enrollment, and patients who fail the first SBT will undergo a weaning phase 
randomization. We will obtain serial measurements of respiratory system capacity, load, 
effort of breathing, and diaphragm architecture throughout the course of MV.  
 
Inclusion Criteria:  
1. Children > 1 month (>44 weeks CGA) and ≤ 21 years of age AND 

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2. Supported on mechanical ventilation with pulmonary parenchymal disease (i.e., 
pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome 
(PARDS)) with Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥) 
AND 
3. Who are within 48 hours of initiation of invasive mechanical ventilation  (allow 
for up to 72 hours for those transferred from another institution)   
Exclusion Criteria:  
1. Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding, 
nasal encephalocele, transphenoidal surgery) OR 
2. Contraindications to use of  RIP bands (i.e. omphalocele, chest immobilizer or 
cast) OR 
3. Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall 
defects, pregnancy) OR 
4. Conditions on enrollment that preclude conventional methods of weaning (i.e., 
status asthmaticus, severe lower airway obstruction, critical airway, intracranial 
hypertension, Extra Corporeal Life Support (ECLS), intubation for UAO, DNR, 
severe chronic respiratory failure, spinal cord injury above lumbar region, 
cyanotic heart disease (unrepaired or palliated)) OR 
5. Primary Attending physician refuses (will be cleared with primary attending 
before approaching the patient).  
 
A high level overview is presented in Figure 1. 
 
Acute Phase: The acute phase is defined as the time 
from intubation until the patient meets weaning 
criteria,15, 
16 passes the initial oxygenation test 
(decrease PEEP to 5 cmH2O and FiO2 to 0.5, 
maintains 
SpO2 
> 
90%), 
and 
undergoes 
a 
Spontaneous Breathing Trial (SBT).   
1. Intervention Arm (REDvent-acute): Patients will 
be managed with pressure control plus pressure 
support ventilation using a computerized decision 
support tool that will recommend changes to 
ventilator settings approximately every 4 hr (with 
or without a new blood gas). If the patient is 
spontaneously breathing, it will incorporate real-
time measures of effort of breathing (esophageal 
manometry) to keep it in a target range.   
2. Control 
Arm 
(Control-acute): 
Ventilator 
management will be per usual care until the 
patient meets weaning criteria and passes the 
oxygenation test.    
 
Weaning Phase: The weaning phase is defined as the time from the first Spontaneous 
Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated 
(whichever comes first). Patients who pass the initial SBT at the end of the acute phase 
will not undergo weaning phase randomization.  
1. Intervention Arm (REDvent-weaning): Patients will be managed in a pressure 
support/CPAP mode of ventilation with assessments or changes to the level of 
Figure 1: Study Schematic 

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pressure support every 4 hours, targeting maintaining effort of breathing (esophageal 
manometry) in a normal range.   An SBT will be conducted daily, and the weaning 
phase will continue until the patient passes the SBT.   
2. Control Arm (Control-weaning): Ventilator management will be per usual care.   An 
SBT will be conducted daily, and the weaning phase will continue until the patient 
passes the SBT.   
 
Endpoints:  
Primary:  
• 
Duration of Weaning (Time from first attempted SBT until SBT passage or 
extubation  [whichever comes first]) 
Secondary 
• 
Ventilator Free Days 
• 
Extubation Failure 
• 
Pre-specified and Unanticipated Adverse Events 
• 
ICU, Hospital, and 90 Day Mortality 
• 
Esophageal Manometry: Maximal Inspiratory Pressure During Airway 
Occlusion (ePiMax) 
• 
Airway Pressure: Maximal Inspiratory Pressure During Airway Occlusion 
(aPiMax) 
• 
Diaphragm Ultrasound: Change in diaphragm thickness on Exhalation (Dte) 
• 
Respiratory Inductance Plethysmography: Phase angle (PA) 
 
Analysis Plan and Sample Size Justification: 
 
Aim 1: The primary outcome is weaning duration. Sample size has been determined to 
adequately power 3 separate comparative analyses: (a) REDvent-acute versus Acute 
Phase control (b) REDvent-weaning phase versus Weaning Phase control (c) REDvent 
both phases versus control both phases.    Power is based on 2 planned methods for 
analysis: cox proportional hazard ratios for multivariable analysis and univariate 
analysis with an independent t-test using log transformation (as needed) to account for 
the expected distribution of weaning duration.  For all three of the planned comparisons 
above, with the proposed sample size we would be adequately powered (>0.8) to detect a 
difference in weaning duration of ≥ 1 day, or a hazard ratio of ≥ 1.4 between groups.  The 
secondary outcomes are ventilator free days and extubation failure.  Directly comparing 
control only patients to REDvent only patients, with an expected standard deviation for 
VFDs between 5 to 9 days, we will be able to detect a 2-day change in VFDs between 
groups with a power between 0.35 and 0.82.  Re-intubation rates are expected to be 10%, 
allowing us to confirm that REDvent is not inferior to usual care in regards to re-
intubation with a non-inferiority margin of 0.10 with a power of 0.8 and alpha of 0.05.     
 
Aim 2: The primary outcome of this aim is weaning duration.  For respiratory muscle 
strength we will compare the first measured aPiMax (after resolution of the acute phase, 
before the first SBT), the trajectory and value of the daily aPiMax during the weaning 
phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the 
day of extubation against weaning duration.  For analysis, aPiMax will be dichotomized 
at 30 cmH2O, and weaning duration  will be compared between patients with aPiMax > 
30 versus ≤ 30 cmH2O using a t-test with or without log-transformation, or Mann-
Whitney U test, depending on the distribution.  From our preliminary data, we anticipate 
at least 35% of patients (n=84) will have aPiMax ≤ 30 cmH2O.    Based on a similar 
power analysis as presented above, this would allow us to determine whether low aPiMax 

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is associated with a ≥ 1-day increase in weaning duration, with an alpha of 0.05 and 
power of 0.8.    We will perform identical analysis for ePiMax.  Diaphragm Thickness 
analysis will compound daily ultrasound measures to detect the relative change in 
diaphragm thickness from study day 1 until passage of an SBT.  We will compare the 
change in thickness after resolution of the acute phase (on the day of the first SBT) 
against weaning duration, in a similar manner as proposed above for aPiMax.  In 
addition to weaning duration, we will also examine whether the respiratory measures 
taken just prior to or during each SBT are associated with the patient passing the SBT. 
For example with aPiMax and ePiMax, we will examine if there is a dose response 
relationship between PiMax measured just before the SBT and the rate of passage of the 
subsequent SBT.   
 
Aim 3: The primary outcome of this aim is aPiMax < 30 cmH2O.The analysis will focus 
on determining whether the degree of patient effort of breathing is independently 
associated with the development of respiratory muscle weakness.  For the acute phase, 
we will generate a time-weighted average PRP during the acute phase and graph it 
against aPiMax at the first SBT.  We will subsequently dichotomize aPiMax at the first 
SBT and compare mean time weighted average PRP in the acute phase between aPiMax 
groups (> 30 vs. ≤ 30 cmH2O).  For the weaning phase, we will graph the changes in 
aPiMax throughout the weaning phase (from first failed SBT until successful SBT) 
against time-weighted average PRP, with the anticipation that low PRP will be associated 
with either further reductions in aPiMax, or no improvement, while PRP in the 
physiologic range of 150-400 will be associated with improvement in aPiMax.  We will 
subsequently dichotomize aPiMax (at 30 cm H2O) at the time of successful passage of an 
SBT and compare time-weighted average PRP in the weaning phase between aPiMax 
groups. Subsequently, we will build a multivariable logistic regression model on the 
outcome of aPiMax ≤ 30 cmH2O to determine if time-weighted PRP in the acute phase, 
weaning phase or both have an independent association with preserving aPiMax, after 
controlling for confounding variables. 
 
Monitoring: The study will one planned interim analysis at 138 patients, with no rules 
planned for early stopping, given the low risk nature of this study and the high degree of 
physiologic data collected.  In addition, there will be an early safety check after 
approximately 50 patients are enrolled, to review rates of adverse events between 
groups. There will be review of adverse events by the DSMB during scheduled meetings 
twice a year, or as requested.   

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A3 Primary Hypothesis and Specific Aims 
Our central hypothesis is that REDvent use will reduce ventilator-induced respiratory 
muscle weakness, leading to shorter time on MV by enhancing the patient’s capacity for 
effective, unsupported ventilation and by facilitating MV weaning.    This will be 
specifically tested with 3 complementary specific aims: 
 
SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the 
duration of weaning from MV (Primary outcome).  We expect that patients randomized 
to receive REDvent-acute will either pass their first SBT or experience a shorter duration 
of weaning when compared to usual care. In addition, patients randomized to receive 
REDvent-weaning will experience a shorter duration of weaning compared to usual care. 
Secondary outcomes include 28-day Ventilator Free Days and extubation failure.     
SA2: To determine if changes to direct measures of respiratory muscle strength, load, 
effort, and architecture throughout the duration of MV are related to weaning outcomes. 
We expect that diminished respiratory muscle strength (low PiMax), and diaphragm 
atrophy (ultrasound) will be prevalent after resolution of the acute phase of MV, and the 
combination of high respiratory load (or effort) with low PiMax will be a major factor 
leading to prolonged weaning and weaning failure (failure of SBT).   
SA3: To determine if patient effort of breathing during both acute and weaning phases of 
MV is independently associated with the development of respiratory muscle weakness.  
We expect that after controlling for confounding variables like age, diagnosis, sedation, 
use of neuromuscular blockade, and other risk factors for neuromuscular weakness, 
children who maintain normal effort of breathing in the acute or weaning phases will 
have higher respiratory muscle capacity as measured by PiMax.  

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B Background 
 
B1 Prior Literature and Studies 
 
 
Children supported by mechanical ventilators in intensive care units contribute 
to over $5 billion dollars a year in US healthcare costs.17, 18  Efficient methods to optimize 
ventilator support in children are lacking, resulting in some children being on ventilators 
longer than necessary.16 Each additional day of ventilation leads to added health risks 
such as exposure to medications that may harm the developing brain, higher risk of 
infection, and critical illness acquired weakness leading to long-term impairment in 
patient quality of life.17, 19-25  Mechanical ventilation (MV) of critically ill adults frequently 
leads to acquired respiratory muscle weakness, particularly of the diaphragm, which is a 
major factor contributing to extra days on MV.1, 2 Mechanisms responsible for ventilator-
induced diaphragm weakness relate to the underlying disease status of the patient, the 
severity of inflammation, the use of therapies like neuromuscular blockade and 
corticosteroids, the degree of protein catabolism, and the degree of diaphragm 
contraction during MV.1, 5, 6, 8-10, 26    Accumulating data indicate that > 50 % of critically 
ill adults who are on MV > 72 hours have thinning of the diaphragm (based on 
ultrasound) within the first few days of MV, 5  and there is a dose response relationship 
between diaphragm atrophy and increasing ventilator driving pressure.5   Moreover, low 
diaphragm contractile activity leads to atrophy, while diaphragm thickness is preserved 
when contractile activity during MV is normal (i.e., patient maintains normal work of 
breathing).27    
 
Many adult studies have demonstrated architectural changes to the diaphragm 
which occur throughout the course of mechanical ventilation, but these changes may not 
directly translate into weakness.5, 7 Respiratory muscle weakness can be objectively 
measured as the inability to generate sufficient changes in airway or esophageal pressure 
with maximal diaphragm contraction (PiMax), either voluntarily or through external 
stimulation of the phrenic nerve.  However, there are limited data quantifying the time 
frame and degree to which these direct measures of respiratory muscle weakness 
(PiMax) become impaired during MV, although evidence suggests that low PiMax at 
extubation is associated with longer lengths of MV and higher mortality in adults.8, 28   
Single direct measures of respiratory muscle strength may be misleading.  Experts in the 
field of pulmonary function testing of the respiratory muscles recommend serial 
measurements, combining multiple techniques to obtain the most comprehensive view 
of the respiratory muscles.   This approach has been used when investigating other 
causes of diaphragm dysfunction, 29  but such a systematic, multi-modal approach has 
not been applied to study ventilator induced diaphragm dysfunction in critically ill 
patients. 
 
 
  
B2 Rationale for this Study 
 
 
Few data are available regarding the prevalence of ventilator induced diaphragm 
weakness and the risk factors for its development in children, although the respiratory 
muscles of the infant and newborn are more susceptible to weakness and fatigue than 

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those of older children because of crucial differences in diaphragm histology.12, 30 
However, the pathophysiology of ventilator-induced diaphragm weakness supports in 
children, as in adults, that ventilator management in both acute and weaning phases of 
MV contribute to diaphragm weakness.4, 11  During the acute phase of MV, the goals are 
to maintain safe gas exchange, reduce excessive patient work of breathing, and prevent 
ventilator-induced lung injury through lung protective ventilation.  While prolonged 
periods of high effort of breathing should be avoided because they worsen gas exchange, 
compromise oxygen delivery and potentiate ventilator induced lung injury,  MV is often 
too highly controlled, resulting in minimal to no patient effort of breathing4 and minimal 
changes of the ventilator settings.   Consistent with other investigations 31, we have found 
that practitioners do not make changes to promote lung protective ventilation 32, 33 and 
do not reduce high ventilator settings over 50% of the time when managing MV without 
an explicit protocol, even in circumstances of respiratory alkalosis and over-ventilation.33  
Ventilator driving pressures are often higher than necessary and respiratory alkalosis 
prevents meaningful patient effort during the acute phase of MV.  This strategy results in 
high rates of fully controlled mechanical ventilation and directly leads to diaphragm 
weakness. 34 35-38 
 
When critical illness has stabilized, weaning towards extubation in current 
practice involves slow, gradual reductions of ventilator pressures until spontaneous 
breathing trials (SBTs) are performed,16, 39 although routine SBTs are only performed in 
< 25% of MV children. 33, 39  While practitioners frequently have the patient initiate 
ventilator breaths (spontaneous breathing) during weaning, the ventilator performs 
most of the required work of breathing. In general, during usual care ventilator 
management, patient breathing effort during both acute and weaning phases of MV is 
well below the normal physiologic range that would be expected if their lungs were 
healthy and off a ventilator. 4, 5 This sub-physiologic patient effort potentiates diaphragm 
weakness. 
 
We hypothesize that maintaining patient effort of breathing closer to a normal, 
physiologic range will protect against diaphragm weakness. In pediatrics, there has been 
little work developing methods to promote early return to more natural breathing in this 
physiologic range. For adults, there are a few commercially available closed-loop 
ventilation weaning systems that provide an estimate of effort of breathing, and 
concurrently reduce ventilator support during weaning.  Such systems have been shown 
to reduce length of MV by 20-40% over conventional weaning, 40 with supportive pilot 
data in older children. 41 Unfortunately, current closed-loop weaning tools are not 
available for most children, and these strategies are not initiated until the weaning phase 
of MV, allowing respiratory muscle weakness to develop during the acute phase of 
illness. 5, 42  New methods to continuously measure effort or work of breathing to guide 
ventilator management in young children are needed. 
 
Through the use of technology systems developed specifically for children, we 
seek to determine whether a physiology-based ventilator management approach can 
prevent acquired respiratory muscle weakness in children, thus facilitating MV weaning 
and earlier recovery from critical illness. 43 The approach promotes the safe reduction in 
controlled ventilation during the acute phase of MV and early return to spontaneous 
breathing with maintenance of normal patient effort of breathing in the weaning phase 
(Real-time Effort Driven ventilator management (REDvent)).  Through this study, we 
seek to understand the importance of respiratory muscle weakness in both the acute and 
weaning phases of MV in children, quantify the importance of patient effort of breathing 
for the development of respiratory muscle weakness, and determine whether REDvent 
can shorten ventilator weaning time.  This study will improve our understanding of the 
pathogenesis of ventilator-induced diaphragm weakness in children and determine 

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whether computer-driven management prevents this weakness and leads to improved 
patient outcomes.  
 
B3 Preliminary Data 
 
B.3.1 Patient effort of breathing is generally very low with usual care 
ventilation: Dr. Khemani led a study of 409 mechanically ventilated children (77% 
consent rate) in which respiratory parameters were measured using esophageal 
manometry and respiratory inductance plethysmography 44 near extubation (K23 
HL103785, PI Khemani).  From secondary analysis of that data, we found that Pressure 
Rate Product (PRP, a direct measure of patient effort of breathing derived from 
esophageal manometry) on the day of extubation under what is considered minimal 
respiratory support (PS of 10/5 cmH20) was nearly 2.5 fold lower (median 90 (50, 140)) 
than PRP post-extubation (median 220 (120, 320)).13, 14,39  Other pediatric investigators 
have demonstrated frequent periods of no detectable diaphragm effort during 
conventional ventilation, with electrical activity of the diaphragm 3 times lower during 
MV  than it was at ICU discharge. 4  Thus, current ventilator strategies do not maintain 
normal patient effort and may contribute to respiratory muscle weakness. We have also 
shown that there is a normal range for effort of breathing that can be maintained by 
adjusting ventilator support.  75% of patients from our cohort who did well after 
extubation (i.e., no re-intubation, no need for post-extubation noninvasive ventilation) 
had a PRP from 150 to 400.   These cut points appear to work across the entire pediatric 
age spectrum (neonate to 21 years), and form the basis for the “optimal range” that will 
be used for titration in this application.   
 
B.3.2 REDvent management protocol:  The computerized decision support (CDS) 
tool used by REDvent-acute is an electronic protocol that makes recommendations at 
user-set time intervals to adjust both ventilation (ventilator pressure or tidal volume and 
ventilator rate) and oxygenation (Positive End Expiratory Pressure and FiO2) to promote 
lung protective ventilation during the acute phase of MV. It implements a pediatric 
modification of the Acute Respiratory Distress Syndrome Network protocol,45 
(R21HD061870, PI Newth).  We have demonstrated that pediatric critical care 
practitioners agree on the recommendations generated by the modified protocol.46, 47  
The CDS tool has been extensively tested in our ICU to provide explicit 
recommendations, and has built-in reporting features to measure protocol adherence.  
REDvent-weaning recommends adjusting supported ventilator pressures based on real-
time direct measures of effort of breathing using RESPivice. RESPivice is an open-loop 
patient monitor that incorporates an esophageal manometry catheter and Respiratory 
Inductance Plethysmography Bands (RIP Bands) connected to a hardware box that  
passes signals to a laptop computer. 48, 49 The esophageal manometry catheter (which has 
an integrated feeding tube) is used for continuous effort of breathing calculations and 
RIP bands allow for measurement of  phase angle (a measure of thoraco-abdominal 
asynchrony), and can be calibrated to measure flow or volume after extubation. 49  
 
B.3.3 Phase I trial using REDvent protocols: To test the feasibility of REDvent in 
MV children, Dr. Khemani led an open label, intervention only Phase I study enrolling 
20 children <18 yr of age with pulmonary parenchymal disease and an anticipated 
intubation of > 48 hours (83% consent rate).  Details of the REDvent management 
protocol are summarized in Figure 2. The acute phase of ventilator management was 

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controlled by the CDS tool with a ventilator recommendation generated every 4 hr, or 
with a new blood gas value.  If a blood gas was not available at the 4 hr interval, then 
non-invasive parameters (pulse oximetry and end-tidal CO2) were used to provide 
estimates for the adequacy of oxygenation and ventilation based on prediction models we 
have previously validated. 50   When patients met weaning criteria (no increase in 
ventilator support for 24 hr, spontaneous breathing, PEEP ≤ 10 cmH2O, FiO2 ≤ 60%), 
they had an oxygenation test (decease PEEP to 5, Fio2 ≤ 0.5, maintain SpO2 > 88%). If 
they passed the oxygenation test, they were then given a SBT on CPAP of 5 cmH2O and 
then extubated (i.e. both clinical and effort of breathing criteria were met).  If they failed 
the SBT, they were initiated on the effort of breathing part of the study and pressure 
support was added to PEEP to maintain PRP in the target range.  After patient 15, we 
modified the weaning protocol to allow 3 ranges for adjustment (Figure 2) to better fit 
with clinical practice and improve adherence.  Every 4 hr, a recommendation was given 
to adjust pressure support by 2 cmH2O to keep PRP in the target range (200-400) .  The 
SBT and extubation evaluation were performed every 24 hr. 
 
B.3.4 The protocol has the potential to shorten duration of ventilation: We 
have completed the Phase I study described above.  During the acute phase, 698/966 
recommendations were accepted (73% adherence). During the weaning phase 136/187 
(73%) recommendations were accepted. However, after the protocol modification for the 
weaning phase, 96% of the recommendations were followed.   Over 40 bedside 
respiratory therapists have used the acute and weaning protocols.  A study respiratory 
therapist has been providing initial training of the bedside RT.  In addition the study RT 
or PI has been available during the day and as needed by phone at night. Specific 
training sheets have been developed, overnight support by research personnel was 
generally minimal, and no safety concerns were identified.  MV is generally weaned 
steadily in both acute and weaning phases.   As the Phase I study did not have a control 
group, we used matched historical controls that were similar with respect to age and 
 
Figure 2: Details of REDvent protocol for both acute and weaning phases.    
 

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Figure 3: Re-intubation rates increase in a dose response fashion as a 
function of low  aPiMax.    
initial hypoxemia severity, with a similar percentage of immune compromise, sepsis and 
pneumonia 
patients 
between groups. Patients 
treated 
with 
REDvent 
had larger changes in 
Peak 
Inspiratory 
Pressure and Ventilator 
Rate per day in the acute 
phase as compared with 
historical 
controls.  
REDvent was associated 
with 
approximately 
2 
fewer days on MV (25% 
reduction) compared to 
historical 
controls 
(p=0.36, Table 1). While not statistically significant due to the small sample size, 
REDvent appears to lead to faster MV weaning.   
 
B.3.5 Ventilator-induced respiratory muscle weakness is common in 
children, leading to failed extubation: Accurate quantification of the severity of 
diaphragm dysfunction is understudied, particularly in pediatrics.  While diaphragm 
ultrasound can provide corroborative data about architectural changes, ultrasound does 
not directly measure strength. 3, 5, 7, 51, 52  Single measures of respiratory muscle strength 
(airway or esophageal PiMax) measured with maximal voluntary efforts during airway 
occlusion are regarded as the most appropriate tests in adults.29 To specifically examine 
diaphragm strength (isolated from the intercostal muscles), two simultaneous pressure 
transducers (one in the esophagus and one in the stomach) can be used to calculate 
trans-diaphragmatic pressure. 29, 53  When patients are intubated, there is divergence in 
the literature as to whether maximal voluntary efforts can be guaranteed,26, 29, 54-57  
prompting 
investigators 
to 
use twitch stimulation of the 
phrenic 
nerve 
through 
electrical or magnetic coils 
with resultant measures of 
airway 
or 
esophageal 
pressure,29, 58 . Although this 
technique has been applied in 
a very limited capacity in 
young children, it has high 
variability 
and 
limited 
reproducibility. 59-64   
 
An analysis of the 409 
patients 
enrolled 
in 
our 
previous study suggested that low PiMax (both airway (aPiMax) and esophageal 
(ePiMax)) measured during airway occlusion while the child is breathing spontaneously, 
was associated with re-intubation. 65 A trained provider (research respiratory therapist 
or study PI) performed airway occlusion maneuvers to measure both aPiMax and 
ePiMax, ensuring that the child was at end-exhalation and that the airway remained 
occluded for at minimum 3 consecutive breaths, but most of the time at least 5,57 just 
before extubation.  Measures of respiratory system capacity were obtained prior to 
extubation during airway occlusion, and measures of respiratory effort were obtained 
Table 1: Comparison between REDvent and 
historical controls 
REDvent 
(n=19) 
Matched Controls 
(n=90) 
Matching Variables   
Age (years) 
9.2 (3.2,12.3) 
7.0 (0.9,14.2) 
Oxygen Saturation Index (OSI) 
15.9 (10.6,16.2) 
14.1 (9.6,19.4) 
High Frequency Oscillator (HFO) 
17% 
17% 
Immune Compromised 
39% 
32% 
Pneumonia 
50% 
58% 
Sepsis 
38% 
39% 
Outcomes  
Daily Change PIP Acute Phase 
4 (2,5) 
1.5 (1,3) 
Daily Change Vent Rate Acute Phase 
3 (0,4) 
1 (0,2) 
        Length of MV (days) 
6.5 (4.9,8.7) 
8.4 (4.5,13.9) 

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both before and after extubation.   Of the 409 patients, 34 were re-intubated within 48 
hours (8.3%).   Prior to extubation, re-intubation risk factors included lower aPiMax, and 
longer length of ventilation.  After extubation, post-extubation upper airway obstruction 
(UAO), high respiratory effort or load (Pressure Rate Product (PRP), Pressure Time 
Product (PTP), Tension Time Index (TTI)) and high Phase Angle (PA) were associated 
with re-intubation.  Because patients in this study had already passed SBTs, they 
generally had near normal compliance (low load), so pre-extubation respiratory effort 
was not associated with re-intubation. When looking specifically at measures of 
respiratory muscle capacity prior to extubation, there was a dose response relationship 
between lower aPiMax and re-intubation risk (Figure 3).  Children with aPiMax ≤ 30 
cmH20 accounted for 33% of all extubated patients, but were responsible for 56% of all 
failed extubations (19/34).  Thus, aPiMax alone is a marker of re-intubation risk (AUC 
0.66 (0.57, 0.75).   
Nevertheless, 
combining 
aPiMax 
with 
measures 
of 
respiratory 
effort 
(after 
extubation) such as PRP better 
predicted 
re-intubation 
risk 
(AUC 0.77).   For children with 
diminished respiratory muscle 
capacity (aPiMax ≤ 30 cmH2O), 
re-intubation rates were always 
higher 
than 
the 
population 
average, 
and 
they 
became 
accelerated as effort increased 
(PRP>500). 
Children 
with 
maintained respiratory muscle 
capacity (aPiMax >30 cmH2O) could tolerate moderate to high levels of load after 
extubation (PRP 500-1000), and re-intubation rates did not exceed the population 
average unless effort was very high (PRP > 1000).  Post-extubation subglottic UAO was 
the most common reason for high respiratory muscle load after extubation, and when 
children with diminished respiratory muscle capacity (aPiMax ≤ 30 cmH2O) had 
subglottic UAO after extubation, their re-intubation rates were 5.7 times higher than the 
population average (47.5% vs. 8.3%, Figure 4).  The rate of aPiMax ≤ 30 cmH2O was 
slightly higher for neonates (47%) compared to the other age groups, although this was 
not statistically significant (p=0.12; 30% infants (1-24 months), 30 % child age (2-11 
years) and 34% adolescents (11-18 years)).  Multivariable risk factors for re-intubation 
include primary intubation for neurologic disease, lower aPiMax, UAO post-extubation, 
higher PEEP before extubation, higher PRP after extubation, and lower height (AUC 
0.823).  This demonstrates that respiratory muscle weakness contributes to 
extubation failure, and maintaining respiratory muscle strength will likely reduce re-
intubation rates even when respiratory load after extubation is high.  These data further 
support the hypothesis that children with respiratory muscle weakness will 
have more trouble weaning from MV when respiratory load (compliance, 
resistance) may still be high.  
 
B.3.6 Summary of Preliminary Data: We have demonstrated that 35% of MV 
children have respiratory muscle weakness at the time of extubation, making them 3 
times more likely to be re-intubated, and nearly 6 times more likely to fail when 
respiratory load is high.65, 66 We have also shown that current ventilator management in 
children likely exacerbates the development of respiratory weakness by lowering patient 
 
Figure 4: When children with low aPiMax develop high respiratory 
load (such as from post extubation UAO), they have very high re-
intubation rates. Solid line is population average.    

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effort of breathing well below normal physiologic values.13, 14  To promote maintaining 
patient effort of breathing in a normal range we have developed and demonstrated the 
feasibility of having bedside providers use a computer-based ventilator management 
system throughout the entire course of MV.  Patients managed with this system 
experienced a median 2 day reduction in the length of MV compared to historical 
controls.  Together these data justify the next phase of this program of research, to test 
whether this ventilator management approach can lead to improved clinical outcomes in 
a robust randomized clinical trial, and to characterize the mechanisms underlying this 
improvement through detailed, serial assessments of the respiratory muscles.   
 
 

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C Study Objectives 
 
C1 Primary Aim 
SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the 
duration of weaning from MV.  We expect that patients randomized to receive REDvent-
acute will either pass their first SBT or experience a shorter duration of weaning when 
compared to usual care. In addition, patients randomized to receive REDvent-weaning 
will experience a shorter duration of weaning compared to usual care. Secondary 
outcomes include 28-day Ventilator Free Days and extubation failure.     
C2 Secondary Aims 
 
SA2: To determine if changes to direct measures of respiratory muscle strength, load, 
effort, and architecture throughout the duration of MV are related to weaning outcomes. 
We expect that diminished respiratory muscle strength (low PiMax), and diaphragm 
atrophy (ultrasound) will be prevalent after resolution of the acute phase of MV, and the 
combination of high respiratory load (or effort) with low PiMax will be a major factor 
leading to prolonged weaning and weaning failure (failure of SBT).   
SA3: To determine if patient effort of breathing during both acute and weaning phases of 
MV is independently associated with the development of respiratory muscle weakness.  
We expect that after controlling for confounding variables like age, diagnosis, sedation, 
use of neuromuscular blockade, and other risk factors for neuromuscular weakness, 
children who maintain normal effort of breathing in the acute or weaning phases will 
have higher respiratory muscle capacity as measured by PiMax.  
C3 Rationale for the Selection of Outcome Measures 
 
C.3.1. Clinical outcome measures:  
 
1. Primary Outcome – Weaning Duration  
Weaning duration is defined as the time from the first spontaneous breathing 
trial (SBT) until successful passage of an SBT or successful extubation (whichever 
comes first).  Successful extubation is defined as removal of the endotracheal 
tube without re-intubation for at least 24 hours.  For tracheostomy patients, 
extubation is defined as removal of positive pressure mechanical ventilation 
without re-initiation for at least 24 hours.  SBT passage will be based on objective 
criteria, based on previous publications.   
 
a.  Criteria for SBT passage: SBTs will be performed when weaning criteria are 
met, and the patient passes the oxygenation test (maintenance of SpO2 > 
90% with FiO2 ≤ 0.5 and PEEP ≤ 5 cmH20).  SBTs will be performed on 
CPAP ≤ 5 cmH2O, for 2 hours duration.  The following criteria represent rules 
for study defined SBT failure at any time point during the 2 hour SBT.   
 
Variable 
Failure within 2 hours 
pH (arterial or capillary) 
< 7.32  

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End tidal CO2 
10 mmHg from baseline 
Oxygenation  
FiO2 >0.5 and SpO2 <90% on PEEP 
=5 cmH20 
HR 
 > 40 BPM over baseline 
Rapid Shallow Breathing Pattern 
(RSBI) (bpm/ml/kg) 
≥ 12 
Pressure.Rate.Product (PRP) 
>500 
Retractions 
Moderate or Severe 
 
 
b. Rationale for passing SBTs vs. extubation in defining weaning duration: SBTs 
systematically assess the patient’s readiness to resume unassisted ventilation, 
while extubation can be delayed after SBT passage (due to respiratory 
secretions, procedures, etc.).  For this reason, SBT passage or successful 
extubation (whichever comes first) will define the end of the weaning phase.  
If a patient passes an SBT but is not extubated within 6 hr, ventilator 
management until extubation will continue as per the group to which the 
patient has been randomized for the current phase of ventilation.  However 
the length of weaning for the primary outcome measure will be calculated as 
the time the patient passed the SBT.   If a patient does not pass the SBT, but 
the clinical team elects to extubate the child (or the child has an unplanned 
extubation), and the child is not re-intubated within 24 hours, then the length 
of weaning for the primary outcome measure will be calculated as the time 
the patient was extubated.   
     
2. Duration of Invasive Mechanical Ventilation (IMV)- Secondary Outcome 
Duration of invasive ventilation is the number of days and hours that the patient 
is intubated (from insertion to removal), censored 60 days after study 
enrollment. For calculations, removal of the ETT will be calculated as the first 
time the tube is continuously absent for at least 24 hours.  For tracheostomy 
patients, the end of intubation is defined as removal of positive pressure 
mechanical ventilation without re-initiation for at least 24 hours. Re-intubation 
after 24 hours and subsequent periods of invasive mechanical ventilation within 
60 days of study enrollment will be summed together to represent total duration 
of IMV. 
 
3. Duration of Non-Invasive Mechanical Ventilation (NIV) after extubation– 
Secondary Outcome  
Duration of non-invasive ventilation after extubation is defined as the number of 
days and hours that the patient is on oro-nasal mask CPAP with minimal 
pressure of 5 cmH20, or Bi-Level ventilation (at any pressure) after extubation, 
censored 60 days after study enrollment. For calculations, the end of Non-
Invasive Ventilation will be calculated as oro-nasal mask CPAP (minimal 5 
cmH2o) or BIPAP as continuously absent for at least 24 hours.  Resumption of 
NIV after 24 hours and subsequent periods of non- invasive mechanical 
ventilation within 60 days of study enrollment will be summed together to 
represent total duration of NIV after extubation. 
 
4. Duration of Non-Invasive Mechanical Ventilation (NIV) before intubation– 
Secondary Outcome  
Duration of non-invasive ventilation before intubation is defined as the number 
of days and hours that the patient is on oro-nasal mask CPAP with minimal 

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pressure of 5 cmH20, or Bi-Level ventilation (at any pressure) prior to 
intubation.  This is necessary to correctly compute ventilator free days.  For 
calculations, the patient must have been on Non-Invasive Ventilation in the 24 
hours prior to intubation.   
 
5. Duration of Non-Invasive Respiratory Support (NRS) after extubation- 
Secondary Outcome 
Non-invasive respiratory support includes: High Flow Nasal Cannula (HFNC) or 
nasal-only modes of non-invasive ventilation (CPAP or Nasal IMV or BiPAP). It 
does not include oxygen therapy via face mask, nasal cannula, oxygen hood, or 
blow by oxygen alone.    Duration of NRS after extubation is defined as the 
number of days and hours that the patient is on NRS after extubation, censored 
at 60 days after study enrollment. For calculations, the end of NRS will be 
calculated as NRS being continuously absent for at least 24 hours.  Resumption 
of NRS after 24 hours and subsequent periods of NRS within 60 days of study 
enrollment will be summed together to represent total duration of NRS after 
extubation. 
 
6. Re-intubation within 48 hours of extubation- Secondary Outcome  
Re-intubation will be defined as re-insertion of the endotracheal tube within 48 
hours of the initial extubation.  For tracheostomy patients, re-intubation is 
defined as re-initiation of positive pressure mechanical ventilation within 48 
hours of discontinuation. 
 
7. Re-intubation within 7 days of extubation- Secondary Outcome 
Re-intubation will be defined as re-insertion of the endotracheal tube within 7 
days of the initial extubation. For tracheostomy patients, re-intubation is defined 
as re-initiation of positive pressure mechanical ventilation within 7 days of 
discontinuation. 
 
8. Ventilator Free Days- Secondary Outcome  
Because the acute phase of ventilation is often long and less predictable, weaning 
duration was chosen as the primary outcome because there is more variability in 
Ventilator Free Days (VFDs) than in weaning duration.   However VFDs is a 
secondary outcome.   VFDs will be calculated at 28 and 60 days, defined as total 
number of days after initiation of MV in which the patient is alive and not on 
ventilation.  The components of length of mechanical ventilation used for VFD 
calculations include length of IMV (2 above), length of NIV after extubation (3 
above) and length of NIV prior to intubation (4) above.  Patients who die within 
the 28 or 60 days will have 0 28 or 60 Day VFDs respectively.   
 
9. Use and duration of rescue therapies - Secondary Outcomes 
We will track daily whether the patient received any of the following “rescue 
therapies” which are frequently used for ARDS management: inhaled nitric oxide, 
High Frequency Oscillatory Ventilation, Prone Positioning, Extra Corporeal Life 
Support, Corticosteroids for lung disease/ARDS, Continuous Neuromuscular 
Blockade, Airway Pressure Release Ventilation.      
 
C.3.2 Physiologic outcome measures: Our primary physiologic outcome surrounds 
respiratory muscle weakness.  Previous research has highlighted the importance of using 
multiple assessments of respiratory muscles, as single tests may be misleading. 67  We 

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will use esophageal manometry, airway pressure, and diaphragm ultrasound to evaluate 
direct and indirect measures of respiratory muscle strength. 
 
1. Respiratory Muscle Strength (aPiMax- Primary Outcome; ePiMax – Secondary 
Outcome):  
a. Physiologic measures of strength include airway and esophageal pressure during 
airway occlusion (aPiMax and ePiMax, respectively).   Primary analysis is 
planned using aPimax (calculated as maximal change in airway pressure at end 
exhalation during airway occlusion for 3-5 breaths).   Secondary analysis will use 
ePimax (calculated as maximal change in esophageal pressure at end exhalation 
during airway occlusion for 3-5 breaths).  Measurements will be obtained daily 
after the patient passes the oxygenation test.   
b. Rationale:  We found aPiMax better predicted re-intubation than ePiMax in our 
preliminary data. We believe that this is due to more artifacts in the esophageal 
pressure signal during airway occlusion, which are not present with airway 
pressure.  To isolate diaphragm weakness, a second balloon catheter would be 
necessary to calculate trans-diaphragm pressure.  However, this is not practical 
for repeated use in children and no double-balloon catheters are commercially 
available for infants. A second catheter in an already small esophagus may alter 
the signals further, and impede clinical care if the catheter is left in place. While 
we will measure both airway and esophageal PiMax, we plan to use aPiMax as the 
primary marker of respiratory system capacity.  Our previous study evaluated 
PiMax parameters only at extubation, but we are confident the technique can be 
applied earlier (i.e., just prior to SBTs), and have obtained them successfully as 
part of our pilot study.   Early in the course of MV, patients may be more sedated 
than they are at the time of extubation (but are still breathing spontaneously), 
but we have successfully measured both airway and esophageal PiMax in  
patients who are considerably more sedated, and in deeply sedated rhesus 
monkeys.48  Sedated patients still produce reliable PiMax measurements when 
using our methodology, particularly when 5 occluded breaths are used.  We will 
also calculate P0.1 (change in airway or esophageal pressure in the first 0.1 
seconds of a breath attempt) which can be used to identify if sedation is affecting 
the results of the PiMax measurements.    All PiMax procedures will be recorded 
for post-processing analysis.  
 
2. Diaphragm Architecture:  Serial measurements from diaphragm ultrasound will be 
performed daily to assess changes in diaphragm thickness during exhalation (Dte) 
during both acute and weaning phases. 3, 5-8, 26, 52, 68-73 For the acute phase, the main 
diaphragm ultrasound outcome is: change in diaphragm thickness from study 
initiation until the end of the acute phase.  For the weaning phase it is: change in 
diaphragm thickness from the end of the acute phase until the end of the weaning 
phase.  Because diaphragm ultrasound is non-invasive, it has advantages although it 
has not been validated against direct measures of respiratory muscle strength or 
weaning outcomes. We will attempt such a validation with this study, but have not 
selected it as the primary physiologic endpoint for that reason.   
 
 
 

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D Study Design  
 
D1 Overview or Design Summary 
We propose a single-center randomized controlled trial (138 children per arm) using 
REDvent (intervention arm) as compared with usual care ventilator management 
including a standardized daily SBT (control arm). Acute phase randomization will occur 
upon study enrollment, and patients who fail the first SBT will undergo a weaning phase 
randomization. We will obtain serial measurements of respiratory system capacity, load, 
effort of breathing, and diaphragm architecture throughout the course of MV. 
D2 Subject Selection  
D.2.1 Inclusion Criteria  
1. Children > 1 month (at least 44 weeks Corrected Gestational Age) and ≤ 21 years 
of age AND 
2. Supported on mechanical ventilation for pulmonary parenchymal disease (i.e., 
pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome 
(PARDS)) with Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥4 
74 AND 
3. Who are within 48 hours of initiation of invasive mechanical ventilation (allow 
for up to 72 hours for those transferred from another institution)   
 
D.2.2 Exclusion Criteria  
1. Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding, 
nasal encephalocele, transphenoidal surgery) OR 
2. Contraindications to use of  RIP bands (i.e. omphalocele, chest immobilizer or 
cast) OR 
3. Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall 
defects, pregnancy) OR 
4. Conditions precluding conventional methods of weaning (i.e., status asthmaticus, 
severe lower airway obstruction, critical airway, intracranial hypertension, Extra 
Corporeal Life Support (ECLS), intubation for UAO, DNR, severe chronic 
respiratory failure, spinal cord injury above lumbar region, cyanotic heart disease 
(unrepaired or palliated)) OR 
5. Primary Attending physician refuses (will be cleared with primary attending 
before approaching the patient).  
D2.3 Screening and Eligibility  
Screening will occur daily to identify eligible patients.  An automated report has been 
generated to facilitate screening which calculates the oxygen saturation index, 
oxygenation index, PF ratio, and SF ratio for all patients on mechanical ventilation in the 
ICU.  Patients who have had qualifying hypoxemia (OSI >5 or OI >4) in the previous 24 
hours will have their chart reviewed to determine complete eligibility based on meeting 
all inclusion criteria and no exclusion criteria.   

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D3 Study Interventions  
The study intervention includes both acute and weaning phase components.  A high level 
view of the study is summarized in figure 5 below.  
D.3.1 Acute Phase: The acute phase is defined as the time from intubation until the 
patient meets weaning criteria,15, 16 and passes the initial oxygenation test (decrease 
PEEP to 5 cmH2O and FiO2 to 0.5, Figure 6).   
 
D.3.2 Acute Phase, Intervention Arm (REDvent-acute): Patients will be 
managed with pressure control plus pressure support ventilation with the CDS tool that 
will recommend changes to ventilator settings every 4 hr or with a new blood gas. The 
computerized decision support (CDS) tool used by REDvent-acute is an electronic 
protocol that makes recommendations at to adjust both ventilation (ventilator pressure 
or tidal volume and ventilator rate) and oxygenation (Positive End Expiratory Pressure 
and FiO2) to promote lung protective ventilation during the acute phase of MV.  Details 
of the rules behind the actual protocols are in section I.  PEEP/FiO2 is based on a 
PEEP/FiO2 table adapted from the Acute Respiratory Distress Syndrome Network 
protocol,45 (R21HD061870, PI Newth).  Ventilation is changed based on pH range, Peak  
Inspiratory Pressure, and Ventilator Rate.  
When the patient is breathing spontaneously 
during 
the 
acute 
phase, 
the 
Pressure.Rate.Product (PRP) is incorporated 
into 
the 
algorithm. 
The 
pH 
based 
recommendations are followed if increasing 
support is recommended. If the pH based 
recommendation is to decrease support, it 
will only do so if the PRP is below 200.  If the 
PRP 
is 
between 
200-400, 
support 
is 
maintained.  If the PRP is above 400, the 
protocol will recommend increasing driving 
pressure (Delta P) by 2 cm H20, to a max of 
35 cmH20.  The use of High Frequency 
Oscillatory (HFO) Ventilation as a rescue 
therapy will be left to the bedside clinicians, 
but HFO management will continue to be 
protocolized using the HFOV CDS tool 
(expected use: 10-15% in this cohort).   This 
protocol has a MAP/FiO2 table, and also 
recommends alterations in Amplitude and 
Hertz based on pH.  Details of the rules of the 
protocols are in section I.   
 
D.3.3 Acute Phase, Control Arm: Ventilator management will be per usual care 
until the patient meets weaning criteria and passes the oxygenation test (Figure 6).    
 
Figure 5: High level view of study interventions for 
both arms, during acute and weaning phases 

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D.3.4 Acute Phase Monitoring, both arms: Patients will be fitted with an 
esophageal manometry catheter, will undergo diaphragm ultrasound measurements, and 
will be connected to RIP bands during SBTs.  Volumetric capnography with an airway 
flow sensor will be placed at the end of the endotracheal tube to measure Carbon dioxide 
concentration, tidal volume, and airway pressures.   
Once the patient passes the oxygenation test, an airway occlusion maneuver will be 
performed to measure neuromuscular strength, followed by a SBT.  Daily SBTs are 
required and will be performed between 9 and 11 AM on CPAP of 5 cmH2O.     The 
primary study outcome (length of the weaning phase) is defined as the time from 
initiation of the first SBT until successful passing of an SBT (or extubation, whichever 
comes first). We will use validated objective criteria to define successful passing of the 
SBT, and track delays in extubation (> 6 hr between SBT passing and extubation).  These 
criteria are based on our previous publications and are detailed in the description of the 
primary outcome above, and again below. 16, 75  Patients who fail the initial SBT will move 
on to the weaning phase, and will undergo the weaning phase randomization to allocate 
treatment or control arms for weaning management.  
 
D.3.5 Spontaneous Breathing Trials and success/failure 
 
Variable 
Failure within 2 hours 
pH (arterial or capillary) 
< 7.32  
End tidal CO2 
10 mmHg from baseline 
Oxygenation  
FiO2 >0.5 and SpO2 <90% on PEEP = 
5 cmH20 
HR 
 > 40 BPM over baseline 
Rapid Shallow Breathing Pattern 
(RSBI) (bpm/ml/kg) 
≥ 12 
 
Figure 6: Acute Phase schematic, both arms 

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Pressure.Rate.Product (PRP) 
>500 
Retractions 
Moderate or Severe Retractions 
 
For the outcome of SBT passage, if any of the above criteria are met during the 2 hour 
SBT, the patient will be labeled as failing the SBT for study purposes. Once any of these 
failure criteria are met, the respiratory therapist will alert the clinical team.  The clinical 
team may choose to stop the SBT, in which case the patient will be returned to the 
previous ventilator settings, and weaning phase randomization will occur.  If the patient 
is randomized to REDvent-weaning, they will be placed in PS/CPAP mode and pressure 
support will be titrated to achieve PRP between 200-400 (to max of 20). PEEP may be 
adjusted between 5 and 10 cmH20.     The clinical team may alternatively choose to 
continue the SBT or to extubate the patient. If the patient is extubated, post-extubation 
management (and subsequent re-intubation management) will be usual care.  If the 
patient is not extubated but the SBT is terminated by the clinical team, then weaning 
phase randomization will occur at that point.    
 
Monitoring during the SBT will include placement of Respiratory Inductance 
Plethysmography (RIP) bands and a spirometer.  Vital signs, physiologic measurements, 
and data from RIP and esophageal manometry will be recorded every 30 minutes during 
the SBT. A study ultrasound to measure diaphragm contractile activity will occur 
approximately 15 minutes into the SBT.   
 
If the patient successfully passes the SBT, extubation readiness criteria will be confirmed 
(i.e. cough, gag, handling secretions, no procedures planned). If the patient meets 
extubation readiness criteria, the recommendation will be for extubation to the clinical 
team.  If the patient does not meet extubation readiness criteria, they return to acute 
phase management (to whichever group they were randomized), and another SBT will be 
repeated 24 hours later.  If a recommendation for extubation was given but actual 
extubation is delayed beyond 6 hours, the reasons will be recorded on the case report 
forms, and the acute phase intervention will be resumed.  If the patient is extubated as 
recommended, the esophageal catheter and RIP bands will remain in place for 1 hour 
after extubation to monitor post-extubation effort of breathing.   
 
If the patient fails the SBT, they will go on to the weaning phase randomization. 
 
D.3.6 Weaning Phase: The weaning phase is defined as the time from the first SBT 
until the patient successfully passes an SBT.  
 
D.3.7 Weaning Phase, Intervention Arm (REDvent-weaning): The weaning 
phase in the intervention arm uses esophageal manometry and a custom built hardware 
and software package for effort of breathing guided management.  The patient will be 
placed in a pressure support mode of ventilation and PRP will be monitored 
continuously, adjusting pressure support (to a max of 20 cmH20) every 4 hr to maintain 
PRP in the target range (Figure 7).  Effort of Breathing guided management will continue 
until the patient passes a SBT.  The esophageal balloon is inflated to a daily prescribed 
volume every 4 hours prior to assessment, based on an optimal filling volume algorithm. 
The median PRP over 10-20 breaths during calm periods of breathing (i.e. not agitated, 
not recently suctioned etc) is inputted into the computer decision support tool, which 
subsequently generates the recommendation regarding changing the level of pressure 
support. 
 

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D.3.8 Weaning Phase, Control Arm: 
Ventilator management will be per usual care 
until the patient passes a SBT.      
 
D.3.9 Weaning Phase, Monitoring both 
groups: In both groups, a daily airway 
occlusion 
maneuver 
and 
SBT 
will 
be 
performed, with the same rules above in 
section D.3.5 regarding SBT passage and 
monitoring.   
 
D.3.10 
Post-extubation 
Management: 
The decision to use non-invasive ventilation 
and other post-extubation management will 
not be protocolized, regardless of study arm.   
Patients who are re-intubated after a planned 
extubation (regardless of study arm) will 
subsequently receive usual care ventilation.  
The esophageal catheter and RIP bands will be 
removed 1 hour after extubation. 
 
D.3.11 Suspension of Weaning Phase: 
Suspension of the weaning phase is permitted for up to 12 hours for situations such as 
procedures, increased need for sedation preventing adequate spontaneous breathing, 
transient increase in ventilator support etc.  As soon as the patient appropriately meets 
weaning criteria (based on weaning criteria screen Figure 6), the weaning phase 
intervention is resumed.   
 
D.3.12 Failure of the Weaning Phase: If the weaning phase is suspended for > 12 
hours and the patient no longer meets weaning criteria at the 12 hour mark (Figure 6), 
then the acute phase of management and monitoring is resumed.  The patient will be 
managed as per their pre-assigned acute phase group (i.e. REDvent-acute or usual care).  
Once weaning criteria are met, an SBT will again be performed. If the patient fails the 
SBT, then the weaning phase intervention to which they were previously randomized 
(REDvent-weaning or usual care) is resumed.  The frequency with which weaning failure 
occurs in both arms will be tracked as an adverse event.   
 
D.3.13 Termination of study interventions at 28 days: If the patient has not 
passed the SBT by day 28 after enrollment, study interventions and daily measurements 
will be terminated.  All ventilator management will be as per usual care.  Clinical 
outcomes will continue to be followed.   
 
D.3.14 Post Enrollment exclusion criteria: Patients who develop exclusion criteria 
after study enrollment that preclude continuation of the study interventions (i.e. use of 
ECLS, new condition requiring removal of esophageal catheter) will have the study 
protocol and measurements terminated, but clinical outcomes will continue to be 
followed and analysis will be as per intention to treat.  For patients who are made allow 
natural death status during the study, parents will be given the option to either continue 
the study protocol, or withdraw from the study.   Clinical outcomes will continue to be 
followed.  Patients who develop a condition which may preclude calculation of secondary 
 
Figure 7: Weaning Phase schematic, both arms 

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outcomes (i.e. diaphragm ultrasound or RIP bands) will continue to receive study 
interventions, and all planned study measurements which can reasonably be obtained.   
D4 Measurement of Study Variables 
Demographics, clinical variables, and outcomes will be measured as detailed in the table 
below (data collection timeline). To ensure the adequacy of randomization and 
understand the risk factors that may contribute to neuromuscular weakness and weaning 
failure, we will gather detailed, serial data for variables that may be related to weaning 
duration and development of neuromuscular weakness.1, 5, 6, 8-10, 26 These variables are 
based upon our recent consensus-based guidelines for clinical trials in children with 
pediatric ARDS. 76     Identical measurements of respiratory parameters will occur for all 
patients enrolled in the study (regardless of study arm) (1) serially during both acute and 
weaning phases, (2) during airway occlusion prior to SBTs, and (3) during SBTs (Table 
below).    
 
D.4.1 Serial respiratory measurements during acute and weaning phases: 
We will measure patient effort of breathing twice daily with esophageal manometry 
(using Pressure Rate Product [PRP] and Pressure Time Product [PTP]) and once daily 
using diaphragm ultrasound (using Diaphragm Contractile Activity [DCA]), during the 
acute and weaning phases in both arms.  DCA is obtained by measuring the thickness of 
the right hemi-diaphragm and calculating the percent difference between diaphragm 
thickness on inspiration and exhalation. Diaphragm ultrasound measurements will be 
performed independently by 2 practitioners, one of whom is specifically trained in acute 
care ultrasound.  We will also use ultrasound to measure diaphragm thickness on 
exhalation and monitor how this changes serially over time as a measure of the 
architecture of the diaphragm. Finally, we will measure respiratory load (resistance, 
compliance) daily using spirometry.  The clinical team will remain blinded to the results 
of these measurements in both arms.  
 
D.4.2. Spontaneous Breathing trial respiratory measurements during 
Airway Occlusion: Prior to each SBT, we will perform a standardized airway occlusion 
maneuver to measure neuromuscular capacity with aPiMax (airway) and ePiMax 
(esophageal), as described in the Preliminary Data.    In addition, during airway 
occlusion we will measure DCA (as above)  5, 7, 51, 52, to provide complementary data to 
PiMax. The clinical team will remain blinded to the results of these measurements in 
both arms.  
 
D.4.3 Weaning trial measurements during SBTs: During SBTs, respiratory effort 
and capacity will be measured with PRP, PTP, inspiratory pressure from esophageal 
manometry (Pi), Pi/ePiMax, Tension Time Index (TTI), Phase angle (PA), and DCA. 
Patients will be monitored continuously during the SBT, and all of these measures will be 
recorded at the beginning of the SBT, and then every 30 minutes (for 5 minute periods) 
to monitor respiratory muscle endurance over time.   The PRP measurements will be 
shared with the clinical team in both arms because they will be used to help define 
passage of SBTs (as above).  Clinical providers will remain blinded to the results of the 
other measurements in both arms.   
 
 
 

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Data Collection timeline  
Enroll-
ment 
Acute 
(Daily) 
Weaning 
(Daily) 
SBT 
Post-
Extubation 
Demographics (age, race, gender, past medical history, 
primary diagnoses, comorbidities, PRISM-III-12 severity of 
illness scores, height, weight, quality of life score) 
 
 
 
 
 
Clinical Variables ( total dose of sedatives, analgesics, 
highest/lowest/modal sedation scores, pain scores, 
corticosteroids, aminoglycosides, fluid balance,  caloric and 
protein intake, hypoxemia markers, dead space markers, 
ventilator type and settings (q6h), blood gasses (all), 
inotropes/vasopressors, organ failure scores (PELOD), 
procedures) 
 
 
 
 
 
Effort of Breathing and Respiratory Load 
Esophageal Manometry: PRP, PTP, TTI, Pi 
 
 
 
 
 
Respiratory Inductance Plethysmography 44: Phase 
Angle (PA) 
 
 
 
 
 
Ultrasound: Diaphragm Contractile Activity (DCA) 
 
 
 
 
 
Spirometry: Resistance, Dynamic and Static 
Compliance 
 
 
 
 
 
Respiratory Muscle  Strength (during airway occlusion) 
Esophageal Manometry: Esophageal PiMax (ePiMax) 
 
 
 
 
 
Airway Pressure: Airway PiMax (aPiMax) 
 
 
 
 
 
Ultrasound: DCA during airway occlusion 
 
 
 
 
 
Diaphragm Architecture (Thickness on Exhalation) 
 
 
 
 
 
Outcomes (Weaning Duration, VFDs and components, re-
intubation, Non-Invasive Ventilation use and duration, ICU, 
Hospital, 90-day mortality, quality of life score)  
 
 
 
 
 
 
D.4.4 Rationale for respiratory measures:  Previous research has highlighted the 
importance of using multiple assessments of respiratory muscles, as single tests may be 
misleading. 67  We will use four classes of respiratory monitoring: esophageal 
manometry, diaphragm ultrasound, RIP, and ventilator/clinical data.    Our primary 
interest is respiratory muscle strength, which is best characterized during airway 
occlusion with PiMax.  PiMax measurements will be done as soon as the acute phase has 
resolved, and daily during the weaning phase, because PiMax is not feasible to measure 
during the acute phase of MV because patients may be too unstable to tolerate airway 
occlusion. Serial measurements from diaphragm ultrasound can and will be performed 
daily to assess changes in diaphragm architecture during both acute and weaning phases 
3, 5-8, 26, 52, 68-73.   Because diaphragm ultrasound is non-invasive, it has advantages 
although it has not been validated against direct measures of respiratory muscle strength 
or weaning outcomes. We will attempt such a validation with this study.  We anticipate 
DCA and PRP will provide complementary information regarding patient effort. To 
isolate diaphragm weakness, a second balloon catheter would be necessary to calculate 
trans-diaphragm pressure.  However, this is not practical for repeated use in children 
and no double-balloon catheters are commercially available for infants. A second 
catheter in an already small esophagus may alter the signals further, and impede clinical 
care if the catheter is left in place. While this leaves open the possibility of intercostal 
muscles contributing to the weakness, we will complement these data with architectural 
changes to the diaphragm on ultrasound. 

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D5 Co-Interventions 
Sedation: Sedation management will be controlled in both arms targeting a State 
Behavioral Scale, based on the sedation protocol used in the NHLBI funded RESTORE 
clinical trial. 75  This scale is being implemented for routine use in the Pediatric Intensive 
Care unit. Each day the clinical team will select an SBS target on morning rounds, based 
on the status of the patient.  The level of sedation and SBS score will be monitored every 
4 hours in each group.  Generally acceptable SBS targets range from -2 to 0.  For the 
acute phase management, the suggested SBS target is -2, and for the weaning phase of 
ventilation the SBS target is -1.  A nurse guided protocol is not currently in place for 
automatic adjustment of sedation to meet the SBS target, but the nurse will administer 
as needed medications to meet the SBS target if it is above target, and will consult with 
the MD to decrease sedation if the SBS is below target.   
 
Inhaled Nitric Oxide: Inhaled Nitric Oxide is frequently used for clinical care in our 
intensive care unit for children with ARDS. Like High Frequency Oscillatory Ventilation 
and other rescue therapies, the decision to begin inhaled nitric oxide will be left to the 
discretion of the clinical team.  However, for patients in REDvent Acute, inhaled nitric 
oxide is built into the computerized protocol management of PEEP/FiO2.  Consistent 
with the ICU protocol for nitric oxide weaning, once FiO2 is reduced to 0.6, if 
oxygenation is adequate or high, weaning of nitric oxide will be recommended (see 
section I for details).   
 
Quadriceps Ultrasound: Critically ill patients lose strength and muscle mass when in 
the intensive care unit, which may contribute to long term functional impairment. While 
functional assessment and strength testing is most accurate, they are difficult to do in 
children, or on sedated, non-cooperative patients.  Ultrasound can measure muscle 
thickness and echogenicity, and can document  progression of muscle atrophy.3 The 
quadriceps femoris muscle group is most commonly measured, with a demonstrated 
relationship between strength and quadriceps femoris muscle thickness.  Adult studies 
have documented that the quadriceps muscle thickness and cross sectional area 
decreases through the ICU course, correlates with length of stay and muscle strength 
and, less consistently, function at discharge. In most studies, ultrasound has high 
accuracy and inter-rater reliability. In children, the literature on quadriceps muscle 
thickness measurement by ultrasound is limited to comparing normal children to those 
with neuromuscular disease. While the proposed REDvent intervention is specifically 
targeting prevention of diaphragm atrophy, critical illness itself can lead to atrophy of 
other muscles. As such, in addition to measuring the change in diaphragm thickness 
daily, we will also measure the change in quadriceps muscle thickness daily, to help 
understand whether REDvent can modulate quadriceps muscle atrophy, of if the degree 
of quadriceps muscle atrophy has an interaction with the potential benefit of REDvent 
on diaphragm atrophy or strength.    In each patient while supine with their feet pointing 
up, we will measure quadriceps muscle thickness at two points, in the midsaggital plane 
for each thigh.  Like diaphragm ultrasound measurements, multiple providers will obtain 
measurements daily, to ensure reproducibility and inter rater reliability.  
 
 
 

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D6 Statistical Considerations 
 
D.6.1. Randomization Strategy and Blinding 
Consenting subjects will be block randomized to intervention or control arms for the 
acute phase based on age group: infant (30 days -365 days), child (366 days to ≤8 years), 
and older child/ adolescent (9-21 years); and immune suppression.  For study purposes 
immune suppressed patients will be defined as: patients with congenital or acquired 
conditions (including medications) which result in marked inability to respond to 
antigenic stimuli.  Examples of immune suppression include: oncologic disease with 
recent chemotherapy or radiation, congenital immunodeficiency, HIV, rheumatologic 
condition on chemotherapy, allogeneic or autologous stem cell transplant, solid organ 
transplant, or any other condition in which immunosuppressive medications are 
prescribed.   Block randomization will be based on random block sizes of 4, 6 and 8 
within the strata above, and loaded into opaque envelopes by the statistician for the 
study team to determine treatment arm at the time of randomization. Weaning phase 
randomization will be block randomized by REDvent-acute phase group, age, and 
immunosuppressed status using the same methodology. Although blinding is not 
possible given the open label nature of the intervention, analysis will be blinded to 
treatment groups, and performed by an independent statistician. 
 
D.6.2 Rationale for Randomization Strategy: Age stratified randomization is 
necessary because age is an important biological variable likely to confound the 
relationship between respiratory muscle weakness and length of weaning.  This will 
ensure an equal age distribution amongst treatment groups.  Age groups are based upon 
accepted pediatric definitions, and have been used in numerous other pediatric RCTs. 
Neonates (< 1 month) have been excluded because they are often managed with different 
ventilator strategies and because normal values for PiMax are lower in neonates 63, 64.   
Immunosuppression is a known risk factor which affects duration of ventilation and 
weaning, and an imbalance in immunosuppression between groups has been shown to 
significantly confound previous pediatric mechanical ventilation studies.   The additional 
weaning phase randomization is necessary because we anticipate an imbalance of the 
number of patients who will be extubated after the acute phase between REDvent-acute 
and control groups. Acute phase management may have a sustained effect on 
neuromuscular strength that will affect the duration of weaning.   To understand 
whether the REDvent strategy during the weaning phase can prevent prolonged 
weaning, risk factors for prolonged weaning (which may be different based on acute 
phase management) need to be rebalanced with a second randomization.  Ultimately, 
this will allow us to determine the independent utility of REDvent-acute and REDvent-
weaning components. 
 
D.6.3 Preparation of the Analysis Data Set  
 
Datasets for analyses consist only of data for which all queries have been resolved. In 
addition to data management steps 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 both the data management team and the biostatistics team. 
 
Preplanned construction of new variables will be conducted in accordance with the study 
hypotheses and analysis plans. Variable transformation may be required for interpretive 

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and statistical purposes.  With respect to the primary outcome of weaning duration, 
patients who do not progress to the weaning phase within 28 days (i.e. death, prolonged 
severe illness) will not be included in analysis of the primary outcome, but will be 
considered for secondary outcomes.   
 
D.6.4 Statistical Analysis Plan 
 
For all variables, descriptive statistics will be calculated, including means, standard 
deviations, medians, and interquartile ranges for continuous variables and frequency 
counts and percentages for categorical variables. Data will be examined for skewness, 
outliers, and systematic missing data. Transformations will be undertaken as needed. 
Comparisons of demographic and baseline variables will be obtained by treatment group. 
 
D.6.4.1 SA 1 Analysis Plan: To determine if REDvent acute and/or weaning phase 
protocols can shorten the duration of weaning from MV (Primary outcome).   
Primary analysis and sample size: The primary outcome for this aim is weaning 
duration. Because we seek to understand 
whether REDvent-acute and/or REDvent 
weaning have an independent effect on 
length of weaning, we propose a sample size 
to adequately power 3 separate comparative 
analyses: (a) REDvent-acute versus Acute 
Phase control (b) REDvent-weaning phase 
versus Weaning Phase control (c) REDvent 
both phases versus control both phases.    
We expect up to 12% mortality before the 
first SBT based on our Preliminary Data. 
These patients will not be included in the 
analysis for the primary outcome.  From our 
pilot data (REDvent in both acute and 
weaning phases), the duration of the weaning phase in the intervention arm was 2.2 
days, compared to 4 days in historical controls with a standard deviation of 2.1 days in 
the intervention arm and 2.8 days in the historical controls.  
Comparison (a) REDvent-acute versus control: A 1-day reduction in length of weaning is 
considered clinically significant (less sedative exposure, fewer nosocomial infections, 
lower healthcare costs).  With a sample size of 276 patients (138 per arm), up to 12% 
mortality and 1% attrition or incorrect randomization, a minimum of 240 patients (120 
per arm) will be available for analysis of the acute phase.  Power is based on 2 planned 
methods for analysis: cox proportional hazard ratios for multivariable analysis and 
univariate analysis with an independent t-test using log transformation (as needed) to 
account for the expected distribution of weaning duration.  For univariate analysis using 
the assumptions above, we would be able to detect a ≥ 1-day reduction in weaning 
duration with an alpha of 0.05 and power of 0.9 (Figure 7).  For the cox proportional 
hazard model, we would be able to detect a relative hazard ratio of 1.5 (ratio between 
control/intervention group) with a power of 0.9 or a hazard ratio of 1.4 with a power of 
0.8.  
Comparison (b) REDvent-weaning versus control:  Patients who fail the initial SBT will 
undergo the weaning phase randomization.  From our pilot data, approximately 25% of 
patients exposed to the intervention passed the initial SBT, corroborating previous 
studies. 15   Thus, at least 180 patients (90 per arm) will receive weaning phase 
interventions.  Using the same assumptions as above, we will be able to detect a ≥ 1 day 
 
Figure 8: Power curve for a 1 day reduction in weaning    

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reduction in the length of the weaning phase (Figure 8), or a hazard ratio of 1.5 with an 
alpha of 0.05 and power of 0.8.  Patients who do not pass the SBT by 28 days post the 
weaning phase randomization will be censored for analysis, as study interventions and 
daily monitoring will end on day 29.          
Comparison (c) REDvent versus control both phases: We will get an assessment of the 
cumulative effect of the intervention by comparing patients who received both REDvent-
acute and REDvent weaning to patients who received only usual care in both phases.  
Because the rates of passage of the first SBT will differ between groups, there will not be 
an equal number of patients exposed to REDvent only as control only. Based on the 
assumptions above, we anticipate that of the 240 patients included in the analysis of 
weaning duration, 78 will be REDvent only, 72 will be control only, and 90 will be mixed.  
As such, the expected sample size comparing REDvent only to control only would allow 
us to detect a ≥ 1.1- day reduction in weaning duration with a hazard ratio of 1.6 with a 
power of 0.8 and alpha of 0.05; or a ≥ 1.3- day reduction in weaning duration with a 
hazard ratio of 1.6 with a power of 0.9.    
All patients will be analyzed in the groups to which they were randomized for weaning 
duration, following intention to treat principles (allow for up to 1% incorrect allocation 
or attrition).   Clinical variables (data collection table) will be tracked and compared 
between intervention and control groups for all 3 of the planned analyses (a-c).    If there 
is an imbalance in any variable that may confound the relationship between weaning 
duration and REDvent, we will build a multivariable cox proportional hazard model to 
ensure that the measured treatment effect on weaning duration is retained after 
multivariable adjustment.   
Secondary Outcomes for SA 1: The 28 and 60 Day Ventilator Free Days (28D VFD, 
60D VFD) will be secondary outcomes of this aim.  Groups for VFD analysis will be 
based on any exposure to the intervention (acute or weaning) because some patients will 
never undergo a weaning phase randomization (i.e. died or were extubated right after the 
acute phase).    If patients who died as well as those who dropped out are included in the 
VFD analysis, with the assumptions above regarding expected passing rate of SBTs, the 
estimated distribution of patients in 3 distinct groups will be:  (a) REDvent only 
(n=108); (b) REDvent and control (n=90); (c) control only (n=102). We anticipate 
children in the REDvent only arm will have the most 28 D VFDs (anticipation 22), and 
those in the control only arm the least (anticipation 20).  Directly comparing control only 
patients to REDvent only patients, with an expected standard deviation for VFDs 
between 5 to 9 days, we will be able to detect a 2-day change in VFDs between groups 
with a power between 0.35 and 0.82.  Re-intubation rates are expected to be 10%, 
allowing us to confirm that REDvent is not inferior to usual care in regards to re-
intubation with a non-inferiority margin of 0.10 with a power of 0.8 and alpha of 0.05.  
Finally, to ensure that REDvent is promoting greater patient effort of breathing and that 
the intervention does not alter clinical practice in the usual care arm, we will compare 
time weighted average values for direct measures of patient effort of breathing (PRP, 
PTP, Diaphragm Contractile Activity), and ventilator settings between intervention and 
control groups, and monitor the separation between groups over the time of the study.    
 
D.6.4.2 SA2 Analysis Plan:  To determine if changes to direct measures of 
respiratory muscle strength, load, effort, and architecture throughout the duration of MV 
are related to weaning outcomes. 
Analysis and Sample Size: The primary outcome of this aim is weaning duration (as 
defined above).  For this analysis, we will compare how each respiratory measure 
detailed in the data collection table relates to weaning duration.  For respiratory muscle 

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strength we will compare the first measured aPiMax (after resolution of the acute phase, 
before the first SBT), the trajectory and value of the daily aPiMax during the weaning 
phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the 
day of extubation against weaning duration.  For analysis, aPiMax will be dichotomized 
at 30 cmH2O (based on our preliminary data), and weaning duration  will be compared 
between patients with aPiMax > 30 versus ≤ 30 cmH2O using a t-test with or without 
log-transformation, or Mann-Whitney U test, depending on the distribution.  From our 
preliminary data, we anticipate at least 35% of patients (n=84) will have aPiMax ≤ 30 
cmH2O.    Based on a similar power analysis as presented above, this would allow us to 
determine whether low aPiMax is associated with a ≥ 1-day increase in weaning 
duration, with an alpha of 0.05 and power of 0.8.    We will perform identical analysis for 
ePiMax. 
Diaphragm Thickness analysis will compound daily ultrasound measures to detect the 
relative change in diaphragm thickness from study day 1 until passage of an SBT.  We 
will compare the change in thickness after resolution of the acute phase (on the day of 
the first SBT) against weaning duration, in a similar manner as proposed above for 
aPiMax.  For analysis, diaphragm thickness will be tested as a continuous variable (with 
Spearman’s or Pearson’s Correlation), but also categorized into 3 groups (loss of > 10% 
in thickness, maintenance of thickness (-10% to +10%), and increase in size of > 10%) to 
account for the potential ill effects of diaphragm hypertrophy (expected in about 10% of 
patients), using Analysis of Variance (ANOVA) to compare weaning duration between 
groups.  We will characterize how diaphragm thickness changes daily during the weaning 
phase compared to the thickness on study day 1, as well as the daily thickness compared 
to that on the day of the first SBT.   This will be used to determine whether patients 
whose trajectory of diaphragm atrophy continues during the weaning phase have a 
longer weaning duration compared to those who maintain diaphragm thickness or have 
increased thickness during the weaning phase.   We anticipate high correlation between 
aPiMax and diaphragm atrophy, such that the proportion of patients with > 10% loss in 
diaphragm thickness will be similar to the proportion of those with aPiMax ≤ 30 
cmH2O, resulting in the same sample size that yield adequate power, as above.   
Respiratory load (resistance and compliance), effort (PRP, PTP) and combination 
measures of capacity, load or effort (TTI, Diaphragm Contractile Activity, Phase Angle) 
will be measured daily during or just before SBTs, as detailed in the data collection table.  
Analysis of each of these measures against the primary outcome will mimic what is 
presented above for aPiMax and Diaphragm thickness, with correlation for continuous 
variables, as well as categorization into distinct ranges for ANOVA.   
Secondary Outcomes, SBT failure: In addition to weaning duration, we will also 
examine whether the respiratory measures in the data collection table taken just prior to 
or during each SBT are associated with the patient passing the SBT. For example with 
aPiMax and ePiMax, we will examine if there is a dose response relationship between 
PiMax measured just before the SBT and the rate of passage of the subsequent SBT (e.g., 
similar to Figure 3).  In addition, we will compare mean or median values for aPiMax 
between patients who pass versus fail the SBT using a t-test or MWU test.  Finally, we 
will examine aPiMax as a continuous variable to determine its ability to discriminate 
passage of the subsequent SBT using the Area Under the Curve (AUC) of the Receiver 
operating Characteristic Plot (ROC).  Similar analysis will be done for all other 
respiratory measures in Table 2, and we will compare the AUCs (using a Chi-squared 
test) for each individual respiratory parameter against the others to identify which of 
these tests have the highest sensitivity, specificity, and overall discrimination of SBT 
failure.     We will subsequently generate multivariate logistic regression models to 
identify which combination of these measures of capacity, architecture, load, and effort 

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retain an independent association with SBT failure. Because SBTs will be repeated daily, 
we will use a hierarchical logistic regression model to control for repeated measures from 
each patient as well as controlling for the other potential confounding variables detailed 
in the data collection table. We anticipate that 240 patients will undergo SBT testing, 
and 90% of these patients will pass the SBT within 28 days of the weaning phase 
randomization.  As such, we would be able to include at least 20 variables in a 
multivariable hierarchical logistic regression model.    Finally, we will determine whether 
common “phenotypes” for weaning failure can be determined. We anticipate four 
possible phenotypes by combining information from all available measures of capacity, 
load, effort, and architecture. Based on our preliminary data, we anticipate that patients 
with high load will be more likely to fail weaning, but that this effect will be more 
pronounced if they have diminished respiratory muscle capacity.  We hypothesize that 
the rates of passage of the SBT will increase incrementally from phenotype 1 to 4:   (1) 
Diminished capacity, high load and effort; (2) Normal capacity, high load and effort; (3) 
Diminished capacity, low load and effort; (4) Normal capacity, low load and effort.  
These phenotypes are exploratory; thus, no power analysis is provided.   
 
D.6.4.3 SA3 Analysis Plan: To determine if patient effort of breathing during both 
acute and weaning phases of MV is independently associated with the development of 
respiratory muscle weakness.   
Analysis and Sample Size: The primary outcome of this aim is aPiMax < 30 
cmH2O.The analysis will focus on determining whether the degree of patient effort of 
breathing is independently associated with the development of respiratory muscle 
weakness. PRP will be the primary measure of effort of breathing, and will be measured 
twice daily in both acute and weaning phases. Secondary measures of effort of breathing 
include DCA and PTP.  For the acute phase, we will generate a time- weighted average 
PRP during the acute phase and graph it against aPiMax at the first SBT, anticipating a 
positive correlation (higher average PRP values associated with higher aPiMax).  We will 
subsequently dichotomize aPiMax at the first SBT and compare mean time weighted 
average PRP in the acute phase between aPiMax groups (> 30 vs. ≤ 30 cmH2O).  For the 
weaning phase, we will graph the changes in aPiMax throughout the weaning phase 
(from first failed SBT until successful SBT) against time-weighted average PRP, with the 
anticipation that low PRP will be associated with either further reductions in aPiMax, or 
no improvement, while PRP in the physiologic range of 150-400 will be associated with 
improvement in aPiMax.  We will subsequently dichotomize aPiMax (at 30 cm H2O) at 
the time of successful passage of an SBT and compare time-weighted average PRP in the 
weaning phase between aPiMax groups. Subsequently, we will build a multivariable 
logistic regression model on the outcome of aPiMax ≤ 30 cmH2O to determine if time-
weighted PRP in the acute phase, weaning phase or both have an independent 
association with preserving aPiMax, after controlling for confounding variables (data 
collection table).  We anticipate that 35% of patients (at least 80) will have aPiMax ≤ 30 
cmH2O, allowing for inclusion of at least 9 variables in the multivariable model. 
Secondary goals are to characterize other variables that retain an independent 
association with low aPiMax, which are likely to include age group, use and dose of 
neuromuscular blockade, driving pressure during the acute phase of ventilation, sepsis, 
corticosteroids and use of aminoglycoside antibiotics.   
 
 
 
D.6.5 Dissemination plan and data archiving 

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The results of this clinical trial will be critically important to disseminate to critical care 
clinicians, both pediatric and adult. In the final two years of the study the Steering 
Committee will develop the strategic plan for the comprehensive presentation and 
publication of the study findings. The biostatistician will assist Dr. Khemani and Steering 
Committee members to prepare abstracts and papers for presentation at the annual 
meetings of American Thoracic Society (ATS), Society of Critical Care Medicine (SCCM), 
the European Society of Pediatric and Neonatal Intensive Care (ESPNIC). Dr. Khemani 
will provide the mechanical ventilation subgroup of the Pediatric Acute Lung Injury and 
Sepsis Investigator (PALISI) network an update on the clinical trial twice yearly to 
maintain disciplinary interest in the study. In addition to primary publication targeted at 
high priority journals, we anticipate numerous secondary publications in critical care, 
physiology, and respiratory journals. Final data sets and statistical analyses will be 
archived and a public use dataset will be made available as per NIH recommendations. 
 
D7 Data and Instrument Management 
 
A significant portion of the data management infrastructure and protocols have been 
developed with previous studies, and we will capitalize on this by modifying existing 
protocols to be relevant to this study.  The devices and software have been used 
extensively, and we will follow existing protocols to maintain calibration, quality control, 
and accuracy of all study devices.  A vast majority of the data (ventilator settings, blood 
gas values, and many of the variables in the data collection table) will be collected 
through automated electronic feeds.  A trained study data collector will use data extracts 
from the electronic feeds in conjunction with data in the electronic health care record to 
populate study specific case report forms.  Data collection will occur in real-time, to 
enable primary source verification. Respiratory measurements will be entered into web-
based case report forms at the time of study measurements. In addition, raw data from 
esophageal manometry and RIP will be recorded during each measurement for a 
minimum of 5 minutes, and the calculations will be post-processed by trained research 
personnel to verify the real-time data entry.  Ultrasound images will be interpreted in 
real-time and calculations entered into the web-based case report form.  In addition, all 
ultrasound images will be uploaded to a secure server for source data verification and 
can be de-identified.  We will develop a series of algorithms to confirm the validity of 
entered data, and will perform detailed queries of entered data monthly.     
 
To ensure data safety and reliability, server back-up procedures will be executed daily to 
back up all electronic study related materials, which include database, Word documents, 
statistical programs, and files. Access to the data management system is strictly 
prohibited and requires user authentication. Authorized users include data-entry 
personnel, research coordinators, the PI, the database programmer, and biostatisticians. 
Any hard copies of eCRFs with subject ID codes will be stored in locked file cabinets, 
accessible by authorized staff only. Identifiable subject data, such as contact information 
and medical record numbers, will be stored separately and securely, and will not be 
entered into the electronic database. 
All application software will be hosted securely on the Children’s Hospital Los Angeles 
Network, which is protected by several firewalls and security is monitored and audited 
regularly.     

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D8 Quality Control Procedures 
D.8.1 Training 
Training materials detailing study protocols have been created and used for the Phase I 
study, and an order set has been created in our electronic health-care record system.   
Research respiratory therapists and data collectors will be directly trained by the PI and 
the Lead Research Respiratory Therapist (J. Hotz).  Detailed training of all bedside staff 
will occur before beginning the study, as well as in real-time with each patient 
enrollment, using a similar model as the Phase I study.     
 
D.8.2. Development of Case Report Forms 
Case report forms will be modified from successfully implemented CRFs we have used 
for the pilot study, as well as a large observational study on Pediatric Acute Respiratory 
Distress Syndrome (PARDIE study).  Form design features include the selection of valid, 
reliable measurements, development and testing of reliability measures, pre-testing of 
forms, formatting of forms to ensure clarity (standard conventions for coding close-
ended questions, minimal use of open ended questions), smooth flow (clear skip 
patterns) to reduce missing data. Members of the Steering Committee will sign off on 
eCRFs before implementation.  
 
D9 Anticipated Problems and Solutions 
D.9.1 What if enrollment is slow? We are confident we can meet enrollment targets 
at CHLA alone and will monitor this with targeted and actual enrollment graphs.  If 
enrollment is slower than anticipated, we will add UCLA Children’s Hospital as a satellite 
ICU.  This is another PICU 15 miles away with at least 100 eligible patients per year.  
Through previous funding from the Collaborative Pediatric Critical Care Research 
Network, we share research infrastructure and resources, and have combined efforts 
(functioning as one site) for over 30 different clinical studies. 77-83      
 
D.9.2 What if aPiMax is not associated with weaning duration? We believe that 
a real strength of this application relies on the multitude of direct and indirect measures 
of respiratory system capacity, load, and effort, which we will associate with highly 
clinically relevant weaning outcomes.   While we anticipate aPiMax will be the best 
measure of strength, the multitude of other measurements concomitantly made will 
allow using alternative measures to aPiMax to assess strength (such as ePiMax, 
diaphragm contractile activity during occlusion, diaphragm thickness, or phase angle). 
Our analysis will allow us to determine which of these parameters has the strongest 
association with clinical outcomes.  
 
D.9.3 Non-compliance with the intervention study protocol? We are confident 
we will maintain high protocol compliance, as we have demonstrated in the pilot study.  
We have iteratively refined the protocol such that adherence to weaning phase 
recommendations exceeds 90%.  The acute phase recommendations generally exceed 
75%, which we view as acceptable.  The protocol is intended to provide a framework for 
ventilator decisions and is not intended to replace clinician’s judgment. For this reason it 
has been implemented as open loop.  The degree of protocol adherence will be tracked 
electronically, as part of the CDS tool itself.  If adherence is lower than anticipated, then 
detailed analysis of the reasons for protocol rejection (tracked with every 
recommendation) will be reviewed, and a protocol modification will be considered.   

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D.9.4. Changes in clinical practice in the ICU during this time period?  The 
impact of changes in pediatric critical care management is expected to affect both groups 
equally so should not bias treatment group comparisons. 
 
D10 Study Timeline and Milestone accrual Policy  
 
 
The Milestone Accrual figure above details targeted enrollment over the course of the 
study. The Yellow, Amber, and Red zone each have corrective action associated with it, as 
part of a separate milestone accrual plan with NHLBI.  In Q2 2019, enrollment crossed 
into the yellow zone on the milestone accrual plan. In discussions with NHLBI and the 
DSMB, a new milestone accrual plan has been created.   
 
The revised milestone accrual plan has been reviewed and approved by the DSMB and 
NHLBI. Initial estimates of mortality and attrition were 13% and 7%, respectively, 
allowing for 20% of patients not meeting the primary outcome measure. Based on 
enrolled patients as of 08/16/2019, no patients have withdrawn from the study, and the 
overall mortality is 11.8%. As a result, the overall sample size estimate has been revised 
using 13% of patients who will not meet the primary outcome, rather than 20%. Target 
study enrollment of 300 total patients has been dropped to 276. The A-priori 
determination of 240 patients meeting the primary outcome measure has not changed.  
 

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Figure 8: Revised Milestone Accrual Plan 

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E Human Subjects Considerations 
 
E1 Ethical Considerations  
 
The human subjects for this study are infants and children who are intubated and 
mechanically ventilated in intensive care unit. It is anticipated that 276 intubated 
children will be enrolled in the study.  The age of children will range from one month (≥ 
44 weeks Post Conceptual Age) to 21 years.  All participants enrolled in the study will be 
critically ill, requiring mechanical ventilation through an endotracheal or tracheal tube. 
The main risk of participation in this study is the placement of an esophageal catheter for 
measurements of esophageal pressure.  While esophageal catheters (or nasogastric 
feeding tubes) are routinely used in children who are mechanically ventilated (it is the 
norm for all endotracheally intubated children to have a feeding tube, either nasogastric, 
orogastric, gastric, or jejunal), because this additional catheter is part of the research 
protocol, it is likely to be considered greater than minimal risk.  However the study does 
provide potential for significant benefit for the patient, and as such the benefits generally 
outweigh the risks.  Use of this catheter has been approved on multiple occasions with 
appropriate informed consent.  The ultrasound measurements and RIP bands are non-
invasive and pose minimal risk to the patient. There are no known risks associated with 
the use of volumetric capnography.  
 
The hardware (device) is minimal risk and has been used on a variety of studies.  All 
sensors (esophageal catheter, RIP, and spirometry) have appropriate clearance through 
FDA approval or 510K equivalence for use in children, and have been used in our 
previous investigations.  The two pieces of the software (tool to help interpret raw signals 
from the sensors), and the CDS ventilator management protocol have both previously 
been deemed non-significant risk because they are primarily implemented in an open-
loop application, incorporate current evidence based guidelines (computer CDS 
protocol), or have been iteratively tested against FDA approved post-processing 
programs as part of our previous investigations.  Moreover, clinicians are free to reject 
protocol recommendations, and to that end this data is to be used simply as an adjunct 
to clinical assessment, rather than a replacement.  
E2 Subject Recruitment Plans and Consent Process 
The subjects of this study are critically ill infants and children who will not be able to 
consent for their own participation in this study.  One or both parents will be informed 
about the study and given an opportunity to voluntarily give their consent/permission 
for their child to participate.  Assent of child subjects will not be possible because they 
are critically ill, intubated on a ventilator, and sedated.  Thus, assent will be waived.  
Families or guardians of any intubated and mechanically ventilated child who meet 
inclusion and do not meet exclusion criteria will be approached for consent.  Consent 
will be attained by the study investigator, co-investigator, or research nurse.  Consent 
will be documented on a consent form, and stored in a study binder, identified by patient 
number.  This binder will be stored in a locked cabinet in the office of the site principal 
investigator.   
 

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E3 Risks and Benefits 
 
E.3.1 Risks:  
1. Placement of the esophageal catheter. While this procedure is very well tolerated, 
there is a very small risk for bleeding, incorrect placement into the lungs or other 
body cavities, or damage to the esophagus, stomach, or nasal or oral mucosa.  
Patients at high risk of bleeding (thrombocytopenia, coagulopathy, mucositis), will 
not be included in the study.   
2. Small amount of discomfort when placing the esophageal catheter, although nearly 
all patients will be receiving analgesia and sedation as part of mechanical ventilation.  
Intermittent doses of already prescribed sedative or analgesia medications may be 
administered to minimize pain during placement. 
3. A particular computer generated recommendation may not be correct for the patient 
at that time, and the clinicians may choose not to follow them. 
4. There is potential of accidental release of confidential information. 
5. There is a possibility of transient fall in oxygen levels during airway occlusion 
maneuvers, although patients will be pre-oxygenated as per ICU standard practices 
prior to measurement, and patients must pass the oxygenation test prior to 
performing these measurements.   
 
E.3.2 Potential Benefits to Subjects 
There is the prospect of direct benefit to subjects in both arms.  For the intervention arm, 
using the intervention tool has the potential to significantly shorten length of assisted 
breathing, lower re-intubation rates, increase Ventilator Free Days (VFDs), shorten ICU 
and hospital length of stay, and reduce exposure to sedatives and analgesics.  Patients in 
the control arm also have potential to benefit as enrollment in the study will prompt 
more consistent use of evidence based weaning guidelines including a daily Spontaneous 
Breathing Trial.  This may also result in more days free of ventilators compared to those 
not enrolled in the study.   
 
E.3.4 Importance of the Knowledge to Be Gained 
Completion of this study will elucidate important information on the pathogenesis and 
timing of respiratory muscle weakness during MV in children, and whether this 
weakness can be mitigated by promoting more normal patient effort during MV.  These 
data can lead to immediate change in practice by implementing mechanical ventilation 
strategies that promote more patient effort of breathing.  They will also form the basis to 
determine whether a larger, Phase III multi-center study of REDvent is indicated, which 
would focus on key clinical outcomes such as 28-day Ventilator Free Days.  Given that 
the risks to the study participants are small, the information gathered will shape the 
design of future trials and will improve our understanding of diaphragm weakness in 
mechanically ventilated children in the ICU.  
 
E.3.5 Procedures to minimize risk 
All patients will be extensively monitored in the intensive care unit throughout the 
duration of the study.  This will include close monitoring of cardio-respiratory 
parameters including heart rate, temperature, blood pressure, oxygen saturation, 
respiratory rate, and work of breathing.  Intensive care unit physicians, nurses, and 
respiratory therapists will be present during the entire study, and will intervene as 
necessary should any treatment be indicated.  In addition, to protect confidentiality of 
data, study forms will only be labeled with a unique number identifier, which can only be 

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linked to identifiable information only through a key with access restricted to the PI or 
research coordinator. 
E4 Early Withdrawal of Subjects  
The subject may be withdrawn from the study by the (1) study investigator or (2) the 
parent or legal guardian at any time after consent.  The primary attending physician can 
also request that the principal investigator consider withdrawal of the patient from the 
study if they believe the study is no longer in the best interest of the patient.   
E.4.1 When and How to Withdraw Subjects  
Subjects can be withdrawn by the parents at any time, simply by requesting that the 
principal investigator withdraw the patient.  The study investigator may withdraw the 
patient from the study if he or she believes that this is necessary to protect the health of 
the child, if the condition of the child changes such that continuation in the study poses 
additional risks, or if the child experiences an adverse event which changes the risk 
benefit profile of continuing in the study.  
 
E.4.2 Data Collection and Follow-up for Withdrawn Subjects  
If consent is withdrawn for participation in the research by the parent/guardian, then 
data collection will cease.  Parents will be asked if we can keep existing data and follow 
clinical outcomes for intention to treat analysis.  However, if they wish, existing data will 
be destroyed.  If the study investigator withdraws the patient, then existing data will be 
preserved, and clinical outcome data detailed in section C.3.1. will continue to be 
collected to enable intention to treat analysis.   
 
F Data Safety Monitoring Plan and Board 
 
Please see separate Data Safety and Monitoring Plan and Data Safety and Monitoring 
Board Charter.  An institutional DSMB has been created for this study.   
 
The Data Safety Monitoring Plan details expected adverse events, with expected rates of 
occurrence.   
 

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G References 
 
 
 
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DiNino E, Gartman EJ, Sethi JM, McCool FD. Diaphragm ultrasound as a 
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Emeriaud G, Larouche A, Ducharme-Crevier L, et al. Evolution of inspiratory 
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Goligher EC, Fan E, Herridge MS, et al. Evolution of Diaphragm Thickness 
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inductance plethysmography calibration for pediatric upper airway obstruction: an 
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50. 
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67. 
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of-hospital cardiac arrest in children. New England Journal of Medicine 2015; 
372:1898-908. 
 

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H Secondary Analyses Related to Patient Ventilator 
Asynchrony 
 
Summary and Rationale 
 
Mechanically ventilated children often have patient-ventilator asynchrony (PVA) 
although this is incompletely characterized in the literature and infrequently recognized 
at the bedside. When a ventilated patient has spontaneous effort, the ventilator attempts 
to synchronize with the patient, but PVA represents a mismatch between what the 
patient wants and what the ventilator delivers.  PVA is common in ventilated adults and 
is associated with longer duration of ventilation, increased risk of infection, lung injury, 
diaphragm dysfunction, and adverse neurocognitive effects.  While there are many types 
of PVA, they are not equally harmful or prevalent. Therapeutic strategies should focus on 
the most harmful forms of PVA.  Although we still don’t know which PVA subtypes are 
truly most harmful, Double Cycled (DC) breaths (where a second breath is delivered 
before the first breath is complete) have the strongest biological plausibility for harm, 
because DC induces lung stress, strain, ventilator induced lung injury and eccentric 
contraction of the diaphragm.   
PVA is understudied in children, even though it may be more common and goes 
largely unrecognized even by highly trained clinicians. Moreover, existing pediatric 
studies have failed to identify a clear relationship between PVA and worse clinical 
outcomes, although these studies have not focused on the highest risk patients (such as 
those with Acute Respiratory Distress Syndrome (ARDS)), have used different 
definitions for PVA and its subtypes, and have been inadequately powered to evaluate 
the relationship between PVA subtypes and outcome.  As part of this additional analyses 
under the REDvent study, we seek to fill crucial knowledge and implementation gaps 
including: (1) harmonizing how PVA is measured and defined, (2) identifying the most 
harmful PVA subtypes and the patients at risk, and (3) using innovative and accurate 
bedside tools to improve the recognition of PVA.  We will leverage the expertise and 
preliminary data from three premier pediatric research groups who have the expertise to 
use precise methods to capture the patient’s neural respiratory effort, which is crucial to 
correctly identify PVA subtypes.  We will perform detailed secondary analysis of existing 
waveforms and clinical data from over 350 children, including all children enrolled in 
the REDvent study.  We will use causal inference and mediation approaches to evaluate 
the relationship between PVA subtypes and clinical and mechanistic outcomes by 
leveraging data from the randomized controlled REDvent trial where PVA rates and 
subtypes likely differ between intervention and control groups.  
Three existing datasets will be used as part of model and definition development, 
and data from the REDvent trial has more extensive clinical outcome and mechanistic 
data and will be used for additional analyses. Each dataset will contain one of three 
direct measures of patient neural respiratory effort (Pes, Children’s Hospital Los 
Angeles; Edi, St. Justine Children’s Hospital; sEMG, Beatrix Children’s Hospital).  The 
data which will be used for analysis has already been collected as part of the parent 
studies, or is planned for collection for the remaining patients in the REDvent trial.   
 
 
 

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Specific Aims  
Asynchrony Specific Aim 1) To identify the frequency and risk factors for PVA and 
its subtypes in ventilated children, with a specific focus on DC breaths.  Hypothesis: 
PVA subtypes related to inadequate ventilator support (flow undershoot and premature 
cycling) and reverse triggering will be the most common causes of DC breaths, with risk 
factors related to respiratory drive and ventilator settings. Study Design: Secondary 
analysis of waveforms and clinical data from anonymous datasets and data from the 
REDvent clinical trial. 
Asynchrony Specific Aim 2: To determine if a ventilator strategy in children with ARDS 
that promotes spontaneous breathing and physiologic levels of patient effort results in 
different rates and subtypes of PVA, and if PVA mediates the relationship between this 
intervention and clinical or mechanistic outcomes. Hypothesis: (a) REDvent intervention 
patients will have a different distribution of PVA subtypes than usual care patients which 
will partially mediate the relationship between REDvent intervention and outcome. (b) DC 
breaths will be associated with worse clinical and mechanistic outcomes.  Study Design: 
Secondary analysis of waveforms and clinical data from the REDvent clinical trial. 
Asynchrony Specific Aim 3) To develop and test a clinical decision support system 
using machine learning techniques to automatically identify common forms of PVA in 
children.  Hypothesis: (a) Machine learning models using waveforms available on all 
mechanical ventilators will accurately identify PVA subtypes compared to gold standard 
annotations which include measures of neural drive. (b) Algorithms can be optimized for 
high sensitivity and low false alert rates to identify children with frequent PVA. Study 
Design: Secondary analysis of waveforms and clinical data from anonymous datasets 
and data from the REDvent clinical trial. 
 
Data Management and aggregation 
Data from CHLA will be coded for analysis.  Data from other sites may be coded or 
anonymous, but if it is coded the key will stay at the individual site. The data to be shared 
does not include any protected health information.  It will include the respiratory 
waveforms gathered on each of the study monitors, as well as demographic and clinical 
information to inform the analyses proposed below.  Data will be transferred from 
participating institutions via One Drive through Children’s Hospital Los Angeles and will 
be loaded onto a CHLA research server for analysis.  Researchers at all 3 institutions will 
be able to view anonymous data on the CHLA research server and annotate waveforms to 
facilitate completion of this project, but will not be able to download or export the data 
directly.   
 
Preliminary Data, Analysis Plan, and Sample Size Justification by Specific 
Aim 
 
Asynchrony Specific Aim 1) To identify the frequency and risk factors for PVA 
subtypes in ventilated children, with a specific focus on DC breaths.  Hypothesis: PVA 
subtypes related to inadequate ventilator support (flow undershoot and premature 
cycling) and reverse triggering will be the most common causes of DC breaths, with risk 
factors related to respiratory drive and ventilator settings.  

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Preliminary Data 
PVA subtype definitions in children which use a measure of neural effort can be 
developed with high inter-rater reliability.  We performed a detailed literature review to 
identify definitions for PVA applicable to children. There were no consistent definitions 
that included a measure of neural respiratory effort for all PVA subtypes.  Definitions 
were modified to include esophageal manometry and were tested for inter-rater 
reliability amongst 2 independent readers using a set of 50 patient recordings from the 
REDvent dataset (Figure 2). While there are slight differences based on asynchrony 
subtype, kappa values were > 0.83 for all asynchrony subtypes which occurred at rates > 
1% of breaths.  As part of this proposal, our three research groups will 
collaborate to harmonize these definitions and incorporate Edi and sEMG.  
Nearly 30% 
of breaths are 
asynchronous, with 
a number of 
distinct PVA 
subtypes identified 
in children.  Each 
of our groups have 
conducted 
observational 
studies on subsets 
of mechanically 
ventilated children, 
using our own 
definitions for PVA 
and its subtypes.  
In an ARDS 
population with 
Pes (preliminary 
analysis of 65 
patients and 54,284 breaths from the REDvent cohort at CHLA), 28.7% of breaths had 
some form of asynchrony, with 63/65 (95.4%) patients demonstrating at least one 
episode of PVA.  The predominant asynchrony subtypes were flow undershoot (13.8%), 
delayed termination (7.4%), premature termination (5.1%), and reverse trigger (1.9%).  
Double cycled breaths occurred 3% of the time (see below).  In a mixed cohort of 74 
children at Beatrix Children’s Hospital that used sEMG, 33% of breaths had some form 
of asynchrony. The predominant asynchrony subtypes were ineffective trigger (68%) 
followed by delayed termination (19%).  DC breaths occurred 4% of the time.  In a mixed 
cohort of 62 children at St. Justine Children’s hospital that used Edi, 27% of breaths had 
some form of asynchrony. The predominant asynchrony subtypes were trigger delay 
(9%), ineffective efforts (10%) and premature termination (4%).  DC breaths occurred 1% 
of the time.  There are high rates of PVA amongst ventilated children, with differences in 
PVA subtypes based on institution, technique of measurement of neural effort, and 
disease state.  These findings underscore the need to have common operational 
definitions for PVA subtypes which can incorporate different methods to measure neural 
effort, with a diverse, heterogeneous sample of ventilated children from multiple 
institutions.   
Double Cycle (DC) occurs in approximately 3% of breaths, with underlying 
asynchrony subtypes nearly equally split between Reverse Trigger and Premature 
Figure 2. PVA subtype examples with operational definitions based on Pes as the 
measure of neural respiratory drive.  

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Termination/Flow Undershoot. A DC breath occurs when the ventilator delivers a 
second breath before the patient has fully exhaled. This is particularly injurious because 
it leads to very high tidal volumes and risk of volutrauma (strain), in addition to high 
transpulmonary pressure and barotrauma (stress). 21,22,24,48-51,60  In the REDvent cohort, 
3.0% of breaths were DC, with at least one DC breath occurring in 46/65 (70.8%) 
patients. The most common PVA associated with DC breaths was reverse trigger (52.5%).  
High patient effort with flow undershoot/premature termination was also very common 
(45.2%, combined for analysis), while auto trigger (1.2%) was rare.  Rates of DC breaths 
were similar in cohorts from St. Justine (1%) and Groningen (4%), but the underlying 
PVA subtype was not characterized.   
Understanding the underlying PVA will inform the therapeutic strategy: The two 
predominant forms of PVA leading to DC breaths are Reverse Trigger (RT) and flow 
undershoot/ premature termination. This has not been explicitly articulated in the 
literature35,38,61 and has crucial therapeutic implications. This can represent a paradigm 
shift in PVA therapeutics, because the most common clinical approach to eliminate DC 
breaths involves adjusting the trigger sensitivity on the ventilator. This will likely only be 
effective 
for auto-
triggering, 
the rarest 
cause of 
DC 
breaths in 
our 
preliminary data. 
We recently 
identified that 
patients were more likely to have RT when the set ventilator rate was close to the 
patient’s neural respiratory rate.53 This fits with the physiologic concepts of respiratory 
entrainment. We have reported recent cases of patients with consistent 1:1 patterns of RT 
with intermittent DC (Figure 3a). In this example, the patient’s neural respiratory rate 
and set ventilator rate were identical at 21 breaths per minute. By reducing the set 
ventilator rate by 6, we were able to abolish the RT (Figure 3b).62 We have seen similar 
manipulations work in other children with RT, although this does not appear to work in 
all patients.  This case emphasizes the importance of identifying the pathogenesis of DC 
breaths, as targeting the intervention to RT ultimately abolished the underlying PVA and 
its subsequent effects. In contrast, if the DC breaths are from flow 
undershoot/premature termination, then strategies involve increasing ventilator 
support, prolonging inspiratory time, or reducing respiratory drive with sedation or 
neuromuscular blockade.    
Methods and analysis plan to complete aim 1 
Standardization of definitions across neural effort type and annotation of 
datasets: The definitions for PVA subtype will be extended to include sEMG and Edi.  
The software system we have developed for breath annotation is cloud-based, enabling 
collaboration across multiple sites.  All waveform files will be coded with a unique study 
number and stripped of identifying information.  An initial set of 10 illustrative files from 
each dataset will be used to harmonize the definitions.  Subsequently, inter-rater 
reliability of the definitions will be tested using a dataset of 60 patient files (20 with each 
method of neural effort) which will be independently annotated by a minimum of two 
investigators, and kappa values per PVA subtype and neural effort measurement will be 
Figure 3. Manipulations to the ventilator targeting reverse trigger PVA (a). where patient effort 
(esophageal pressure) begins after ventilator insufflation (airway pressure). We were able to 
abolish the PVA and its subsequent DC breaths (b.) by lowering the ventilator rate. 

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generated. If a kappa value is > 0.8 (as per preliminary data above), then the PVA 
subtype will be considered to have high reliability.  If kappa is < 0.8, breaths with 
disagreement will be reviewed and definitions modified or clarified as necessary.  An 
additional 20 files (targeting that neural effort measure) will again be read by a 
minimum of two investigators, and the process repeated until all relevant kappa values 
are > 0.8 for PVA subtypes which occur at a frequency > 1%.   After inter-rater reliability 
is established, one trained reader will annotate future files.  If there is uncertainty about 
a particular breath, it will be reviewed as part of a weekly meeting to arrive at a final 
annotation.  If a particular breath type is unable to achieve a kappa >0.8, then all 
potential breaths of that breath type will also be reviewed at a team meeting.   
Analysis of PVA 
subtypes leading to DC 
breaths, and identification 
of risk factors: Each dataset 
contains detailed diagnostic 
data, demographics, 
ventilator settings, and 
medication data. Using data 
from existing datasets, all 
patients and all days of 
ventilation will be analyzed 
to describe the frequency of 
PVA subtypes leading to DC 
breaths. For each DC breath 
(anticipated 3% of all 
breaths), one of three 
underlying PVA subtypes will 
be annotated (Reverse 
Trigger, Flow 
Undershoot/Premature 
Termination, Auto-trigger, Figure 4).  Flow undershoot and premature termination 
represent the same physiologic concepts of inadequate ventilator support, so they will be 
combined for analysis of DC breaths.  We anticipate that RT and Flow 
Undershoot/Premature Termination will continue to comprise > 95% of the causes of DC 
and will be the primary focus of analysis.  We will evaluate ventilator and patient specific 
risk factors for PVA subtypes which lead to DC. 
Sample Size and Power: From existing datasets, we are anticipating having over 
1,000,000 breaths for analysis, from 371 patients, with more than 1,000 patient days.  
Based on our preliminary data, 3% of breaths are DC, and 70% of patients have at least 
one episode of DC. This should give us a minimum of 30,000 DC breaths from 260 
patients. This will permit inclusion of dozens of variables in the risk factor analyses, 
although we anticipate between 3-5 in each model.  Analysis will be conducted on the 
breath and on the patient level.   
The goal of the breath level model is to understand why DC occurs when a 
specific PVA subtype is present.  We will create two prediction models, one to identify 
risk factors for DC related to RT and one to identify DC related to flow 
undershoot/premature termination.   Variables considered in the breath-by-breath 
model include parameters with biological plausibility to be in the causal pathway for the 
PVA subtype or DC including ventilator mode (including NAVA), respiratory rate, 
ventilator rate (RRvent), spontaneous or neural respiratory rate (RRneural) and neural 
Figure 4. Asynchrony subtypes leading to DC breaths.  Flow undershoot/ 
premature termination represent inadequate ventilator support for the 
patient’s respiratory drive, while Reverse trigger leading to DC occurs when 
patient effort begins after lung insufflation.  Auto trigger is relatively rare and 
occurs when a second breath is delivered with no patient effort.   

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initiation and termination, peak inspiratory pressure (PIP), Tidal Volume, PEEP, 
inspiratory time, and an estimate for patient effort (ΔPes, peak Edi, or sEMG).  We will 
first perform univariate analysis on the predictor variables of interest, stratified by DC 
versus non-DC in each of the subtypes.  Mixed logistic regression models will then be 
created to first control for patient level effects with repeated measurements per patient, 
retaining variables with an independent association with DC breaths.  
The goal of the patient level model is to identify patients who are at high risk for 
DC.  Because RT and flow undershoot/ premature termination are the PVA subtypes 
which lead to DC over 95% of the time, variables for consideration will focus on risk 
factors for each of these PVA subtypes, in addition to risk factors for DC specifically.  
Univariable analysis will examine the Spearman’s correlation between the frequency of 
DC breaths per patient in each PVA subtype category and static patient related variables 
of interest such as age, gender, height, body weight, risk factors and severity of lung 
injury, blood gas data, sedation and analgesia (cumulative dose of drugs, pain and 
sedation scale).  In addition, median values for respiratory parameters from breath-by-
breath analysis over the entire 30-minute recording will also be used.  Subsequently, 
patients will be categorized into groups based on the frequency of DC breaths from each 
subtype. Those with DC occurring in more than 5% of breaths will be labeled DC patients 
for analysis. Our preliminary data supports this occurs in approximately 20% of patients.  
Subsequently, mixed logistic regression models will be created to identify the patient 
specific factors associated with DC, stratified by each of the PVA subtypes.    
 
  
Specific Aim 2: To determine if a ventilator strategy in children with ARDS that promotes 
spontaneous breathing and physiologic levels of patient effort results in different rates and 
subtypes of PVA, and if PVA mediates the relationship between this intervention and 
clinical or mechanistic outcomes. Hypothesis: (a) REDvent intervention patients will have 
a different distribution of PVA subtypes than usual care patients which will partially 
mediate the relationship between REDvent intervention and outcome. (b) PVA subtypes 
which lead to DC breaths will be associated with clinical and mechanistic outcomes.  Study 
Design: Secondary analysis of waveforms and clinical data from the REDvent clinical 
trial.  
 
Preliminary Data 
The relationship 
between PVA and clinical 
outcomes is complex 
because PVA is more likely 
to occur in patients with 
more spontaneous 
breathing. A conventional 
ventilator management 
strategy for patients with 
ARDS promotes controlled 
ventilation with high 
degrees of sedation or 
neuromuscular blockade 
with low rates of 
spontaneous breathing early during ventilation, followed by spontaneous breathing 
Figure 5: 
Conceptual model 
for Aim 2  

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when evaluating for readiness for ventilator liberation.21    These patients may have lower 
rates of PVA because they are not permitted to breathe spontaneously until the ARDS is 
largely resolved, but they may have longer length of ventilation because of the lack of 
spontaneous breathing.  A balanced lung and diaphragm protective strategy, like what is 
being tested in the REDvent trial, promotes spontaneous breathing earlier during 
ventilation.   We hypothesize that this will result in shorter time on ventilation by 
reducing the rates of over and under assistance myotrauma (VIDD) as well as more lung 
protection (VILI).22,24,45 However, earlier spontaneous breathing may result in a higher 
overall rate of PVA in REDvent versus control patients, but a different distribution of 
PVA subtypes.  Because REDvent targets physiologic levels of respiratory effort, it is 
likely that the under-assistance related causes of PVA which lead to double cycling (flow 
undershoot/premature termination) will occur less frequently.  However, the lung 
protective component of REDvent frequently uses a higher ventilator rate than usual 
care, which may make Reverse Trigger more common, with double cycling.  It is 
therefore highly plausible that PVA frequency and subtype may mediate the 
relationship between REDvent intervention and outcome (Figure 5).  It is 
therefore important to understand when the benefits of spontaneous breathing related to 
prevention of diaphragm atrophy are outweighed by any additional risks related to PVA.  
The analytic framework must consider these potentially competing principles.  Adult 
data confirms associations between PVA (and its subtypes) and adverse clinical 
outcomes. 12-16  Nevertheless, human studies have not confirmed mechanistic pathways 
involved, although pre-clinical data support these proposed mechanisms of injury. 64-67   
While this study will primarily establish associations, a mediation approach (see below) 
to the analysis allows for causal inference and specifically leverages the randomized 
nature of the REDvent trial.  To decouple these effects, when analyzing the relationship 
between PVA variables and length of ventilation, we stratify or control for the time to 
spontaneous breathing. 
Preclinical data confirms that PVA leads to VIDD 
and VILI.  Several mechanistic studies, including published 
analysis by our group, confirms that PVA leads to VIDD and 
VILI.64-67  In a rabbit model, we identified that VIDD was 
reduced with a ventilation strategy promoting spontaneous 
breathing using pressure support ventilation compared to 
controlled ventilation, but that this injury could be further 
reduced with Neutrally Adjusted Ventilatory Assist (NAVA) 
by reducing the rates of PVA.67  Interestingly, 
diaphragmatic injury from over-assistance myotrauma 
(common during controlled ventilation without 
spontaneous breathing) resulted in atrophy, while 
diaphragmatic injury from PVA was mediated by 
sarcomere disruption.  There was a dose response 
relationship between Asynchrony Index and fraction of 
sarcomere disruptions in the diaphragm (Figure 6). Both 
sarcomere disruption and atrophy result in functional impairments seen in VIDD, albeit 
with different mechanisms.  
 
Figure 6: Relationship between 
Asynchrony index and 
sarcomere disruption of the 
diaphragm in a rabbit model for 
PVA  

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PVA subtypes are associated with clinical and mechanistic outcomes.  
Preliminary analysis from 65 patients in the REDvent dataset evaluated the association 
between PVA rates on the first day of 
spontaneous breathing and outcomes. 
While the sample size from this preliminary 
data is under-powered, it highlights the 
potential magnitude of effect we may see 
with the larger sample size in this 
application.   We have not conducted 
group-based comparison (REDvent versus 
control), as study investigators need to 
remain blinded to group-based analyses 
until completion of REDvent (Dec 2023).  
Flow undershoot represents inadequate 
support on the ventilator and not 
surprisingly was associated with longer 
length of ventilation (p<0.05, Figure 7a) 
perhaps through hypertrophy of the 
diaphragm (Dte increased), although this 
analysis is limited by sample size with only 
7/65 patients in the hypertrophy group 
(p=0.4, Figure 7b).   Moreover, patients 
who had DC breaths had higher rates of 
delirium, as measured by the Cornell 
Assessment of Pediatric Delirium (CAPD) 
screener (p< 0.01, Figure 7c). This may 
relate to agitation from PVA which 
manifests with the same symptoms as 
delirium, or it may be that delirium itself 
makes it harder for patients to synchronize 
with the ventilator.  Children with reverse trigger received higher doses of opioids 
(p<0.01, Figure 7d), which re-enforces that alteration of neural respiratory rate 
(suppressed with opioids) may make RT more common.  
 
Methods and Analysis Hypothesis A: Here we seek to test whether the REDvent 
intervention results in different rates and subtypes of PVA than usual care. This type of 
analysis is perfectly suited to secondary analysis of a randomized trial, where the 
intervention is striving to promote more spontaneous breathing with a downstream 
influence on PVA.  This would not be possible to do with an observational cohort, 
because of inherent selection bias in which patients are permitted to have more 
spontaneous breathing.  We believe the forms of asynchrony which lead to DC breaths 
(flow undershoot/premature cycling) and reverse trigger may be different in REDvent 
versus control patients.   This aim will use all available patients with spontaneous 
breathing in the REDvent dataset (expected 235).  For each patient day with 
spontaneous breathing, PVA subtypes will be analyzed.  The proportion of breaths which 
fall into a particular PVA subtype will be expressed in addition to global asynchrony 
index, calculated as the total number of asynchronous breaths over the total number of 
breaths.30  Because rates of PVA may vary from day to day, analysis will focus on both an 
area under the curve of PVA over all days (calculated as the total number of 
asynchronous breaths over the total number of breaths available for analysis) in addition 
Figure 7: (a, top left) Length of ventilation (days) is higher 
in children with flow undershoot forms of PVA when 
spontaneous breathing does not occur until after the 3rd 
day of ventilation (b, top right) Diaphragm hypertrophy 
may be more likely to occur in children with flow-
undershoot forms of PVA (c, bottom left) Delirium scores 
are higher in children with high rates of Double Cycled 
breaths. (d, bottom right) Reverse Trigger patients receive 
higher doses of opioids.  

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to the highest rate of PVA on any day for each patient, by PVA subtype. PVA and PVA 
subtype rates per patient will be expressed as a continuous variable and compared 
between REDvent and usual care patients using a Mann Whitney U test given it is not 
expected to be normally distributed.  PVA subtypes which are different between 
REDvent and control patients will be considered for mediation analysis (below).    
The REDvent study will evaluate wither the REDvent intervention results in 
improvement in length of mechanical ventilation (clinical outcome), as well as 
mechanistic outcomes (PiMax and Diaphragm Atrophy).  The impact of REDvent group 
on time to event variables (i.e. length of ventilation) will be analyzed with competing risk 
regression (competing risk of death), continuous outcomes (i.e. PiMax) with linear 
regression, and dichotomous variables (i.e. mortality) with logistic regression.  In 
mediation analysis we will add the PVA subtypes which are different between REDvent 
and control patients to multivariable models.  The PVA subtype will be considered a 
mediator if it changes the parameter estimate of the REDvent intervention by more than 
20%.  If the PVA subtype significantly strengthens the association between REDvent 
intervention and outcomes, then therapeutic trials which seek to decrease that PVA 
subtype maybe beneficial (e.g Reverse Trigger). In contrast, if controlling for PVA 
subtype weakens the association between REDvent and outcome, then strategies to 
mitigate that type of PVA may be more harmful (e.g. Flow Undershoot).  This approach 
allows us to simultaneously evaluate the potential benefits of a lung and diaphragm 
protective strategy and understand the extent to which PVA subtypes which are different 
between intervention and control groups affects outcomes.  This type of causal inference 
analysis is possible because of the randomized nature of the REDvent trial in which the 
intervention is likely to affect PVA rates and subtypes.    
Sample Size and Power: We anticipate 235 patients available for analysis, with a 
median time from first day of spontaneous breathing to extubation of 4 days.  Using a 
proposed mediation analysis with a conservative estimate for a partial “r” of 0.3 of the 
PVA variable with the mediator outcome, a partial “r” of 0.3 for the mediator outcome 
with the clinical variable, then we would have a power of 0.84 to detect the overall effect 
estimate in the mediation model.   
 
Methods and Analysis Hypothesis B: Here we seek to understand which PVA 
subtypes and frequency are independently associated with clinical or mechanistic 
outcomes.  The primary clinical outcome is length of mechanical ventilation after the 
first day of spontaneous breathing. This is the primary outcome because the relationship 
between PVA rates and length of ventilation is confounded by time to first day of 
spontaneous breathing, as discussed above.  Patients who have highly controlled 
ventilation without spontaneous breathing for several days inherently cannot develop 
PVA, as there is no significant patient effort.   Secondary short-term clinical outcomes 
include length of mechanical ventilation, length of the weaning phase of mechanical 
ventilation (time from first spontaneous breathing trial until extubation), 90-day 
mortality and re-intubation.   Secondary longer-term clinical outcomes include 
pulmonary function, neurocognitive function, and health related quality of life for the 2 
years after ICU discharge amongst survivors. Mechanistic outcomes will focus on 
pathways of injury hypothesized to be associated with PVA, summarized by PVA subtype 
in Table 2.   
 
 

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PVA Subtype 
Mechanistic 
Pathway 
Variables to be considered 
“Inadequate Support”: 
Flow Undershoot or 
Premature Cycling 
VILI, VIDD (Over-
use) 
Transpulmonary Pressure, Tidal Volume, 
Resolution of Organ Dysfunction, Resolution of 
Lung Injury, PiMax, Diaphragm Thickness  
Reverse Trigger 
VIDD (Eccentric 
Contraction), 
Delirium, Excess 
Sedation 
PiMax, Diaphragm Thickness, Cornell 
Assessment of Pediatric Delirium, Cumulative 
Dose of Sedatives and Opioids 
Double Cycle (All 
causes) 
VILI 
Transpulmonary Pressure, Tidal Volume, 
Resolution of Organ Dysfunction, Resolution of 
Lung Injury 
Asynchrony Index (All 
PVA) 
Delirium, Excess 
Sedation 
Cornell Assessment of Pediatric Delirium, State 
Behavioral Scale, FLACC Score, Cumulative 
Dose of Sedatives and Opioids 
Table 2: Analytic Plan with PVA variable of interest, mediation variables to be investigated, and 
hypothesized mechanistic pathway.  
Univariable analysis will focus on the relationship between the PVA variables 
above and clinical and mechanistic outcomes.  Nearly all the variables of interest are 
continuous, so analyses will focus on strength of association and dose response.  
Nonparametric or parametric correlations will explore the relationships between 
continuous variables.  The primary clinical outcome of length of ventilation after the first 
day of spontaneous breathing will be modelled with a competing risk regression to look 
at time to extubation against the competing risk of death. This type of model is necessary 
rather than traditional survival analysis or linear regression because both death and 
prolonged ventilation are undesired outcomes, and some proportion of children (likely 5-
10%) will die even after the first day of spontaneous breathing.  We have successfully 
used this framework in previous investigations.68-72  We will then add in variables which 
may confound the relationship between PVA and clinical outcomes including 
demographic factors (age, co-morbidities), severity of initial lung injury, diagnostic data 
and medications.  Similar analyses will be repeated all clinical and mechanistic 
outcomes.  For mechanistic analysis (table 2), within each of the proposed mechanisms 
(VILI, VIDD, Delirium), the variable with the strongest association with PVA (or its 
subtype) will be included as the outcome variable.  
 
 
 
 
 
 
 
 
 
 

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Specific Aim 3) To develop and test a clinical decision support system using machine 
learning techniques to automatically identify common forms of PVA in children.  
Hypothesis: (a) Machine learning models using waveforms available on all mechanical 
ventilators will accurately identify PVA subtypes compared to gold standard annotations 
which include measures of neural drive. (b) Algorithms can be optimized for high 
sensitivity and low false alert rates to identify children with frequent PVA.  
 
Preliminary Data 
Machine learning 
methods can detect DC breaths 
and the PVA subtypes leading to 
DC.  We have been developing a 
machine learning framework 
using Spectral Analysis with a 
Convolutional Neural Network to 
detect PVA subtypes.  Details 
about the methods used (and 
intend to employ here) are 
described below.  Preliminary 
models were trained on 34, 
validated on 13 and tested on 18 patients from the REDvent dataset.  Gold standard 
annotations were provided using the 
methods and data described in SA 1.   The 
machine learning model (a Convolutional 
Neural Network) was trained using flow 
and airway pressure alone, although the 
gold standard annotations (from humans) 
also used esophageal pressure.   When 
evaluating the performance of the models in 
the test set (18 patients, >49,000 breaths) to 
detect DC, the model was very accurate with 
an Area Under the Cure (AUC) of the 
Receiver Operating Curve (ROC) of 0.984 
(Figure 8a).  This would be able to detect 
50% of all DC breaths, with a false alarm 
rate of 1 in 14, or 75% of all DC breaths, 
with a false alarm rate of 1 in 3. 
Furthermore, when evaluating the 
underlying asynchrony subtype 
responsible for the DC breath, the models 
accurately distinguished between Flow 
Undershoot/ Premature Cycling and 
Reverse Trigger, with AUCs > 0.97 (Figure 
8b). 
Machine Learning Methods may be more accurate than highly trained clinicians.     
We have identified that these machine learning methods are also accurate at identifying 
Flow Undershoot/Premature termination and Reverse Trigger even when not associated 
with a Double Cycled Breath.  We applied the methods on 13 patient files in the 
validation set (REDvent dataset only). Out of 10,326 breaths, the gold standard (human) 
Figure 8: (a, left) The machine learning model has outstanding 
discrimination of double cycled breaths (b, right.) and the individual PVA 
subtypes leading to DC breaths 
Figure 9: (a) Flow-undershoot detected by both human 
annotators and the machine learning algorithm with 
concave rising limb of flow, rise in airway pressure 
(horizontal lines) and falling esophageal pressure with 
airway pressure plateau (dotted line).  (b) Flow-
undershoot by machine learning algorithm but did not 
meet thresholds required by human annotators, 
although still represents same physiologic phenomena.  
(c) normal breath  

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method labeled 1,926 (18.65%) of breaths as Flow Undershoot and 251 (2.43%) of 
breaths as Premature Termination.  The machine learning methods identified 1486/1926 
(77.14%) of the breaths which were labeled as Flow Undershoot by the gold standard 
method, and 176/251 (70.11%) of the breaths that were labeled as Premature 
Termination. Interestingly, the machine learning method also identified 1,993 breaths as 
Flow Undershoot and 987 breaths as Premature Termination which were not initially 
labeled as such by the expert readers. Several of these files were subsequently re-
reviewed by the expert readers, and in nearly all cases, the patterns detected by the 
machine learning algorithms did in fact demonstrate the correct physiologic phenomena, 
although they did not meet the exact threshold criteria used for the definitions.  (Figure 
9).  This highlights that these methods may be more sensitive than the 
human eye.  Additional training of these algorithms to adjust threshold values that 
balance sensitivity and specificity between the more overt versus subclinical forms of 
flow undershoot, in addition to developing algorithms to identify the other forms of PVA 
will be a focus for the approach.  
Methods: On a high level, a spectral tensor is 
used as input to a Convolutional Neural Network 
(CNN) model, which generates predictions that 
show the likelihood of a breath having 
asynchrony, with a specific asynchrony subtype. 
CNN are widely used in computer vision tasks73, 
which make them appropriate for this 
application. Our group has extensive experience 
with machine learning models in the ICU 
environment.74-80  The methods are based on 
analysis of three contiguous breaths, called a 
breath triplet with the breath of interest being 
the central breath (Figure 10). Breath triplets 
are generated from the two readily available 
clinical waveforms (flow spirometry and 
airway pressure). Each triplet is labeled with 
the asynchrony types associated with its central breath. A sliding Discrete Fourier 
Transform (DFT) is used to transform each of the waveforms of a triplet into two 
spectrograms: one with the power spectral density (PSD), which measures the energy of 
sinusoids in each channel, and another containing phase, which measures the angular 
shift of the sinusoids. This results in four spectral images for each triplet (Figure 10). 
Methods are employed to remove noise81 and the spectrograms are aggregated in a stack 
to create a 4-channel image. This is analogous to the typical input used in CNNs, a three 
channel (RGB) image, except each channel corresponds to a single generated 
spectrogram as opposed to a color. Very subtle changes and patterns in the airway 
pressure and flow channels can be more readily apparent in their spectral representation 
than in their raw waveforms. CNNs, which are state-of-the-art in image processing, can 
accurately and efficiently recognize patterns in stacks of spectrograms. This powerful 
combination of spectrograms and CNNs is what makes our machine learning technique 
superior to automation-based approaches (i.e. hard coding the rulesets). Further, the 
technique can be ventilator agnostic.   
Analysis Plan:  The existing datasets from all 3 institutions will be combined 
and patients will be randomly assigned to one of three datasets for derivation (50%), 
validation (25%), and final testing (25%).   
Hypothesis a (algorithm development and testing): We anticipate having nearly 
1,000,000 breaths for analysis from existing datasets (500,000 training, 250,000 
Figure 10: Example of a synchronous breath (a) 
compared to an asynchronous breath (b) and the spectral 
tensor conversions for each, with the DC breath 
highlighted in orange. 

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validation and 250,000 in the final test set). Our models will first concentrate on DC 
breaths using the methods described above.  Machine learning experts will work with the 
clinical team to review breaths in the validation set which have been classified as a 
certain PVA subtype, but which were not labeled the same way by human annotators 
(using one of 3 gold standard measures of neural effort). We anticipate many of the PVA 
annotations by the machine learning algorithm will represent “sub-clinical” PVA, where 
the breaths are representative of a specific type of PVA, but do not meet the threshold 
determined by the clinical reviewers.  Models will be fine-tuned to differentiate “sub-
clinical” from more overtly “clinical” PVA. Final performance will be assessed using the 
test set only once to ensure an unbiased estimate of the ability of the model to 
discriminate DC breaths and synchronous breaths. The performance of the models will 
be assessed using AUROC to assess the overall ability of the model to discriminate 
between DC breaths and other breaths. Additionally, the recall of the model at various 
levels of Number Needed to Alert (1.01, 1.1, 1.5, 2) will be analyzed to understand the 
potential clinical utility. Similar analysis will then follow to identify the underlying PVA 
subtype leading to the DC breath, and finally to identify other forms of asynchrony, 
independent of whether it results in a DC breath.  
Hypothesis b (development of a clinical alert to identify when PVA is occurring 
with high frequency).  To improve the recognition of PVA and support trials focused on 
PVA prevention, it is necessary to have real-time tools which balance the benefits of 
identification of potentially injurious forms of PVA against false alarms.  The focus of 
this sub-aim is to develop a decision support system to continuously read in flow and 
airway pressure waveforms, apply the machine learning algorithms, provide relevant 
summary data about PVA frequency and subtypes, and potentially alert clinicians when 
patients have high rates of dangerous forms of PVA.  We will build the relevant pipelines 
necessary for these systems, using raw waveform data from the three different hospitals.  
We will develop alert algorithms to identify patients who are having frequent PVA, while 
minimizing false alarms.  This will mimic the real-world deployment scenario of 
detecting PVA on a new patient (not previously seen).  The system and alert algorithms 
will be developed and internally validated from the data available in the existing 
datasets, evaluating sliding windows of 30-60 breaths to identify patients that exceed 
thresholds for PVA subtypes during that window (i.e. > 20% of breaths are flow 
undershoot in that window).   This is important because it may not be possible (or 
desired) to eliminate all forms of PVA, particularly if the PVA event is rare.  The 
unintended consequence of adjusting ventilator settings to eliminate one form of PVA, 
may result in other forms of PVA, or other consequences such as over-assistance of the 
patient.  We will adjust the alert thresholds to optimize detection of true PVA events, 
against false alarm rates, with the goal of maintaining false alarm detection as low as 
possible (i.e. less than 5%).  As seen in the preliminary data with DC breaths, on the 
individual breath level, our false alarm rate is 1/3-1/14 when sensitivity is in the 50-75% 
range.  We anticipate the requirement for a certain number (or percentage) of breaths to 
be classified as a certain PVA subtype will greatly improve the sensitivity and specificity 
for identifying patients with frequent PVA.   
 
 
 
 

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the clinical setting: meaning, usefulness and perspectives. Intensive Care Med 
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ventilator asynchrony by reducing tidal volume during pressure-support 
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Heulitt MJ, Clement KC, Holt SJ, Thurman TL, Jo CH. Neurally triggered breaths 
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Bhalla AK, Klein MJ, Emeriaud G, et al. Adherence to Lung-Protective Ventilation 
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Laksana E, Aczon M, Ho L, Carlin C, Ledbetter D, Wetzel R. The impact of 
extraneous features on the performance of recurrent neural network models in 
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Carlin CS, Ho LV, Ledbetter DR, Aczon MD, Wetzel RC. Predicting individual 
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Pediatr Crit Care Med 2018;19(10):1004-1005. (In eng). DOI: 
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Belief in Observed Gradients. NeurIPS 2020; 2020. 
 
 
 

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I Ventilation Protocols (Intervention group) 
 
 
Acute phase management is based on SIMV pressure control/pressure support mode of 
ventilation. Oxygenation targets are 88-93% during the acute phase, and PEEP and FiO2 
are managed as per the PEEP/FiO2 tables on the subsequent pages.  If inhaled nitric 
oxide is used by the clinical team, then rules for weaning nitic oxide have been built into 
the protocol, as detailed below.  Ventilation management during the acute phase uses 
pH, ventilator rate, and PIP to suggest changes to embrace permissive hypercapnia. 
When the patient is breathing spontaneously, rules regarding Pressure Rate Product are 
also implemented, to keep work of breathing in a physiologic range.    
 
 
If High frequency oscillatory ventilation is used for patients randomized to RED-vent 
Acute, then HFOV rules have been created. There is no requirement to transition to 
HFOV, but it will be permitted for rescue therapy.  Similar to the conventional 
ventilation, Oxygenation is managed with a MAP/FiO2 table, with rules for inhaled nitric 
oxide if used.  Ventilation adjusts Hz, Amp based on pH. There are no PRP based rules 
during HFOV, since most patients are not spontaneously breathing.  There are 
recommendations for minimal therapy with HFOV, when conversion back to 
conventional ventilation should be considered, although the clinical team will ultimately 
make the decision regarding conversion back to conventional ventilation.   
 
 
Details of the protocols are summarized on the following pages.

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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• 
For patients on inhaled nitric oxide, escalation of iNO is per the clinical team.  
• 
For weaning of inhaled nitric oxide, if FiO2 ≤ 0.6 and an FiO2 wean would normally be recommended, this recommendation 
is replaced with a recommendation to decrease inhaled nitric oxide until it is discontinued. 

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Weaning Phase Protocol 
 
 
 
 
• 
During weaning phase, PEEP ≤ 10 cmH20, FiO2 ≤ 0.6, PS ≤ 20 cmH20.   PEEP and FiO2 management can be changed within 
PEEP range of 5-10 cmH20 and FiO2 from 0.21-0.6 by the clinical team.   
• 
Suspension of the weaning phase is permitted for up to 12 hours for situations such as procedures, increased need for sedation 
preventing adequate spontaneous breathing, or other circumstances requiring transient need for increase in ventilator 
support etc.  As soon as the patient appropriately meets weaning criteria (spontaneous breathing, pH 7.32-7.47, PEEP ≤ 10 
cmH20, FiO2 ≤ 0.6 ), the weaning phase intervention is resumed.   
• 
If the weaning phase is suspended for > 12 hours and the patient no longer meets weaning criteria, the acute phase 
intervention will be resumed, until the patient again meets weaning criteria.  This will be labeled weaning failure, and tracked 
in both arms. 

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The table below summarizes all protocol changes and the dates the amendments were approved by the 
Children’s Hospital Institutional Review Board.  Changes related to conduct of the trial (modifications of 
inclusion and exclusion criteria, sample size etc) were approved by the DSMB and NHLBI. Minor changes 
related to additional surveys or additional funding for secondary analysis are also included in the table 
below but did not result in substantive changes to the conduct of the trial.   
 
Amendment Date 
Summary of Changes 
10/10/2018 
Exclusion criteria revised to allow inclusion of patients with tracheostomy 
without home mechanical ventilation. Protocol change approved by NHLBI 
and DSMB to help increase enrollment to stay aligned with milestone accrual 
plan.    
5/30/2019 
Inclusion of Health-Related Quality of Life questions (surveys) at ICU admit 
and Discharge (additional funding received) 
10/14/2019 
Sample size reduced from 300 to 276.  Inclusion of Phillips NM3 volumetric 
capnography device (ancillary study funding).  Protocol change approved by 
NHLBI and DSMB. 
3/18/2020 
COVID-19 related changes including allowing up to 72 hours from intubation 
for enrollment of all patients (previously restricted to those admitted from an 
outside ICU). This was to facilitate recruitment while staying compliant with 
institutional protocols related to COVID-19. Protocol change approved by 
NHLBI and DSMB. 
08/08/2020 
Addition of survey related to Vaping/Smoking exposure (ancillary study 
funding) 
11/17/2022 
Age range for inclusion increased from 18 to 21 years of age. Protocol change 
approved by NHLBI and DSMB to help increase enrollment to stay aligned 
with milestone accrual plan.   
03/28/2023 
Details added regarding secondary analysis related to patient-ventilator 
asynchrony (additional funding obtained). 

REDvent Statistical Analysis Plan (Fall 2019) 
Inclusion Criteria  
1. Children > 1 month (at least 44 weeks corrected gestational age) and ≤18 years of age AND 
2. Supported on MV for pulmonary parenchymal disease (radiographic evidence of alveolar or 
interstitial opacifications with a  clinical risk factor for lung disease e.g. pneumonia, acute 
respiratory distress syndrome, aspiration, etc.) with Oxygen Saturation Index (OSI= (FiO2 * Mean 
Airway Pressure*100)/SpO2) ≥ 5 or Oxygenation Index (OI= FiO2 * Mean Airway 
Pressure*100)/PaO2)) ≥4 1 AND 
3. Within 48 hours of initiation of invasive MV  (up to 72 for those transferred from another hospital) 
Exclusion Criteria  
1. Contraindications to an esophageal catheter (i.e. severe mucosal bleeding, nasal encephalocele, 
trans-sphenoidal surgery) OR 
2. Contraindications to use of Respiratory Inductance Plethysmography (RIP) bands (i.e. 
omphalocele, chest immobilizer or cast) OR 
3. Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall defects, 
pregnancy) OR 
4. Conditions precluding conventional methods of weaning (i.e., status asthmaticus, severe lower 
airway obstruction, critical airway, intracranial hypertension, Extra Corporeal Life Support (ECLS), 
limitation of care, severe chronic respiratory failure, spinal cord injury above lumbar region, 
cyanotic heart disease (unrepaired or palliated) OR 
5. Primary Attending physician refusal  
 
Randomization Strategy and Blinding 
For the acute phase, subjects will be block randomized to either arm in a 1:1 allocation ratio, 
stratified by age group: infant (30 days -365 days), child (366 days to ≤8 years), and older child/ adolescent 
(9-18 years); and immune suppression (congenital or acquired conditions that result in marked inability to 
respond to antigenic stimuli).    Block randomization will use random block sizes of 4, 6 and 8 within the 
strata above. Weaning phase randomization is block randomized by acute phase group and age, using the 
same methodology. Although blinding is not possible given the open label nature of the intervention, 
analysis will be blinded to treatment groups.  Randomization schema will be loaded into the central 
REDCAP database by the unblinded statistician.   
 
Statistical Analysis Plan  
Baseline characteristics at the time of randomization will be computed for each treatment group 
(REDvent and usual care) and within each phase (Acute and Weaning). For all analyses, assumptions for 
data distribution will be assessed, and normalizing transformations of the data or nonparametric analysis 
will be performed as necessary. The mean and standard deviation will be reported for normally 
distributed continuous variables, and the median and interquartile ranges will be reported for non-
normally distributed continuous variables. Given this is an RCT, we anticipate balanced baseline 
characteristics. To evaluate this, we will calculate effect sizes for measures of central tendency (Cohen d, 
Cramer v) across groups. For non-parametric variables, effect sizes defined for the Mann-Whitney U will 
be calculated to produce r. For frequency counts and percentages the rate ratio will be evaluated to 
calculate the effect size. Variables that have more than a small effect size (d > 0.2, v > 0.01, or r > 0.1, 

categorical effect size>1.2) indicate potential imbalances in baseline characteristics between groups. 
These variables will be included in sensitivity analyses after the primary ITT analyses are performed or 
included as covariates using multivariable models.  
Retention, adherence, and missing data will be compared across groups. High levels of missing data are 
not anticipated given the nature of the study. If the missing data are determined to be related to the 
outcome (not missing at random) or related to group or a covariate (missing at random), we will explore 
the impact of these biases in sensitivity analyses after the primary ITT analyses using multiple imputation 
processes. Our primary approach to imputing missing data is the Markov Chain Monte Carlo (MCMC) 
simulation. Statistical Analysis Software (SAS) procedures will be used.  
The primary analysis seeks to address if there are differences in length of weaning between: 1) REDvent-
acute compared to usual care acute, 2) REDvent-weaning compared to usual care-weaning, and 3) 
REDvent-acute and weaning (combined) compared to usual care acute and weaning (combined). 
Analyses of these aims will follow the ITT principle. The primary analyses will compare median weaning 
duration between groups using a Mann-Whitney U test, or a t-test with transformation as necessary. The 
effect size (r) will also be computed to assess the magnitude of treatment effect. If imbalances in 
baseline characteristics are found between or across randomized treatment groups, a Cox proportional 
hazard model will be performed to adjust for covariates. The estimates (mean, median, or hazard ratio) 
and the associated 95% confidence interval, as well as the p-values, will be presented for interpretation.  
Power analysis: For the primary outcome (weaning duration), a 1-day change in length of weaning is 
considered clinically significant. It is anticipated that up to 20% of patients may not achieve the primary 
outcome (successful passage of an SBT or extubation due to death or dropout); these patients will not be 
included in the primary outcome analysis but will be included in secondary outcomes. We are targeting 
an overall sample size of 300 patients, with a minimum of 240 patients (120 per arm) available for 
analysis of the primary outcome. Using the planned statistical tests above, this sample size would be 
able to detect a ≥ 1-day change in weaning duration with a two-sided alpha of 0.05 and power of 0.9, or 
a relative hazard ratio of 1.5 (ratio between control/intervention group) with a power of 0.9 or a hazard 
ratio of 1.4 with a power of 0.8. Patients who fail the initial SBT will undergo the weaning phase 
randomization. From our pilot data, approximately 25% of patients exposed to the intervention passed 
the initial SBT. Anticipating 180 patients (90 per arm) will receive weaning phase interventions, there will 
be adequate power to detect a ≥ 1 day change in the length of the weaning phase, or a hazard ratio of 
1.5 with an alpha of 0.05 and power of 0.8 in the weaning phase. 
The analytic approach for secondary aims and outcomes such as mortality and ventilator free days will 
follow those described above. For categorical data, a χ2 or Fisher's exact test will be used to compare 
difference between groups. Logistic regression will be used to assess binary outcomes, and a 
multinomial/ordinal logistic regression will be used for categorical outcomes (> 2 categories) while 
adjusting for covariates. To assess the association between 2 continuous variables, a Pearson or 
Spearman correlation will be used, and analysis of covariance (ANCOVA) will be used to adjust for 
covariates. Generalized Estimating Equations (GEE) or mixed effect models will be used when necessary 
to analyze repeated measures. Because of the physiologic nature of the study with a Phase II design, 
multiple comparisons adjustment is not planned for secondary outcomes.  Analyses will be performed 
using the appropriate recent version of the SAS statistical software (SAS Institute Inc., Cary, NC).  

In order to increase precision around the effect estimates for the primary and secondary aims and to 
reflect the stratified sampling, all analyses will be adjusted for block randomization variables.2 For acute 
phase these are age group (infant, child, and adolescent) and whether or not the subject was 
immunocompromised. For the weaning phase this is acute phase randomization grouping and age 
group. In addition, variables thought to be potential confounders on the relationship between 
intervention and outcome with large differences between groups (standardized effect sizes as detailed 
above) will also be included in all adjusted analyses.  Unadjusted analyses will be presented to 
summarize data; all primary and secondary outcomes will present adjusted analyses controlling for age 
category, immunosuppression and imbalanced baseline variables.  
Model assumptions and fit for multiple linear regression (with or without log transformation) will be 
assessed visually for normality of residuals as well as variance inflation factor and difference in betas 
(DFBETAS) for influential points. Model fit for binary multiple logistic regression will be assessed with 
Pearson Chi-square and deviance. Firth’s penalized likelihood method will be used in subgroup analyses 
when event rates are small to reduce bias in the parameter estimates.3 When using negative binomial 
regression, model fit will be assessed for over and underdispersion with the scaled Pearson Chi-
square/deviance and influential points assessed as previously described. The proportional hazards 
assumption will be assessed when using Cox proportional hazards modeling using graphical approaches 
(“log-log” figures and Kaplan-Meier curves) for each covariate.  
A detailed outline of each outcome’s analysis approach to control for blocking variables and confounders 
is given in the Table 1. Pre-specified comparisons of interest are REDvent acute vs. usual care acute, 
REDvent weaning vs. usual care weaning, and four group combination: 1) REDVent acute + REDvent 
weaning 2) REDvent acute + usual care weaning 3) Usual care acute + usual care weaning 4) usual care 
acute + REDvent weaning.  The four group combinations comparisons are exploratory and will only be 
considered if there are noted differences between both acute and weaning phase interventions. 
 
 
References 
 
1. 
Khemani RG, Smith LS, Zimmerman JJ, Erickson S, et al. Pediatric Acute Respiratory Distress 
Syndrome: Definition, Incidence, and Epidemiology: Proceedings From the Pediatric Acute Lung Injury 
Consensus Conference. Pediatric Critical Care Medicine. Jun 01 2015;16(5_suppl):S23-S40. 
doi:10.1097/PCC.0000000000000432 
2. 
Holmberg MJ, Andersen LW. Adjustment for Baseline Characteristics in Randomized Clinical 
Trials. JAMA. Dec 06 2022;328(21):2155-2156. doi:10.1001/jama.2022.21506 
3. 
Firth D. Bias Reduction of Maximum Likelihood Estimates. Biometrika 1993. p. 27-38. 

Table 1: Detailed analytic plan for each outcome variable  
Variable 
Description 
Imputation & Exclusion 
Initial Analytic Approach 
Misc. Notes 
Length of Weaning 
(primary outcome) 
Time from first attempted 
SBT until successful SBT 
passage or extubation, 
whichever comes first. 
Successful extubation is 
removal without re-
intubation or death for at 
least 24 hours.  
 
Patients no longer undergo 
SBTs after the 28 day 
intervention but they will 
be clinically assessed for 
extubation and will be 
followed up to 90 days. If a 
patient remains intubated 
at 90 days their length of 
weaning becomes 90 days. 
 
Patients who never attempt 
an SBT are excluded. 
Patients who attempt an 
SBT but never pass an SBT 
and die within 24 hours of 
extubation are excluded. 
Cox proportional hazards 
model controlling for 
blocking variables and 
confounders. 
Proportional hazards 
assumption will be 
assessed. 
 
 
 
Expect 20% exclusion rate for this 
outcome. Patients who pass the 
SBT will have a length of weaning of 
around 2 hours (SBT duration).  
 
Length of weaning will be 
expressed in days and will take on 
values of 0.0833 (2 hours) to 90 
days. 
 
The adjusted hazard ratio and 95% 
C.I. will be presented for REDvent 
vs. usual care. 
IMV duration in 
survivors 
(Secondary 
Outcome) 
Time from start of index 
intubation to successful 
liberation. Successful 
liberation is defined as no 
death or re-intubation within 
24 hours of extubation.  
Patients who die within 24 
hours of extubation are 
excluded. 
Log transformed multiple 
linear regression 
controlling for blocking 
variables and 
confounders.  
IMV duration will be expressed in 
days.  
Adjusted mean difference and 95% 
C.I.  for REDvent vs. usual care will 
be back transformed with 
exp(estimate) and interpreted as a 
relative change.  

NIV duration after 
extubation 
(secondary 
outcome) 
Duration of non-invasive 
ventilation after extubation 
is defined as the number of 
days and hours that the 
patient is on oro-mask CPAP 
or Bi-level ventilation after 
successful extubation.  
 
Successful extubation is 
defined as no death or re-
intubation within 24 hours of 
extubation. 
Patients who die within 24 
hours of IMV or who never 
receive NIV post-extubation 
are excluded.  
 
Patients who die while on 
NIV will have their death 
date as end of NIV duration. 
Log transformed multiple 
linear regression 
controlling for blocking 
variables and 
confounders. 
NIV duration will be expressed in 
days.  
 
Adjusted mean difference and 95% 
C.I.  for REDvent vs. usual care will 
be back transformed with 
exp(estimate) and interpreted as a 
relative change.  
NRS duration after 
extubation 
(secondary 
outcome) 
Duration of NRS after 
extubation is defined as the 
number of days and hours 
that the patient is on NRS 
after successful liberation.  
End of NRS is defined as 
absent continuously for at 
least 24 hours.   
 
Successful extubation is 
defined as no death or re-
intubation within 24 hours of 
extubation. 
Patients who die within 24 
hours of IMV or who never 
receive NRS post-
extubation are excluded.  
 
 
Patients who die while on 
NRS will have their death 
date as end of NIV duration. 
Log transformed multiple 
linear regression 
controlling for blocking 
variables and 
confounders. 
NRS duration will be expressed in 
days.  
 
Adjusted mean difference and 95% 
C.I. for REDvent vs. usual care will 
be back transformed with 
exp(estimate) and interpreted as a 
relative change.  
 
Re-intubation 
within 48 hours of 
extubation 
(secondary 
outcome) 
Binary variable for re-
insertion of endotracheal 
tube within 48 hours of 
initial extubation.   
Patients who remain on 
IMV for their index 
intubation or die within 48 
hours of index extubation 
are excluded.  
 
Multivariable logistic 
regression for the event 
re-intubation = yes. 
Adjusting for blocking 
variables and 
confounders. 
Binary yes/no variable. Adjusted 
odds ratio for re-intubation with 
95% C.I. for REDvent vs. Usual care 
will be presented.  
  

28-day ventilator 
free days 
(secondary 
outcome) 
Number of days between 
index intubation and 28-
days post-index intubation 
in which patient is alive 
and not on IMV.  
No exclusions. 
  
Competing risks 
regression adjusting for 
blocking variables and 
confounders. Censoring 
indicators: 
0=those who do not die 
but are not extubated 
within 28 days 
1=those that have 
successful liberation 
within 28-days 
2=those that die within 
28-days  
If patient is re-intubated within 24 
hours of extubation the time in 
between intubations is not counted 
towards VFDs.  If a patient in 
extubated for >24 hours and then 
subsequently re-intubated they get 
credit for those days without IMV. 
 
Values are 0 to 28 days. 
 
Adjusted hazard ratio and 95% C.I. 
will be presented. 
PiMax on day of 1st 
SBT (secondary 
outcome) 
PiMax value on the day the 
1st SBT was performed. 
Patient with values >100 
will be truncated to 100. 
Exclude patients who never 
attempted an SBT in the 28-
days study period. 
 
Multiple linear regression 
adjusting for blocking 
variables and 
confounders.  
Adjusted mean difference with 95% 
C.I. will be presented for REDvent 
vs. Usual care. 
 
PiMax on day of 
extubation 
(secondary 
outcome) 
PiMax value on the day of 
extubation. Restricted to 
those who met primary 
outcome (SBT passage or 
successful extubation).   
Exclude patients who died 
within 24 hours of 
extubation or remained 
intubated at 90 days. 
Multiple linear regression 
adjusting for blocking 
variables and 
confounders. 
Adjusted mean difference with 95% 
C.I. will be presented for REDvent 
vs. Usual care. 
ICU mortality 
(secondary 
outcome) 
Yes/no binary variable for did 
patient die in the ICU. 
No exclusions 
Multivariable logistic 
regression controlling for 
blocking variables and 
confounders. 
Adjusted odds ratios for death in 
REDvent vs. Usual care with 95% 
C.I. will be presented. 
90-day mortality 
(secondary 
outcome) 
Yes/no binary variable for did 
patient die in the hospital 
and within 90 days. 
No exclusions 
Multivariable logistic 
regression controlling for 
blocking variables and 
confounders.  
Adjusted odds ratios for death in 
REDvent vs. Usual care with 95% 
C.I. will be presented. 

Time to 1st SBT 
(secondary 
outcome) 
Number of days from start of 
index intubation to either 
first SBT or successful 
extubation, whichever came 
first. 
 
Successful extubation 
defined as no death or re-
intubation within 24 hours of 
extubation. 
Exclude patients who never 
had an SBT or never 
successfully extubated in 
study observation period. 
Log transformed multiple 
linear regression 
controlling for blocking 
variables and 
confounders. 
Time will be expressed in days.  
 
Adjusted mean difference and 95% 
C.I. for REDvent vs. usual care will 
be back transformed with 
exp(estimate) and interpreted as a 
relative change.  
 
Time to 1st SBT 
passage 
(secondary 
outcome) 
Number of days from start of 
index intubation to either 
first SBT passage or 
successful extubation, 
whichever came first.  
 
Successful extubation 
defined as no death or re-
intubation within 24 hours of 
extubation. 
Exclude patients who never 
had an SBT or never 
successfully extubated in 
study observation period. 
Log transformed multiple 
linear regression 
controlling for blocking 
variables and 
confounders. 
Time will be expressed in days.  
 
Adjusted mean difference and 95% 
C.I. for REDvent vs. usual care will 
be back transformed with 
exp(estimate) and interpreted as a 
relative change.  
 
Decline in PCPC 
from baseline to 
ICU discharge 
Change in PCPC defined as 
baseline minus ICU discharge 
value. This change was 
dichotomized into a change 
of ≥0 (no change or 
increased) vs. change of <0 
(decline in PCPC).  
Patients who did not survive 
to ICU discharge were 
excluded.  
Multiple logistic 
regression controlling for 
blocking variables and 
confounders.  
Adjusted odds ratio for the 
outcome decline in PCPC from 
baseline to ICU discharge with 95% 
C.I. for REDvent vs. usual care will 
be presented.  
Decline in POPC 
from baseline to 
ICU discharge 
Change in POPC defined as 
baseline minus ICU discharge 
value. This change was 
dichotomized into a change 
of ≥0 (no change or 
increased) vs. change of <0 
(decline in POPC).  
Patients who did not survive 
to ICU discharge were 
excluded.  
Multiple logistic 
regression controlling for 
blocking variables and 
confounders.  
Adjusted odds ratio for the 
outcome decline in POPC from 
baseline to ICU discharge with 95% 
C.I. for REDvent vs. usual care will 
be presented.  

Improvement in 
FSS from baseline 
to ICU discharge 
Change in FSS defined as 
baseline minus ICU discharge 
value. This change was 
grouped into ordinal 
categories: no 
change/improvement 
(change of ≥0), 1-2 point 
decline, and >2 point decline. 
Patients who did not survive 
to ICU discharge were 
excluded. 
Proportional odds logistic 
regression controlling for 
blocking variables and 
confounders. Ordered on 
the probability towards 
improvement. 
Adjusted odds for the improvement 
(change going towards positive) 
with 95% C.I. for REDvent vs. usual 
care. 
Decline in PCPC 
from baseline to 
hospital discharge 
Change in PCPC defined as 
baseline minus hospital 
discharge value. This change 
was dichotomized into a 
change of ≥0 (no change or 
increased) vs. change of <0 
(decline in PCPC).  
Patients who did not survive 
to hospital discharge 
(censored at 90 days) 
discharge were excluded.  
Multiple logistic 
regression controlling for 
blocking variables and 
confounders.  
Adjusted odds ratio for the 
outcome decline in PCPC from 
baseline to hospital discharge with 
95% C.I. for REDvent vs. usual care 
will be presented.  
Decline in POPC 
from baseline to 
hospital discharge 
Change in POPC defined as 
baseline minus hospital 
discharge value. This change 
was dichotomized into a 
change of ≥0 (no change or 
increased) vs. change of <0 
(decline in POPC).  
Patients who did not survive 
to hospital discharge 
(censored at 90 days) 
discharge were excluded.  
Multiple logistic 
regression controlling for 
blocking variables and 
confounders.  
Adjusted odds ratio for the 
outcome decline in POPC from 
baseline to hospital discharge with 
95% C.I. for REDvent vs. usual care 
will be presented.  
Improvement in 
FSS from baseline 
to hospital 
discharge 
Change in FSS defined as 
baseline minus hospital 
discharge value. This change 
was grouped into ordinal 
categories: no 
change/improvement 
(change of ≥0), 1-2 point 
decline, and >2 point decline. 
Patients who did not survive 
to hospital discharge 
(censored at 90 days) 
discharge were excluded. 
Proportional odds logistic 
regression controlling for 
blocking variables and 
confounders. Ordered on 
the probability towards 
improvement. 
Adjusted odds for the improvement 
in FSS (change going towards 
positive) with 95% C.I. for REDvent 
vs. usual care. 
 
 
 
 

REDvent Statistical Analysis Plan Final with Summary of Changes (July 2024) 
Inclusion Criteria  
1. Children > 1 month (at least 44 weeks corrected gestational age) and ≤ 21 years of age AND 
2. Supported on MV for pulmonary parenchymal disease (radiographic evidence of alveolar or 
interstitial opacifications with a  clinical risk factor for lung disease e.g. pneumonia, acute 
respiratory distress syndrome, aspiration, etc.) with Oxygen Saturation Index (OSI= (FiO2 * Mean 
Airway Pressure*100)/SpO2) ≥ 5 or Oxygenation Index (OI= FiO2 * Mean Airway 
Pressure*100)/PaO2)) ≥4 1 AND 
3. Within 72 hours of initiation of invasive MV   
Exclusion Criteria  
1. Contraindications to an esophageal catheter (i.e. severe mucosal bleeding, nasal encephalocele, 
trans-sphenoidal surgery) OR 
2. Contraindications to use of Respiratory Inductance Plethysmography (RIP) bands (i.e. 
omphalocele, chest immobilizer or cast) OR 
3. Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall defects, 
pregnancy) OR 
4. Conditions precluding conventional methods of weaning (i.e., status asthmaticus, severe lower 
airway obstruction, critical airway, intracranial hypertension, Extra Corporeal Life Support (ECLS), 
limitation of care, severe chronic respiratory failure, spinal cord injury above lumbar region, 
cyanotic heart disease (unrepaired or palliated) OR 
5. Primary Attending physician refusal  
 
Randomization Strategy and Blinding 
For the acute phase, subjects will be block randomized to either arm in a 1:1 allocation ratio, 
stratified by age group: infant (30 days -365 days), child (366 days to ≤8 years), and older child/ adolescent 
(9-18 years); and immune suppression (congenital or acquired conditions that result in marked inability to 
respond to antigenic stimuli).    Block randomization will use random block sizes of 4, 6 and 8 within the 
strata above. Weaning phase randomization is block randomized by acute phase group and age, using the 
same methodology. Although blinding is not possible given the open label nature of the intervention, 
analysis will be blinded to treatment groups.  Randomization schema was loaded into the central REDCAP 
database by the unblinded statistician.  Patients were consented for the study by one of the study 
investigators, and randomization in the central REDCAP database was conducted by one of the research 
respiratory therapists or study investigators. Prior to randomization, blocking strata variables were double 
checked with a second member of the study team or the primary attending physician.     
 
Statistical Analysis Plan  
Additional details are also available in the published study protocol.2  Baseline characteristics at the time 
of randomization will be computed for each treatment group (REDvent and usual care) and within each 
phase (Acute and Weaning). For all analyses, assumptions for data distribution will be assessed, and 
normalizing transformations of the data or nonparametric analysis will be performed as necessary. The 
mean and standard deviation will be reported for normally distributed continuous variables, and the 
median and interquartile ranges will be reported for non-normally distributed continuous variables. 
Given this is an RCT, we anticipate balanced baseline characteristics. To evaluate this, we will calculate 
effect sizes for measures of central tendency (Cohen d, Cramer v) across groups. For non-parametric 

variables, effect sizes defined for the Mann-Whitney U will be calculated to produce r. For frequency 
counts and percentages the rate ratio will be evaluated to calculate the effect size. Variables that have 
more than a small effect size (d > 0.2, v > 0.01, or r > 0.1, categorical effect size>1.2) indicate potential 
imbalances in baseline characteristics between groups. These variables will be included in sensitivity 
analyses after the primary ITT analyses are performed or included as covariates using multivariable 
models.  
Retention, adherence, and missing data will be compared across groups. High levels of missing data are 
not anticipated given the nature of the study. If the missing data are determined to be related to the 
outcome (not missing at random) or related to group or a covariate (missing at random), we will explore 
the impact of these biases in sensitivity analyses after the primary ITT analyses using multiple imputation 
processes. Our primary approach to imputing missing data is the Markov Chain Monte Carlo (MCMC) 
simulation. Statistical Analysis Software (SAS) procedures will be used.  
The primary analysis seeks to address if there are differences in length of weaning between: 1) REDvent-
acute compared to usual care acute, 2) REDvent-weaning compared to usual care-weaning, and 3) 
REDvent-acute and weaning (combined) compared to usual care acute and weaning (combined). 
Analyses of these aims will follow the ITT principle. The primary analyses will compare median weaning 
duration between groups using a Mann-Whitney U test, or a t-test with transformation as necessary. The 
effect size (r) will also be computed to assess the magnitude of treatment effect. If imbalances in 
baseline characteristics are found between or across randomized treatment groups, a Cox proportional 
hazard model will be performed to adjust for covariates. The estimates (mean, median, or hazard ratio) 
and the associated 95% confidence interval, as well as the p-values, will be presented for interpretation.  
Power analysis: For the primary outcome (weaning duration), a 1-day change in length of weaning is 
considered clinically significant. It is anticipated that up to 20% of patients may not achieve the primary 
outcome (successful passage of an SBT or extubation due to death or dropout); these patients will not be 
included in the primary outcome analysis but will be included in secondary outcomes. We are targeting 
an overall sample size of 300 patients, with a minimum of 240 patients (120 per arm) available for 
analysis of the primary outcome. Using the planned statistical tests above, this sample size would be 
able to detect a ≥ 1-day change in weaning duration with a two-sided alpha of 0.05 and power of 0.9, or 
a relative hazard ratio of 1.5 (ratio between control/intervention group) with a power of 0.9 or a hazard 
ratio of 1.4 with a power of 0.8. Patients who fail the initial SBT will undergo the weaning phase 
randomization. From our pilot data, approximately 25% of patients exposed to the intervention passed 
the initial SBT. Anticipating 180 patients (90 per arm) will receive weaning phase interventions, there will 
be adequate power to detect a ≥ 1 day change in the length of the weaning phase, or a hazard ratio of 
1.5 with an alpha of 0.05 and power of 0.8 in the weaning phase. 
The analytic approach for secondary aims and outcomes such as mortality and ventilator free days will 
follow those described above. For categorical data, a χ2 or Fisher's exact test will be used to compare 
difference between groups. Logistic regression will be used to assess binary outcomes, and a 
multinomial/ordinal logistic regression will be used for categorical outcomes (> 2 categories) while 
adjusting for covariates. To assess the association between 2 continuous variables, a Pearson or 
Spearman correlation will be used, and analysis of covariance (ANCOVA) will be used to adjust for 
covariates. Generalized Estimating Equations (GEE) or mixed effect models will be used when necessary 
to analyze repeated measures. Because of the physiologic nature of the study with a Phase II design, 

multiple comparisons adjustment is not planned for secondary outcomes.  Analyses will be performed 
using the appropriate recent version of the SAS statistical software (SAS Institute Inc., Cary, NC).  
In order to increase precision around the effect estimates for the primary and secondary aims and to 
reflect the stratified sampling, all analyses are adjusted for block randomization variables.3 For acute 
phase these are age group (infant, child, and adolescent) and whether or not the subject was 
immunocompromised. For the weaning phase this is acute phase randomization grouping and age 
group. In addition, variables thought to be potential confounders on the relationship between 
intervention and outcome with large differences between groups (standardized effect sizes as detailed 
above) will also be included in all adjusted analyses.  Unadjusted analyses will be presented to 
summarize data; all primary and secondary outcomes will present adjusted analyses controlling for age 
category, immunosuppression and imbalanced baseline variables. Potential confounders will be assessed 
for multicollinearity and if present, the confounder with the highest biological plausibility to impact the 
effect of the intervention on the outcome will be selected for inclusion as a model covariate. 
Model assumptions and fit for multiple linear regression (with or without log transformation) will be 
assessed visually for normality of residuals as well as variance inflation factor and difference in betas 
(DFBETAS) for influential points. Model fit for binary multiple logistic regression will be assessed with 
Pearson Chi-square and deviance. Firth’s penalized likelihood method will be used in subgroup analyses 
when event rates are small to reduce bias in the parameter estimates.4 When using negative binomial 
regression, model fit will be assessed for over and underdispersion with the scaled Pearson Chi-
square/deviance and influential points assessed as previously described. The proportional hazards 
assumption will be assessed when using Cox proportional hazards modeling using graphical approaches 
(“log-log” figures and Kaplan-Meier curves) for each covariate. Repeated measures analysis for ventilator 
settings, lung mechanics, and respiratory measures will be assessed with linear mixed models and 
generalized linear mixed models that include a variable for time from randomization to control for 
correlation of values within each patient using the first-order autoregressive structure. The robust 
sandwich estimators for standard errors will be used to reduce heteroscedasticity when appropriate.   
A detailed outline of each outcome’s analysis approach to control for blocking variables and confounders 
is given in the Table 1. Pre-specified comparisons of interest are REDvent acute vs. usual care acute, 
REDvent weaning vs. usual care weaning, and four group combination: 1) REDVent acute + REDvent 
weaning 2) REDvent acute + usual care weaning 3) Usual care acute + usual care weaning 4) usual care 
acute + REDvent weaning.  The four group combinations comparisons are exploratory and will only be 
considered if there are noted differences between both acute and weaning phase interventions. 
October 2019- new milestone accrual plan 
After the first 75 patients were enrolled in the study a new milestone accrual plan was created to 
account for the increase in the percentage of patients meeting the primary outcome. Previously, it was 
assumed 20% of patients would not meet the outcome, however, data after 75 patients revealed this 
was 13% and the total sample size requirement was adjusted down from 300 to 276 patients.  The 
number of patients targeted per group to meet the primary outcome was unchanged, at 120 per group. 
This updated milestone accrual plan was reviewed and accepted by the NLHBI and DSMB. 
January 2023 - Change in primary analysis for length of weaning 

Blinded, non-inferential summary statistics and distributions were assessed for the length of weaning 
outcome by the primary statistician as part of the data cleaning process. It was revealed that length of 
weaning might not be optimally analyzed as a continuous variable because SBTs were conducted once a 
day, with most patients passing their SBT within the first three days. In addition, enrollment had been 
affected by the COVID-19 pandemic and a new milestone accrual plan was requested by the NHLBI.  As 
the observed distribution appeared more count-like, the primary analysis model was changed to Poisson 
or Negative binomial regression to better fit the data and satisfy assumptions. This decision was made by 
the senior biostatistician who was blinded to the randomization groups.  
The sample size was re-estimated based on a minimum detectable difference for a reduction in the 
number of weaning days in the REDvent-acute vs. usual care-acute group using negative binomial 
regression. This yielded a minimal sample size of 230 patients to detect a reduction of 0.36 to 0.75 days 
when usual care had an average number of weaning days between 1 and 4, respectively with a power of 
80%. This estimate of 230 patients accounted for the 13% loss in those meeting the primary outcome. 
This updated sample size estimate was reviewed and accepted by the NHLBI and DSMB. Based on this, 
the milestone accrual plan was revised, and enrollment was planned to continue through March 2024 
with a target sample size between 230-276.   
May 2024 – Change in primary analysis for length of weaning and PiMax 
Data collection and cleaning were completed at the end of May 2024. During the analysis phase, the 
unblinded statistician checked assumptions and diagnostics for the primary analysis using negative 
binomial for outcome length of weaning. During this process two influential outliers were discovered in 
the usual care group who had attempted a SBT but never had a successful SBT; these two patients 
remained on IMV at 90 days. These patients were eligible for the primary outcome analysis, so were not 
removed from analysis, however, they were very influential and biased the estimate for the difference in 
length of weaning days.  
Three sensitivity analyses were proposed to address these outliers: 1) truncate length of weaning to 28 
days (instead of 90) using log transformed multiple linear regression, 2) categorize length of weaning into 
clinically relevant groups and conduct a proportional odds logistic regression model, and 3) revert back 
to the Cox proportional hazards model and censor patients at 28 days. Each of these sensitivity analyses 
adjusted for the same blocking variables and confounders used in the pre-specified negative binomial 
regression model. The truncation approaches failed because the assumptions of both log transformed 
linear regression and time to event analysis were not met. Residuals were highly skewed in linear 
regression even after truncation and log-transformation. The PH assumption was violated when 
adjusting for blocking variables when running the Cox proportional hazards model. The proportional 
odds logistic regression model categorized length of weaning as follows <0.5 day, 0.5 to <1.5, 1.5 to <2.5, 
2.5 to <4.5, 4.5 to <7.5, and ≥7.5 days. Patients who had a long length of weaning were therefore in the 
highest category of ≥7.5 days. The proportional odds model uses a rank-based non-parametric approach 
to model the probability of a lower ordered value, or in our case, a lower length of weaning which can be 
thought of a latent continuous variable bucketed into meaningful cutoffs. This model also allowed 
interpretation of the intervention effect on length of weaning in a stepwise manner, which is more 
representative of what happens clinically with daily SBTs and does not require that the difference 
between categories be equal. The proportional odds assumption for each independent variable was 
assessed graphically using their empirical cumulative logits and overall with the score Chi-square test.5-7 

Because the pre-specified plan was to use a negative binomial model, those findings have been 
presented in the main results, but because the model does not appropriately fit the data due to the 
highly influential outliers, the conclusions and abstract results reflect the more appropriate proportional 
odds model. This model was agreed upon by the study statistical team and DSMB statisticians in June 
2024 at the final DSMB meeting. 
PiMax was planned to be modeled with linear regression, with truncation of values >100.  In the analysis, 
no transformation could satisfy the assumptions of linear regression, with poor model diagnostics and 
non-normality of residuals.  PiMax was therefore modeled with the proportional odds model given the 
non-parametric nature of the data.  No specific categories were created for PiMax, but instead it was 
treated as a rank-based variable with comparisons of ranks between groups, adjusting for blocking 
variables and confounders (oxygenation index). The model allowed us to compare the odds of a higher 
PiMax ranking for the REDvent vs. usual care groups. Table 1 has been revised and now presents the 
description of all outcome variables, initial planned analyses, and modifications to initial proposed 
analyses and the timing of those changes.  In addition, since all outcomes are presented as adjusted 
analyses, Table 2 details the four main modeling approaches used in these analyses, and interpretation 
of the model intervention parameter estimates.  
 
 
References 
 
1. 
Khemani RG, Smith LS, Zimmerman JJ, et al. Pediatric Acute Respiratory Distress Syndrome: 
Definition, Incidence, and Epidemiology: Proceedings From the Pediatric Acute Lung Injury Consensus 
Conference. Pediatric Critical Care Medicine. Jun 01 2015;16(5_suppl):S23-S40. 
doi:10.1097/PCC.0000000000000432 
2. 
Khemani RG, Hotz JC, Klein MJ, et al. A Phase II randomized controlled trial for lung and 
diaphragm protective ventilation (Real-time Effort Driven VENTilator management). Contemp Clin Trials. 
Jan 2020;88:105893. doi:10.1016/j.cct.2019.105893 
3. 
Holmberg MJ, Andersen LW. Adjustment for Baseline Characteristics in Randomized Clinical 
Trials. JAMA. Dec 06 2022;328(21):2155-2156. doi:10.1001/jama.2022.21506 
4. 
Firth D. Bias Reduction of Maximum Likelihood Estimates. Biometrika 1993. p. 27-38. 
5. 
Koch G, Amara I, Singer J. A Two-Stage Procedure for the Analysis of Ordinal Categorical Data. 
Biostatistics: Statistics in Biomedical, Public Health, and Environmental Science. 1985. 
6. 
Harrell F. Resources for Ordinal Regression Models. Statistical Thinking 2023. 
7. 
Harrell F. Equivalence of Wilcoxon Statistic and Proportional Odds Model. Statistical Thinking 
2022. 

Table 1: Detailed analytic plan for each outcome variable, including any changes which were made to the analytic approach and when those 
changes were made.   
Variable 
Description 
Imputation & Exclusion 
Initial Analytic Approach 
Misc. Notes 
 
Changes to Analytic Plan  
Length of Weaning 
(primary outcome) 
Time from first attempted 
SBT until successful SBT 
passage or extubation, 
whichever comes first. 
Successful extubation is 
removal without re-
intubation or death for at 
least 24 hours.  
 
Patients no longer 
undergo SBTs after the 28 
day intervention but they 
will be clinically assessed 
for extubation and will be 
followed up to 90 days. If 
a patient remains 
intubated at 90 days their 
length of weaning 
becomes 90 days. 
 
Patients who never 
attempt an SBT are 
excluded. Patients who 
attempt an SBT but never 
pass an SBT and die within 
24 hours of extubation are 
excluded. 
Cox proportional hazards 
model controlling for 
blocking variables and 
confounders. Proportional 
hazards assumption will be 
assessed. 
 
 
 
 
 
 
 
 
Expect 20% exclusion rate 
for this outcome. Patients 
who pass the SBT will have 
a length of weaning of 
around 2 hours (SBT 
duration).  
 
Length of weaning will be 
expressed in days and will 
take on values of 0.0833 (2 
hours) to 90 days. 
 
The adjusted hazard ratio 
and 95% C.I. will be 
presented for REDvent vs. 
usual care. 
October 2019- Expected 
exclusion rate adjusted to 
13% 
 
January 2023- Revised 
analytic plan to reflect data 
distribution as count 
variable with SBTs daily.  
Over-dispersed for Poisson 
so plan to use negative 
binomial model.   
 
May 2024- During analysis, 
2 patients with very long 
length of weaning found to 
have large effect on 
adjusted Incidence Rate 
Ratio for negative binomial 
model.  Revised to a non-
parametric Proportional 
Odds Logistic Regression.  
IMV duration in 
survivors (Secondary 
Outcome) 
Time from start of index 
intubation to successful 
liberation. Successful 
liberation is defined as no 
death or re-intubation 
within 24 hours of 
extubation. 
Patients who are 
intubated past 90 days of 
index intubation are 
imputed as 90 days. 
 
Patients who die within 24 
hours of extubation are 
excluded. 
Log transformed multiple 
linear regression controlling 
for blocking variables and 
confounders.  
IMV duration will be 
expressed in days.  
Adjusted mean difference 
and 95% C.I.  for REDvent 
vs. usual care will be back 
transformed with 
exp(estimate) and 
interpreted as a relative 
change.  
None 

Received NIV after 
extubation (secondary 
outcome) 
Yes/no binary variable for 
receiving oro-mask CPAP 
or Bi-level ventilation after 
successful extubation.  
 
Successful extubation is 
defined as no death or re-
intubation within 24 hours 
of extubation. 
Patients who die within 24 
hours of IMV or remain on 
IMV at 90 days are not 
included. 
Multivariable logistic 
regression controlling for 
blocking variables and 
confounders. 
Adjusted odds ratio for 
receiving NIV post-
extubation with 95% C.I. 
for REDvent vs. Usual care 
will be presented.  
January 2024 added as 
necessary component to 
interpret length of NIV after 
extubation more 
appropriately. 
NIV duration after 
extubation (secondary 
outcome) 
Duration of non-invasive 
ventilation after 
extubation is defined as 
the number of days and 
hours that the patient is 
on oro-mask CPAP or Bi-
level ventilation after 
successful extubation.  
 
Successful extubation is 
defined as no death or re-
intubation within 24 hours 
of extubation. 
Patients who die within 24 
hours of IMV or who 
never receive NIV post-
extubation are excluded.  
 
Patients who remain on 
NIV at 90 days will have 
90 days imputed. 
 
Patients who die while on 
NIV will have their death 
date as end of NIV 
duration 
Log transformed multiple 
linear regression controlling 
for blocking variables and 
confounders. 
NIV duration will be 
expressed in days.  
 
Adjusted mean difference 
and 95% C.I.  for REDvent 
vs. usual care will be back 
transformed with 
exp(estimate) and 
interpreted as a relative 
change. 
None 

Received Non-invasive 
respiratory support 
(NRS) post-extubation 
(secondary outcome) 
Yes/no binary variable for 
receiving NRS after 
successful extubation. NRS 
includes: High Flow Nasal 
Cannula (HFNC) or nasal-
only modes of non-
invasive ventilation (CPAP 
or Nasal IMV or BiPAP 
 
Successful extubation is 
defined as no death or re-
intubation within 24 hours 
of extubation. 
Patients who die within 24 
hours of IMV or remain on 
IMV at 90 days are not 
included. 
Multivariable logistic 
regression controlling for 
blocking variables and 
confounders. 
Adjusted odds ratio for 
receiving NRS post-
extubation with 95% C.I. 
for REDvent vs. Usual care 
will be presented.  
January 2024 added as 
necessary component to 
interpret length of NRS after 
extubation more 
appropriately. 
NRS duration after 
extubation (secondary 
outcome) 
Duration of NRS after 
extubation is defined as 
the number of days and 
hours that the patient is 
on NRS after successful 
liberation.  End of NRS is 
defined as absent 
continuously for at least 
24 hours.   
 
Successful extubation is 
defined as no death or re-
intubation within 24 hours 
of extubation. 
Patients who die within 24 
hours of IMV or who 
never receive NRS post-
extubation are excluded.  
 
Patients who remain on 
NRS at 90 days will have 
90 days imputed. 
 
Patients who die while on 
NRS will have their death 
date as end of NIV 
duration. 
Log transformed multiple 
linear regression controlling 
for blocking variables and 
confounders. 
NRS duration will be 
expressed in days.  
 
Adjusted mean difference 
and 95% C.I. for REDvent 
vs. usual care will be back 
transformed with 
exp(estimate) and 
interpreted as a relative 
change.  
 
None 
Re-intubation within 
48 hours of extubation 
(secondary outcome) 
Binary variable for re-
insertion of endotracheal 
tube within 48 hours of 
initial extubation.   
Patients who remain on 
IMV for their index 
intubation or die within 
48 hours of index 
extubation are excluded.  
 
Multivariable logistic 
regression for the event re-
intubation = yes. Adjusting 
for blocking variables and 
confounders. 
Binary yes/no variable. 
Adjusted odds ratio for re-
intubation with 95% C.I. 
for REDvent vs. Usual care 
will be presented.  
  
None 

28-day ventilator free 
days (secondary 
outcome) 
Number of days 
between index 
intubation and 28-days 
post-index intubation in 
which patient is alive 
and not on IMV.  
No exclusions. 
  
Competing risks regression 
adjusting for blocking 
variables and confounders. 
Censoring indicators: 
0=those who do not die but 
are not extubated within 28 
days 
1=those that have successful 
liberation within 28-days 
2=those that die within 28-
days  
If patient is re-intubated 
within 24 hours of 
extubation the time in 
between intubations is not 
counted towards VFDs.  If a 
patient in extubated for 
>24 hours and then 
subsequently re-intubated 
they get credit for those 
days without IMV. 
 
Values are 0 to 28 days. 
 
Adjusted hazard ratio and 
95% C.I. will be presented. 
January 2023- Updated 
competing risk regression to 
negative binomial model to 
align with analysis plan for 
primary outcome and 
because the variable is a 
count of the number of 
days. Negative binomial also 
treats death and those on 
IMV for 28 days as the same 
(zero VFDs). This aligns with 
the hypothesis that the 
influence of the treatment 
variable is on the days of 
ventilation, and we do not 
expect any treatment effect 
for death. 
PiMax on day of 1st SBT 
(secondary outcome) 
PiMax value on the day 
the 1st SBT was 
performed. 
Patient with values >100 
will be truncated to 100. 
Exclude patients who 
never attempted an SBT in 
the 28-days study period. 
 
Multiple linear regression 
adjusting for blocking 
variables and confounders.  
Adjusted mean difference 
with 95% C.I. will be 
presented for REDvent vs. 
Usual care. 
 
June 2024- unable to satisfy 
assumptions of linear 
regression with any 
transformation. Modeled as 
non-parametric 
proportional odds logistic 
regression. 

PiMax on day of 
extubation (secondary 
outcome) 
PiMax value on the day of 
extubation. Restricted to 
those who met primary 
outcome (SBT passage or 
successful extubation).   
 
Patient with values >100 
will be truncated to 100. 
Exclude patients who died 
within 24 hours of 
extubation or remained 
intubated at 90 days. 
Multiple linear regression 
adjusting for blocking 
variables and confounders. 
Adjusted mean difference 
with 95% C.I. will be 
presented for REDvent vs. 
Usual care. 
June 2024- unable to satisfy 
assumptions of linear 
regression with any 
transformation. Modeled as 
non-parametric 
proportional odds logistic 
regression. 
ICU mortality 
(secondary outcome) 
Yes/no binary variable for 
did patient die in the ICU. 
No exclusions 
Multivariable logistic 
regression controlling for 
blocking variables and 
confounders.  
Adjusted odds ratios for 
death in REDvent vs. Usual 
care with 95% C.I. will be 
presented 
None 
90-day mortality 
(secondary outcome) 
Yes/no binary variable for 
did patient die in the 
hospital and within 90 
days. 
No exclusions 
Multivariable logistic 
regression controlling for 
blocking variables and 
confounders.  
Adjusted odds ratios for 
death in REDvent vs. Usual 
care with 95% C.I. will be 
presented. 
None 
Time to 1st SBT 
(secondary outcome) 
Number of days from start 
of index intubation to 
either first SBT or 
successful extubation, 
whichever came first. 
 
Successful extubation 
defined as no death or re-
intubation within 24 hours 
of extubation. 
Patients who never 
received an SBT and were 
successfully extubated 
after 31 days (time from 
start of IMV to end of 
protocol) were truncated 
to 31 days.  
Log transformed multiple 
linear regression controlling 
for blocking variables and 
confounders. 
Time will be expressed in 
days.  
 
Adjusted mean difference 
and 95% C.I. for REDvent 
vs. usual care will be back 
transformed with 
exp(estimate) and 
interpreted as a relative 
change.  
None 
Time to 1st SBT passage 
(secondary outcome) 
Number of days from start 
of index intubation to 
either first SBT passage or 
successful extubation, 
whichever came first.  
 
Successful extubation 
defined as no death or re-
intubation within 24 hours 
of extubation. 
Patients who never 
passed an SBT and were 
successfully extubated 
after 31 days (time from 
start of IMV to end of 
protocol) were truncated 
to 31 days.  
 
Log transformed multiple 
linear regression controlling 
for blocking variables and 
confounders. 
Time will be expressed in 
days.  
 
Adjusted mean difference 
and 95% C.I. for REDvent 
vs. usual care will be back 
transformed with 
exp(estimate) and 
interpreted as a relative 
change.  
 
None 

Decline in PCPC from 
baseline to ICU 
discharge 
Change in PCPC defined as 
baseline minus ICU 
discharge value. This 
change was dichotomized 
into a change of ≥0 (no 
change or increased) vs. 
change of <0 (decline in 
PCPC).  
Patients who did not 
survive to ICU discharge 
were excluded.  
Multiple logistic regression 
controlling for blocking 
variables and confounders.  
Adjusted odds ratio for the 
outcome decline in PCPC 
from baseline to ICU 
discharge with 95% C.I. for 
REDvent vs. usual care will 
be presented.  
April 2024- Evaluated 
possibility of using 
continuous variable but was 
highly skewed with little 
variability so it was 
dichotomized. 
Decline in POPC from 
baseline to ICU 
discharge 
Change in POPC defined 
as baseline minus ICU 
discharge value. This 
change was dichotomized 
into a change of ≥0 (no 
change or increased) vs. 
change of <0 (decline in 
POPC).  
Patients who did not 
survive to ICU discharge 
were excluded.  
Multiple logistic regression 
controlling for blocking 
variables and confounders.  
Adjusted odds ratio for the 
outcome decline in POPC 
from baseline to ICU 
discharge with 95% C.I. for 
REDvent vs. usual care will 
be presented.  
April 2024- Evaluated 
possibility of using 
continuous variable but was 
highly skewed with little 
variability so it was 
dichotomized. 
Improvement in FSS 
from baseline to ICU 
discharge 
Change in FSS defined as 
baseline minus ICU 
discharge value. This 
change was grouped into 
ordinal categories: no 
change/improvement 
(change of ≥0), 1-2 point 
decline, and >2 point 
decline. 
Patients who did not 
survive to ICU discharge 
were excluded. 
Proportional odds logistic 
regression controlling for 
blocking variables and 
confounders. Ordered on the 
probability towards 
improvement. 
Adjusted odds for the 
improvement (change 
going towards positive) 
with 95% C.I. for REDvent 
vs. usual care. 
April 2024- Evaluated 
possibility of using 
continuous variable but was 
highly skewed with little 
variability so it was grouped 
into categories. 
Decline in PCPC from 
baseline to hospital 
discharge 
Change in PCPC defined as 
baseline minus hospital 
discharge value. This 
change was dichotomized 
into a change of ≥0 (no 
change or increased) vs. 
change of <0 (decline in 
PCPC).  
Patients who did not 
survive to hospital 
discharge (censored at 90 
days) discharge were 
excluded.  
Multiple logistic regression 
controlling for blocking 
variables and confounders.  
Adjusted odds ratio for the 
outcome decline in PCPC 
from baseline to hospital 
discharge with 95% C.I. for 
REDvent vs. usual care will 
be presented.  
April 2024- Evaluated 
possibility of using 
continuous variable but was 
highly skewed with little 
variability so it was 
dichotomized. 

Decline in POPC from 
baseline to hospital 
discharge 
Change in POPC defined 
as baseline minus hospital 
discharge value. This 
change was dichotomized 
into a change of ≥0 (no 
change or increased) vs. 
change of <0 (decline in 
POPC).  
Patients who did not 
survive to hospital 
discharge (censored at 90 
days) discharge were 
excluded.  
Multiple logistic regression 
controlling for blocking 
variables and confounders.  
Adjusted odds ratio for the 
outcome decline in POPC 
from baseline to hospital 
discharge with 95% C.I. for 
REDvent vs. usual care will 
be presented.  
April 2024- Evaluated 
possibility of using 
continuous variable but was 
highly skewed with little 
variability so it was 
dichotomized. 
Improvement in FSS 
from baseline to 
hospital discharge 
Change in FSS defined as 
baseline minus hospital 
discharge value. This 
change was grouped into 
ordinal categories: no 
change/improvement 
(change of ≥0), 1-2 point 
decline, and >2 point 
decline. 
Patients who did not 
survive to hospital 
discharge (censored at 90 
days) discharge were 
excluded. 
Proportional odds logistic 
regression controlling for 
blocking variables and 
confounders. Ordered on the 
probability towards 
improvement. 
Adjusted odds for the 
improvement in FSS 
(change going towards 
positive) with 95% C.I. for 
REDvent vs. usual care. 
April 2024- Evaluated 
possibility of using 
continuous variable but was 
highly skewed with little 
variability so it was grouped 
into categories. 
 
 
 
 
 

 
Table 2:  Outcome variables, modelling approaches, and interpretation of models 
Model Name 
Outcomes 
Methods 
Interpretation 
Negative Binomial Model 
Length of Weaning (initial 
plan- revised); Ventilator 
Free Days 
Count variables with adjustment for blocking 
variables and confounders.  Model assumptions and 
methods to evaluate model fit: Pearson Chi-
square/deviance for over and under-dispersion, 
DFBETAS and variance inflation factor. 
Raw estimate and 95% C.I. for REDvent vs. usual care 
exponentiated to obtain Incidence Rate Ratio with 95% 
CI.  Patients in the REDvent group had a decreased rate 
of length of weaning by x% compared to usual care 
after adjusting for blocking variables and confounders. 
Logistic regression  
First SBT success; re-
intubation, NIV/NRS use 
post extubation; ICU and 
90 day mortality; decline in 
PCPC or POPC; 
Binary outcomes with adjustment for blocking 
variables and confounders.  Firth’s penalized 
likelihood method was used in subgroup analyses 
when event rates were small to reduce bias in the 
parameter estimates. 
Odds Ratio with 95% CI.  Patients in the REDvent group 
had higher odds (if OR>1) of achieving the outcome 
than usual care after adjustment for blocking and 
confounding variables.  
Linear Regression 
Days to first SBT and SBT 
passage; length of IMV; 
length of NRS/NIV post 
extubation; ICU Length of 
Stay; Hospital Length of 
Stay 
Continuous outcomes with adjustment for blocking 
variables and confounders.  Residuals evaluated for 
normality, homoscedasticity. DFBETAS and variance 
inflation factors assessed for influence of 
observations. Log transformation of the outcome 
used when appropriate. 
Relative change (slope) of regression coefficient with 
95% confidence interval.  Patients in the REDvent group 
had a reduction in length of IMV by x compared to usual 
care. 
 
If log transformation used the estimate for the adjusted 
mean difference and 95% C.I. on the log scale were 
exponentiated. Outcome decreased by x% in the 
REDvent group compared to usual care. 
Proportional Odds 
Logistic Regression  
Length of weaning, PiMax 
variables, Functional 
Status Scale 
Proportional odds assumption checked for each 
covariate with empirical cumulative logit figures for 
parallel slopes, also overall using the score Chi-square 
test (null hypothesis is that there is no evidence of 
non-proportional odds).  
Odds were ordered appropriately depending on the 
outcome (length of weaning= odds lower length of 
weaning, PiMax= odds of higher PiMax, FSS= odds of 
higher change in PiMax). The odds of decreased length 
of weaning in the REDvent group vs. usual care, while 
controlling for blocking variables and confounders. 
 
 
 
 

Summary of Changes and timeline for REDvent SAP. 
 Full details are provided in the final SAP with the rationale for changes in the text, and a summary of the 
changes in the table. 
 
Date 
Summary of changes 
November 2017 
Initial protocol approved and enrollment began.  Basic SAP detailed in initial 
study protocol, with ongoing work with statistical team to develop each 
outcome and analytic approach in fully detailed SAP.  
Fall 2019 
Full detailed SAP developed with definitions for all outcome variables and 
detailed analytic plan for each outcome variable.  
October 2019 
Target Sample size reduced from 300 to 276 based on number of patients 
meeting primary outcome 
January 2023 
Analytic plan for primary outcome variable changed to align with count like 
distribution of data.  Power analysis reconsidered, minimum sample size revised 
to 230, with target between 230-276.   
January 2024 
Mock tables finalized with all specified outcomes.  Added use of NIV and NRS as 
count variables in addition to the duration variables to aid interpretation of 
duration.   
April/May 2024 
Primary outcome found to be highly influenced by few observations with count-
model approach (negative binomial). Revised to proportional odds approach.  
Consideration of modeling FSS/POPC/PCPC as continuous but data too sparse 
and stuck with ordinal/dichotomous. 
June 2024 
PiMax variables did not satisfy assumptions of linear regression with 
transformation- changed to proportional odds regression.  Clarification and 
articulation of methods used to assess for co-linearity, assessment of model 
assumptions, and interpretation of output of each of the models.