Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: The PROMIZING Study
Phase: NA
Conditions: Critically Ill, Acute Respiratory Failure
Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Cover Letter 
 
Official Title of the study: Proportional Assist Ventilation for Minimizing the Duration of 
Mechanical Ventilation: The PROMIZING Study 
NCT number: NCT02447692 
Document: Clinical Study Protocol 
Date of document: 01 December 2019 

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Clinical Study Protocol 
Proportional Assist Ventilation for  
Minimizing the Duration of Mechanical Ventilation: 
The PROMIZING Study 
Co-Principal  
Sponsor-Investigators:  
 
 
Dr. Karen Bosma and Dr. Laurent Brochard  
 
 
In Collaboration with: 
The Canadian Critical Care Trials Group (CCCTG) 
Réseau Européen de Recherche en Ventilation Artificielle (REVA) 
 
Study Type 
Randomized Controlled Trial 
 
Funding Entity:   
 
CIHR-industry-partnered operating grant (2014-2018) 
CIHR project grant (2019-2022) 
 
Version Date: 
December 1, 2019 
Version Number: 
5.0 
 
Confidentiality Statement:  This clinical study protocol contains scientific information that is privileged and confidential, 
and may not be reproduced or disclosed unless permission is granted by its investigators. Any verbal or electronic 
dissemination of this clinical study protocol, reproduction or dissemination of its contents therein, unless otherwise stated 
by its investigators, is strictly prohibited.  
 

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Signature Page for Sponsor 
Study Title: 
Proportional Assist Ventilation for Minimizing the Duration of Mechanical 
Ventilation:  The PROMIZING Study 
Version: 
5.0 
Version Date: 
December 1, 2019 
Approved by the following: 
Dr. Karen Bosma, MD, FRCPC 
Date 
Co-Principal Sponsor-Investigator 
(please print) 
Dr. Laurent Brochard, MD 
Date 
Co-Principal Sponsor-Investigator 
(please print) 
 
6HSWHPEHU
September 11, 2020

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Signature Page for Investigator 
Study Title: 
Proportional Assist Ventilation for Minimizing the Duration of Mechanical 
Ventilation:  The PROMIZING Study 
Version: 
5.0 
Version Date: 
December 1, 2019 
I have read and understand this protocol and concur with the study design. I agree to conduct this trial in accordance with 
all stipulations of the protocol and in accordance with Good Clinical Practice (GCP) and relevant local regulatory 
requirements that govern the conduct of clinical research. 
Investigator Name 
Signature 
 
 
 
Date 
(please print) 
  
 
 
 
 
(please print) 
 
 
 
September 11, 2020

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Table of Contents 
 
1.0 
Key Study Contacts ................................................................................................................................................................... 7 
2.0 
Synopsis ................................................................................................................................................................................... 8 
3.0 
Abbreviations ......................................................................................................................................................................... 10 
4.0 
Introduction ........................................................................................................................................................................... 11 
4.1 
Study Conduct ............................................................................................................................................................................ 11 
4.2 
Background ................................................................................................................................................................................ 11 
4.2.1 
Study Rationale ................................................................................................................................................................ 11 
4.3 
Description of Intervention ........................................................................................................................................................ 11 
4.4 
Clinical Data to Date .................................................................................................................................................................. 12 
4.4.1 
Clinical Data...................................................................................................................................................................... 12 
4.4.2 
Safety Data ....................................................................................................................................................................... 12 
4.4.3 
Pilot Data for this study design ........................................................................................................................................ 13 
5.0 
Study Objectives .................................................................................................................................................................... 13 
6.0 
Study Design .......................................................................................................................................................................... 13 
6.1 
General Design........................................................................................................................................................................... 13 
6.2 
Primary Study Endpoints ............................................................................................................................................................ 13 
6.3 
Secondary Study Endpoints ........................................................................................................................................................ 13 
6.4 
Primary Safety Endpoints ........................................................................................................................................................... 14 
7.0 
Participant Identification ........................................................................................................................................................ 14 
7.1 
General Characteristics of the Proposed Participant Population ............................................................................................... 14 
7.2 
Anticipated Number of Research Participants ........................................................................................................................... 15 
7.3 
Eligibility Criteria ........................................................................................................................................................................ 15 
8.0 
Study Procedures ................................................................................................................................................................... 21 
8.1 
Ventilation Strategy:  Proportional Assist Ventilation (PAV+) ................................................................................................... 21 
8.1.1 
General Approach: PAV+ .................................................................................................................................................. 21 
8.1.2 
Initiating PAV+ .................................................................................................................................................................. 21 
8.1.3 
Adjusting PAV+ ................................................................................................................................................................. 22 
8.1.4 
Resuming PAV+ after A/C ventilation .............................................................................................................................. 24 
8.2 
Ventilation Strategy:  Pressure Support Ventilation (PSV) ......................................................................................................... 25 
8.2.1 
General Approach: PSV .................................................................................................................................................... 25 
8.2.2 
Initiating PSV .................................................................................................................................................................... 25 
8.2.3 
Adjusting PSV ................................................................................................................................................................... 26 
8.2.4 
Resuming PSV after A/C ventilation ................................................................................................................................. 28 
8.3 
Procedures Common to Both Groups ......................................................................................................................................... 28 
8.3.1 
Weaning from Mechanical Ventilation ............................................................................................................................ 28 
8.3.2 
Ventilation on A/C mode.................................................................................................................................................. 30 

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8.3.3 
Routine Ventilatory Care and Monitoring ........................................................................................................................ 30 
8.3.4 
Ventilation during Patient Transfers ................................................................................................................................ 30 
8.3.5 
Post-extubation Ventilatory Care ..................................................................................................................................... 30 
8.3.5.1 
Noninvasive Ventilation Guideline ................................................................................................................................... 30 
8.3.5.2 
Re-intubation Guideline ................................................................................................................................................... 31 
8.3.6 
Tracheostomy .................................................................................................................................................................. 32 
8.4 
Co-interventions......................................................................................................................................................................... 32 
8.4.1 
Sedation Guidelines ......................................................................................................................................................... 32 
8.4.2 
Nutrition Guidelines ......................................................................................................................................................... 33 
8.4.3 
Early Mobilization Guidelines........................................................................................................................................... 33 
9.0 
Data Management ................................................................................................................................................................. 33 
9.1 
Data Collection .......................................................................................................................................................................... 33 
9.2 
Outcome Measures and Duration of Follow-up ......................................................................................................................... 34 
9.3 
Confidentiality ........................................................................................................................................................................... 34 
9.4 
Source Documents ..................................................................................................................................................................... 35 
9.5 
Case Report Forms ..................................................................................................................................................................... 35 
9.6 
Record Retention ....................................................................................................................................................................... 36 
10.0 
Study Schedule of Events ................................................................................................................................................... 36 
10.1 
Run-In Phase ......................................................................................................................................................................... 36 
10.2 
Screening and Eligibility Assessment .................................................................................................................................... 36 
10.3 
Randomization & Blinding .................................................................................................................................................... 37 
10.3.1 
Randomization ............................................................................................................................................................ 37 
10.3.2 
Blinding ........................................................................................................................................................................ 37 
10.4 
Baseline Assessment ............................................................................................................................................................. 37 
10.5 
Administration of Intervention .............................................................................................................................................. 37 
10.6 
Follow up assessments and Final Study Visit ........................................................................................................................ 38 
10.7 
Protocol Amendments and Deviations .................................................................................................................................. 38 
11.0 
Safety Assessments ........................................................................................................................................................... 39 
11.1 
General Comments ............................................................................................................................................................... 39 
11.2 
Assessment and Reporting of a Serious Adverse Event (SAE) ............................................................................................... 40 
11.3 
Definition and Reporting of an Adverse Device Effect .......................................................................................................... 41 
11.4 
Data Safety Monitoring Board (DSMB) ................................................................................................................................. 42 
12.0 
Statistical Plan ................................................................................................................................................................... 42 
12.1 
Sample Size Determination ................................................................................................................................................... 42 
12.2 
Statistical Methods Analysis ................................................................................................................................................. 43 
13.0 
Trial Management ............................................................................................................................................................. 45 

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13.1 
Study Oversight ..................................................................................................................................................................... 45 
13.2 
Study Monitoring .................................................................................................................................................................. 45 
13.3 
Auditing and Inspecting ........................................................................................................................................................ 46 
14.0 
Ethical Considerations ....................................................................................................................................................... 46 
14.1 
Declaration of Helsinki / ICH Guidelines for Good Clinical Practice ...................................................................................... 46 
14.2 
Research Ethics Board Approval ........................................................................................................................................... 46 
14.3 
Informed Consent .................................................................................................................................................................. 46 
15.0 
Study Finances ................................................................................................................................................................... 47 
15.1 
Funding Source ...................................................................................................................................................................... 47 
15.2 
Conflict of Interest ................................................................................................................................................................. 47 
16.0 
Publication Plan ................................................................................................................................................................. 47 
17.0 
References ......................................................................................................................................................................... 47 
Appendices ...................................................................................................................................................................................... 50 
Appendix A:  Enrolment Algorithm ...................................................................................................................................................... 50 
Appendix B:  Criteria to Change Mode of Ventilation ......................................................................................................................... 52 
Appendix C:  PAV+ Ventilation Strategy .............................................................................................................................................. 53 
Appendix D:  PSV Ventilation Strategy ................................................................................................................................................ 54 
Appendix E: Richmond Agitation Sedation Scale (RASS) ..................................................................................................................... 55 
Appendix F: Sedation Agitation Scale (SAS)......................................................................................................................................... 56 
 
 
 

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1.0 Key Study Contacts 
 
Sponsor and  
Co-Principal 
Investigators 
Dr. Karen Bosma, Dr. Laurent Brochard 
Coordinating Centre 
Lawson Health Research Institute, London, Ontario (contracts, trial 
insurance, financial disbursements) 
Applied Health Research Centre (AHRC), Li Ka Shing Knowledge 
Institute, Toronto (trial coordination, study monitoring and data 
management) 
Executive Steering 
Committee 
Dr. Karen Bosma,  
Dr. Laurent Brochard,  
Dr. Karen Burns,  
Dr. Claudio Martin,  
Dr. Jordi Mancebo,  
Dr. Yoanna Skrobik,  
AHRC Statistician (Kevin Thorpe),  
AHRC Project Manager (Stephanie DeMasi , 
Sarah Douglas, Shristi Bhatia,  
Nicole Cooke)  
Data Safety Monitoring 
Board Members 
Dr. Taylor Thompson (Chair) 
Dr. Maureen Meade 
Dr. Jean-Daniel Chiche 
 

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2.0 Synopsis 
 
Short Title  The PROMIZING Study 
Study Title Proportional Assist Ventilation for Minimizing the Duration of 
Mechanical Ventilation: The PROMIZING Study 
Trial Design Multi-centre, open-label RCT 
Study Participants 
Adult patients receiving MV for acute respiratory failure  who are 
ventilated in A/C mode, ready to be maintained with partial ventilatory 
support (PSV) but not yet ready for extubation (not yet ready for an SBT 
or failed an SBT) 
Investigational 
Product/Device 
Proportional Assist Ventilation with load-adjustable gain factors (PAV+), 
PB 840 or 980 ventilator, (Covidien LP, a Medtronic company) 
Investigational 
Intervention 
Study participants will be randomized to one of two arms.  The control 
is the standard of care PSV ventilation strategy, designed to adjust the 
level of support according to usual clinical parameters.  The 
intervention is a PAV+ ventilation strategy, designed to adjust the level 
of support (gain) to target a predefined range of respiratory muscle 
pressure. 
Planned Sample Size 558(279 each PAV+ and PSV) is the minimum planned sample size.   
Treatment/Follow up 
Duration 
The expected duration of patient participation is approximately 21-90 
days, including screening and follow-up procedures and depends on the 
length of time the patient remains on MV in the ICU. 
Patients will be followed with daily data collection until they remain 
free of invasive mechanical ventilation for 7 days.  Date of live ICU 
discharge or ICU death, live hospital discharge or hospital death will 
also be recorded for each randomized patient.  Vital status will be 
determined at 14, 21, 28 and 90 days post randomization. 
 
Planned Study Period 
Planned enrolment period is Sept 2016- Sept 2021.  The study will 
continue to enrol patients until we have complete data on participants 
containing required number of events for analysis.  Patient follow up is 
targeted to end December 2021.  
Primary Outcome Time from randomization to successful liberation from invasive 
mechanical ventilation 

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Secondary Outcomes 
(i) 
Ventilator-free days at day 14, 21,28 days post randomization,  
(ii) 
Time from randomization to live ICU discharge (up to day 90),  
(iii) Time from randomization to live hospital discharge (up to day 90),  
(iv) Mortality, measured as ICU mortality; hospital mortality; 14, 21, 
28, and 90 day mortality  
(v) 
Weaning Progress, measured as time from randomization to: first 
SBT; first successful SBT; first extubation.  
(vi) Weaning Difficulties, measured as the number of patients failing 
first SBT or first extubation attempt and requiring up to 7 days to 
extubate (difficult weaning group/ group 2); failing first SBT or first 
extubation attempt and requiring more than 7 days to extubate 
(prolonged weaning group/ group 3),  
(vii) Weaning Complications, measured as the number of patients: 
requiring non-invasive ventilation post-extubation; ventilated 
more than 7 days post randomization, ventilated more than 21 
days from time of intubation (prolonged MV group); receiving 
tracheostomy post randomization, requiring reintubation (up to 
7d after planned extubation)  
(viii) Tolerance of modes, measured as number of patients ever 
requiring A/C mode post randomization; number of patient-days 
requiring A/C mode post randomization,  
(ix) Cumulative dose of narcotics (converted to morphine 
equivalents); benzodiazepines (converted to midazolam 
equivalents); propofol, and dexmedetomidine  
(x) 
Number of patients and number of patient-days receiving any 
antipsychotic medication 
(xi) Sensitivity analyses of primary and secondary outcomes defining 
“successful extubation” as “48 hours without reintubation” 
(xii) Sensitivity analyses of primary and secondary outcomes assigning 
a value of 0 ventilator-free days to any participant who dies at any 
time during the study period  
A priori Subgroup 
Analyses  
(i) duration of MV prior to randomization greater than 5 days 
(ii) failed SBT vs. failed CPAP 0 trial vs. failed weaning criteria prior to 
randomization 
(iii) failed extubation prior to randomization 
(iv) mild, moderate, severe frailty 
 
 

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3.0 Abbreviations 
 
A/C 
Assist/Control 
AE 
Adverse Event 
AHRC 
Applied Health Research Centre 
CC 
Coordinating Centre 
CMV 
Controlled Mechanical Ventilation 
CPAP 
Continuous Positive Airway Pressure 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
EC 
Executive Committee 
eCRF 
Electronic Case Report Form 
ICU 
Intensive Care Unit 
MV 
Mechanical Ventilation 
PAV+ 
Proportional Assist Ventilation with load-adjustable gain factors 
PEEP 
Positive End-Expiratory Pressure 
PSV 
Pressure Support Ventilation 
RCT 
Randomized Controlled Trial 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SBT 
Spontaneous Breathing Trial 
SDM 
Substitute Decision Maker 
VFD 
Ventilator-Free Day 

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4.0 Introduction 
 
4.1 Study Conduct 
This study will be conducted in compliance with the protocol approved by Research Ethics Boards (REBs) and 
according to ICH Good Clinical Practice standards.   
 
The study has been registered on www.clinicaltrials.gov prior to participant enrolment (NCT02447692). 
 
4.2 Background 
 
4.2.1 
Study Rationale 
Patients with acute respiratory failure require invasive mechanical ventilation (MV) to support their work of 
breathing and provide adequate gas exchange until they recover from their acute illness.  Upon initiation of 
invasive MV, the goal is to wean and liberate patients from MV as soon as they can manage breathing 
unsupported.  However, MV itself may induce respiratory muscle weakness,[1-3] patient-ventilator 
dyssynchrony,[4;5] and necessitate the administration of sedative drugs, all of which have been associated with 
a prolonged duration of dependence on MV.  Prolonged dependence on MV contributes to increased patient 
complication rates, intensive care unit (ICU) length of stay, and is associated with increased mortality.[6;7]  
Therefore, a major goal in caring for patients with acute respiratory failure is to reduce the duration of weaning 
and increase the number of patients successfully liberated from MV[8].  Avoidance of respiratory muscle 
atrophy, patient-ventilator dyssynchrony, and heavy sedation are potential means of achieving this goal, 
although this has not been definitively proven.  Theoretically, respiratory muscle atrophy and patient-ventilator 
dyssynchrony should be minimized if the level of ventilator assistance is adjusted to target normal or reasonable 
levels of respiratory effort.[5;9;10]  
 
Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mode of mechanical ventilation 
which delivers assistance to breathe in proportion to the patient's effort. The proportional assistance, called the 
gain, can be adjusted by the clinician to maintain the patient's respiratory effort or workload within a reasonable 
range. This is the only mode of ventilation which allows for measurement and targeting of a specific range of 
respiratory muscle activity by the patient.  Pressure support ventilation (PSV) is a mode of ventilation which is 
considered the current standard of care for assisting breathing of patients during the recovery phase of acute 
respiratory failure. Several studies have shown short term advantages of PAV over PSV, including improved 
patient-ventilator synchronization, improved adaptability to changes in patient effort, and improved sleep 
quality.[5;11-14]  
 
The objective of this multi-centre randomized controlled trial is to determine if, for patients with acute 
respiratory failure, ventilation with PAV+ will result in a shorter duration of time spent on mechanical ventilation 
than ventilation with PSV. 
 
4.3 Description of Intervention 
 
The intervention is proportional assist ventilation with load-adjustable gain factors:  
PAV+™, Puritan Bennett™ 840 or 980 ventilator (Covidien LP, a Medtronic company, Boulder, USA). Sites will 
confirm prior to participation that the correct device and settings are available.  
   
This mode of ventilation (PAV+) and this device (Puritan Bennett™ 840 or 980 ventilator) are approved for use in 
all countries with participating centres: 
 

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Health Canada Information:  First Issue Date: 19Sep2005, Device name: 840 VENTILATOR SYSTEM - PAV 
UPGRADE KIT, Device Identifiers are 4-078204-00 and 4-078206-00 
 
Europe Information:  Issue Date:  19Jan2005, Release/Change per ECO-R151570, Device name: 840 
VENTILATOR SYSTEM, SOFTWARE OPTIONS AND 806 COMPRESSOR, 840 Ventilator CE Marked Software 
Options , Device Identifiers for PAV+ Option are 4-078195-00 (Spanish), 4-078196-00 (French), 4-
078198-00 (Italian)  and Device Identifiers for PAV+ Upgrade are 4-078205-00 (Spanish), 4-078206-00 
(French) and 4-078208-00 (Italian). 
 
 Argentina Information: First Issue Date: 06June2011, Device name: SISTEMA DE VENTILACION 840- 
KIT DE ACTUALIZACION PAV, Device Identifier is 4-078205-00. 
 
Proportional assist ventilation with load-adjustable gain factors (PAV+) is a unique ventilatory mode that delivers 
assistance in proportion to patient effort, thereby allowing for titration of the balance between respiratory muscle 
capacity and load, and ensuring that the respiratory muscles are utilized throughout the breath and not just for 
triggering the breath. In PAV+ mode, the ventilator measures the instantaneous flow and volume generated by 
the patient and calculates the instantaneous pressure needed to overcome the elastic and resistive pressures. 
This is achieved by performing automated and repeated measurements of respiratory system compliance and 
resistance. This automatic adjustment has been implemented recently, justifying the acronym PAV”+”.  Assistance 
(or gain) from the ventilator, which is adjusted by the clinician, is expressed as a percentage of the total pressure 
needed to inflate the respiratory system.  Because of its working principles, PAV+ is the only mode which enables 
estimation of the pressure generated by the respiratory muscles. This can be made at the bedside from the values 
of the gain and the driving inspiratory airway pressure.  
 
Patients will be randomized to either the PAV+ Ventilation Strategy, using a Puritan Bennett 840™ ventilator 
equipped with PAV+™, (intervention arm) or the PSV Ventilation Strategy, using any ventilator equipped with 
PSV (control arm).  
 
In the PAV+ strategy, the level of support (gain) will be adjusted to target a respiratory muscle pressure within 
normal range. In the PSV strategy, the level of support will be adjusted according to usual clinical parameters (See 
Appendix C and Appendix D respectively). In both arms, patients developing respiratory distress or clinical 
instability will be changed to A/C mode and reassessed within 24 hours for criteria to resume PAV+ or PSV 
according to treatment allocation. 
 
4.4 Clinical Data to Date 
 
4.4.1 
Clinical Data 
Several physiological studies have shown important potential advantages of PAV compared to PSV including 
improved synchronization adaptation to changes in ventilator demand and improved sleep quality during short 
term ventilation. A relatively large single centre RCT but limited to a 48 hour period showed that significantly more 
patients could be ventilated with PAV+ than with PSV (94.4% vs 71.0%, p<0.001) [15]  and a pilot single centre RCT 
by Bosma showed a two day reduction in ICU length of stay with PAV+ compared to PSV (median[IQR] 7.3[5.2-
11.4] days on PAV+ vs. 12.4[7.5-30.8] days on PSV, p=0.03.[16] 
4.4.2 
Safety Data 
In the study by Bosma, there were no adverse events (pneumothorax, arrhythmia or death) resulting from the 
study interventions (n=54 patients) [16].  As a safety mechanism, studies of PAV+ have utilized “intolerance 
criteria” for switching to another mode of ventilation, typically utilizing assist-control as the default mode for 

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patients who meet pre-specified criteria for respiratory distress despite optimization of PAV+ or PSV.  As such, 
there are no reported cases of patients experiencing an adverse event as a physiological consequence of excessive 
work of breathing or instability due to PAV+.   
 
The studies of PAV+ have demonstrated that PAV+ is generally well tolerated in patients meeting enrolment 
criteria for these studies.  In the study by Bosma, patients tolerated PAV+ an average of 18.1 ± 5.9 hours/day 
and tolerated PSV 18.8 ± 5.0 hours/day in the PSV group (p=0.64).  Over the duration of the study, total time 
spent on PAV+ ranged from 18 to 565 hours, or 10 to 100% of the study period (mean 75.3 ± 24.6%), and in the 
PSV group, time spent on PSV ranged from 19 to 743 hours, or 28 to 100% of the study period (mean 78.4 ± 
21.0%).[16]  A study by Xirouchaki et al., which examined tolerance of PAV+ and PSV for 48 hours in critically ill 
patients, found successful tolerance in 89% and 78% of patients on these respective modes.[15]   A pilot study 
by Carteaux et al. study found one of 53 patients to be intolerant to PAV+; median time spent on PAV+ was 3 
days [IQR 1-5] for the remaining 98% of patients who tolerated PAV+ for some duration of the study period.[17] 
4.4.3 
Pilot Data for this study design  
The design of this trial is based upon two pilot studies. The eligibility criteria, method of recruitment, staged 
enrolment process, randomization to two equivalent ventilation strategies, criteria to initiate and method of 
weaning were piloted by Bosma and coworkers in the single centre pilot RCT (n=54).  [16] The ventilation algorithm 
to adjust PAV+ gain to maintain respiratory muscle workload within the normal range was piloted by Brochard 
and colleagues in a multi-centre study (n=52). [17] Most of the centres participating in The PROMIZING Study were 
involved in one of these two studies. Both studies demonstrated safety, feasibility, and compliance with study 
protocol. 
 
5.0    Study Objectives 
 
The primary objective of this study is to determine if, for patients with acute respiratory failure, ventilation with 
PAV+, instituted early in the recovery phase and set to maintain a workload of breathing within the normal range, 
will result in a shorter duration of time spent on mechanical ventilation than ventilation with PSV. 
 
The secondary objective of the study is to determine if other clinically important outcome measures are better 
with PAV+ as compared to PSV.  
 
6.0 Study Design  
 
6.1   General Design 
This clinical study is a multi-centre open-label, RCT.  
 
6.2   Primary Study Endpoints 
The primary outcome is time from randomization to successful liberation from invasive mechanical ventilation. 
 
6.3   Secondary Study Endpoints 
The secondary outcome measures are: 
(i) 
Ventilator-free days at day 14, 21 and 28 post randomization,  
(ii) 
Time from randomization to live ICU discharge (up to day 90),  
(iii) Time from randomization to live hospital discharge (up to day 90),  
(iv) Mortality, measured as ICU mortality; hospital mortality; 14, 21, 28, and 90 day mortality  
(v) 
Weaning Progress, measured as time from randomization to: first SBT; first successful SBT; first extubation.  

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(vi) Weaning Difficulties, measured as the number of patients failing first SBT or first extubation attempt and 
requiring up to 7 days to extubate (difficult weaning group/group 2); failing first SBT or first extubation 
attempt and requiring more than 7 days to extubate (prolonged weaning group/group 3),  
(vii) Weaning Complications, measured as the number of patients: requiring non-invasive ventilation post-
extubation; ventilated more than 7 days post randomization, ventilated more than 21 days from time of 
intubation (prolonged MV group); receiving tracheostomy post-randomization, requiring re-intubation (up 
to 7d after planned extubation)  
(viii) Tolerance of modes, measured as number of patients ever requiring A/C mode post randomization; number 
of patient-days requiring A/C mode post randomization,  
(ix) Cumulative dose of narcotics (converted to morphine equivalents); benzodiazepines (converted to 
midazolam equivalents); propofol, and dexmedetomidine  
(x) 
Number of patients and number of patient-days receiving any antipsychotic medication 
(xi) Sensitivity analyses of primary and secondary outcomes defining “successful extubation” as “48 hours 
without reintubation” 
(xii) Sensitivity analyses of primary and secondary outcomes assigning a value of 0 ventilator-free days to any 
participant who dies at any time during the study period  
 
The subgroups for a priori subgroup analyses are: 
(i) Duration of mechanical ventilation prior to randomization greater than 5 days 
(ii) Failed SBT vs. failed CPAP 0 trial vs. failed weaning criteria prior to randomization 
(iii) Failed extubation prior to randomization 
(iv) Mild, moderate, severe frailty 
 
6.4   Primary Safety Endpoints 
Safety analyses will be based on all participants who were randomized to either intervention or control arm, and 
received either PAV+ or PSV according to study protocol.   
Safety will be assessed by evaluating and comparing: 
 
(i) 
Frequency and incidence of reported serious adverse events between intervention and control groups. 
(ii) Mortality difference between intervention and control groups   
 
7.0 Participant Identification 
 
7.1   General Characteristics of the Proposed Participant Population 
The participant population will be adult patients receiving invasive MV for acute respiratory failure for at least 24 
hours, who are ventilated in A/C mode and ready to be maintained with partial ventilatory support (PSV) but not 
yet ready for extubation (not yet ready for an SBT or failed an SBT).  In summary, we aim to enrol patients as they 
enter the recovery phase of their illness (see Figure 1 below, which summarizes the MV modes and the goals of 
MV at each phase of critical illness). 

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Figure 1 
 
7.2   Anticipated Number of Research Participants 
558 (279 each PAV+ and PSV) 
 
7.3  Eligibility Criteria 
A staged enrolment process will be used to identify patients eligible to be enrolled and randomized in the study.  
At each stage of the enrolment process, a patient must meet inclusion criteria and not meet exclusion criteria 
in order to pass. To progress to the next stage, patients must continue to pass criteria from the prior stages.  
After enrolment, there are also specific tests to perform (with pass/fail criteria) to determine eligibility to be 
randomized. The five stages (sets of criteria and tests) are: 
 
A. Screening Criteria  
B. Enrolment Criteria and Obtaining Consent 
C. Pressure Support Trial Criteria and the Pressure Support Trial 
D. Weaning Criteria and the CPAP Trial and the Spontaneous Breathing Trial (SBT) 
E. Randomization Criteria  
 
The first stage of enrolment is called (A) Screening.  Patients are screened while they are in the acute phase of 
their respiratory failure.   
To be considered eligible for Screening, a participant must satisfy each of the following inclusion criteria: 
 
A. Screening Inclusion Criteria: 
A1. 
Age ≥18 years 
A2. 
Intubated and receiving any mode of invasive MV ≥24 hours 
 
All patients admitted to a participating site ICU during the study period meeting the above screening inclusion 
criteria will be entered into a screening log and followed until they satisfy all inclusion criteria, are enrolled and 
randomized, or meet an exclusion criterion and exit the screening/enrolment process.   
Acute 
Phase
Stabilize Patient:
Rest respiratory 
muscles as needed
Full Ventilatory Support
-Assist/Control Mode
Recovery 
Phase
Initiate Rehabilitation:
Allow patient to share 
work of breathing
Partial Ventilatory 
Support
-PSV
-PAV
Weaning 
Phase
Initiate Weaning:
Assess readiness to 
wean, test readiness to 
wean, attempt SBT
Spontaneous Breathing 
Trials
-T-piece / trach mask
-Low PSV, low PEEP

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A participant will be ineligible for participation in this study and will be counted as a “screen failure” if he or 
she satisfies any one or more of the following exclusion criteria: 
 
A. Screening Exclusion Criteria: 
A3 
Anticipating withdrawal of life support  and/or shift to palliation as the goal of care 
A4  
Severe central neurologic disorder (eg. Hemorrhage, stroke, tumour) causing elevated 
intracranial pressure, or impaired control of breathing, or requiring specific ventilator 
adjustments (i.e. To attain specific CO2 target)  or requiring neurosurgical intervention 
A5 
Known or suspected severe or progressive neuromuscular disorder likely to result in 
prolonged or chronic ventilator dependence (eg. Guillain-Barré syndrome, Myasthenia 
Gravis, ALS, MS, high spinal cord injury, kyphoscoliosis, or other restrictive disorder) (Note 
that obesity hypoventilation syndrome that may be managed with nocturnal non-invasive 
ventilation is NOT an exclusion under A5) 
A6 
Severe COPD: Baseline daytime hypercapnea (pCO2> 50 mmHg) OR GOLD 4 airflow 
limitation (FEV1<30% predicted) OR MRC class 4 symptoms (“I am too breathless to leave 
the house” OR “I am breathless when dressing”) 
A7 
Broncho-pleural fistula 
A8 
Tracheostomy present at ICU admission for the purpose of chronic or prolonged 
mechanical ventilation (>21 days).  (Note that a patient who was endotracheally 
intubated for acute respiratory failure and received a tracheostomy during their ICU 
admission, prior to enrolment, is not excluded under A8). 
A9 
Current enrolment in a confounding study, as assessed by the steering committee 
A10 
Previous randomization in the PROMIZING Study 
A11 
Severe, end-stage, irreversible respiratory or cardiac disease (e.g.  interstitial lung 
disease, pulmonary fibrosis, cardiomyopathy, valvulopathy) likely to result in prolonged 
or chronic  ventilator dependence /unlikely to wean from mechanical ventilation [Note: 
patients who are candidates for intervention to treat the underlying respiratory/cardiac 
disease (e.g. lung transplant, heart transplant, cardiac surgery) may be re-evaluated once 
intervention is complete and  they no longer meet criteria A11.] 
 
Patients satisfying all of the Screening inclusion criteria and none of the Screening exclusion criteria will be classified 
as “eligible” and will be followed daily until they meet all of the following criteria  to be approached for consent.  
This is the second stage, called (B) Enrolment and Obtaining Consent, and it occurs as the patient approaches the 
“recovery phase” of his/her critical illness, as defined by passing the “Enrolment Inclusion Criteria” listed below. 
 
B. Enrolment Inclusion Criteria: 
B1. Ability or potential ability to trigger ventilator breaths (i.e. not receiving 
neuromuscular blockade).   
B2. On Assist/Control volume-cycled ventilation: Technically satisfactory plateau pressure ≤ 
30 cm H2O (see Operations Manual) OR 
On Assist/Control pressure-controlled ventilation or similar mode: Pressure control plus 
PEEP ≤ 30 cm H2O OR 
On Pressure Support ventilation: Pressure support plus PEEP ≤ 30 cm H2O  OR 
On Proportional Assist ventilation: PAV gain <85% 
B3. PaO2 ≥ 60 mmHg or SpO2 ≥ 90% on FiO2 ≤ 0.60 and PEEP ≤ 15 cm H2O 
B4. Metabolic disorders corrected: pH ≥7.32  

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B5.  Stable hemodynamic status: stable or decreasing doses of vasopressors for ≥6 hours  
B6. Anticipate ongoing need for ventilation >24 hours  
 
 
B. Enrolment Deferral Criteria: 
B11 
Plan to extubate/discontinue mechanical ventilation within <24 hours (Reassess within 
24 hours) 
B12 
Patient currently on ECMO (Reassess patient once off ECMO) 
C9. 
Plan for surgery or complex procedure that will require full ventilation to be done prior 
to attempting extubation (e.g. Procedure requiring neuromuscular blockade and/or 
heavy sedation, such that patient would be apneic, or not be able to trigger ventilator) 
(Reassess after surgery/procedure complete) 
 
B. Enrolment Exclusion Criteria: 
B7 
Extubated 
B8 
Died 
B9 
Patient has met enrolment inclusion criteria B1-B5 AND has tolerated pressure support 
of 0-20 cm H2O or proportional assist ventilation of 0-85% for ≥24 consecutive hours 
(including time on CPAP, t-piece, or tracheostomy mask).  (Note (1):that it is acceptable 
to include a patient who has been tried on pressure support or proportional assist 
ventilation but has required pressures >20 cmH2O or assistance >85% or has required 
return to A/C ventilation within the 24 hour time window; Note (2):  B9 does not apply 
to patients on ECMO.) 
B10 
Patient transferred to a non-participating centre 
 
For patients meeting all A. Screening and B. Enrolment Criteria, the treating ICU physician will be asked to provide 
verbal consent to (i) enroll the patient, (ii) proceed with standardized tests to determine eligibility for 
randomization, (iii) randomize the patient if eligibility criteria are met, and (iv) enable the research team to 
approach the patient/SDM for consent.  The standardized tests are part of routine clinical care and include a trial 
of pressure support and screening for a trial of spontaneous breathing.  If the ICU physician plans to extubate 
the patient within 24 hours, enrolment may be deferred until the next calendar day and the patient reassessed 
to determine if the patient has passed an SBT or is extubated.  If the patient is not extubated by the following 
morning and/or fails an SBT, the patient should then be enrolled and proceed to randomization criteria.  Patients 
on ECMO are not eligible for enrolment until off ECMO. 
 
Eligible patients or their substitute decision makers (SDMs) will be approached for consent to participate in the 
clinical trial as soon as possible after the treating physician has provided verbal consent.  The patient/SDM will be 
provided a Letter of Information and asked to provide written informed consent to proceed with (i) 
randomization if eligibility criteria are met during standardized tests and (ii) use of data collected from time of 
enrolment through to study termination.  Obtaining informed consent prior to randomization is preferred; 
however, randomization of eligible patients may proceed with deferred consent if the patient is incapable and no 
SDM can be contacted despite at least two documented attempts.  (See section 14.3 for further information on 
obtaining informed consent). 
 
Physicians may institute pressure support at any time according to clinical discretion and usual care.  The 
pressure support trial is intended for cases where the patient has not yet been placed on pressure support ≤20 
cm H2O (above PEEP) by the treating physician. The Pressure Support Trial (PST) is the first test in a series of 

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tests to determine if a patient is ready for randomization.  Prior to initiating the PST, the treating physician must 
approve proceeding with the standardized tests and randomization if eligible. 
 
C. Pressure Support Trial Inclusion Criteria: 
C2. 
Upon review of Screening and Enrolment criteria (A and B), the patient still passes. 
C3. 
Treating physician has provided verbal consent to proceed with standardized tests and 
randomization if eligibility criteria are met 
 
C. Pressure Support Trial Deferral Criteria 
C6. High dose vasopressor requirements (i.e. epinephrine or norepinephrine >0.5 g/kg/min 
or equivalent) OR patient requiring an increase in dose of vasopressor within 6 hrs 
C7. Active cardiac ischemia (dynamic ST changes on monitor or ECG within 6 hours)  
C8. Unstable arrhythmias (HR>140 or <50) with clinical signs of low cardiac output or or 
SBP<80 mmHg  
  
C10. Receiving a “strict lung protective” ventilation strategy for ARDS (eg.  Order on chart to 
keep Vt ≤6 mL/kg PBW)   
  
 
C. Pressure Support Trial Exclusion Criteria 
C12. Treating physician has declined consent 
 
Patients already on pressure support of ≤20 cm H2O (above PEEP) for >30 minutes will be considered to have 
passed the Pressure Support Trial and will move on to the next stage of enrolment. 
 
Patients on A/C ventilation (or similar mode) or PAV or on pressure support >20 cmH2O will be assessed daily and 
will undergo a daily Pressure Support Trial, provided none of the Pressure Support Deferral Criteria are present.   
 
In the presence of any of the Pressure Support Trial Deferral Criteria, the pressure support trial may be deferred 
up to 24 hours.  Patients should be reassessed at least daily and can proceed to the Pressure Support trial after 
discussion with the site PI, provided the patient still passes Criteria C and no deferral criteria are present.  If deferral 
criteria remain present, the Pressure Support Trial may be deferred on a daily basis after daily reassessment.   
 
Once no deferral criteria are present, patients proceed as follows: 
 
Patients already on pressure support of ≤20 cm H2O for >30 minutes will be considered to have passed the 
Pressure Support Trial and will move on to the next stage of enrolment 
 
Patients on A/C mode or similar mode or PAV or on pressure support >20 cmH2O will undergo the Pressure 
Support Trial 
 
The Pressure Support Trial (PST) is conducted as follows:  patients will be placed on PSV 5-20 cmH2O (above 
PEEP) for at least 30 minutes under direct clinical observation, at the same PEEP and FiO2 settings they were on 
prior to the PST.  The maximum settings allowed for the PST are a pressure support of 20 cmH2O or PS+PEEP=30 
cmH2O. The PST can be stopped at any time for prolonged apnea, Respiratory Distress or Clinical Instability (see 
definitions below).   At the end of 30-120 minutes, an arterial blood gas will be drawn.   
 

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Patients fail the Pressure Support Trial if they develop prolonged apnea, Respiratory Distress, Clinical Instability 
(see definitions below), or require PS >20 cmH2O, PS + PEEP > 30 cmH2O, or require FiO2>60% to maintain 
SpO2>90%, or respiratory acidosis with pH <7.32 despite maximum PS of 20 cmH2O. The PST is terminated 
immediately upon reaching any failure criteria.  Patients who fail a PST are returned to their previous ventilator 
settings or settings that restore respiratory comfort.  Patients who pass the PST may remain on pressure support 
5-20 cmH2O. 
 
Definition of Respiratory Distress 
At least 2 of the following: 
1. SpO2 <90% 
2. Sustained (>5 min) respiratory rate >35 b/min 
3. Heart rate >140 b/min or a sustained (>5 min) increase of 20% from baseline 
4. Systolic blood pressure >180 or <80 mmHg and/or systolic BP changes >30% from baseline 
5. Increased anxiety 
6. Use of accessory muscles 
7. Complaint of dyspnea 
8. Diaphoresis 
 
Definition of Clinical Instability 
Any 1 of the following: 
1. Unstable hemodynamic status (SBP<80 mmHg) with or without vasoactive drug 
2. Vasopressor requirements >0.5 g/kg/min epinephrine/norepinephrine or equivalent 
3. Active cardiac ischemia (dynamic ST changes on cardiac monitor or electrocardiogram 
4. Unstable arrhythmias (HR >140 or <50) with clinical signs of low cardiac output or SBP<80 mmHg 
5. Uncontrolled hypertension (SBP>180 mmHg) 
6. Abrupt decrease in the level of consciousness (RASS -4 or -5 or SAS 1 or 2) 
7. Dangerous agitation (RASS +4 or +3 or SAS 7) 
8. Metabolic  (or mixed) acidosis with pH <7.32 
9. Emergency situation that merits return to full ventilation (A/C)  according to best clinical judgement 
 
Patients who fail the Pressure Support Trial will be re-evaluated daily, and, provided that they still pass Criteria 
C and no deferral criteria are present, will undergo a Pressure Support Trial at least once daily.   Patients who 
pass the Pressure Support Trial will proceed to the next stage to be evaluated for (D) Weaning Criteria.  
 
D. Weaning Criteria: 
D1. SpO2≥ 90% on FiO2 ≤0.40 and PEEP ≤8 cmH2O 
D2. pH ≥7.32 
D3. Vasopressor requirements no higher than norepinephrine 0.1 g/kg/min or equivalent. 
 
 
Patients must meet all 3 of the Weaning Criteria to pass.  Patients who do NOT meet all 3 of the Weaning Criteria 
FAIL the Weaning Criteria and proceed to the final stage, (E).  Patients who meet all the Weaning Criteria PASS the 
Weaning Criteria and proceed to a screening test using a ZERO  CPAP trial. .   
 
The ZERO CPAP Trial screening test is performed as follows:  
1. With patient’s ETT connected to the ventilator circuit, change the ventilator mode to CPAP at 0 cmH2O 
and FiO2 0.40 

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2. Monitor patient for 2 min 
3. On the ventilator, assess the f/Vt ratio after 1-2 minutes at 0 cmH2O CPAP: 
4. FAIL:  If the f/Vt >100, or SpO2<90% or Clinical Instability, patient has failed the ZERO CPAP trial and will 
not proceed to SBT.  Resume ventilation with the ventilator settings used immediately prior to the ZERO 
CPAP test 
5. PASS:  If the f/Vt is ≤100, and SpO2 ≥90%, proceed to SBT 
 
Patients who fail the ZERO CPAP trial will proceed to the final stage (E).  Patients who pass the ZERO CPAP trial 
will proceed to a Spontaneous Breathing Trial (SBT). 
 
The SBT is performed as follows:   
1. Disconnect endotracheal tube from ventilator circuit and place patients on T-piece* with FiO2 0.40.  (For 
patients with tracheostomy, place patients on tracheostomy mask trial with FiO2 0.40) 
2. Monitor patient for 30-120 minutes: 
3. FAIL/ SBT Termination:  Terminate the SBT and return patient to prior ventilator settings if at any time 
one of the following occur: 
a. Respiratory Distress 
b. Clinical Instability 
c. Increased somnolence with elevated pCO2 and/or pH<7.32 
d. Desaturation with SpO2 <90% on FiO2 0.40 
*for the purposes of this study, the Sponsor considers SBT performed with patients connected to ventilator on 
flow-by with CPAP of 0 cmH2O and FiO2 0.40 to be equivalent to SBT performed on T-piece with FiO2 0.40.  
 
Following the SBT, proceed to the final stage (E).   
 
In the final stage (E), patients will be considered eligible for randomization if the following criteria are met. 
 
E. Randomization Inclusion Criteria 
C1. Patient/SDM has provided consent OR Plan to obtain deferred consent as Patient 
incapable and no SDM available to provide consent within the randomization window 
E1. Upon review of Criteria A, B, and C, the patient still passes and the patient has passed 
the PST.  
E2. Does not meet Weaning Criteria OR 
Fails the ZERO CPAP Trial OR 
Fails the SBT  
 
E. Randomization Exclusion Criteria: 
B9 Patient has met enrolment inclusion criteria B1-B5 AND has tolerated pressure support 
of 0-20 cm H2O or proportional assist ventilation of 0-85% ≥24 consecutive hours 
(including time on CPAP, t-piece, or tracheostomy mask).  Note (1): It is acceptable to 
include a patient who has been tried on pressure support or proportional assist 
ventilation but has required pressures >20 cmH2O or assistance >85% or has required 
return to A/C ventilation within the 24 hour time window;  Note (2):  B9 does not apply 
to patients while on ECMO  
C4. Patient/SDM has declined consent 
C5. Patient incapable and no SDM available to provide consent (not applicable if plan to 
obtain deferred consent) 

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E3. Passed SBT on t-piece, FiO2 0.40 for 30-120 minutes  
E4. Approval withdrawn (by physician or patient/SDM)  
*Note:  there may be patients who pass the SBT but remain intubated for other reasons (airway protection, 
pulmonary toilet).  Such patients should be reassessed within 24 hrs and may be reconsidered for randomization 
if their ventilatory requirements increase and/or they fail subsequent SBTs, provided they are not excluded based 
on criteria B9, above. 
 
Patients who pass the Randomization criteria will proceed to randomization according to the method described 
in section 10.3.1.  Randomization should occur as soon as possible after meeting Randomization Criteria and must 
occur within the randomization window.  The randomization window opens when the patient passes a Pressure 
Support Trial (tolerates 30-120 minutes of PSV ≤20 cmH2O and closes once a patient tolerates 24 consecutive 
hours of PSV ≤20 cmH2O while meeting inclusion criteria B1-B5. 
 
Figures depicting the Enrolment and Randomization Algorithm and Eligibility Criteria are located in Appendix A 
and B, respectively. 
 
8.0 Study Procedures 
 
The Ventilator Algorithms for PAV+ and PSV are located in Appendices C and D, respectively.  
 
8.1 Ventilation Strategy:  Proportional Assist Ventilation (PAV+) 
 
8.1.1 
General Approach: PAV+ 
Patients randomized to the PAV+ group are treated with PAV+ on a PB840 or PB980 ventilator (Covidien LP, a 
Medtronic company).    Only PAV+™ (Covidien LP, a Medtronic company) will be used.  Proportional Pressure 
Support on the Draeger Evita 4 Ventilator may NOT be used.  Patients will follow the PAV+ algorithm both day 
and night. 
 
In the PAV+ strategy, the level of support (%Support or “gain”) will be adjusted to target a respiratory muscle 
pressure within normal range, without evidence of respiratory distress.  At a minimum, patients will be assessed 
at least every 8 hours (or according to standard practice in each ICU if patient assessments are routinely 
performed more frequently than every 8 hours) to determine if adjustments need to be made to maintain 
respiratory muscle pressure (Pmus) within the target range.  The Pmus target range is 5-10 cmH2O, the clinical 
targets are a RR <35 and Vte > 5mL/kg PBW, while maintaining a pH in the range of 7.32-7.47.  FiO2 and PEEP are 
titrated clinically to maintain a SpO2 90-96%. Patients developing clinical instability or respiratory distress that 
cannot be alleviated on PAV+ will be changed to A/C mode and reassessed within 24 hours for criteria to resume 
PAV+.   
8.1.2 
Initiating PAV+ 
Ensure the patient’s correct Body Weight is entered and displayed on the ventilator screen.  Although the 
ventilator monitor uses the term “Ideal Body Weight” (IBW), enter the “Predicted Body Weight” (PBW) calculated 
as follows: 
 
PBW (kg) Men = 50 +0.91(Height[cm] – 152.4) 
PBW (kg) Women = 45.5 +0.91(Height[cm]-152.4) 
 

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(The ventilator “IBW” is preset at 50 kg, so if that is not the Predicted Body Weight of the patient, turn the 
ventilator off and restart as for a new patient, select “Invasive” and adjust IBW as needed).  Set the correct type 
and size of tube, eg. Tube type=ET (endotracheal), Tube I.D. = diameter of endotracheal tube, in mm, and type of 
humidification.   
 
Guidelines for the administration of sedation and analgesia are provided, (see section 8.4.1) with a strong 
recommendation for using the lowest possible dose of sedating drugs in both arms (or none at all) as required 
to keep the patient calm and cooperative, avoiding over-sedation whenever possible. Over-sedation during 
PAV+ may result in respiratory acidosis so patients emerging from heavy sedation must be closely monitored and 
light sedation or no sedation should be targeted. 
 
Prior to initiating PAV+, record the patient’s respiratory rate, heart rate, blood pressure, tidal volume (Vte) and 
minute ventilation (VE).  The baseline vital signs will be needed to determine if the patient is developing signs of 
respiratory distress.  The baseline Vt and VE required to maintain a normal pH (>7.32) will be used to monitor if 
the patient is developing a respiratory acidosis or respiratory alkalosis.   
 
PAV+ is initiated at the following settings: 
 
PAV+ %Support (gain) : start at 70% 
 
Inspiratory trigger: per clinician  
 
Expiratory trigger (Esens): 3 L/min (default) 
 
PEEP: start at previous level patient was on prior to randomization 
 
FiO2: at lowest level required to maintain SpO2 90-96% 
 
Alarm settings: 
 
Ppeak (Paw max): 40 cmH2O 
 
RR max: 38 b/min 
 
Vte max: 12 mL/kg IBW 
 
Vte min: 0 mL 
 
VE max:  20 L/min 
 
VE min: 5 L/min 
 
Apnea setting: 20 s 
8.1.3 
Adjusting PAV+ 
Adjustments are made to the ventilator settings immediately (5 minutes) after initiating PAV+ and at a minimum 
every 8 hours thereafter (or according to standard practice in each ICU if patient assessments are routinely 
performed more frequently than every 8 hours).  If pH on arterial blood gas (ABG) is outside of the target range 
of 7.32-7.47, serial adjustments should be made immediately post ABG and ABG’s repeated every 30-60 minutes 
post ventilator adjustments until pH is back within the target range or patient meets criteria to switch to A/C.   
 
The goal is to support patients’ breathing while maintaining an adequate amount of respiratory muscle activity 
to avoid atrophy of the diaphragm, or help to rehabilitate an already weakened diaphragm.  The target range for 
respiratory muscle pressure (Pmus) is 5-10 cmH2O, while maintaining a pH of 7.32-7.47.  Some patients may be 
able to be supported within this target range comfortably, while others may not be able to generate a Pmus of 5 
cmH2O without developing clinical signs of respiratory distress.  Therefore, adjustments are made to the 
ventilator settings according to whether Respiratory Distress is present or absent. FiO2 and PEEP are titrated 
clinically to maintain a SpO2 90-96%.  PEEP is set by the clinician according to clinical judgment at the bedside, 
but may be titrated taking into account clinically suspected intrinsic PEEP (PEEPi) and the ventilator automated 

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measurements of dynamic compliance (CPAV) as described below.  FiO2 should be set and adjusted to the lowest 
level required to maintain SpO2 90-96%.  Patients developing prolonged apnea, respiratory distress or clinical 
instability will be changed to A/C mode and reassessed within 24 hours for criteria to resume PAV+. 
 
The study protocol defines Respiratory Distress as the presence of 2 or more of the following signs: 
 
Definition of Respiratory Distress 
At least 2 of the following: 
1. SpO2 <90% 
2. Sustained (>5 min) respiratory rate >35 b/min 
3. Heart rate >140 b/min or a sustained (>5 min) increase of 20% from baseline 
4. Systolic blood pressure >180 or <80 mmHg and/or systolic BP changes >30% from baseline 
5. Increased anxiety 
6. Use of accessory muscles 
7. Complaint of dyspnea 
8. Diaphoresis 
 
Immediately after initiating PAV+, and at least every 8 hours (minimum, see above) while on PAV+, determine if 
adjustments need to be made to the ventilator settings.  Adjustments are made according to whether Respiratory 
Distress is present or absent. 
 
Adjusting PAV+ if Respiratory Distress is present: 
 
If Respiratory Distress is present, complete the following steps: 
1. Assess PAV+ Resistance (R) and Compliance (C) measurements.  If RTOT is high (> 10 cmH2O/L/s), treat any 
apparent cause of high resistance (eg. Secretions, bronchospasm).  If CPAV is low (<35 mL/cmH2O), treat any 
apparent cause of decreased compliance (e.g., Pulmonary edema).  Treat any cause of metabolic acidosis, if 
present. 
2. Increase PEEP in steps of 2 cmH2O until compliance no longer increases. 
3. Increase FiO2 as needed to keep SpO2 90-96% 
4. Increase PAV+ %Support in steps of 10% until respiratory distress resolves and pH>7.32 
5. Switch to A/C mode if one or more of the following occur during steps 1-4: 
a. PAV+ %Support >85%  
b. FiO2 >60% required to maintain SpO2 ≥90% 
c. Clinical Instability  
d. Requiring neuromuscular blockade and/or sedation such that patient is no longer able to trigger 
the ventilator  
 
Definition of Clinical Instability 
Any 1 of the following: 
1. Unstable hemodynamic status (SBP<80 mmHg) with or without vasoactive drug 
2. Vasopressor requirements >0.5 g/kg/min epinephrine/norepinephrine or equivalent 
3. Active cardiac ischemia (dynamic ST changes on cardiac monitor or electrocardiogram) 
4. Unstable arrhythmias (HR >140 or <50 with clinical signs of low cardiac output or SBP<80 mmHg) 
5. Uncontrolled hypertension (SBP>180 mmHg) 
6. Abrupt decrease in the level of consciousness (RASS -4 or -5 or SAS 1 or 2) 
7. Dangerous agitation (RASS +4 or +3 or SAS 7) 
8. Metabolic  (or mixed) acidosis with pH <7.32 

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9. Emergency situation that merits return to full ventilation (A/C) according to best clinical judgement 
 
Patients requiring A/C ventilation should be reassessed within 24 hours for Criteria for Switching from A/C to 
PAV. 
 
Adjusting PAV+ if Respiratory Distress is Absent: 
 
If respiratory distress is absent, complete the following steps for adjusting %Support, PEEP and FiO2: 
1. Adjust the PEEP according to clinical judgment at the bedside.  When determining best PEEP level for the 
patient, consider the following: 
a. Does increasing/decreasing the extrinsic (set) PEEP reduce the intrinsic PEEP (PEEPi)? 
b. Does increasing/decreasing the extrinsic (set) PEEP improve compliance (CPAV)? 
c. Choose the set PEEP which results in the lowest PEEPi and highest CPAV 
2. Adjust the FiO2 to the lowest level required to maintain SpO2 >90% (and in the range 90-96%). 
3. Using the Pmus Calculator card, calculate the Pmus, peak as follows: 
a. Observe the Peak airway pressure (Paw,peak) over 3-5 breaths and subtract the PEEP from the Paw, peak 
to obtain the Delta Paw (Delta Paw=Paw,peak – PEEP) 
b. Line up the Delta Paw number with the white arrow by sliding the inner card of the Pmus calculator 
c. The Pmus peak is the number displayed in the Pmus calculator window corresponding to the % Support 
set on the ventilator 
4. Adjust the % Support according to the Pmus,peak as follows: 
a. Pmus,peak <5  cmH2O:  Decrease gain in steps of 5-10% until Pmus,peak is in the target range of 5-10 
cmH2O;  If Respiratory Distress develops while decreasing the gain, follow the algorithm for Respiratory 
Distress 
b. Pmus, peak >10 cmH2O:  Increase the gain in steps of 5-10% until Pmus,peak is in the target range of 5-10 
cmH2O; If Respiratory Distress develops while increasing the gain, follow the algorithm for “Respiratory 
Distress” 
c. Pmus, peak 5-10 cmH2O: Target range achieved:  no adjustments required unless:   
i. RR <12 or >35 or Vte<5 or >10 mL/kg PBW, obtain arterial blood gas (ABG): 
1. If ABG demonstrates a respiratory alkalemia, treat any apparent cause of 
hyperventilation, (eg. pain, anxiety, metabolic acidosis), then decrease gain in steps of 5-
10% until Vte <8 mL/kg PBW OR pH<7.47 
2. If ABG demonstrates a respiratory acidemia OR respiratory distress develops:  
a. Increase PEEP in steps of 2 cmH2O until compliance no longer increases. 
b. Increase FiO2 as needed to keep SpO2>90% 
c. Increase PAV %Support in steps of 10% until pH>7.32 and respiratory distress 
resolves 
d. Switch to A/C mode if one or more of the following occur during steps a-c: 
i. PAV %Support >85% 
ii. FiO2 >60%  required to maintain SpO2 ≥90% 
iii. Clinical Instability (see definition) 
iv. Requiring neuromuscular blockade and/or sedation such that patient is 
no longer able to trigger the ventilator  
8.1.4 
Resuming PAV+ after A/C ventilation 
Patients switched to A/C ventilation as per study protocol should be reassessed within 24 hours, and at least once 
daily thereafter, for Criteria for Switching from A/C to PAV+.  These are the minimum criteria for switching from 
A/C back to PAV+.  If all of the criteria for switching from A/C to PAV are present, the patient must be tried on 

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PAV+:  follow the Initiation of PAV+ protocol, with initial and subsequent adjustments made to PAV+ settings 
according to the Algorithm for Adjusting PAV+.  After a trial of PAV+, patients may be switched back to A/C mode 
if they meet criteria according to the PAV+ ventilation strategy algorithm.  The Criteria for Switching from A/C to 
PAV+ are as follows: 
 
Criteria for Switching from A/C to PAV+: 
1. Able to trigger ventilator breaths 
2.  On assist/control with the following settings: 
a. AC/VC: Pplat≤30cmH2O with Vt 6-8 ml/kg OR 
b. AC/PC: PC+PEEP≤30cmH2O  
3. PaO2 ≥ 60 mmHg or SpO2 ≥ 90% on FiO2≤ 0.60 and PEEP  ≤ 15 cm H2O  
4. Metabolic disorders corrected; pH >7.32 
5. Stable hemodynamic status: stable or decreasing doses of vasopressors for ≥6 hours 
6. Absence of Clinical Instability (see definition, above) 
 
8.2 Ventilation Strategy:  Pressure Support Ventilation (PSV) 
8.2.1 
General Approach: PSV 
Patients randomized to the PSV group are treated with PSV on any ventilator capable of delivering standard 
pressure support mode.  The make and model of the ventilator used to deliver PSV will be recorded as part of the 
data set.  Patients will follow the PSV algorithm both day and night. 
 
In the PSV strategy, the level of pressure support will be adjusted according to routine clinical parameters, 
targeting a comfortable respiratory rate and tidal volume.  At a minimum, patients will be assessed at least every 
8 hours (or according to standard practice in each ICU if patient assessments are routinely performed more 
frequently than every 8 hours) to determine if adjustments need to be made to maintain patient comfort, and 
ensure adequate ventilation and oxygenation.  The clinical targets are a RR 12-35 and Vte 5-10 mL/kg PBW, while 
maintaining a pH in the range of 7.32-7.47.  FiO2 and PEEP are titrated clinically to maintain a SpO2 90-96%.  PEEP 
is set by the clinician according to clinical judgment at the bedside.  FiO2 should be set and adjusted to the lowest 
level required to maintain SpO2 90-96%.  Patients developing respiratory distress or clinical instability will be 
changed to A/C mode and reassessed within 24 hours for criteria to resume PSV. 
8.2.2 
Initiating PSV 
Guidelines for the administration of sedation and analgesia are provided, (see section 8.4.1) with a strong 
recommendation for using the lowest possible dose of sedating drugs in both arms (or none at all) as required 
to keep the patient calm and cooperative, avoiding over-sedation whenever possible. 
 
Prior to initiating PSV, record the patient’s respiratory rate, heart rate, blood pressure, tidal volume (Vte) and 
minute ventilation (VE).  The baseline vital signs will be needed to determine if the patient is developing signs of 
respiratory distress.  The baseline Vt and VE required to maintain a normal pH (>7.32) will be used to monitor if 
the patient is developing a respiratory acidosis or respiratory alkalosis.   
 
PSV is initiated at the following settings: 
 
PS level: start at 10-20 cmH2O (or start at level patient was on prior to randomization) 
 
Inspiratory trigger: per clinician  
 
Expiratory trigger: 25% of peak inspiratory flow (default) 
 
PEEP: start at previous level patient was on prior to randomization 
 
FiO2: start at previous level patient was on prior to randomization 

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Alarm settings: 
 
Ppeak (Paw max):   Per clinician 
 
RR max: 38 b/min 
 
Vte max: 12 mL/kg IBW 
 
Vte min: 0 mL 
 
VE max:  20 L/min 
 
VE min: 5 L/min 
 
Apnea setting: 20 s 
8.2.3 
Adjusting PSV 
Adjustments are made to ventilator settings immediately (5 minutes) after initiating PSV and at a minimum every 
8 hours thereafter (minimum, see above).  If pH on arterial blood gas (ABG) is outside of the target range of 7.32-
7.47, serial adjustments should be made immediately post ABG and ABG’s repeated every 30-60 minutes post 
ventilator adjustments until pH is back within the target range or patient meets criteria to switch to A/C.   
 
The algorithm to adjust pressure support is based on usual clinical parameters, keeping the RR ≤35 breaths/minute 
and Vte 5-10 mL/kg PBW, while maintaining a pH of 7.32-7.47.  Some patients may be able to be supported within 
this target range comfortably on pressure support, while others may not be able to tolerate pressure support 
without developing clinical signs of respiratory distress.   Therefore, adjustments are made to the ventilator 
settings according to whether Respiratory Distress is present or absent. 
 
The study protocol defines Respiratory Distress as the presence of 2 or more of the following signs: 
 
Definition of Respiratory Distress 
At least 2 of the following: 
1. SpO2 <90% 
2. Sustained (>5 min) respiratory rate >35 b/min 
3. Heart rate >140 b/min or a sustained (>5 min) increase of 20% from baseline 
4. Systolic blood pressure >180 or <80 mmHg and/or systolic BP changes >30% from baseline 
5. Increased anxiety 
6. Use of accessory muscles 
7. Complaint of dyspnea 
8. Diaphoresis 
 
Immediately after initiating PSV, and at least every 8 hours (minimum, see above) while on PSV, determine if 
adjustments need to be made to the ventilator settings. 
 
Adjusting PSV if Respiratory Distress is present: 
 
If Respiratory Distress is present, complete the following steps: 
1. Treat any apparent cause of respiratory distress (eg. Secretions, bronchospasm, pulmonary edema, 
metabolic acidosis) 
2. Increase pressure support in steps of 2-3 cmH2O until respiratory distress resolves and pH>7.32 
3. Increase PEEP and/or FiO2 as needed to keep SpO2 90-96% 
4. Switch to A/C mode if one or more of the following occur during steps 1-3: 
a. Pressure support >20 cmH2O 
b. Pressure support + PEEP > 30 cmH2O 

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c. FiO2 >60% required to maintain SpO2 ≥90% 
d. Clinical Instability  
e. Requiring neuromuscular blockade and/or sedation such that patient is no longer able to trigger 
the ventilator  
 
Definition of Clinical Instability 
Any 1 of the following: 
1. Unstable hemodynamic status (SBP<80 mmHg) with or without vasoactive drug 
2. Vasopressor requirements >0.5 g/kg/min epinephrine/norepinephrine or equivalent 
3. Active cardiac ischemia (dynamic ST changes on cardiac monitor or electrocardiogram) 
4. Unstable arrhythmias (HR >140 or <50) with clinical signs of low cardiac output or SBP<80 mmHg) 
5. Uncontrolled hypertension (SBP>180 mmHg) 
6. Abrupt decrease in the level of consciousness (RASS -4 or -5 or SAS 1 or 2) 
7. Dangerous agitation (RASS +4 or +3 or SAS 7) 
8. Metabolic  (or mixed) acidosis with pH <7.32 
9. Emergency situation that merits return to full ventilation (A/C)  according to best clinical judgement 
 
Patients requiring A/C ventilation should be reassessed within 24 hours for Criteria for Switching from A/C to 
PSV. 
 
Adjusting PSV if Respiratory Distress is Absent: 
 
If respiratory distress is absent, adjust the level of pressure support, PEEP and FiO2 as follows: 
 
1. 
Adjust the PEEP according to clinical judgment at the bedside 
2. 
Adjust the FiO2 to the lowest level required to maintain SpO2>90% and in the range 90-96%. 
3. 
If patient appears comfortable (RR 12-35 and Vt 5-10 mL/kg PBW): target range achieved.   
No adjustments required unless one of the following occurs: 
a. If RR <12 or >35 or Vte<5 or >10 mL/kg PBW, obtain arterial blood gas (ABG): 
i. If ABG demonstrates respiratory alkalemia, treat any apparent cause of hyperventilation (eg. 
pain, anxiety, metabolic acidosis), then decrease PS in steps of 2-3 cmH2O until pH <7.47 OR 
Vte <8 mL/kg PBW  
ii. If ABG demonstrates respiratory acidemia OR respiratory distress develops:   
1. Increase PS in steps of 2-3 cmH2O until pH>7.32 and respiratory distress resolves 
 
2. Switch to A/C mode if one or more of the following occur during above steps: 
a. PS > 20 cmH2O 
b. PS + PEEP > 30 cmH2O 
c. FiO2 > 60% required to maintain SpO2 ≥90% 
d. Clinical Instability  
e. Requiring neuromuscular blockade and/or sedation such that the patient is 
no longer able to trigger the ventilator 
 
Patients requiring A/C ventilation should be reassessed within 24 hours for Criteria for Switching from A/C to 
PSV. 

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8.2.4 
Resuming PSV after A/C ventilation 
Patients switched to A/C ventilation as per study protocol should be reassessed within 24 hours, and at least once 
daily thereafter, for Criteria for Switching from A/C to PSV.  If all of the criteria for switching from A/C to PSV are 
present, the patient must be tried on PSV: follow the Initiation of PSV protocol, with initial and subsequent 
adjustments made to PSV setting according to Algorithm for Adjusting PSV.  After a trial of PSV, patients may be 
switched back to A/C mode if they meet criteria according to the PSV ventilation strategy algorithm.  The Criteria 
for Switching from A/C to PSV are as follows: 
 
Criteria for Switching from A/C to PSV: 
1. Able to trigger ventilator breaths 
2.  On assist/control with the following settings: 
a. AC/VC: Pplat≤30cmH2O with Vt 6-8 ml/kg OR 
b. AC/PC: PC+PEEP≤30cmH2O  
3. PaO2 ≥ 60 mmHg or SpO2 ≥ 90% on FiO2≤ 0.60 and PEEP  ≤ 15 cm H2O 
4. Metabolic disorders corrected; pH >7.32  
5. Stable hemodynamic status: stable or decreasing doses of vasopressors for ≥6 hours  
6. Absence of Clinical Instability (see definition, above) 
 
8.3 Procedures Common to Both Groups  
8.3.1 
Weaning from Mechanical Ventilation 
Weaning will be conducted in the same way in the two arms.  The PSV level or the PAV+ %Support will not be used 
to assess readiness to wean.  At a minimum, patients in both arms will be assessed at least once daily for Criteria 
to Initiate Weaning, and will undergo the weaning trials at least once daily if criteria at each stage of weaning 
are met.  However, additional screening, additional pre-SBT readiness assessments, or additional SBTs may be 
performed at any time at the physician’s discretion or as per institutional standard.  
 
Criteria to Initiate Weaning: 
 
1. SpO2 ≥ 90% 
2. FiO2 ≤ 0.40 
3. PEEP ≤ 8 
4. pH ≥ 7.32 
5. vasopressor requirements no higher than norepinephrine 0.1 g/kg/min or equivalent and at a stable or 
decreasing dose ≥6 hours 
6. No Respiratory Distress (see definition) 
7. No Clinical Instability (see definition)) 
 
If all criteria are present except PEEP >8 cmH2O, decrease PEEP to ≤ 8 cmH2O and if all criteria still present after 
30 min, proceed to next step, the pre-SBT readiness assessment. 
 
Pre-SBT screening test (ZERO CPAP Trial) 
Patients meeting above Criteria to Initiate Weaning will undergo a Pre-SBT readiness assessment to measure the 
Rapid Shallow Breathing Index (RSBI) as follows: 
1. With patient’s ETT connected to the ventilator circuit, change the ventilator mode to CPAP at 0 
cmH2O and FiO2 0.40 
2. Monitor patient for 2 min 
3. On the ventilator, assess the f/Vt ratio after 1-2 minutes at 0 cmH2O CPAP: 

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4. FAIL:  If the f/Vt >100, or SpO2<90% or Clinical Instability, patient has failed the ZERO CPAP trial and 
will not proceed to SBT.  Resume ventilation according to assigned ventilation algorithm at the 
ventilator settings used immediately prior to the CPAP test. 
5. PASS:  If the f/Vt is ≤100, and SpO2 ≥90%, proceed to SBT 
 
SBT 
Patients who pass the Pre-SBT readiness assessment, will proceed to SBT as follows: 
1. Disconnect endotracheal tube from ventilator circuit and place patients on T-piece* with FiO2 0.40.  
(For patients with tracheostomy, place patients on tracheostomy mask trial with FiO2 0.40) 
2. Monitor patient for 30-120 minutes: 
3. FAIL/ SBT Termination:  Terminate the SBT and return patient to ventilator settings according to 
assigned algorithm if at any time one of the following occur: 
a. Respiratory Distress 
b. Clinical Instability 
c. Increased somnolence with elevated pCO2 and/or pH<7.32 
4. Pass:  Patients will be considered to have passed the SBT if, after a minimum of 30 minutes and 
maximum of 120 minutes, none of the failure/SBT termination criteria have occurred.  Proceed to 
evaluate patient for extubation criteria (or disconnection criteria for patients with tracheostomy, 
see below) 
 
*for the purposes of this study, the Sponsor considers SBT performed with patients connected to ventilator on 
flow-by with CPAP of 0 cmH2O and FiO2 0.40 to be equivalent to SBT performed on T-piece with FiO2 0.40.  
 
Extubation Criteria: 
Patients are assessed for extubation criteria after successfully passing an SBT: 
1. Criteria to initiate weaning still present 
2. Passed SBT 
3. A level of consciousness sufficient to ensure airway protection (as judged by the clinician) 
4. A cough strong enough to clear secretions (as judged by the clinician) and not requiring suctioning more 
than every 2 hours 
 
Note that Extubation Criteria do not need to be present prior to performing the pre-SBT assessment or the SBT .  
Patients who pass the SBT AND meet Extubation Criteria should be extubated immediately (within 2 hours).  
Extubation may be deferred (up to a maximum 24 hours after meeting all extubation criteria) if a procedure or 
surgery that will require intubation is planned within 24 hours or at the discretion of the treating physician 
(justification must be provided on the eCRF).  In the event that extubation is deferred (beyond 2 hours from time 
of meeting extubation criteria), patients must be reassessed for extubation criteria within 24 hours and either 
extubated or justification provided on the eCRF on a daily basis for any further deferrals.  Patients who pass the 
SBT but do NOT meet Extubation Criteria are returned to ventilator settings according to the assigned algorithm 
and reassessed for Extubation Criteria at least once daily.  SBT will be repeated as needed, or as indicated by the 
clinician.  If, upon reassessment, the Criteria to Initiate Weaning are no longer present, patients will continue on 
the assigned ventilation strategy and undergo daily assessments to restart the weaning process from the 
beginning. 
 
In sites where Maximal Inspiratory Pressure (MIP) and Maximal Expiratory Pressure (MEP) are routinely measured 
prior to extubation and recorded in the medical chart, these scores will be collected as part of the eCRF.   

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8.3.2 
Ventilation on A/C mode 
Patients meeting criteria to switch to A/C mode may be ventilated with pressure control (AC/PC) or volume control 
(AC/VC) according to standard practice in each ICU.  Ventilator settings on A/C mode will be determined by the 
clinician/respiratory therapist.  PEEP and FiO2 will be titrated clinically.  The FiO2 should be weaned to the lowest 
level required to keep SpO2 90-96% as soon as the clinical status of the patient is stable, as judged by the clinician.  
Once all the following criteria are reached, the patient must be tried on PAV+ or PSV, according to their 
randomization assignment.   
 
Criteria for Switching from A/C to PAV+ or PSV: 
1. Able to trigger ventilator breaths 
2.  On assist/control with the following settings: 
a. AC/VC: Pplat≤30cmH2O with Vt 6-8 ml/kg OR 
b. AC/PC: PC+PEEP≤30cmH2O  
3. PaO2 ≥ 60 mmHg or SpO2 ≥ 90% on FiO2≤ 0.60 and PEEP  ≤ 15 cm H2O 
4. Metabolic disorders corrected; pH >7.32  
5. Stable hemodynamic status: stable or decreasing doses of vasopressors for ≥6 hours  
6. Absence of Clinical Instability (see definition, above) 
8.3.3 
Routine Ventilatory Care and Monitoring 
Patients in both groups should be ventilated with the head of the bed elevated to 30⁰ unless otherwise 
contraindicated; in-line suction catheters and heated humidifiers are recommended. 
 
Patients in both groups shall be monitored using continuous SpO2 monitors and electrocardiography.  Blood 
pressure may be monitored either intermittently with inflatable cuff or continuously with an arterial catheter.  
Arterial blood gases shall be performed at baseline after passing the pressure support trial, and after initiating the 
assigned ventilation strategy (30-60 minutes post initiation), with any significant changes in minute ventilation 
and as needed according to clinician assessment or to satisfy the ventilation algorithm requirements (eg.  when 
Vte <5 or >10 mL/kg PBW, a blood gas should be done to assess for respiratory acidosis or alkalosis). 
 
Patients will be assessed at minimum every 8 hours for adjusting ventilator settings or more frequently as per 
routine practice in each participating ICU.  Frequency of assessments will be the SAME for patients in both study 
groups in each participating ICU. 
8.3.4 
Ventilation during Patient Transfers 
The assigned ventilation strategy may be interrupted during patient transfers away from the ICU, and alternative 
means may be used (e.g. Manual ventilation, anaesthetic gas machines, transport ventilators, etc.)  Upon return 
to the ICU, patients will immediately resume their assigned strategy, including the use of A/C ventilation as 
required until patients meet the Criteria for Switching from A/C to PAV+ or PSV. 
8.3.5 
Post-extubation Ventilatory Care 
 
8.3.5.1 Noninvasive Ventilation Guideline 
Noninvasive ventilation (NIV) may be used post-extubation at the discretion of the treating clinician.  We will 
collect data regarding use of NIV (refers to CPAP or Bilevel) and reason(s) for NIV initiation: 
 
Reasons for Initiation of Noninvasive Ventilation post extubation: 
1. To treat confirmed or suspected sleep-disordered breathing 
2. To treat post-extubation respiratory distress or failure 

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3. To prevent post-extubation respiratory distress or failure 
 
In both patient groups, NIV settings for IPAP/EPAP or CPAP and FiO2 are prescribed and adjusted by the clinician 
according to clinical judgment.  NIV should be delivered with the patient in a seated position with the upper body 
elevated to a minimum of 30 degrees and with a comfortable interface well fitted to the patient.  Patients should 
be monitored closely for response to NIV therapy, with resolution of respiratory distress and improvement in 
arterial blood gases expected within 60 minutes of initiation.  In the setting of post-extubation respiratory failure, 
NIV should NOT be continued beyond 120 minutes if, despite NIV, there is persistent or worsening signs of 
respiratory distress, persistent respiratory acidosis, or persistent hypoxemia, as defined above.  In such cases, 
consideration should be given to reintubation.   
 
NIV is relatively contraindicated if patient has: 
1. High risk of aspiration due to recent vomiting (within 6 hours) 
2. Decreased level of consciousness with impaired ability to protect the airway (as judged by clinician) 
3. Weak cough required deep suctioning or cough assistance more frequently than every 2 hours 
4. Severe Agitation (RASS ≥+3 or SAS 7) 
 
NIV Failure is defined as any of the following occurring while on NIV: 
1. Persistent or worsening signs of Respiratory Distress 
2. Persistent respiratory acidosis (pH<7.32 with PaCO2>45) OR worsening PaCO2  
3. Refractory hypoxemia (SpO2 <90% or PaO2<60mmHg with FiO2 >0.60) OR worsening PaO2 
4. Abundant secretions that cannot be effectively cleared or are associated with lobar collapse, acidosis, 
hypoxemia, or change in mental status 
5. Change in mental status (decrease in level of consciousness or severe agitation) rendering patient 
unable to tolerate NIV 
 
8.3.5.2  Re-intubation Guideline 
Reintubation is performed at the discretion of the treating clinician.  Time of reintubation and reason(s) for 
reintubation will be recorded: 
  
Reasons for Re-intubation:   
1. Cardiac arrest 
2. Respiratory arrest (respiratory pauses with loss of consciousness or gasping for air) 
3. Respiratory distress (see definition) or respiratory failure and NIV relatively contraindicated 
4. Respiratory distress (see definition) or respiratory failure and NIV Failure 
5. Decreased level of consciousness impairing ability to protect airway 
6. Hemoptysis or hematemesis impairing ability to protect airway 
7. Abundant secretions that cannot be effectively cleared or are associated with lobar collapse, acidosis, 
hypoxemia, or change in mental status 
8. Clinical instability (see definition) 
9. Surgical/invasive procedure requiring sedation/anaesthesia +/- neuromuscular blockade such that 
patient will no longer be able to sustain unassisted breathing 
10. Other (specify) 
 
If a patient remains in ICU and requires reintubation within 7 days of extubation, that patient will remain in the 
study, and will resume ventilation according to the assigned ventilation strategy (i.e. using A/C and PAV+ only for 
patients in the PAV+ arm, and using A/C and PSV only for patients in the PSV arm).  Patients initially supported 
with assist/control mode will be switched to PAV+ or PSV according to their assigned ventilation strategy upon 

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meeting Criteria for Switching from A/C to PAV+ or PSV.  If a patient is discharged from ICU but readmitted to ICU 
within 48 hours of discharge, and requires reintubation within 7 days of extubation, that patient will remain in the 
study and will resume ventilation according to the assigned ventilation strategy, as per above.   
8.3.6 
Tracheostomy 
Tracheostomy may be performed in either group when clinically indicated.  Notwithstanding, there is no proven 
benefit to early tracheostomy and therefore we encourage clinicians to delay decisions regarding elective 
tracheostomy until day 10 post randomization. 
 
Disconnection Procedure for Patients with Tracheostomy 
For patients with tracheostomies, SBT will be performed on tracheostomy mask, with FiO2 0.40.  Tracheostomized 
patients who pass their initial SBT by completing 120 minutes of tracheostomy mask trial shall remain off the 
ventilator and on tracheostomy mask trial provided they do not develop any criteria for SBT termination.  
Tracheostomized patients who fail their initial SBT within 120 minutes may undergo gradual increments in 
tracheostomy mask trials according to local ICU site practice, provided local standards of care are applied equally 
to patients regardless of treatment group.  When not undergoing tracheostomy mask trials, patients should be 
ventilated according to their assigned ventilation strategy, until successful termination of invasive MV is achieved.   
“Successful extubation/termination of invasive mechanical ventilation” will be defined as remaining off of invasive 
ventilation for 7 consecutive days, or discharge from hospital.  Decanulation will be decided based on local 
practices. 
 
8.4 Co-interventions 
8.4.1 
Sedation Guidelines 
Each site will submit their clinical sedation procedures or preprinted orders to the CC and this procedure will be 
acknowledged by the sponsor prior to site activation.  Guidelines for the administration of sedation and 
analgesia are provided, with a strong recommendation for using the lowest possible dose of sedating drugs in 
both arms (or none at all) as required to keep the patient calm and cooperative, avoiding over-sedation 
whenever possible.  When sedation is necessary, we recommend assessing analgesia and intervening with 
appropriate pharmacological measures prior to administering sedatives.  We will record the daily doses of 
sedatives, analgesics, and neuroleptic medications administered to the patient. 
 
Guidelines for Sedation Administration 
1. The critical care nurse should assess the patient (at least once per 8 or 12 hour shift) for pain, agitation, and 
delirium.   
2. Pain should be assessed first, with attempts made to distinguish etiology of pain, and analgesia administered 
as needed to relieve pain.  We recommend using a psychometrically validated self-report tool such as the 
Numeric Rating Scale (NRS).  In patients unable to self-report, we recommend a validated behavioural pain 
scoring tool such as the Behavioral Pain Scale (BPS) or Critical-Care Pain Observation Tool (CPOT). 
3. Level of alertness/sedation should be assessed after pain is adequately treated.  We recommend using a 
validated sedation scale such as the Richmond Agitation-Sedation Scale (RASS) or Sedation-Agitation Scale 
(SAS) and targeting a RASS score of 0 or SAS score of 4 (equivalent).  Some patients may need no sedation or 
only intermittent sedation as needed to maintain the target RASS or SAS score.  If sedative medications are 
required, maintaining light levels of sedation is strongly recommended.  If RASS or SAS score is below the 
target, attempts should be made to wean, withhold or discontinue sedating medication.  If dangerous 
agitation is present, attempts should be made to distinguish etiology of agitation; anxiolytic or sedative 
medications may be administered as needed to relieve agitation and achieve target RASS/SAS score.   

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4. Patients should be assessed for the presence of delirium, with attempts made to distinguish and remove or 
treat contributing factors to delirium.   We recommend using a validated delirium screening tool, such as the 
Intensive Care Delirium Screening Checklist (ICDSC) or the Confusion Assessment Method for the ICU (CAM-
ICU).   
 
In sites where validated pain, sedation, and delirium scoring systems are routinely used and recorded in the 
medical chart, these scores will be collected as part of the eCRF.  In centres where a validated sedation score is 
not routinely recorded, a validated sedation scale (RASS or SAS) will be measured and recorded by research 
personnel at minimum once daily as required for completion of the relevant eCRF.   See Appendix E and 
Appendix F for procedure for assessing RASS or SAS score respectively.  
8.4.2 
Nutrition Guidelines 
Every attempt should be made to ensure patients are receiving adequate calories, protein and nutrients to meet 
their energy requirements.  Nutrition may be administered enterally or parenterally.  We strongly encourage 
consultation with a registered dietician with experience in critical care whenever possible. 
8.4.3 
Early Mobilization Guidelines 
Patients should be assessed for ability to participate in passive and active exercises with the aim of mobilizing as 
early as possible, even while still on the ventilator, as per clinical practice protocols within each ICU.  We 
strongly encourage consultation with a physiotherapist with experience in critical care whenever possible.   
 
9.0   Data Management  
 
9.1 Data Collection 
We will collect the following demographic data on study participants:  gender, birth month and year, race, 
height, and weight.  We will collect data regarding reason for ICU admission, reason for intubation, 
comorbidities and severity of illness, including APACHE III score on admission, and code status.  We will collect 
data regarding cumulative fluid balance and sedative medications administered pre-randomization.  Pre and 
post randomization on selected days, we will collect data at a point in time each morning, including respiratory 
data (including ventilator mode and settings, respiratory rate, tidal volume, peak and mean airway pressure, 
blood pressure and heart rate, PAV resistance and PAV compliance, and arterial blood gas results if available), 
sedation score and SOFA score.  In participating centres with technical capability, we will collect respiratory data 
continuously from the Puritan Bennett ventilators directly, which will also allow us to evaluate driving pressure 
on PAV+ as well as time on PAV+ mode.  To ensure that differences in outcome are not due to differences in 
other therapies that may impact duration of mechanical ventilation, we will document daily fluid balance, and 
use of sedatives, narcotics, antipsychotics, corticosteroids and vasoactive drugs, attempts at enteral or  
parenteral feeding, and early mobilization.  To document protocol adherence, we will collect daily information 
regarding screening for Criteria to Initiate Weaning, and results of the Pre-SBT readiness assessment and SBTs, 
as well as use of assist/control mode, PAV+ and PSV throughout the study period, and any deviations from 
protocol.  We will collect data regarding interventions such as tracheostomy or use of non-invasive ventilation 
(NIV) post-extubation, and reintubation.  Safety data will be collected using the serious adverse event form.  
Data used to calculate outcomes will include time and date of all SBTs, extubations, reintubations, tracheostomy 
mask trials, ICU discharge, hospital discharge, and vital status at ICU and hospital discharge.  Vital status will also 
be determined at day 90 post randomization.   
 

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9.2 Outcome Measures and Duration of Follow-up 
Liberation from invasive mechanical ventilation is achieved at the moment of “successful extubation” for patients 
with an endotracheal tube, or at the moment of “successful termination of invasive MV” for patients with a 
tracheostomy tube. 
 
For patients with an endotracheal tube, “successful extubation” is defined as removal of the endotracheal tube 
AND remaining alive with no need for reintubation/reinstitution of invasive mechanical ventilation for 7 days post 
extubation, or until successful ICU discharge, or until live hospital discharge, whichever comes first.      
 
For patients with a tracheostomy tube, “successful termination of invasive MV” is defined as having the 
tracheostomy tube disconnected from the ventilator AND remaining alive with no need for reinstitution of 
invasive MV for 7 consecutive days, or until successful discharge from ICU, or until live hospital discharge, 
whichever comes first. 
 
“Successful ICU discharge” is defined as leaving the ICU where the patient was receiving invasive MV, AND 
remaining alive with no need for reinstitution of invasive MV AND no need for readmission to ICU within 48 hours 
of ICU discharge. 
 
“Ventilator-free days” (VFDs) are defined as the number of days alive and free of INVASIVE ventilation post 
SUCCESSFUL EXTUBATION or post successful termination of invasive MV.  Non-invasive ventilation may be used 
post extubation, but is not counted as “invasive ventilation.”  If the patient dies before achieving successful 
extubation or successful termination of invasive MV, that patient will have 0 VFDs.  However, if a patient dies 
AFTER achieving successful extubation, successful termination of invasive MV, or successful ICU discharge, that 
patient will have the number of VFDs counted as the number of days alive and free of invasive MV occurring 
between time of successful extubation/successful termination and time of death. 
All time intervals and durations will be measured in days (to the nearest 1/10 of a day) and calculated from the 
day and hour of randomization to the day and hour of the event (eg. day and hour of successful extubation, 
successful termination of invasive MV, successful ICU discharge, live hospital discharge, or death). 
 
Patients will remain in the study and will continue on the assigned ventilation strategy until: successful extubation, 
successful ICU discharge, live hospital discharge, death, or 90 days post randomization, whichever comes first.  All 
intubations and extubations (or for patients with tracheostomy, all disconnections lasting >48 hrs and 
reconnections following 48 hrs off ventilator) will be tracked from date of hospital admission to day 90 or date of 
death.  Date of last follow-up will be 90 days post-randomization, when vital status will be assessed. 
 
9.3 Confidentiality 
Original records for each participant in the study will be maintained in separate files in a secure, limited access 
location at the study site for the duration of the study and after study completion for 15 years. 
 
Copies of the de-identified documents may be made and supplied to the sponsor representative for the purposes 
of ongoing data monitoring and analysis of results.  
 
Participants’ identities will be kept confidential by assigning each participant a participant ID upon enrollment into 
the study.  
 
The investigator must assure that participant confidentiality will be maintained and that participant identities shall 
be protected from unauthorized parties. On eCRFs or other documents submitted to the CC, participants should 
not be identified by their names, but by their participant identification code, which is assigned in the eCRF. The 

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investigator should keep a participant code log relating codes to the names of participants. The investigator should 
maintain study documents that are not for submission to the CC (e.g., participants’ written consent forms), in 
strict confidence. 
 
Information about study participants will be kept confidential and managed according to national and local 
requirements. Consistent with these regulations a signed authorization will be obtained that informs each 
participant of the following: 
   
 
What protected health information (PHI) will be collected from participants in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of participant authorization.  For participants 
that have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the participant is alive) at the end of their scheduled study period. 
 
9.4   Source Documents 
Source data are all original information (i.e. the first recorded instance of data), records of clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the study.  
Source data are contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical charts, laboratory results, evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, x-rays, and participant files.  
 
All entries in the eCRF must be backed up by source data.  Source data must be made available if requested by the 
Sponsor or CC. Study records should be kept in accordance with applicable national and local laws and regulations. 
 
Sites will be provided with a printout of the eCRF which may be used as a tool for data collection.  Whenever 
possible, source data should be transcribed directly into the eCRF from source.  E.g. if a lab report is available, this 
is considered source data and these values should be entered to the eCRF, and not transcribed onto the paper 
copy of the CRF.  However, the paper CRF will serve as the source document for any assessments that are 
completed only by the investigator and not otherwise documented in the patient’s medical chart.  
 
9.5 Case Report Forms 
Medidata RAVE® will be used for this study for web-based randomization and data collection. All study data will 
be entered in electronic case report forms (eCRF) at the study site. Data collection will be completed by authorized 
study site personnel designated by the site Investigator. Appropriate security measures will be taken to authorize 
study site personnel using unique usernames and passwords prior to any data being entered into the system.   
 
The study data will be housed on a secure in-house server at St. Michael’s Hospital in Toronto throughout the 
duration of study, and up to 15 years after the study is complete.  
 
All eCRF corrections are to be made by an Investigator or other authorized study site personnel. The site 
Investigator must confirm by his/her electronic signature in a specific section of the eCRF to confirm that he/she 
has reviewed the data, and that the data is complete and accurate. 
 

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Data validation procedures will be described in detail in the Data Validation and Management Plans. 
 
9.6 Record Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented and the study data to be subsequently verified. The investigator study file (ISF), commonly referred 
to as the regulatory binder, will contain the study’s Essential Documents as noted by local regulatory guidelines. 
 
Should the investigator wish to assign the study records to another party or move them to another location, the 
investigator must notify the CC and the CC must provide acknowledgment in advance.  Study records at each site 
should be stored as per local requirements.  If there are no local requirements they should be retained for 15 
years after the completion of the trial. 
 
10.0 Study Schedule of Events 
 
The Ventilator Algorithms for PAV+ and PSV are located in Appendices C and D, respectively. The Enrolment 
Algorithm is located in Appendix A.    
 
 
10.1   Run-In Phase  
To assess for feasibility and compliance a run-in phase will be implemented at each site prior to randomizing 
patients in the trial.  Each site will have a contract and ethics approval in place, and will have received training as 
needed on use of the ventilation algorithms for PSV and PAV+ and use of the data capturing system prior to 
beginning the run-in phase.  During the run-in phase, each site will follow the screening and enrolling procedure 
as outlined in the protocol.  After obtaining consent (a priori or deferred) to participate, the first eligible patient in 
participating ICUs will be assigned to the PAV+ algorithm, and the second eligible patient will be assigned to the 
PSV algorithm.  The PAV+ run-in patient will receive the study intervention and follow-up until day 7, or until 
completing the study, as defined in the study protocol, whichever comes first, and the PSV run-in patient will 
receive the study intervention and follow-up until day 3, or until completing the study, as defined in the study 
protocol, whichever comes first.  After patients exit the run-in phase, no further safety assessments or data 
collection will occur.  After exiting the run-in phase, all treatment decisions, including ventilation strategy, will be 
at the discretion of the treating physician.  Upon completion of the first and second run-in patients, the 
completed CRFs will be evaluated by the CC to assess (i) the ability of the participating centre to screen and enroll 
patients, (ii) compliance with study procedures, (iii) data completeness and timeliness of data collection.   Should 
the CC or the participating site identify problems in any of these 3 areas of assessment, further run-in patients will 
be enrolled and the process will be re-evaluated.  Once the approval is granted from the CC, the run-in phase is 
concluded and sites will be able to enroll and randomize patients in the PROMIZING trial. 
 
The initial start-up fee is inclusive of the run-in phase.  No per-patient fees are allotted to sites for patients in the 
run-in phase.  Patients in the run-in phase will not be included in the final data set. 
 
10.2   Screening and Eligibility Assessment  
All patients admitted to a participating site ICU during the study period meeting the screening inclusion criteria 
will be entered into a screening log and followed daily until they satisfy all inclusion criteria, are enrolled and 
randomized, or meet one of the exclusion criteria and exit the screening/enrolment process.  A participant will be 
ineligible for participation in this study and will be counted as a “screen failure” if he or she satisfies any one or 
more of the exclusion criteria. A staged enrolment process will be used to identify patients eligible to be enrolled 
and randomized in the study.  The five stages of enrolment are: 
 

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A. Screening Criteria  
B. Consenting Criteria and Obtaining Consent 
C. Pressure Support Trial Criteria and the Pressure Support Trial 
D. Weaning Criteria and the ZERO CPAP Trial and the Spontaneous Breathing Trial (SBT) 
E. Randomization Criteria  
 
See section 7.0: Participant Identification and Appendix B for additional information on screening and eligibility 
assessment. 
 
Informed consent will be administered prior to any study procedures and will be compliant with local 
institutional/REB requirements. See sec. 15.3 for additional information on consent. 
 
10.3   Randomization & Blinding  
10.3.1 Randomization 
Participants will be randomized once eligibility is determined, by having satisfied all of the inclusion criteria and 
none of the exclusion criteria, have passed the Pressure Support Trial and either not meeting Weaning Criteria or 
failing the ZERO CPAP Trial or failing the SBT.  Each participant in this study will be randomized to either PSV or 
PAV+ in a 1:1 ratio in Medidata RAVE. 
 
Participant allocation to procedure group will be via variable block randomization with varying block sizes and 
stratified by site to minimize the likelihood of predicting the next procedure assignment. Randomization will be 
attained using computer generation sequence methodology, ensuring that the randomization methodology and 
the generated allocation sequence are concealed from the investigator and participants. 
10.3.2 Blinding 
Neither the clinical team nor the study investigators will be blind to the study intervention. The study statistician 
will be blind to the study arm. 
 
10.4   Baseline Assessment 
A Pre-Randomization assessment will be recorded immediately prior to implementing PSV or PAV+ to provide a 
baseline measure for evaluation.   The Pre-Randomization assessment will include: 
 
Ventilator settings and most recent arterial blood gas (ABG) results prior to the Pressure Support Test (PST) 
 
Ventilator settings used for the PST, and respiratory parameters, vital signs, and arterial blood gas results 
at the end of the PST 
A Randomization form will be completed to document: 
 
Weaning Criteria  
 
ZERO CPAP Trial result (RR and Vt or RSBI) 
 
SBT result: failure criteria   
 
Randomization assignment 
 
10.5   Administration of Intervention 
Switching ventilator mode to PSV or PAV+ with adjustment of the settings according to the assigned PSV or PAV+ 
Ventilation Strategy will indicate administering the intervention.  The intervention (the PSV or PAV+ Ventilation 
Strategy) is administered continuously from time of randomization until study completion (study completion 
occurs at time of successful extubation/successful termination of invasive MV, successful ICU discharge, hospital 
discharge, death or 90 days post randomization, whichever comes first.   

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10.6   Follow up assessments and Final Study Visit 
A Post-Randomization assessment will be recorded 1 hour post-randomization and will include: 
 
 
Make and model of ventilator, ventilator settings, respiratory parameters and vital signs 
 
Day of randomization is considered Day 1, until 0700 a.m.  Each subsequent study day is from 0700 a.m. to 0700 
a.m.  Daily follow-up “snapshot” assessments are completed daily (or on selected days) between 0800 a.m. -1200 
p.m. and will include daily assessment for Criteria to Initiate Weaning and results of Pre-SBT readiness assessments 
and SBTs. 
Daily follow-up “cumulative” assessments are completed based on the 0700 – 0700 hrs time frame and will 
include data on co-interventions administered in each 24 hour interval.   
 
Event-based assessments are conducted at the time of the following events:  extubation, use of NIV post-
extubation, reintubation, tracheostomy, protocol deviation, or serious adverse events.   
 
An outcome assessment will be recorded to document time of successful extubation, time of successful ICU 
discharge, time of hospital discharge, or death. 
 
A final study visit will occur on Day 90 to document vital status and outcome assessment if not previously 
completed. 
 
 
10.7   Protocol Amendments and Deviations 
Investigators must read, understand and follow the study protocol.  
 
Amendments are changes to the protocol (or protocol procedures) that are planned and that are approved by the 
REB prior to implementation.  Changes to the protocol shall only be made by the EC in the form of protocol 
amendments. The CC is responsible for the distribution of any protocol amendments to site Investigators. Site 
Investigators are responsible for the distribution of an amendment to all staff involved in the study and for 
obtaining approval for the amendment from the local REB as required by local institutional guidelines. 
 
Deviations differ from amendments in that they generally apply to a single occurrence or participant, and are not 
intended at the time to modify the entire protocol.  Examples of protocol deviations that must be recorded and 
reported to the CC and may be reported to the REB per local institutional requirements include the following: 
 
 
Implementation of additional procedures for monitoring participants, beyond the standard of care;  
 
Suspension of enrollment of new participants;  
 
Suspension of research procedures in currently enrolled participants  
 
In the event that a patient is randomized in error (e.g. incorrect eligibility assessment) the site should notify the CC 
immediately, and make a note in the patient’s source documents.  Patients randomized in error will be withdrawn 
from the study.  The site will be required to document and implement a preventative action plan to avoid future 
errors.   
 
If an unanticipated deviation or divergence from the approved research protocol, consent document(s) or study 
addenda jeopardizes participants, study efficacy or data integrity, it must be promptly reported to the CC and 

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may be reported to the local REB per local institutional requirements, if it has not otherwise been reported 
through an amendment to the protocol or consent form.  Specific examples of reportable deviations (i.e., if they 
place participants at a greater risk) include the following:  
 
 
Informed consent improperly obtained or not obtained;  
 
Participant enrolment without meeting the eligibility criteria and without prior sponsor approval;  
 
Eligibility Waiver: participant enrolment without the eligibility criteria with prior sponsor approval;  
 
Assigned ventilation strategy not administered per protocol with increased risk of harm to participant; 
 
Major, non-emergent deviations without prior approval;  
 
Emergency deviations to the research protocol initiated by the investigator prior to obtaining REB 
approval to (e.g., eliminate apparent immediate hazards to participants). 
 
Emergency deviations to the research protocol (e.g. to eliminate apparent immediate hazards to 
participants) will also be reported to funding agencies according to contract stipulations, no later than five 
(5) working days after the emergency situation occurred.  Protocol Deviations that lead to an SAE must be 
reported according to guidelines set forth in section 11.3.   
 
11.0 Safety Assessments 
 
11.1 General Comments 
The ventilation algorithms and study protocol provide a variety of measures to ensure the safety of enrolled 
patients, including instructions to use assist/control ventilation in case of clinical instability , or in the event that 
respiratory distress or impaired gas exchange does not resolve with optimizing ventilator settings on PAV+ or PSV.  
Based on the 2 pilot studies performed by the co-primary investigators, we anticipate no increase in risk to 
participants in this trial.  Nonetheless, the target population for this trial is critically ill patients with a high 
baseline risk of complications and death.  We expect that some patients may die during the course of their 
enrolment in the study.  If the patient expires the site investigator is required to complete a SAE assessment in 
their source documents.  A death due to a decision to withdraw life support, or a decision to not re-intubate 
post extubation, or a change in the goals of care, does not constitute a serious adverse event and does not need 
to be reported as such.  We are interested in reviewing Serious Adverse Events that may be related to the study 
interventions, rather than adverse events that occurred due to the underlying critical illness.  An independent 
Data Safety Monitoring Board (DSMB) will review each Serious Adverse Event for which a possible, probable, or 
definite relationship to the study intervention exists. 
 
Notwithstanding the safety measures provided within the ventilation algorithm, in the event of an emergency 
situation, the site PI and/or attending physician will ensure that best medical judgment is used to protect the life 
or well-being of the participant, which may include deviations from the Protocol.  The safety and welfare of 
participants in the study takes absolute precedence over the evaluation goals and objectives of the study, in any 
emergency situation.  Reporting of protocol deviations is described in section 10.7, and reporting of serious 
adverse events is described below in section 11.3. 
 
A Serious Adverse Event (SAE) in the PROMIZING Study is defined as: 
 
Any adverse event that results in 1 of the following: 
 
 
Results in unanticipated/non-palliative death 
 
 
Life-threatening 
 
Results in persistent or significant disability/incapacity: 
 

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 
Requires medical or surgical intervention to prevent one of the above outcomes 
 
Examples of reportable SAEs:  
 
Criteria for SAE 
Definition 
Results in unanticipated/ non-
palliative death 
An adverse event which directly results in the patient's death,   
excluding one-way extubations, withdrawal of life support, or 
expected deaths occurring in patients who have been made 
palliative (eg. Cardiac arrest with unsuccessful attempt at 
resuscitation) 
Life-threatening  
An event in which the subject was at risk of death at the time 
of the event (eg. respiratory or circulatory arrest with return of 
spontaneous circulation) 
Results in persistent or significant 
disability/incapacity 
An event which results in significant, persistent disability 
AFTER the event has resolved/ been treated (eg. hypotension 
leading to stroke with resulting hemiplegia) 
Requires medical or surgical 
intervention to prevent one of the 
above outcomes 
An important medical event that may not result in death or be 
life-threatening but may jeopardize the subject and requires 
medical or surgical intervention to prevent one of the above 
outcomes, based on appropriate medical judgment. (e.g. a 
patient has an episode of major agitation leading to self-
extubation, requiring re-intubation) 
 
11.2 Assessment and Reporting of a Serious Adverse Event (SAE) 
An SAE may be due to the participant’s underlying critical illness, or may be directly related to enrolment in the 
study (i.e. it is unlikely to have occurred if the patient were not enrolled in the study).   
It is the responsibility of the site PI to ensure all SAE’s are assessed to determine causality, that is, to 
determine the likelihood that the SAE was caused by a study intervention.   
The site PI should ask the attending physician caring for the patient at the time the SAE occurred to assist with 
assessment of causality.  An SAE may be assessed as being unrelated, unlikely related, possibly related, probably 
related, or definitely related to the study intervention, according to the definitions provided below.  In cases 
where causality is “unknown” or the site PI and attending physician have disagreement or doubt regarding 
whether an SAE has “unlikely” relation vs. “possible”relation to the study intervention, the site PI must contact 
one of the study co-PIs/sponsors (Dr. Bosma or Dr. Brochard) to discuss and adjudicate the SAE.    
 
Causality 
Unrelated 
A definitive alternative etiology for the AE must exist 
Unlikely 
Must have 2: 
 No temporal relationship to the intervention 
 Could readily have been produced by the patient’s clinical state or have been due to 
environmental or other interventions 
 Does not follow a known pattern of response to intervention 
 Does not reappear or worsen upon intervention re-exposure  
Possible 
Must have 2: 
 Reasonable temporal relationship to the intervention 

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 Could not have readily been produced by the patient’s clinical state or have been due 
to environmental or other interventions 
 Follows a known pattern of response to intervention 
 Disappears or decreases with replacement of intervention with standard of care 
procedures and recurs with re-exposure 
Probable 
Must have 3: 
 Reasonable temporal relationship to the intervention 
 Could not have readily been produced by the patient’s clinical state or have been due 
to environmental or other interventions 
 Follows a known pattern of response to intervention 
 Disappears or decreases with replacement of intervention with standard of care 
procedures and recurs with re-exposure 
Definite 
Must have all 4: 
 Reasonable temporal relationship to the intervention 
 Could not have readily been produced by the patient’s clinical state or have been due 
to environmental or other interventions 
 Follows a known pattern of response to intervention 
 Disappears or decreases with replacement of intervention with standard of care 
procedures and recurs with re-exposure 
 
It is the responsibility of the site investigator to identify and report SAEs occurring between patient enrolment 
and study completion (enrolment occurs once patient or SDM has provided consent and study completion occurs 
once patient achieves successful extubation, successful ICU discharge, hospital discharge, dies, or day 90 post 
randomization, whichever comes first).   
 
SAEs are to be documented in source and in the Serious Adverse Events eCRF.  Whenever possible, if a unifying 
diagnosis can be made, all associated complications should be grouped together and reported as one SAE.   If the 
patient expires the site investigator is required to complete a SAE assessment in their source documents.  Sites 
can refer to the Data Entry Guidelines for instructions on how to access the eCRF.  The eCRF system (Medidata 
RAVE) will notify the study PI, CC and Medical Monitor of the SAE so that it may be immediately assessed for 
further action in any applicable local or federal requirements. 
 
The investigator or his/her designate will promptly report SAEs with probable or definite relation to study 
intervention within 24 hours of becoming aware of the event, and update as additional information becomes 
known.  Each site will also need to report SAEs with probable or definite relation to a study intervention to the local 
REB according to local institutional requirements. 
 
The site may be asked for additional information to assist with the assessment, and a narrative with appropriate 
clinical context should be included in each SAE reported. 
 
 
11.3  Definition and Reporting of an Adverse Device Effect 
Subject to section 59 of the Medical Device Regulations, any incident that comes to the attention of the 
investigator which meets the following conditions must be reported to the coordinating centre within 24 hours of 
becoming aware of the incident: 
 
(1) Incident is related to a failure of the device or deterioration in its effectiveness, or any inadequacy in its 
labeling or in its directions for use;  

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AND 
 
(2) Has led to the death or a serious deterioration in the state of health of a patient, user or other person, or 
could do so were it to recur.  
 
In such a situation, the investigator must complete the study Incident Report and submit the report to the 
coordinating centre within 1 business day of becoming aware of the incident. The following information will be 
required: date of the incident, details of the incident, course of action taken, and other relevant details.  
 
Follow-up reports must be provided to the coordinating centre as any new information becomes available. The 
device manufacturer will report these incidents to the Medical Devices Bureau of Health Canada within the 
timelines specified in section 60 of the regulations.  
(http://laws-lois.justice.gc.ca/eng/regulations/sor-98-282/page-13.html#h-42) 
11.4 Data Safety Monitoring Board (DSMB) 
The DSMB will review safety reports biannually. The DSMB will have the ability to request additionally safety 
analyses and make recommendations about the safe conduct of the trial.  The DSMB Chair will review all serious 
adverse events classified as probably or definitely related to enrolment in the trial within 7 days and 
communicate directly with the co-principal investigators, who in turn will communicate back to the Steering 
Committee. 
 
12.0 Statistical Plan 
 
12.1 Sample Size Determination 
Primary and secondary outcomes will be analyzed at the conclusion of the trial. 
A table of sample sizes for time from randomization to first successful extubation/liberation is shown below. 
These calculations incorporate death by treating death as censoring. The current hazard rate for death is used in 
this calculation. The final column is obtained by dividing the “Total N” column by 0.95 to account for the 5% 
dropout. Assuming this increase is sufficient to observe the required number of events in the presence of the 
drop-out, it should be a reasonable target. 
All calculations are using 80% power and 2-sided Type I error of 5%.   Exponential survival is assumed for the 
purposes of hazard calculations. The expected median time to extubation in PAV is determined from the PSV 
value by converting to the hazard scale, multiplying by the hazard ratio and converting back to time. 
Median Time (PSV) Median Time (PAV) Difference Hazard Ratio Required Events Total N Total N (5% lost) 
7.40 
6.17 
1.23 
1.20 
944 
1095 
1153 
7.40 
5.92 
1.48 
1.25 
630 
729 
768 
7.40 
5.69 
1.71 
1.30 
456 
526 
554 
7.50 
6.25 
1.25 
1.20 
944 
1097 
1155 
7.50 
6.00 
1.50 
1.25 
630 
731 
770 
7.50 
5.77 
1.73 
1.30 
456 
527 
555 
7.55 
6.29 
1.26 
1.20 
944 
1098 
1156 
7.55 
6.04 
1.51 
1.25 
630 
731 
770 

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7.55 
5.81 
1.74 
1.30 
456 
528 
556 
7.60 
6.33 
1.27 
1.20 
944 
1099 
1157 
7.60 
6.08 
1.52 
1.25 
630 
732 
771 
7.60 
5.85 
1.75 
1.30 
456 
528 
556 
7.70 
6.42 
1.28 
1.20 
944 
1101 
1159 
7.70 
6.16 
1.54 
1.25 
630 
733 
772 
7.70 
5.92 
1.78 
1.30 
456 
529 
557 
 
As planned a priori, we used aggregate, blinded data from the first 120 patients to re-estimate our sample size.  
Using a time to event analysis, median time to successful liberation in the entire cohort was 
6.8 days.  The minimum clinically important difference in time to successful liberation is deemed to be 1.0 day.  
Using a hazard ratio of 1.30, to demonstrate a reduction in the median duration of ventilation by 1.78 days 
(assuming 7.70 days versus 5.92), alpha of 0.05 (two-sided) and a power of 80%, requires 529 patients.  
Anticipating a maximum loss to follow-up (e.g. consent withdrawn) rate of 5%, 558 patients 
(279 per group) should be randomized in the study.  Using a hazard ratio of 1.25, to demonstrate a reduction in 
the median duration of ventilation by 1.51 days would require770 patients (385 per group) to be randomized in 
the study.   
 
We anticipate being able to enroll a minimum of 558 patients within the planned 5 year enrolment period.  If 
enrolment exceeds expectations, we will be powered to show a smaller difference between the 2 groups, which 
will still be clinically important.  The enrolment period will continue until we have complete data on randomized 
participants and have attained the minimum number of required events in our study cohort. 
 
12.2   Statistical Methods Analysis 
 
Analysis will follow the intention-to-treat principle. Baseline data will be analyzed descriptively (e.g. 
mean and standard deviation, median and interquartile range, counts and percentages as appropriate). 
Time to extubation will be summarized by cumulative incidence curves with death treated as a 
competing risk and compared between groups with the Gray test. The treatment effect will be expressed 
as a hazard ratio with 95% confidence interval from a multistate generalization of the Cox model. 
Additionally, a cause-specific Cox model where death is treated as a censoring event will be fit for 
comparison. Patients with missing outcome data will be censored at last contact. The secondary 
outcomes of ventilator-free days will be compared between the groups by means of a Wilcoxon test. The 
treatment effect will be expressed as the difference in median ventilator free days along with a 95% 
confidence interval obtained by bootstrap methods. The time-to-event outcomes ICU discharge and 
hospital discharge present the same special challenge as the primary outcome because death is a 
competing risk. Furthermore, "survivor-only" analyses are an improper subgroup which further 
complicates interpretation. To mitigate these problems, cumulative incidence curves will be constructed 
that provide estimates of the outcome of interest, accounting for death. Cause-specific treatment effects 
will be given as hazard ratios with 95% confidence intervals from Cox models. Time-to-death will be 
analyzed using standard methods for survival data (Kaplan-Meier curve, log-rank test) and the treatment 
effect will be expressed as a hazard ration with 95% confidence interval. Four of the secondary 
outcomes describe weaning difficulties in various ways. These also suffer from the competing risk of 
death and other improper subgroup issues. These outcomes will be looked at primarily from a 
descriptive perspective. The outcome, "requiring A/C" will be compared by a chi-square test (or Fisher's 
Exact Test) and treatment difference will be expressed as an odds ratio with 95% confidence interval. 

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For days requiring A/C, patients not receiving A/C will be assigned a value of zero. Although a t-test is the 
appropriate parametric approach, the non-parametric Wilcoxon rank-sum will be favoured if there 
are many ‘null’ (zeros) entries. Total medication dose, pain, agitation, and delirium scores will be 
compared by a t-test between study arms. Ordinal regression analyses will be used to assess factors 
associated with weaning group classification (short/difficult/prolonged weaning groups). Exploratory 
analyses using multiple regressions will be used to identify factors associated with duration of MV. 
 
The secondary outcome of Ventilator-Free Days (VFD) has a number of difficulties, one of which is that death is 
indistinguishable from someone alive at day 21 but still ventilated. Analysis of survivors only results in an improper 
sub-group and potentially loses the benefits of balanced confounders due to randomization. Therefore a number 
of secondary and supplemental analyses are planned to fully understand any observed treatment effect. One 
analysis will assign -1 to deaths (instead of zero) to make that distinction. We will also examine time on ventilator 
in a number of ways (some of which subsume secondary outcomes). A Poisson regression model can be used 
which considers number of days on ventilator as the outcome and uses the logarithm of the number of days 
observed (up to 21) as an offset. Another analysis will consider time to extubation as the outcome with death 
treated as a competing risk. Cumulative incidence curves will be produced and suitable competing risks survival 
model will be used to estimate a treatment effect. Finally, a marginal structural model will be employed where 
first the probability of surviving will be modeled and then the weighted analysis of the survivors will be carried 
out using the inverse of the survival probability as the weight. 
 
There are 4 planned subgroup analyses based on: (a) duration of MV prior to randomization greater than 5 days, 
which is associated with prolonged weaning; (b) failed SBT prior to randomization, depicting a subgroup classified 
as difficult weaning vs. failed CPAP 0 trial vs. failed weaning criteria prior to randomization; (c) failed extubation 
prior to randomization, depicting a subgroup classified as difficult weaning; and (d) mild vs. moderate vs. severe 
frailty. 
 
There are 2 planned sensitivity analyses of primary and secondary outcomes, based on:  (a) defining “successful 
extubation” as “48 hours without reintubation”; and (b) assigning a value of 0 ventilator-free days to any 
participant who dies at any time during the study period. 
 
The secondary VFD outcomes will be analyzed similarly to the primary outcome. Similar methods will also be 
applied to ICU free days as these outcomes suffer from the same limitations as VFD. The time-to-event outcomes 
(except mortality) present special challenge because death is a competing risk. Furthermore, as stated above 
"survivor-only" analyses are an improper sub-group which further complicates interpretation. To mitigate these 
problems, cumulative incidence curves will be constructed that provide estimates of the outcome of interest, 
accounting for death. Cause-specific treatment effects will be given as hazard ratios with 95% confidence intervals 
from Cox models. Time to death will be analyzed using standard methods for survival data (Kaplan-Meier curve, 
log-rank test) and the treatment effect will be expressed as a HR with 95% confidence interval. Four of the 
secondary outcomes describe weaning difficulties in various ways. These also suffer from the competing risk of 
death and other improper sub-group issues. These outcomes will be looked at primarily from a descriptive 
perspective. The complication outcome, "ever requiring A/C" will be compared by a chi-square test (or Fisher's 
Exact Test if needed) and treatment difference will be expressed as an odds ratio with 95% confidence interval. 
For days requiring A/C, patients not receiving A/C will be assigned a value of zero. Although a t-test is the 
appropriate parametric approach here, it may be preferable to use the non-parametric Wilcoxon rank-sum if there 
are many zeros. Finally, total medication dose will be compared by a t-test. 
 
 

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13.0 Trial Management  
 
13.1 Study Oversight 
Lawson Health Research Institute (Lawson) in London, Ontario, Canada will oversee all contracts, trial insurance 
and financial disbursements. 
 
The Applied Health Research Centre (AHRC) in Toronto, Ontario, Canada will serve as the Coordinating Centre 
(CC) for the study. 
 
The Executive Steering Committee (EC) will consist of the lead investigators (KJB, LB, KEAB, CM, JM, YS) with 
support from the study statistician (KT) and the AHRC coordination centre. The executive committee will 
oversee all aspects of the study including implementation of all policies and the daily operations. The EC will 
meet weekly during the planning phase of the trial and bimonthly thereafter.  Regular meetings with Site 
Investigators by region (eg. Europe, Canada, Argentina, Saudi Arabia) will occur before enrollment begins, and 
monthly or bi-monthly to discuss enrollment rates and non-adherence and at the completion of the study. 
 
13.2 Study Monitoring 
Participating sites will be contacted by the coordinating centre during the study to follow the recruitment and the 
return of study documents (e.g. copy of screening/enrollment log forms), and to address any issues that the site 
may have or any questions related to the study.  
 
In addition, on-site monitoring visits will be planned by the coordinating centre. A risk-based approach will govern 
the monitoring activities for this study. A combination of centralized and on-site monitoring activities will be used 
to ensure the quality of the data captured, the study operations, and the safety of patients.  
 
Source data verification on critical data elements will be performed on a selection of the participants by comparing 
the data in the patient’s files (source documents) with data in the CRF, and will be conducted as per the Sponsor-
approved Monitoring and Quality Plan. Electronic CRF will not constitute source documentation and data entered 
in the CRF must be traceable to an original source record (electronic or paper) either as part of the electronic 
database or in the patient’s file. For selected patients, the presence of a signed written informed consent as well 
as compliance with inclusion and exclusion criteria will be checked. 
 
The Investigators must agree to monitoring visits at the site, providing direct access to source/data verification 
and cooperation with the monitors. Key study personnel must be available to assist the monitor during these 
visits. 
 
The purpose of monitoring visits is, but is not limited to, the following: 
 
Evaluate study progress; 
 
Check compliance with the study protocol; 
 
Discuss safety issues; and 
 
Assure continuous good clinical practice (GCP) compliance of the site. 
 
A monitoring report will be provided to the Sponsor for each visit in which the progress of the study is documented 
and all issues will be described. The monitor has the right to compare entries in the CRFs with original data in the 
patient’s files and must treat patient data as confidential. Patients must have consented to data inspection. The 
Investigator(s) must maintain source documents for each patient in the study, consisting of case and visit notes 
containing demographic and medical information, relevant laboratory data, and the results of any other tests or 
assessments. The Investigator(s) must also keep the original copy of the signed ICF. No information in source 

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documents about the identity of the patients will leave the study site. If it is necessary to provide any personal 
information of the patients, all data will be sent without personal health identifiers. 
 
13.3   Auditing and Inspecting  
The investigator will permit study-related monitoring, audits, and inspections by the REB, the Sponsor, the CC and 
government regulatory bodies, of all study-related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. intensive care units, etc.). 
 
14.0 Ethical Considerations 
 
14.1 Declaration of Helsinki / ICH Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with the principles of the Declaration of 
Helsinki and with the ICH Guidelines for Good Clinical Practice. 
 
14.2 Research Ethics Board Approval 
According to local laws and regulations, the study protocol and the participant informed consent form (in the local 
language) must be approved by an REB for each participating centre. 
 
14.3 Informed Consent 
It is an obligation of the participating site to administer informed consent with the participant or Substitute 
Decision Maker (SDM) by means of a dated and signed informed consent form.  Consent should be obtained 
prior to randomization whenever possible; however, if the participant is incapable of providing informed 
consent and no SDM is available within the randomization window, consent must be sought as soon as possible 
after randomization (provided that the local Research Ethics Board has provided approval for deferred consent). 
The informed consent form must be written in the local language in accordance with local laws and regulations.  
 
‘Informed consent’ also implies individual discussion with the participant/SDM about the nature of study 
treatment and examinations to be conducted in a language that is easy to comprehend. The participant/SDM 
should fully understand that his/her refusal to participate in the study will not affect the quality of medical care. 
In addition, the participant/SDM must be informed that, without disclosing his/her name, relevant medical data 
will be disclosed to the Coordinating Centre (CC), that his/her medical records will be inspected during on-site 
monitoring, and may be inspected again by auditors and/or regulatory authorities. 
 
The participant/SDM should be informed in writing that his/her medical data relevant to this study will be stored 
and analyzed while maintaining confidentiality in accordance with local data protection laws. All data transferred 
to the eCRF and any process derived from the eCRF will be de-identified.  In cases where the participant dies prior 
to being capable of providing informed consent, and there is no SDM available, the de-identified data will be 
included in the eCRF in centres where the Research Ethics Board permits waived consent under such 
circumstances. 
 
Should a protocol amendment be made, the informed consent form may be revised to reflect the changes in the 
protocol. It is the responsibility of the investigator to ensure that an amended informed consent form is reviewed 
and approved by the local REB, and that it is signed by all participants/SDMs subsequently entered in the study 
and those currently in the study, if affected by the amendment. 
 

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15.0 Study Finances 
 
15.1 Funding Source 
This study is funded by a Canadian Institutes of Health Research (CIHR) Operating Grant: Industry-partnered 
Collaborative Research Grant, with Covidien LP, a Medtronic company as the industry partner, and by a CIHR 
Project Grant.  Funding from Covidien LP, a Medtronic company, is provided through the Covidien Investigator 
Sponsored Research (ISR) Program and subsequently the Medtronic External Research Program (ERP). 
 
15.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study must disclose it to the CC or sponsor/principal 
investigator immediately upon becoming aware of the conflict.  The conflict will be reviewed by the 
sponsor/principal investigator and a decision will be made regarding how to proceed with the affected 
investigator’s involvement in the study. 
 
16.0 Publication Plan 
 
Since the PROMIZING study is a multicenter study, it is the intention of the co-Principal Investigators that the 
first publication or presentation of the results and data of this study will be made to our collaborators in the two 
scientific networks supporting this study:  the Canadian Critical Care Trials Group (CCCTG) and the Réseau 
Européen de Recherche en Ventilation Artificielle (REVA), and in conjunction with presentation of the study 
results and data with the investigators and the institutions from all appropriate sites contributing data, analyses 
and comments.  Site principal investigators will be invited to contribute to writing and reviewing the primary 
manuscripts and abstracts.  The primary manuscript and abstracts will undergo review by the steering 
committee and internal peer review by the CCCTG. 
 
For the main results, we plan to submit an abstract for presentation at an international critical care meeting and 
possibly to national meetings, and we plan to submit a manuscript for publication in an international medical 
journal.   
 
Additional secondary analyses, using the database, can be proposed by investigators and will be discussed with 
the steering committee. 
 
17.0 References 
 
 [1]  S. Levine, T. Nguyen, N. Taylor, M. E. Friscia, M. T. Budak, P. Rothenberg, J. Zhu, R. Sachdeva, S. Sonnad, L. R. 
Kaiser, N. A. Rubinstein, S. K. Powers, and J. B. Shrager, "Rapid disuse atrophy of diaphragm fibers in mechanically 
ventilated humans," N. Engl. J. Med, vol. 358, no. 13, pp. 1327-1335, Mar.2008. 
 [2]  S. Jaber, B. J. Petrof, B. Jung, G. Chanques, J. P. Berthet, C. Rabuel, H. Bouyabrine, P. Courouble, C. Koechlin-
Ramonatxo, M. Sebbane, T. Similowski, V. Scheuermann, A. Mebazaa, X. Capdevila, D. Mornet, J. Mercier, A. 
Lacampagne, A. Philips, and S. Matecki, "Rapidly progressive diaphragmatic weakness and injury during 
mechanical ventilation in humans," Am. J. Respir. Crit Care Med, vol. 183, no. 3, pp. 364-371, Feb.2011. 
 [3]  M. B. Hudson, A. J. Smuder, W. B. Nelson, C. S. Bruells, S. Levine, and S. K. Powers, "Both high level pressure 
support ventilation and controlled mechanical ventilation induce diaphragm dysfunction and atrophy," Crit Care 
Med, vol. 40, no. 4, pp. 1254-1260, Apr.2012. 

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 [4]  A. W. Thille, P. Rodriguez, B. Cabello, F. Lellouche, and L. Brochard, "Patient-ventilator asynchrony during assisted 
mechanical ventilation," Intensive Care Med, vol. 32, no. 10, pp. 1515-1522, Oct.2006. 
 [5]  K. Bosma, G. Ferreyra, C. Ambrogio, D. Pasero, L. Mirabella, A. Braghiroli, L. Appendini, L. Mascia, and V. M. 
Ranieri, "Patient-ventilator interaction and sleep in mechanically ventilated patients: pressure support versus 
proportional assist ventilation," Crit Care Med., vol. 35, no. 4, pp. 1048-1054, 2007. 
 [6]  A. Esteban, A. Anzueto, F. Frutos, I. Alia, L. Brochard, T. E. Stewart, S. Benito, S. K. Epstein, C. Apezteguia, P. 
Nightingale, A. C. Arroliga, and M. J. Tobin, "Characteristics and outcomes in adult patients receiving mechanical 
ventilation: a 28-day international study," JAMA, vol. 287, no. 3, pp. 345-355, 2002. 
 [7]  A. Torres, R. Aznar, J. M. Gatell, P. Jimenez, J. Gonzalez, A. Ferrer, R. Celis, and R. Rodriguez-Roisin, "Incidence, risk, 
and prognosis factors of nosocomial pneumonia in mechanically ventilated patients," Am. Rev. Respir. Dis., vol. 
142, no. 3, pp. 523-528, 1990. 
 [8]  N. R. MacIntyre, "Evidence-based assessments in the ventilator discontinuation process," Respir. Care, vol. 57, no. 
10, pp. 1611-1618, Oct.2012. 
 [9]  A. W. Thille, P. Rodriguez, B. Cabello, F. Lellouche, and L. Brochard, "Patient-ventilator asynchrony during assisted 
mechanical ventilation," Intensive Care Med., vol. 32, no. 10, pp. 1515-1522, 2006. 
[10]  M. J. Tobin, F. Laghi, and A. Jubran, "Narrative review: ventilator-induced respiratory muscle weakness," Ann. 
Intern. Med, vol. 153, no. 4, pp. 240-245, Aug.2010. 
[11]  V. M. Ranieri, S. Grasso, L. Mascia, S. Martino, F. Tommasco, A. Brienza, and R. Giuliani, "Effects of proportional 
assist ventilation on inspiratory muscle effort in patients with chronic obstructive pulmonary disease and acute 
respiratory failure. (Clinical Investigation)," Anesthesiology, vol. 86, no. 1, pp. 79-91, 1997. 
[12]  M. Wysocki, P. Meshaka, J.-C. Richard, and T. Similowski, "Proportional-assist ventilation compared with pressure-
support ventilation during exercise in volunteers with external thoracic restriction," Crit Care Med, vol. 32, no. 2, 
pp. 409-414, 2004. 
[13]  M. Younes, A. Puddy, D. Roberts, R. B. Light, A. Quesada, K. Taylor, L. Oppenheimer, and H. Cramp, "Proportional 
assist ventilation.  Results of an initial clinical trial," Am Rev Respir Dis, vol. 145, no. 1, pp. 121-129, 1992. 
[14]  V. M. Ranieri, R. Giuliani, L. Mascia, S. Grasso, V. Petruzzelli, N. Puntillo, G. Perchiazzi, T. Fiore, and A. Brienza, 
"Patient-ventilator interaction during acute hypercapnia: pressure-support vs. proportional-assist ventilation," J 
Appl Physiol, vol. 81, no. 1, pp. 426-436, 1996. 
[15]  N. Xirouchaki, E. Kondili, K. Vaporidi, G. Xirouchakis, M. Klimathlianaki, G. Gavriilidis, E. Alexandopoulou, M. 
Plataki, C. Alexopoulou, and D. Georgopoulos, "Proportional assist ventilation with load-adjustable gain factors in 
critically ill patients: comparison with pressure support," Intensive Care Med, vol. 34, no. 2026, p. 2034, 2008. 
[16]  Bosma KJ, Read B, Nikoo M, Bentall T, Harris C, Jones P, Priestap F, and VanderHeide R, "A Randomized Trial 
Comparing Weaning from Mechanical Ventilation on Pressure Supoprt vs. Proportional Assist Ventilation: A Pilot 
Study," Chest, vol. 144, no. 4 (MeetingAbstracts), p. 892A, Oct.2013. 

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[17]  G. Carteaux, J. Mancebo, A. Mercat, J. Dellamonica, J. C. Richard, H. Aguirre-Bermeo, A. Kouatchet, G. Beduneau, 
A. W. Thille, and L. Brochard, "Bedside adjustment of proportional assist ventilation to target a predefined range 
of respiratory effort," Crit Care Med, vol. 41, no. 9, pp. 2125-2132, Sept.2013. 
 
 
 

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Appendices  
Appendix A:  Enrolment Algorithm 
 

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D. Weaning Criteria 
 
C. Pressure Support   
Trial Criteria 
 
B. Enrolment 
Criteria 
 
Inclusion Criteria 
B1. Ability or potential ability to trigger ventilator 
breaths 
B2. Pplat  ≤ 30 cm H2O on volume cycled mode 
 OR PC + PEEP  ≤ 30 cm H2O on pressure-control  
 OR PS + PEEP  ≤ 30 cm H2O on pressure support 
 OR PAV gain <85% on proportional assist 
ventilation mode  
B3. PaO2 ≥ 60 mmHg or SpO2 ≥ 90% on            
FiO2 ≤ 0.60 and PEEP ≤ 15 cm H2O 
B4. Metabolic disorders corrected: pH ≥7.32 
B5. Stable hemodynamic status: stable or 
decreasing doses of vasopressors for ≥6 hours 
B6. Anticipate ongoing need for MV >24 hours 
Exclusion Criteria  
B7. Extubated 
B8. Died 
B9. On PSV 0-20 cm H2O or PAV 0-85% 
AND has met criteria B1-B5 for ≥24 
consecutive hours 
B10. Patient transferred to a non-participating 
centre 
 
Enrolment Deferral Criteria 
B11. Plan to extubate/discontinue MV within 
<24 hours  
B12. Patient currently on ECMO 
C9. Plan for surgery/procedure that will 
require full ventilation prior to extubation  
Inclusion Criteria 
C2. Upon review, 
patient still passes 
Criteria A and B 
C3. Treating MD 
consents  
Exclusion Criteria 
C12. Treating 
physician has 
declined consent 
Deferral Criteria 
C6. High dose vasopressors (i.e. epinephrine 
norepinephrine >0.5 g/kg/min or equivalent) OR 
↑dose of vasopressor within 6 hrs 
C7. Active cardiac ischemia (dynamic ST changes on 
monitor or ECG within 6 hours) 
C8. Unstable arrhythmias with HR>140 or SBP<90 
mmHg 
C10. Receiving a “strict lung protective” ventilation 
strategy for ARDS (eg.  Order on chart to keep Vt ≤6 
mL/kg PBW)   
Weaning Criteria 
Pass Pressure Support Trial AND 
D1. SpO2≥ 90% on FiO2 ≤0.40 and PEEP ≤8 cmH2O 
D2. pH ≥7.32 
D3. Vasopressor requirements ≤ norepinephrine 0.1 g/kg/min or equivalent. 
E. Randomization 
Criteria 
 
Inclusion Criteria 
C1. Patient/SDM has provided consent OR           
      Plan to obtain deferred consent  
E1. Upon review of Criteria A, B, and C, the 
patient still passes and the patient has passed 
the PST. 
E2. Does not meet Weaning Criteria OR 
       Fails the CPAP Trial OR  
       Fails the SBT 
Exclusion Criteria 
C4. Patient/SDM has declined consent 
C5. Patient incapable and no SDM available (not 
applicable if plan to obtain deferred consent) 
E3. Passed SBT on t-piece, FiO2 0.40 for 30-120 
minutes 
E4. Approval withdrawn by physician 
orpatient/SDM 
A. Screening 
Criteria 
Exclusion 
A3. Anticipating withdrawal of life support and/or shift to palliation  
A4. Severe central neurologic disorder  
A5. Known or suspected severe or progressive neuromuscular 
disorder 
A6. Severe COPD  
A7. Broncho-pleural fistula 
A8. Tracheostomy present at ICU admission for prolonged MV (>21 
days).   
A9. Current enrolment in a confounding study 
A10. Previous randomization in the PROMIZING Study 
A11. Severe, end-stage, irreversible respiratory or cardiac disease  
Inclusion 
A1. Age ≥18 years 
A2. Intubated, invasive MV     
≥24 hours 

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Appendix B:  Criteria to Change Mode of Ventilation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

•Criteria to Initiate Weaning:
•SpO2 ≥ 90%
•FiO2 ≤ 0.40
•PEEP ≤ 8
•pH ≥ 7.32
•vasopressors: norepinephrine 
≤0.1 ug/kg/min or equivalent 
and at a stable or decreasing 
dose ≥6 hours
•No Respiratory Distress (see 
definition
•No Clinical Instability (see 
definition)
•Criteria to Extubate:
•Criteria to initiate weaning still 
present
•Passed SBT
•A level of consciousness 
sufficient to ensure airway 
protection (as judged by the 
clinician)
•A cough strong enough to clear 
secretions (as judged by the 
clinician) and not requiring 
suctioning more than every 2 
hours
•Criteria to Switch from A/C to 
PSV or PAV+:
•Able to trigger ventilator 
breaths
•On assist/control with the 
following settings:
•AC/VC: Pplat≤30cmH2O with 
Vt 6-8 ml/kg OR
•AC/PC: PC+PEEP≤30cmH2O 
•PaO2 ≥ 60 mmHg or SpO2 ≥ 
90% on FiO2≤ 0.60 and PEEP  ≤ 
15 cm H2O 
•Metabolic disorders 
corrected; pH ≥7.32
•Stable hemodynamic status: 
stable or decreasing doses of 
vasopressors for ≥6 hours
•Absence of Clinical Instability 
(see definition)
•
•Criteria to Switch from PSV or 
PAV+ to A/C mode if ≥ 1 of:
•PS >20 cmH2O
•PS + PEEP > 30 cmH2O
•PAV+ >85%
•FiO2>60% required for SpO2
≥90% or
•Clinical instability (see 
definition)
•Unable to trigger vent 
(NMB/sedation)
Acute  
Phase:
Assist/Control
Recovery 
Phase:
PSV or PAV+
Weaning 
Phase:
Pre-SBT 
assessment, 
SBT
Liberation  
Phase:
Extubate
(NIV, 
reintubate)
Definition of Clinical Instability 
Any 1 of the following: 
1. Unstable hemodynamic status (SBP<80 mmHg) with or without 
vasoactive drug 
2. Vasopressor requirements >0.5 Pg/kg/min 
epinephrine/norepinephrine or equivalent 
3. Active cardiac ischemia (dynamic ST changes on cardiac monitor or 
electrocardiogram) 
4. Unstable arrhythmias (HR >140 or <50) with clinical signs of low 
cardiac output or SBP<80 mmHg) 
5. Uncontrolled hypertension (SBP>180 mmHg) 
6. Abrupt decrease in the level of consciousness (RASS -4 or -5 or SAS 1 
or 2) 
7. Dangerous agitation (RASS ≥+3 or SAS ≥6) 
8. Metabolic (or mixed) acidosis with pH <7.32 
 Emergency situation that merits return to full ventilation (A/C)  
according to best clinical judgement

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Appendix C:  PAV+ Ventilation Strategy 
 
ALGORITHM TO ADJUST PAV BASED ON PHYSIOLOGIC AND CLINICAL PARAMETERS 
Assess at least 
once daily while 
on A/C for 
Criteria for 
Switching from 
A/C to PAV 
Assess at least 
every 8 hours 
while on PAV to 
determine if 
adjustments are 
needed to 
maintain Target 
Range 
 
 
*Repeat blood 
gas q 30 min as 
needed to 
confirm pH 
7.32-7.47 
 
 
 
 
 
†Best clinical 
judgement 
should always 
prevail in 
setting of 
deterioration, 
with frequent 
reassessment 
until stable   
 
ALGORITHM FOR WEANING 
Assess at least 
once daily while 
on PAV for 
Criteria to 
Initiate Weaning; 
Attempt to wean 
FiO2 to 0.40 and 
PEEP to ≤8 cmH2O 
INITIATION OF PAV 
Ventilator Settings: 
 
 
 
 
 
Alarm Settings: 
IBW (Ideal Body Weight): Correct PBW (Predicted Body Weight 
Paw max: 40 cmH2O 
Tube Type: ET or Trach  
 
 
 
 
 
RR max:  38 b/min 
PAV %support/gain:70%  
 
 
 
 
Vte max: 12 mL/kg of PBW 
Inspiratory trigger: per clinician 
 
 
 
 
Vte min:  0 mL 
Expiratory trigger (Esens): 3 L/min   
 
 
 
VE max: 20 L/min 
PEEP: at previous level  
 
 
 
 
 
VE min: 5 L/min 
FiO2: at lowest level required to keep SpO2 90-96% 
 
 
Apnea setting: 20 s 
Respiratory Distress with ≥2 signs: 
See definition 
No Respiratory Distress: 
Calculate Pmus,Peak 
Assess PAV+ Resistance (R) and 
Compliance (C) measurements.  
Treat any apparent cause of 
increased R (eg. secretions, 
bronchospasm) or decreased C (eg. 
pulmonary edema) 
Increase PEEP in steps of 2 cmH2O 
until Compliance no longer increases 
Increase PAV %support/gain in steps of 
10% until respiratory distress resolves 
and pH ≥7.32 (confirm on blood gas*) 
Switch to A/C mode if ≥ 1 of: 
PAV gain>85% 
FiO2>60% required for SpO2 ≥90% 
Clinical instability (see definition)† 
Unable to trigger vent (NMB/sedation) 
Respiratory alkalemia  
Respiratory acidemia or 
Respiratory Distress (see 
definition) 
Treat any apparent cause of 
hyperventilation  
(eg. Pain, anxiety, metabolic acidosis) 
Decrease gain in steps of 10% until Vte 
<8 mL/kg PBW and/or pH≤7.47 
 
Reassess within 24 hours for Criteria 
for Switching from A/C to PAV 
Increase FiO2 as needed to keep 
SpO2>90%  
Pmus,Peak 
<5 cmH2O 
Pmus,Peak 
5-10 cmH2O 
Pmus,Peak 
>10 cmH2O 
Decrease 
gain in steps 
of 10% until 
Pmus,Peak 5-10 
cmH2O 
Target range 
achieved: 
No adjustments 
required unless:  
 
Increase the 
gain in steps 
of 10% until 
Pmus,Peak 5-10 
cmH2O 
RR <12 or >35 or Vte <5 or >10 mL/kg PBW: 
Obtain arterial blood gas. 
No adjustments required unless: 
Criteria to Initiate Weaning: 
SpO2  ≥90% 
FiO2 ≤0.40  
PEEP ≤8 cmH2O 
pH ≥ 7.32 
vasopressors no higher than 
norepinephrine 0.1 
g/kg/min 
Pre-SBT readiness 
assessment: 
CPAP 0 cmH2O and 
FiO2 0.40 for 2 min; 
assess f/Vt 
f/Vt<100 
SBT: t-piece,  
FiO2 0.40 for 30 min 
f/Vt ≥100 
Return to PAV 
Reassess within 24 hr 
Pass SBT: 
assess for 
extubation 
Fail SBT 

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Appendix D:  PSV Ventilation Strategy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INITIATION OF PSV 
Ventilator Settings: 
 
 
 
 
 
Alarm Settings: 
PS level: 10-20 cmH2O or at previous  level  
 
 
Paw max: per clinician 
Inspiratory trigger: per clinician  
 
 
 
 
RR max:  38 b/min 
Expiratory trigger: 25% of peak flowi 
 
 
 
Vte max: 12 mL/kg of PBW 
PEEP: at previous level 
 
 
 
 
 
Vte min:  0 mL 
FiO2:at lowest level required to keep SpO2 90-96% 
 
 
VE max: 20 L/min 
 
 
 
 
 
 
 
 
VE min: 5 L/min 
 
 
 
 
 
 
 
 
Apnea setting: 20 s 
Assess at least 
once daily while 
on A/C for 
Criteria for 
Switching from 
A/C to PSV 
ALGORITHM TO ADJUST PSV BASED ON CLINICAL PARAMETERS 
Assess at least 
every 8 hours 
while on PSV to 
determine if 
adjustments are 
needed to 
maintain Target 
Range 
 
 
 
 
*Repeat blood 
gas q 30 min as 
needed to 
confirm pH 7.32-
7.47 
 
 
 
†Best clinical 
judgement 
should always 
prevail in setting 
of deterioration, 
with frequent 
reassessment 
until stable   
 
ALGORITHM FOR WEANING 
 
Assess at least 
once daily while 
on PSV for 
Criteria to 
Initiate Weaning; 
Attempt to wean 
FiO2 to 0.40 and 
PEEP to ≤8 cmH2O 
 
Respiratory Distress with ≥2 signs: 
See definition 
No Respiratory Distress: 
Patient appears comfortable  
RR 12-35 and Vte 5-10 mL/kg PBW 
Treat any apparent cause of respiratory 
distress (eg. secretions, bronchospasm, 
pulmonary edema) 
Increase FiO2 and/or PEEP as needed to 
keep SpO2>90% 
Increase PS in steps of 2-3 cmH2O until 
respiratory distress resolves and pH ≥7.32 
(confirm with repeat blood gas*) 
Switch to A/C mode if ≥ 1 of: 
PS >20 cmH2O 
PS + PEEP > 30 cmH2O 
FiO2>60% required for SpO2 ≥90% 
Clinical instability (see definition)† 
Unable to trigger vent (NMB/sedation) 
Respiratory alkalemia  
Respiratoryacidemia or 
Respiratory Distress 
(see definition) 
Treat any apparent cause 
of hyperventilation  
(eg. Pain, anxiety, 
metabolic acidosis) 
Decrease PS in steps of 2-3 cmH2O until 
Vte <8 mL/kg PBW and/or pH≤7.47 
 
Reassess within 24 hours for Criteria for 
Switching from A/C to PSV 
RR <12 or >35 or  Vte <5 or >10 mL/kg PBW: 
Obtain arterial blood gas. 
No adjustments required unless: 
Target range achieved. 
No adjustments required unless one of the 
following occurs: 
Criteria to Initiate Weaning: 
SpO2 ≥90% 
FiO2 ≤0.40  
PEEP ≤8 cmH2O 
pH ≥ 7.32 
vasopressors no higher than 
norepinephrine 0.1 
g/kg/min 
Pre-SBT readiness 
assessment: 
CPAP 0 cmH2O and 
FiO2 0.40 for 2 min; 
assess f/Vt 
f/Vt<100 
SBT: t-piece,  
FiO2 0.40 for 30 min 
f/Vt ≥100 
Return to PSV 
Reassess within 24 hr 
Pass SBT: 
assess for 
extubation 
Fail SBT 

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Appendix E: Richmond Agitation Sedation Scale (RASS) 
C. Sessler,M.  Gosnell, M.  Grap , G. Brophy, P. O’Neal , K. Keane, E. Tesoro, R. Elswick. "The Richmond 
Agitation–Sedation Scale", Am. J. Respir. Crit Care Med, vol. 166, no. 10 (2002), pp. 1338-1344. 
 
Score 
Term 
Description 
+4 
Combative 
Overtly combative, violent, immediate danger to staff 
+3 
Very Agitated 
Pulls or removes tube(s) or catheter(s) or has aggressive 
behavior toward staff 
+2 
Agitated 
Frequent nonpurposeful movement or patient-ventilator 
dyssynchrony 
+1 
Restless 
Anxious but movements not aggressive or vigorous 
0 
Alert and Calm 
 
-1 
Drowsy 
Not fully alert, but has sustained (> 10 seconds) 
awakening, with eye contact, to voice 
-2 
Light Sedation 
Any movement (but no eye contact) to voice 
-3 
Moderate 
Sedation 
Movement or eye opening to voice (but no eye contact) 
-4 
Deep Sedation 
No response to voice, but any movement to physical 
stimulation 
-5 
Unarousable 
No response to voice or physical stimulation 
 
Procedure 
 
1. Observe patient. Is patient alert and calm (score 0)?  
 
Does patient have behavior that is consistent with restlessness or agitation (score +1 to +4 using the 
criteria listed above, under description)? 
 
 
2. If patient is not alert, in a loud speaking voice state patient's name and direct patient to open eyes 
and look at speaker. Repeat once if necessary. Can prompt patient to continue looking at speaker. 
Patient has eye opening and eye contact, which is sustained for more than 10 seconds (score −1). 
Patient has eye opening and eye contact, but this is not sustained for 10 seconds (score −2). 
 
 
Patient has any movement in response to voice, excluding eye contact (score −3). 
 
 
3. If patient does not respond to voice, physically stimulate patient by shaking shoulder and then 
rubbing sternum if there is no response to shaking shoulder. 
 
 
Patient has any movement to physical stimulation (score −4). 
 
 
Patient has no response to voice or physical stimulation (score −5). 
 
 
 

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Appendix F: Sedation Agitation Scale (SAS) 
Riker Sedation-Agitation Scale (SAS)[Need to Verify/reconcile citation, likely Prospective evaluation of the 
sedation-agitation scale in adult ICU patients. Crit Care Med 1999;27:1325-1329.] 
 
Score 
Term 
Description 
7 
Dangerous 
Agitation 
Pulling at ET tube, trying to remove catheters, climbing 
over bedrail, striking at staff, thrashing side-to-side 
6 
Very Agitated 
Requiring restraint and frequent verbal reminding of 
limits, biting ETT 
5 
Agitated 
Anxious or physically agitated, calms to verbal 
instructions 
4 
Calm and 
Cooperative 
Calm, easily arousable, follows commands 
3 
Sedated 
Difficult to arouse but awakens to verbal stimuli or 
gentle shaking, follows simple commands but drifts off 
again 
2 
Very Sedated 
Arouses to physical stimuli but does not communicate or 
follow commands, may move spontaneously 
1 
Unarousable 
Minimal or no response to noxious stimuli, does not 
communicate or follow commands 
 
Procedure for SAS Assessment 
 
1. Agitated patients are scored by their most severe degree of agitation as described 
2. If patient is awake or awakens easily to voice (“awaken” means responds with voice or head 
shaking to a question or follows commands), that’s a SAS 4 (same as calm and appropriate – 
might even be napping). 
3. If more stimuli such as shaking is required but patient eventually does awaken, that’s SAS 3. 
4. If patient arouses to stronger physical stimuli (may be noxious) but never awakens to the 
point of responding yes/no or following commands, that’s a SAS 2. 
5. Little or no response to noxious physical stimuli represents a SAS 1. 
This helps separate sedated patients into those you can eventually wake up (SAS 3), those who 
can't awaken but can arouse (SAS 2), and those you can’t arouse (SAS 1).