Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial
Phase: NA
Conditions: Respiratory Failure
Sponsor: Vanderbilt University Medical Center

1 
 
Supplementary Appendix: 
Study Protocol and Statistical Analysis Plan 
 
 
Trial:   
 
Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial 
 
Manuscript: 
Lower, intermediate, and higher oxygen saturation targets for 
mechanically ventilated critically ill adults 
 
ClinicalTrials.gov: NCT03026322 
 
Authors:  
Matthew W. Semler; Jonathan D. Casey; Bradley D. Lloyd; Pamela 
G. Hastings; Margaret A. Hays; Joanna L. Stollings; Kevin G. Buell; 
John H. Brems; Edward T. Qian; Kevin P. Seitz; Li Wang; 
Christopher J. Lindsell; Robert E. Freundlich; Jonathan P. 
Wanderer; Jin H. Han; Gordon R. Bernard; Wesley H. Self; Todd 
W. Rice; for the PILOT Investigators and the Pragmatic Critical 
Care Research Group. 
 
This Supplementary Appendix contains the following items: 
1) Original Trial Protocol [dated 5/1/2018] 
2) Final Trial Protocol [dated 4/7/2021] 
3) Summary of changes to Trial Protocol 
4) Original Statistical Analysis Plan [dated 4/2/2021] 
5) Final Statistical Analysis Plan [dated 10/28/2021] 
6) Summary of changes to Statistical Analysis Plan 
 
 
 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
1 
 
 
 
 
 
  
 
 
Preliminary Investigation of optimaL Oxygen Targets 
(PILOT) trial 
 
Version 1.0 
 
 
Principal Investigator 
Matthew W. Semler, MD, MSc 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
Mentors 
Gordon R. Bernard, MD, Wesley H. Self, MD, MPH, & 
Todd W. Rice, MD, MSc 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
2 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Study Summary 
2.0 
Background 
3.0 
Rationale, Aims, and Hypotheses 
4.0 
Study Description 
5.0 
Inclusion/Exclusion Criteria 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Risks and Benefits 
9.0 
Adverse Events 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Privacy/Confidentiality Issues 
13.0 
Follow-up and Record Retention 
14.0 
References 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
3 
 
 
1.0 
Study Summary 
 
Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
 
Background:  Mechanical ventilation of ICU patients universally involves titration of the 
fraction of inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2).  Despite 
decades of ICU practice, however, the optimal SpO2 target remains unknown.  Higher 
SpO2 targets (96-100%) provide a margin of safety against hypoxia but increase 
exposure to hyperoxia.  Lower SpO2 targets (88-92%) minimize hyperoxia, but may 
increase the risk of hypoxia.  An intermediate SpO2 target (92-96%) may avoid the risks 
of both hyperoxia and hypoxia, or may expose patients intermittently to both sets of 
risks.  Current guidelines offer divergent recommendations as to the optimal SpO2 target 
and clinical safety and efficacy data are lacking.  Therefore, we propose a 2,250-patient 
cluster-randomized cluster-crossover trial comparing a lower SpO2 target (90%), an 
intermediate SpO2 target (94%), and a higher SpO2 target (98%) with regard to the 
outcome of days alive and free of invasive mechanical ventilation.  
 
Primary Aim: 
• To compare the effect of higher, intermediate, and lower SpO2 targets on days 
alive and free of invasive mechanical ventilation among mechanically ventilated 
critically ill adults. 
 
Primary Hypotheses: 
• Use of a lower SpO2 target (90%) for mechanically ventilated ICU patients will 
result in more days alive and free of invasive mechanical ventilation than use of 
an intermediate SpO2 target (94%) or a higher SpO2 target (98%). 
 
Inclusion Criteria: 
• We will include adults (≥ 18 years old) receiving mechanical ventilation through 
an endotracheal tube or tracheostomy who are admitted to the study ICU or for 
whom admission to the study ICU from the emergency department is planned.   
 
Exclusion Criteria:  
• We will exclude patients who are pregnant or who are prisoners. 
 
Consent: Because [1] the study enrolls only patients who would have been exposed to 
oxygen therapy as a part of clinical care outside of the study, [2] all SpO2 targets 
examined are currently used in routine care in the study ICU, [3] no high-quality data 
suggest that the choice of SpO2 target affects clinical outcomes, and [4] during the trial 
treating clinicians retain discretion to control the SpO2 target when felt to be required 
for the safe treatment a specific patient, we feel the study qualifies as minimal risk.  

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
4 
 
Given the minimal risk, the implementation of SpO2 targets at an ICU level, and the 
impracticability of consenting each patient during initiation of mechanical ventilation in 
the ICU or emergency department, we will request a waiver of informed consent. 
 
Randomization:  In the PILOT trial, the entire study ICU will be assigned to a single SpO2 
target (cluster-randomized) and the ICU will switch between lower, intermediate, and 
higher SpO2 targets every two months in a randomly generated sequence (cluster-
crossover). 
 
Study Interventions: 
• Lower SpO2 Target – FiO2 will be titrated according to an oxygen therapy 
protocol to a target SpO2 of 90% with a range considered compliant of 88-92%.   
• Intermediate SpO2 Target – FiO2 will be titrated according to an oxygen therapy 
protocol to a target SpO2 of 94% with a range considered compliant of 92-96%.   
• Higher SpO2 Target – FiO2 will be titrated according to an oxygen therapy 
protocol to a target SpO2 of 98% with a range considered compliant of 96-100%. 
 
Primary Outcome:   
• Ventilator-free days (VFDs) to study day 28, defined as the number of days from 
liberation from invasive mechanical ventilation to day 28 after enrollment. 
 
Secondary Outcomes: 
• Secondary Clinical Outcomes: ICU mortality, in-hospital mortality, vasopressor-
free days, duration of vasopressor receipt, renal replacement therapy-free days, 
duration of renal replacement therapy receipt, ICU-free days, ICU-length of stay, 
hospital length of stay. 
• Secondary Organ Function Outcomes: daily SOFA score, creatinine, lactate, 
presence of acute respiratory distress syndrome, Stage II or greater AKI by 
KDIGO criteria. 
• Secondary Safety Outcomes: Atrial arrhythmia, ventricular arrhythmia, cardiac 
arrest, pneumothorax. 
• Secondary Feasibility Outcomes: SpO2, SaO2, FiO2, PaO2, percentage of SpO2 
values outside target range, <88% with FiO2 <1.0, PaO2 < 55 with FiO2 <1.0, SpO2 
>98% with FiO2 > 0.21, PaO2 >120 with FiO2 >0.21, episodes of SpO2 ≤ 85% lasting 
> 5 minutes, PaO2/FiO2 ratio. 
• Secondary Process of Care Outcomes: Tidal volume, positive end expiratory 
pressure, peak airway pressure, net fluid balance, receipt of mandatory 
ventilator mode, number of arterial blood gasses, hemoglobin, red cell 
transfusion.  
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
5 
 
2.0 
Background 
 
Each year 2-3 million intensive care unit (ICU) patients receive invasive mechanical 
ventilation,1–3  at a cost of more than $20 billion dollars.4,5  Despite recent advances,6 in-
hospital mortality among mechanically ventilated ICU patients remains 25-35%,7 and 
survivors often face cognitive, psychiatric, and physical dysfunction.8–11   
 
Mechanical ventilation of ICU patients universally involves titration of the fraction of 
inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2).  Despite decades of 
ICU practice, however, the optimal SpO2 target remains unknown.  Higher SpO2 targets 
(96-100%) provide a margin of safety against hypoxemia, but may increase exposure to 
excess FiO2, hyperoxemia, and tissue hyperoxia, causing oxidative damage, 12–14 
inflammation,15,16 and increased alveolar-capillary permeability.17  Lower SpO2 targets 
(88-92%) minimize hyperoxia,6,18,19 but may increase the risk of hypoxemia, tissue 
hypoxia, and organ dysfunction.20,21  An intermediate SpO2 target (92-96%) may avoid 
the risks of both hyperoxia and hypoxia, or, conversely, may expose patients 
intermittently to both sets of risks.   
 
Current guidelines offer divergent recommendations – ranging from tolerating SpO2 
values as low as 88% (ARDS Network)22,23 to pursuing SpO2 values as high as 98% (British 
Thoracic Society)24.  The relative risks and benefits of different SpO2 targets have been 
extensively examined in the setting of the neonatal ICU,25–28 but have only been 
investigated in adult ICU patients in three small trials.29–31  Targeting lower SpO2 
resulted in improved survival in one trial and trends toward improved survival in the 
other two.   
 
In clinical practice, however, hyperoxemia remains common.32,33  In our recent 
observational study of 2,200 mechanically ventilated ICU patients at 50 centers across 
the United States (see Figure), 
the majority of patients had a 
lowest PaO2 value on the first 
study day > 100 mm Hg (~SpO2 
> 97%).  The wide variation in 
current practice (frequently 
favoring higher SpO2 targets), 
conflicting guidelines, and pilot 
trial data favoring lower SpO2 
targets have led to calls for a 
large, randomized trial to 
determine the effect of SpO2 
target on patient outcomes.18 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
6 
 
3.0 
Rationale, Aims, and Hypotheses 
 
In order to determine the effect of SpO2 targets during mechanical ventilation of 
critically ill adults on clinical outcomes, a randomized trial is needed. 
 
Study Aims: 
• Primary:  To compare the effect of higher, intermediate, and lower SpO2 targets 
on days alive and free of invasive mechanical ventilation among mechanically 
ventilated critically ill adults. 
• Secondary:  
o To evaluate the effect of the same intervention in the same population 
on pre-specified Secondary Clinical Outcomes, Secondary Organ Function 
Outcomes, Secondary Safety Outcomes, Secondary Feasibility Outcomes, 
and Secondary Process of Care Outcomes. 
o To evaluate the effect of the same intervention on days alive and free of 
invasive mechanical ventilation in clinically relevant pre-specified patient 
subgroups. 
 
Study Hypotheses: 
• Primary:  Use of a lower SpO2 target (90%) for mechanically ventilated ICU 
patients will result in more days alive and free of invasive mechanical ventilation 
than use of an intermediate SpO2 target (94%) or a higher SpO2 target (98%). 
 
• Secondary: 
o Compared with use of an intermediate SpO2 target (94%) or higher SpO2 
target (98%), use of a lower SpO2 target (90%) for mechanically ventilated 
ICU patients will result in: 
▪ Lower ICU and in-hospital mortality 
▪ No difference between in other Secondary Clinical Outcomes 
▪ Lower daily SOFA score 
▪ Lower incidence of acute respiratory distress syndrome 
▪ No difference in other Secondary Organ Function Outcomes 
▪ No difference in Secondary Safety Outcomes 
▪ Lower SpO2, SaO2, FiO2, PaO2, and incidence of SpO2 >98% with 
FiO2 > 0.21 or PaO2 >120 with FiO2 >0.21 
▪ Higher PaO2/FiO2 ratio and incidence of SpO2 <88% with FiO2 <1.0 
or PaO2 < 55 with FiO2 <1.0 
▪ No difference in episodes of SpO2 ≤ 85% lasting > 5 minutes 
▪ No difference in Secondary Process of Care Outcomes 
 
4.0 
Study Description 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
7 
 
In order to address the aims outlined above, we propose the Preliminary Investigation 
of optimaL Oxygen Targets (PILOT) trial.  The PILOT trial will be a prospective, un-
blinded, cluster-randomized, cluster-crossover trial conducted between July 1, 2018 and 
June 30, 2021 in the medical ICU at Vanderbilt University Medical Center examining the 
effect of SpO2 targets on days alive and free of mechanical ventilation among 
mechanically ventilated ICU patients.   For the 36 months of the PILOT trial, the entire 
medical ICU will be assigned to a single SpO2 target and the ICU will switch between 
lower, intermediate, and higher SpO2 targets every two months in a randomly 
generated sequence (Figure below).  Patients who fulfill inclusion criteria without 
meeting exclusion criteria will be enrolled at the initiation of mechanical ventilation in 
the study ICU or in the emergency department when admission to the study ICU is 
planned.  The PILOT trial will control only the SpO2 target and all other aspects of 
patients clinical care will remain at the discretion of the treating clinicians. 
 
 
5.0 
Inclusion and Exclusion Criteria 
 
5.1  
Inclusion Criteria: 
1. Age ≥ 18 years 
2. Receiving mechanical ventilation through an endotracheal tube or tracheostomy 
3. Admitted to the study ICU or admission to the study ICU from the emergency 
department is planned 
 
5.2  
Exclusion Criteria:  
1. Known pregnancy or beta hCG level greater than the laboratory upper limit of 
normal in a patient capable of becoming pregnant 
2. Known to be a prisoner 
 
6.0 
Enrollment/Randomization 
 
6.1 
Study Sites:   
• Medical Intensive Care Unit at Vanderbilt University Medical Center 
• Emergency Department at Vanderbilt University Medical Center 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
8 
 
6.2  
Study Population:  All adults located in the study ICU (or for whom admission to 
the study ICU from the emergency department is planned) for whom the treating 
clinicians have decided invasive mechanical ventilation is required will be enrolled 
unless meeting exclusion criteria.  Patients will be included regardless of age, gender, 
race, weight or body mass index, initial oxygen saturation, or other clinical factors.  
 
6.3  
Enrollment:  All adult patients who do not meet exclusion criteria will be 
enrolled immediately upon receipt of invasive mechanical ventilation in the study ICU or 
in the emergency department when admission to the study ICU is planned.   
 
6.4  
Consent:  
All patients receiving invasive mechanical ventilation in an intensive care unit 
receive oxygen therapy titrated to maintain SpO2 as a part of routine care.  In clinical 
practice, 98% of SpO2 values experienced by mechanically ventilated adults fall between 
88-100%.32,33  Within this range, current guidelines for oxygen therapy in mechanically 
ventilated adults outline three contrasting approaches: [1] tolerating SpO2 values as low 
as 88% (NIH/NHLBI ARDS Network),22 [2] titrating within the range 92-96% (Thoracic 
Society of Australia and New Zealand),34 or [3] pursuing SpO2 values as high as 98% 
(British Thoracic Society).24  The lower SpO2 target (90%), intermediate SpO2 target 
(94%), and higher SpO2 target (98%) examined in this study are all intermittently used in 
routine care in the study ICU and recommended by at least one international guideline.  
There are currently no high-quality data to suggest that one SpO2 target is better than 
the others with regard to clinical outcomes.  Although there are no clear data to support 
the choice of SpO2 target, during the PILOT trial, treating clinicians in the study ICU will 
be allowed to change the SpO2 target at any point if it is felt to be required for the safe 
treatment a specific patient.   
Because the interventions studied [1] are used as part of routine care in the 
study ICU, [2] are interventions o which the patient would be expected even if not 
participating in the study, [3] have no prior data to suggest the superiority of one 
approach over the other, and [4] are equivalent options from the perspective of the 
treating clinicians (otherwise the treating clinician retains control of SpO2 target), we 
feel the study presents minimal risk. 
  
Additionally, obtaining informed consent prior to participation in the study 
would be impractical.  Endotracheal intubation and initiation of mechanical ventilation 
for critically ill patients is frequently a time-sensitive procedure.  Despite the availability 
of a formal informed consent document for the endotracheal intubation and initiation 
of mechanical ventilation, time allows discussion of risks and benefits in less than 10% of 
airway management events in the study ICU.  The oxygen titration protocol used to 
target SpO2 in this trial begins immediately at the initiation of mechanical ventilation to 
capture the period of mechanical ventilation with the highest risk for hyperoxia and 
hypoxia.  Moreover, in this cluster-randomized trial, the entire ICU is assigned to a single 
SpO2 target delivered by the unit’s respiratory therapist through a unit-wide oxygen 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
9 
 
titration protocol.  Obtaining informed consent from every eligible patient in the ICU 
each day would be logistically infeasible and patients who declined to participate would 
need to be transferred between ICUs which might adversely impact their care. 
 
Because the study presents minimal risk, would not adversely affect the welfare 
or privacy rights of the participant, and consent would be impracticable, we will request 
a waiver of informed consent. 
 
 
6.5  
Randomization:   
During each two-month block of the study, the ICU will be assigned to either a 
higher SpO2 target (98%), an intermediate SpO2 target (94%), or a lower SpO2 target 
(90%).  The order of study group assignments will be generated by computerized 
randomization using permuted blocks of 3 to minimize the impact of seasonal variation.  
The last 7 days of each two-month block will be a washout period during which the ICU 
will continue to target the assigned SpO2 but new patients will not be enrolled.  
Assuming a duration of mechanical ventilation similar to that observed for mechanically 
ventilated patients admitted to the study ICU in a prior year (median 3 [IQR 3-5] days), a 
7-day washout period will ensure that 98% patients do not experience a “crossover” 
from one assigned SpO2 target to another. 
 
 
  
7.0 
Study Procedures 
 
7.1       Study Interventions 
 
Choice of SpO2 targets: In clinical practice, 98% of SpO2 values experienced by 
mechanically ventilated adults fall between 88-100%.32,33  Within this range, current 
guidelines for oxygen therapy in mechanically ventilated adults outline three contrasting 
approaches: [1] tolerating SpO2 values as low as 88% (NIH/NHLBI ARDS Network),22 [2] 
titrating within the range 92-96% (Thoracic Society of Australia and New Zealand),34 or 
[3] pursuing SpO2 values as high as 98% (British Thoracic Society).24  The PILOT trial will 
have three study 
groups, each 
emulating an 
approach to SpO2 
targets represented in 
guidelines and clinical 
practice (Table). 
 
SpO2 versus PaO2:  SpO2 is measured continuously via non-invasive pulse oximetry for 
nearly all mechanically ventilated ICU patients.  In contrast, PaO2 is assessed via arterial 
puncture intermittently and selectively, particularly among more severely ill patients 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
10 
 
earlier in their clinical course.  Similar to prior studies of oxygen therapy during 
mechanical ventilation29, the PILOT trial will target ranges of SpO2 for all patients with 
functioning non-invasive pulse oximetry monitoring.  For patients in the PILOT trial for 
whom non-invasive pulse oximetry monitoring is unavailable (e.g., inadequate 
plethysmography signal due to hypoperfusion), PaO2 values corresponding to the 
assigned SpO2 target will be used to guide oxygen therapy (see above Table).35 
 
Oxygen Titration Protocol:  In current usual care in the study ICU, titration of FiO2 to 
maintain SpO2 for mechanically ventilated adults is performed by respiratory therapists, 
with input from nurses and physicians.  Other aspects of mechanical ventilation 
(selection of tidal volume, titration of positive end-expiratory pressure, screening for 
spontaneous breathing trials) are governed by respiratory therapy protocols jointly 
developed by respiratory therapy and physician leaders.  In preparation for the PILOT 
trial, we have collaborated with respiratory therapy leaders in the study ICU to develop 
an oxygen titration protocol for each SpO2 target group (see Figure below).  Each block 
of the study, the mechanical ventilators in the study ICU will be outfitted by study 
personnel with paper copies of the oxygen titration protocol targeting the assigned 
SpO2.  The oxygen titration protocol will also be available to respiratory therapists, 
nurses, and physicians through the electronic order entry system. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
          
 
 
 
 
 
 
 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initiation of Mechanical Ventilation:  The oxygen titration protocol guides respiratory 
therapists and treating clinicians to begin titrating FiO2 to the target SpO2 value within 
15 minutes of the initiation of mechanical ventilation in the participating ED or ICU.  This 
initial 15-minute window is intended to give the treating clinicians adequate time after 
emergent tracheal intubation to stabilize the patient’s hemodynamics and initiate basic 
ventilator settings, but also to intervene early enough to control the FiO2 and SpO2 
during the critical early period of mechanical ventilation when exposure to excess FiO2 
and hyperoxemia is most common.   
 
Oxygen Titration during Mechanical Ventilation:  SpO2 will be assessed by continuous 
pulse oximetry.  The respiratory therapist managing the patient’s ventilator will target 
an SpO2 value of 98% in the higher SpO2 group, 94% in the intermediate SpO2 group, 
and 90% in the lower SpO2 group.  The respiratory therapist will titrate FiO2 as directed 
by the oxygen titration protocol when SpO2 values are outside of the range 96-98% in 
the higher SpO2 group, 92-96% in the intermediate SpO2 group, and 88-92% in the lower 
SpO2 group.  SpO2 will be reassessed 5 minutes after each change in FiO2. 
 
Liberation from Mechanical Ventilation:  Each day of mechanical ventilation, all patients 
in the study ICU are assessed for safety of a spontaneous awakening trial (SAT) and 
spontaneous breathing trial (SBT)36 using the SAT and SBT safety criteria from the 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
12 
 
Awakening and Breathing Controlled trial.37  To prevent patients in the higher SpO2 
target group from experiencing delays in qualifying for an SBT based on receipt of higher 
FiO2 to achieve the higher SpO2 target, during the PILOT trial we will allow patients in all 
groups to qualify for an SBT with an FiO2 ≤ 0.6.  Definitions of SAT and SBT failure and 
the ventilator settings and duration of the SBT will not be changed from those used in 
the ABC trial and during usual care in the study ICU.  For patients who have passed an 
SBT and SAT, the decision to discontinue invasive mechanical ventilation will be made by 
the treating clinicians. 
 
Modification of SpO2 Targets: At any time during the course of the study, if a treating 
clinician feels an SpO2 target other than that assigned by the study is required for the 
safe treatment of a specific patient, the SpO2 target for that patient may be modified.  
To modify the target, the supervising physician will complete a one-page SpO2 target 
modification sheet documenting the rationale for modifying the target and prompting 
reassessment of the need for modification every twelve hours.  Details of each SpO2 
target modification will be collected and monitored.  In our prior cluster-crossover trial 
using the same approach to modification of therapy assignment, treating clinicians 
exercised the ability to modify the assigned therapy for < 5% of patients.38 
 
Anticipated examples of conditions for which treating clinicians may elect to override 
the assigned SpO2 target include:  
• pneumothorax,  
• pneumomediastinum,  
• carbon monoxide poisoning,  
• decompression sickness,  
• bleomycin toxicity, 
• paraquat toxicity 
 
SpO2 Monitoring:  For all mechanically ventilated patients in the study ICU, SpO2 is 
continuously monitored using Nellcor™ SpO₂ Adhesive Sensors (Medtronic, Minneapolis, 
MN), which measure changes in red and infrared light absorption in an arteriolar bed 
throughout the pulse cycle to report a non-normalized real-time plethysmographic 
waveform and arterial hemoglobin saturation values averaged over the prior 6 seconds 
with a mean difference between SpO2 and SaO2 < 2% for SpO2 values 80-100%.39  
Plethysmography and SpO2 values are displayed [1] on IntelliVue MP90 bedside patient 
monitors (PHILIPS, Amsterdam, Netherlands) in each ICU room, [2] on telemetry 
monitors located at ICU nursing stations and adjacent to the respiratory therapy office, 
and [3] in real-time in the institutional EHR, available from any physical location.  SpO2 
values are archived every 60 seconds into an intuitional data warehouse.40,41  Collecting 
SpO2 values every 60 seconds will allow the PILOT trial report with far greater 
accuracy the incidence, severity, and duration of desaturation than prior trials in 
which SpO2 values were collected every 4-24 hours.29,30 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
13 
 
 
Feedback on SpO2 Target Adherence: [1] During the study, the IntelliVue MP90 bedside 
patient monitors in each room will be set to generate a low priority alarm for SpO2 
values 1-3% outside the assigned target range and a high priority alarm for SpO2 values 
≥ 4% outside the assigned target range (see Figure below).  For example, for patients in 
the lower SpO2 target group, SpO2 values 88-92% will generate no alarm, SpO2 values 
85-87% or 93-95% will generate a low priority alarm, and SpO2 values ≤ 84% or ≥ 96% 
will generate a high-priority alarm.  [2] For the first 6 months of the PILOT trial, study 
personnel will remotely monitor SpO2 values in real-time 8am-5pm Monday through 
Friday and during a 
10% sample of night 
and weekend hours 
to identify instances 
of lag between out of 
range SpO2 values 
and FiO2 titration, 
provide feedback 
and reinforcement to 
bedside nurses and 
respiratory 
therapists, and 
identify any barriers 
to SpO2 target 
compliance.  [3] For 
the entire period of 
the PILOT trial, study 
personnel will attend 
quarterly respiratory 
therapy group 
meetings, monthly 
nursing unit board 
meetings, and 
monthly ICU physician leadership meetings to educate staff about the study, solicit 
safety concerns and adverse events, and identify and address barriers to SpO2 target 
compliance.  This approach to daily monitoring and intermittent feedback to clinical 
personnel successfully achieved 95% compliance with the assigned intervention in a 
prior cluster-crossover trial in the same ICU.38 
 
Co-interventions:  Institutional protocols in the study setting will ensure that 
mechanically ventilated patients in PILOT receive: [1] ventilation targeting 6 mL/kg of 
predicted body weight and plateau pressure ≤ 30 cm H2O,6 [2] PEEP titration according 
to the ARDSNet Lower PEEP/higher FiO2 table (except for patients with severe ARDS, for 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
14 
 
whom the Higher PEEP/lower FiO2 table is applied),42,43 [3] management of pain, 
agitation, and delirium44 targeting Critical Care Pain Observation Tool (CPOT),45 
Richmond Agitation-Sedation Scale (RASS),46,47 and Confusion Assessment Method for 
the ICU (CAM-ICU) scores,48,49 and [4] daily spontaneous awakening trials (SAT) and 
spontaneous breathing trials (SBT).36,37 
 
 
7.2  
Blinding:  Similar to prior SpO2 target studies among critically ill adults29,30, 
patients and clinicians will not be blinded to study group assignment.  Observer bias will 
be minimized by use of objective endpoints collected in duplicate by [1] study personnel 
blinded to group assignment and [2] automated data extraction from the EHR (see Data 
Collection below). 
 
 
7.3  
Data Collection:  The PILOT trial will primarily use structured data collected in 
routine clinical care, exported daily from the institution’s EHR into an Enterprise Data 
Warehouse, along with data from the patient registration, billing, and laboratory clinical 
information systems.  We have previously validated the quality of this method of data 
collection against the reference standard of two-physician manual chart review,50 and 
the planned approach to electronic dataset generation for the PILOT trial has already 
been successfully employed for the conduct of three prior pragmatic trials.38,38,51   
 
Electronically extracted data elements will include:  
Enrollment (Day 0): age; sex; race; ethnicity; height, weight; APACHE II score;52 SOFA 
score;53 Glasgow Coma Scale score;54 Elixhauser Comorbidity Index;55 vital signs 
(temperature, heart rate, systolic blood pressure, diastolic blood pressure, SpO2); 
mechanical ventilator settings (mode, set and exhaled tidal volume, set and actual 
respiratory rate, positive end-expiratory pressure, peak pressure, FiO2); serum 
laboratory values (white blood cell count, hemoglobin, platelet count, sodium, 
potassium, bicarbonate, creatinine, bilirubin, alanine aminotransferase, aspartate 
aminotransferase, lactate, arterial pH, PaO2, SaO2).   
 
Daily On-Study (Days 0-28): Vital signs, ventilator settings, and serum laboratory values 
(as above); net fluid balance; receipt of red cell transfusion; number of arterial blood 
gases; SOFA score; ARDS by Berlin criteria;56 Stage II or greater AKI by KDIGO criteria;57 
atrial arrhythmia, ventricular arrhythmia, cardiac arrest, or pneumothorax.   
 
Termination (Days 0-28):  Vital status at 28 days; time of liberation from invasive 
mechanical ventilation; receipt and duration of vasopressors; receipt and duration of 
renal replacement therapy; duration of ICU and hospital admission.   
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
15 
 
Data elements collected manually by study personnel will include: [1] all data 
elements for a randomly selected 10% of participants to ensure the quality of 
electronically extracted data, [2] all primary and secondary outcomes collected at study 
termination for 100% of participants to ensure duplicate data collection of key study 
outcomes, and [3] any data elements for which electronic data extraction has not been 
developed and validated, including etiology of respiratory failure, indication for 
mechanical ventilation, protocol violations, and adverse events.  Data will be stored, 
curated, and secured in the online database, REDCap.58 
 
7.4 
 Outcome Measures 
 
Primary Outcome:  Ventilator-free days (VFDs) to study day 28, defined as the number 
of days from liberation from invasive mechanical ventilation to day 28 after enrollment.  
Patients who continue to receive invasive mechanical ventilation at day 28 or have died 
prior to day 28 will receive zero VFDs.  For patients who return to invasive mechanical 
ventilation and are subsequently liberated from invasive mechanical ventilation prior to 
day 28, VFDs will be counted from final liberation from mechanical ventilation.  We 
chose VFDs as the primary outcome for the PILOT trial as choice of SpO2 target may 
simultaneously affect both mortality and duration of invasive mechanical ventilation. 
 
Secondary Clinical Outcomes:  
1. ICU mortality 
2. In-hospital mortality 
3. Vasopressor-free days 
4. Duration of vasopressor receipt 
5. Renal replacement therapy-free days 
6. Duration of renal replacement therapy receipt 
7. ICU-free days 
8. ICU-length of stay 
9. Hospital length of stay. 
 
Secondary Organ Function Outcomes: (All secondary organ function outcomes will 
employ only laboratory values and imaging obtained as a part of routine clinical care)  
1. Daily SOFA score 
2. Daily creatinine 
3. Daily lactate 
4. Presence of acute respiratory distress syndrome 
5. Stage II or greater AKI by KDIGO criteria 
 
Secondary Safety Outcomes:   
1. Atrial arrhythmia 
2. Ventricular arrhythmia 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
16 
 
3. Cardiac arrest 
4. Pneumothorax. 
 
Secondary Feasibility Outcomes:   
1. SpO2 
2. SaO2 
3. FiO2 
4. PaO2 
5. Percentage of SpO2 values outside target range 
6. <88% with FiO2 <1.0 
7. PaO2 < 55 with FiO2 <1.0 
8. SpO2 >98% with FiO2 > 0.21 
9. PaO2 >120 with FiO2 >0.21 
10. Episodes of SpO2 ≤ 85% lasting > 5 minutes 
11. PaO2/FiO2 ratio 
 
Secondary Process of Care Outcomes:   
1. Tidal volume 
2. Positive end expiratory pressure 
3. Peak airway pressure 
4. Net fluid balance 
5. Receipt of mandatory ventilator mode 
6. Number of arterial blood gasses 
7. Hemoglobin 
8. Red cell transfusion 
 
8.0 
Risks and Benefits: 
 
Among adult patients for whom the treating clinicians have decided invasive 
mechanical ventilation is required, there are currently no established risks or benefits to 
targeting a higher, intermediate, or lower SpO2.  At this time, there is no reason to 
believe that participation in this study would expose patients to greater medical risks or 
benefits than those experienced by critically ill patients receiving invasive mechanical 
ventilation as a part of routine care.  The greater benefit of the study would be to 
society in the form of improved understanding of safe and effective provision of oxygen 
therapy during mechanical ventilation for critically ill patients. 
 
A potential risk to patients participating in this study involves the collection of 
protected health information (PHI).  In order to limit the associated risks, the minimum 
amount of PHI necessary for study conduct will be collected.  After collection, the data 
will be stored in a secure online database (REDCap) only accessible by the investigators.  
After publication, a de-identified database will be generated to protect participant 
privacy. 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
17 
 
 
9.0 
Safety Monitoring and Adverse Events: 
 
9.1 Safety Monitoring 
 
 
The PILOT trial will take place in a high-acuity clinical care environment during 
delivery of a high-acuity procedure required for routine clinical care.  During the time of 
the study intervention, the patient will have a critical care or emergency medicine nurse 
with a low patient-to-nurse staffing ratio, immediate access to a respiratory therapist, 
and a team of critical care physicians physically located on the study unit twenty-four 
hours a day.  As a part of routine care all patients will be receiving continuous invasive 
or non-invasive monitoring of heart rate, blood pressure, respiratory rate, and oxygen 
saturation.   
Study personnel will monitor compliance with the study inclusion and exclusion 
criteria, study protocol, and study safety measures daily.  Study personnel will be readily 
available to answer questions at any time from patients, legally authorized 
representatives, or treating clinicians.  If, at any point in a patient’s clinical course, the 
treating clinicians believe an SpO2 target different from the assigned target is required 
for the safe treatment of the patient, the SpO2 target will be modified to the target the 
treating clinicians judge to be safest. 
A structured plan for prospective collection of study outcomes has been 
specified, in addition to a process by which Adverse Events and Serious Adverse Events 
will be managed and reported as required to regulatory bodies. 
A Data and Safety Monitoring Board (DSMB) will be appointed to oversee the 
study. The DSMB will be available throughout the trial to monitor enrollment, protocol 
compliance, safety, and adverse events.  Additionally the DSMB will perform an interim 
analysis for safety and efficacy. 
 
9.2 Adverse Event Reporting 
 
A system has been established to report and track clinical outcomes and adverse 
events (AEs). Study personnel will monitor the safety of subjects and follow AEs until the 
event resolves or is explained. 
 
Clinical Outcomes (not considered Adverse Events). In this study of critically ill patients 
who are at high risk for death or other adverse outcomes due to their underlying critical 
illness, clinical outcomes, including death and organ dysfunction, will be systematically 
tracked (collected in the case report form) and will be included as part of the analyses 
for this study. For the purposes of reporting, death and organ dysfunction will not be 
recorded as AEs unless the investigator believes the event may have been caused by the 
study or is more severe or prolonged than expected given the underlying critical illness. 
This approach—considering death and organ dysfunction as outcomes rather than AEs 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
18 
 
and systemically tracking expected outcomes for analysis rather than solely recording 
individual AEs—is common in ICU trials because these outcomes/events occur 
commonly in the ICU and this system mandates that data regarding death, organ 
dysfunction, and expected outcomes be tracked systematically for all patients and 
analyzed appropriately. Clinical outcomes will be systemically tracked throughout the 
study period. Listed below are events that will be tracked as primary or secondary 
clinical outcomes and will not therefore be reported as AEs during this study (unless 
believed to be study related and more severe or prolonged than expected given the 
underlying critical illness): 
 
1. Death (all deaths occurring prior to hospital discharge will be reported on the 
CRF in the vital status at hospital discharge section); 
2. Recurrence of respiratory failure, including need for re-intubation or non-
invasive mechanical ventilation, presence of acute respiratory distress 
syndrome, or presence of pneumothorax; 
3. Circulatory failure, including cardiac arrest or shock with or without receipt of 
vasopressors; 
4. Incidence of sustained atrial and ventricular arrhythmias; 
5. Acute kidney injury, including leading to increased creatinine or receipt of renal 
replacement therapy; 
6. Hepatic injury or failure leading to increased bilirubin, AST, or ALT; 
7. Coagulation derangements leading to elevated PT/INR or PTT, DIC, 
thrombocytopenia, or thrombocytosis; 
8. Lactic acidosis; 
9. Delirium, disability, and physical or cognitive impairment believed to be newly 
acquired; 
10. All values for SpO2, SaO2, FiO2, PaO2, or PaO2/FiO2 ratio; 
11. All values for vital signs (e.g., temperature, respiratory rate, SpO2); 
12. Receipt of co-interventions (e.g., net fluid balance, number of arterial blood 
gasses, red cell transfusion) 
13. Duration of ICU admission, ICU readmission; 
14. Duration of hospitalization, hospital readmission; 
15. Alterations in routine labs, including chemistries, complete blood counts, liver 
function tests, and hemostasis profiles. 
 
Adverse Event Classifications. An Adverse Event (AE) will be any untoward medical 
occurrence for a patient enrolled in the trial that is not tracked as a clinical outcome, 
regardless of whether the event is considered study related or not. All AEs occurring 
during the observational study period will be recorded on the CRF. All AEs will then be 
assessed as to whether they are (1) related to study procedures, (2) serious, and/or (3) 
unexpected according to the following definitions: 
 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
19 
 
I. 
Related to study procedures. AEs that the investigator suspects are related to 
the study will be classified as study related. Certainty of relatedness is not 
required as long as a reasonable possibility exists that the AE is related to a study 
procedure. 
 
II. 
Serious. AEs that meet any of the criteria below will be considered Serious 
Adverse Events (SAEs): 
a. Results in death 
b. Is life-threatening (defined as an event in which the participant was at risk of 
death at the time of the event and NOT an event that hypothetically might have 
caused death if it would have been more severe) 
c. Prolongs an existing hospitalization 
d. Results in persistent or significant disability or incapacity 
e. Results in a congenital anomaly or birth defect 
f. Important medical event that requires an intervention to prevent any of a-e 
above. 
 
III. 
Unexpected. AEs that are more severe or prolonged than expected based on the 
investigator’s discretion will be considered Unexpected.  
 
The PILOT trial will monitor, track, and report all Clinical Outcomes and AEs as required 
by regulatory bodies. 
 
Communication and Reporting of Adverse Events. In order to ensure proper and timely 
reporting of all adverse events, there will be a clear communication plan for all study 
personnel to follow. AEs will be recorded in the AE CRF in the electronic database and 
reported to the PI within 5 days of occurrence. The PI will provide a report of all AEs 
annually to the IRB and DSMB as part of the annual review process as required. All SAEs 
will be reported to the PI within 72 hours of occurrence. The PI will, in turn, report all 
SAEs to the IRB, DSMB, and funding body within 7 calendar days of occurrence. 
 
9.3 Frequency of Monitoring and Interim Analysis.   
Study personnel will continuously monitor enrollment, protocol compliance, and 
AEs and SAEs throughout the course of the trial.  Annually, the DSMB will formally 
review enrollment, protocol compliance, and AEs and SAEs as part of a formal DSMB 
meeting.  Additionally, the DSMB will be available to convene a meeting at any point in 
the course of the trial to review urgent issues related to AEs, protocol compliance, or 
unexpected adverse events.  Study personnel and DSMB members will adhere to the 
expectations for reporting and managing AEs and unexpected adverse events outlined in 
the DSMB charter. 
Interim Analysis.  In addition to ongoing monitoring of safety throughout the 
trial, the DSMB will conduct a single interim analysis for efficacy and safety at the 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
20 
 
anticipated halfway point of the PILOT trial.  The interim analysis will include patients 
enrolled during the first 18 months of the trial.  The stopping boundary for efficacy will 
be met if the P value for the difference between groups is <0.001.  Use of the 
conservative Haybittle-Peto boundary (P < 0.001) will allow the final analysis to be 
performed using an unchanged level of significance (P = 0.05).  Given the minimal risk 
nature of the study and current use of all SpO2 target as a part of usual care, there will 
be no stopping boundary for futility.  The DSMB will reserve the right to stop the trial at 
any point, request additional data or interim analyses, or request modifications of the 
study protocol as required to protect patient safety. 
 
9.4 Data and Safety Monitoring Board (DSMB).  A formal independent DSMB will 
oversee the conduct of the trial and the planned interim analysis.  The DSMB will be 
composed of at least one physician outside the study institution experienced in the conduct 
of critical care clinical trials and one biostatistical expert who will assist with study 
monitoring and performance of the interim analysis. 
 
9.5 Data Monitoring Plan. To ensure data are accurately and completely collected 
during the PILOT trial, the study team will follow a specific Data Monitoring Plan. All 
clinical outcomes will be collected in duplicate by both electronic data collection and by 
the study nurse.  All study data from random sample of 10% of study records will be 
collected in duplicate by electronic data collection and by the study nurse.  Each of 
these records will also be reviewed annually by the primary investigator to ensure data 
collection is accurate, complete, and current.  The study biostatistician will run periodic 
data cleans throughout the study looking for outliers or overtly erroneous data. This 
Monitoring Plan will serve as a method for identifying and resolving systematic 
problems and therefore increase data quality. We will submit progress reports to the 
local IRB annually, or more frequently if requested. 
 
 
10.0 
Study Withdrawal/Discontinuation 
 
Patients can be withdrawn from study participation in the following circumstances: 
• The investigator decides that the patient should be withdrawn for safety 
considerations. 
• There is a significant protocol violation in the judgment of the PI. 
 
The reason and date of every withdrawal will be recorded in the patient study records.  
Follow-up will be performed for all patients who discontinue due to an adverse event or 
any other safety parameter.  Follow-up will also be performed for all patients who end 
participation in the protocol for another reason, but who also have an adverse event or 
other safety parameter that could have led to discontinuation.  Follow-up will be 
conducted until the condition has resolved, until diagnosis of the adverse event or 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
21 
 
safety parameter is deemed chronic and stable, or as long as clinically appropriate.  This 
follow-up will be documented in the patient study record as well.   
 
 
11.0 
Statistical Considerations 
 
Power calculation.  In a prior cluster-randomized cluster-crossover trial in the same 
ICU,51 880 mechanically ventilated adults were enrolled per year (73.3 per month), with 
a median of 22 VFDs [IQR 0-25 VFDs] and an intra-cluster intra-period correlation of 
0.01.  During the planned 36 month PILOT trial, we estimate 2,640 mechanically 
ventilated adults will be admitted to the study ICU, of whom 390 will be excluded during 
washout periods and 2,250 will be enrolled.  With a total enrollment of 2,250 patients, a 
standard deviation in the primary outcome of VFDs of 11.4 days, and a two-sided alpha 
of 0.05, the PILOT trial will have 92 percent statistical power to detect an absolute 
reduction in VFDs of 2.0 days (similar to the numerical difference in VFDs between SpO2 
target groups reported in prior studies29,30). 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
22 
 
 
Primary analysis.  The primary analysis will be an intention-to-treat comparison of the 
number of VFDs experienced by patients in each study group using the Kruskal–Wallis 
test.  Secondary analyses will include [1] intention-to-treat comparisons of the pre-
specified secondary outcomes between study groups; [2] intention-to-treat comparison 
of the SpO2 target groups with regard to ventilator free days using a generalized linear 
mixed-effects model adjusting for fixed effects (age, sex, race, source of admission, 
vasopressor receipt, acute diagnosis) and random effects (study period) to account for 
intra-period correlation, and [3] examination of the differential effects of the 
intervention for patients with different baseline characteristics (heterogeneity of 
treatment effect) (see Figure below).   
 
All of secondary analyses will be considered hypothesis-generating, and no corrections 
for multiple comparisons will be performed.  No imputations will be made for missing 
baseline or on-study laboratory or physiologic data.  Continuous variables will be 
described as mean and standard deviation or median and 25th percentile – 75th 
percentile or bootstrapped 95% confidence intervals as appropriate.  Categorical 
variables will be given as number and percentage.  All between-group comparisons with 
continuous variables will be performed using Kruskal–Wallis tests; categorical variables 
will be compared with chi-square testing or Fisher’s exact test as appropriate. A 
complete pre-specified statistical analysis plan will be published prior to the completion 
of enrollment. 
 
Interim Analysis 
 
We will plan for the DSMB to conduct a single interim analysis for efficacy and 
safety at the anticipated halfway point of the trial.  The interim analysis will include 
patients enrolled during the first 18 months of the trial.  The stopping boundary for 
efficacy will be met if the P value for the difference between groups is <0.001.  Use of 
the conservative Haybittle-Peto boundary (P < 0.001) will allow the final analysis to be 
performed using an unchanged level of significance (P = 0.05).  Given the minimal risk 
nature of the study and current use of all SpO2 target as a part of usual care, there will 
be no stopping boundary for futility.  The DSMB will reserve the right to stop the trial at 
any point, request additional data or interim analyses, or request modifications of the 
study protocol as required to protect patient safety. 
 
             
12.0 
Privacy/Confidentiality Issues 
At no time during the course of this study, its analysis, or its publication will 
patient identities be revealed in any manner.  The minimum necessary data containing 
patient or provider identities will be collected.  All patients will be assigned a unique 
study ID number for tracking.  Data collected from the medical record will be entered 
into the secure online database REDCap.  Hard copies of the treating clinician 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
23 
 
modification of SpO2 target sheet will be stored in a locked room until after the 
completion of enrollment and data cleaning.  Once data are verified and the database is 
locked, all hard copies of data collection forms will be destroyed.  All data will be 
maintained in the secure online database REDCap until the time of study publication.  At 
the time of publication, a de-identified version of the database will be generated. 
 
13.0 
Follow-up and Record Retention 
Patients will be followed after enrollment for 28 days or until hospital discharge, 
whichever occurs first.  Data collected from the medical record will be entered into the 
secure online database REDCap.  Once data are verified and the database is locked, all 
hard copies of data collection forms will be destroyed.  All data will be maintained in the 
secure online database REDCap until the time of study publication.  At the time of 
publication, a de-identified version of the database will be generated. 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
24 
 
 
14.0 
References 
1.  
Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn 
JM. The epidemiology of mechanical ventilation use in the United States. Crit Care Med 
2010;38(10):1947–53.  
2.  
Wunsch H, Angus DC, Harrison DA, Linde-Zwirble WT, Rowan KM. 
Comparison of medical admissions to intensive care units in the United States and United 
Kingdom. Am J Respir Crit Care Med 2011;183(12):1666–73.  
3.  
Adhikari NKJ, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the 
global burden of critical illness in adults. Lancet Lond Engl 2010;376(9749):1339–46.  
4.  
Dasta JF, McLaughlin TP, Mody SH, Piech CT. Daily cost of an intensive care 
unit day: the contribution of mechanical ventilation. Crit Care Med 2005;33(6):1266–71.  
5.  
Halpern NA, Pastores SM. Critical care medicine in the United States 2000-2005: 
an analysis of bed numbers, occupancy rates, payer mix, and costs. Crit Care Med 
2010;38(1):65–71.  
6.  
Ventilation with lower tidal volumes as compared with traditional tidal volumes 
for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory 
Distress Syndrome Network. N Engl J Med 2000;342(18):1301–8.  
7.  
Esteban A, Frutos-Vivar F, Muriel A, et al. Evolution of mortality over time in 
patients receiving mechanical ventilation. Am J Respir Crit Care Med 2013;188(2):220–
30.  
8.  
Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of 
the acute respiratory distress syndrome. N Engl J Med 2003;348(8):683–93.  
9.  
Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute 
respiratory distress syndrome. N Engl J Med 2011;364(14):1293–304.  
10.  
Kahn JM, Benson NM, Appleby D, Carson SS, Iwashyna TJ. Long-term acute 
care hospital utilization after critical illness. JAMA 2010;303(22):2253–9.  
11.  
Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment 
after critical illness. N Engl J Med 2013;369(14):1306–16.  
12.  
Fridovich I. Oxygen toxicity: a radical explanation. J Exp Biol 1998;201(Pt 
8):1203–9.  
13.  
Heffner JE, Repine JE. Pulmonary strategies of antioxidant defense. Am Rev 
Respir Dis 1989;140(2):531–54.  
14.  
Freeman BA, Crapo JD. Hyperoxia increases oxygen radical production in rat 
lungs and lung mitochondria. J Biol Chem 1981;256(21):10986–92.  
15.  
Waxman AB, Einarsson O, Seres T, et al. Targeted lung expression of interleukin-
11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA 
fragmentation. J Clin Invest 1998;101(9):1970–82.  
16.  
Griffith DE, Garcia JG, James HL, Callahan KS, Iriana S, Holiday D. Hyperoxic 
exposure in humans. Effects of 50 percent oxygen on alveolar macrophage leukotriene 
B4 synthesis. Chest 1992;101(2):392–7.  
17.  
Davis WB, Rennard SI, Bitterman PB, Crystal RG. Pulmonary oxygen toxicity. 
Early reversible changes in human alveolar structures induced by hyperoxia. N Engl J 
Med 1983;309(15):878–83.  

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
25 
 
18.  
Aggarwal NR, Brower RG. Targeting normoxemia in acute respiratory distress 
syndrome may cause worse short-term outcomes because of oxygen toxicity. Ann Am 
Thorac Soc 2014;11(9):1449–53.  
19.  
Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal 
volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung 
injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA J 
Am Med Assoc 2008;299(6):637–45.  
20.  
Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and mortality in 
mechanically ventilated patients. Intensive Care Med 2012;38(1):91–8.  
21.  
de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered 
oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated 
intensive care unit patients. Crit Care Lond Engl 2008;12(6):R156.  
22.  
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome 
(ARDS) Clinical Trials Network, Rice TW, Wheeler AP, et al. Initial trophic vs full 
enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA J 
Am Med Assoc 2012;307(8):795–803.  
23.  
Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-
linolenic acid, and antioxidant supplementation in acute lung injury. JAMA J Am Med 
Assoc 2011;306(14):1574–81.  
24.  
O’Driscoll BR, Howard LS, Earis J, Mak V, British Thoracic Society Emergency 
Oxygen Guideline Group, BTS Emergency Oxygen Guideline Development Group. BTS 
guideline for oxygen use in adults in healthcare and emergency settings. Thorax 
2017;72(Suppl 1):ii1-ii90.  
25.  
Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity 
(STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 
2000;105(2):295–310.  
26.  
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal 
Research Network, Carlo WA, Finer NN, et al. Target ranges of oxygen saturation in 
extremely preterm infants. N Engl J Med 2010;362(21):1959–69.  
27.  
Schmidt B, Whyte RK, Asztalos EV, et al. Effects of targeting higher vs lower 
arterial oxygen saturations on death or disability in extremely preterm infants: a 
randomized clinical trial. JAMA 2013;309(20):2111–20.  
28.  
BOOST II United Kingdom Collaborative Group, BOOST II Australia 
Collaborative Group, BOOST II New Zealand Collaborative Group, et al. Oxygen 
saturation and outcomes in preterm infants. N Engl J Med 2013;368(22):2094–104.  
29.  
Panwar R, Hardie M, Bellomo R, et al. Conservative versus Liberal Oxygenation 
Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized 
Controlled Trial. Am J Respir Crit Care Med 2016;193(1):43–51.  
30.  
Girardis M, Busani S, Damiani E, et al. Effect of Conservative vs Conventional 
Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-
ICU Randomized Clinical Trial. JAMA 2016;316(15):1583–9.  
31.  
Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline 
in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, 
randomised, clinical trial. Lancet Respir Med [Internet] 2017 [cited 2017 Feb 
20];Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260017300462 

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
26 
 
32.  
Panwar R, Capellier G, Schmutz N, et al. Current oxygenation practice in 
ventilated patients-an observational cohort study. Anaesth Intensive Care 
2013;41(4):505–14.  
33.  
Suzuki S, Eastwood GM, Peck L, Glassford NJ, Bellomo R. Current oxygen 
management in mechanically ventilated patients: a prospective observational cohort 
study. J Crit Care 2013;28(5):647–54.  
34.  
Beasley R, Chien J, Douglas J, et al. Thoracic Society of Australia and New 
Zealand oxygen guidelines for acute oxygen use in adults: “Swimming between the 
flags.” Respirol Carlton Vic 2015;20(8):1182–91.  
35.  
Severinghaus JW. Simple, accurate equations for human blood O2 dissociation 
computations. J Appl Physiol 1979;46(3):599–602.  
36.  
Stollings JL, Foss JJ, Ely EW, et al. Pharmacist leadership in ICU quality 
improvement: coordinating spontaneous awakening and breathing trials. Ann 
Pharmacother 2015;49(8):883–91.  
37.  
Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and 
ventilator weaning protocol for mechanically ventilated patients in intensive care 
(Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet Lond 
Engl 2008;371(9607):126–34.  
38.  
Semler MW, Noto MJ, Stollings J, et al. Effect Of Saline Versus Balanced 
Crystalloids On Major Adverse Kidney Events In The Medical Intensive Care Unit: The 
Salt Randomized Trial. Am J Respir Crit Care Med 2016;193:A4290.  
39.  
Harris BU, Char DS, Feinstein JA, Verma A, Shiboski SC, Ramamoorthy C. 
Accuracy of Pulse Oximeters Intended for Hypoxemic Pediatric Patients. Pediatr Crit 
Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 
2016;17(4):315–20.  
40.  
Ehrenfeld JM, Funk LM, Van Schalkwyk J, Merry AF, Sandberg WS, Gawande 
A. The incidence of hypoxemia during surgery: evidence from two institutions. Can J 
Anaesth J Can Anesth 2010;57(10):888–97.  
41.  
Lopez MG, Pretorius M, Shotwell MS, et al. The Risk of Oxygen during Cardiac 
Surgery (ROCS) trial: study protocol for a randomized clinical trial. Trials 
2017;18(1):295.  
42.  
Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-
expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J 
Med 2004;351(4):327–36.  
43.  
Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory 
pressure in patients with acute lung injury and acute respiratory distress syndrome: 
systematic review and meta-analysis. JAMA J Am Med Assoc 2010;303(9):865–73.  
44.  
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the 
management of pain, agitation, and delirium in adult patients in the intensive care unit. 
Crit Care Med 2013;41(1):263–306.  
45.  
Gélinas C, Fortier M, Viens C, Fillion L, Puntillo K. Pain assessment and 
management in critically ill intubated patients: a retrospective study. Am J Crit Care Off 
Publ Am Assoc Crit-Care Nurses 2004;13(2):126–35.  
46.  
Sessler CN, Grap MJ, Brophy GM. Multidisciplinary management of sedation 
and analgesia in critical care. Semin Respir Crit Care Med 2001;22(2):211–26.  

Principal Investigators: Matt Semler            Version Date: 5/1/2018 
Study Title: Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
27 
 
47.  
Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU 
patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). 
JAMA 2003;289(22):2983–91.  
48.  
Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill 
patients: validation of the Confusion Assessment Method for the Intensive Care Unit 
(CAM-ICU). Crit Care Med 2001;29(7):1370–9.  
49.  
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. 
Clarifying confusion: the confusion assessment method. A new method for detection of 
delirium. Ann Intern Med 1990;113(12):941–8.  
50.  
Semler MW, Rice TW, Shaw AD, et al. Identification of Major Adverse Kidney 
Events Within the Electronic Health Record. J Med Syst 2016;40(7):167.  
51.  
for the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) 
Investigators, the Pragmatic Critical Care Research Group, Semler MW, et al. Balanced 
crystalloids versus saline in the intensive care unit: study protocol for a cluster-
randomized, multiple-crossover trial. Trials [Internet] 2017 [cited 2017 Mar 17];18(1). 
Available from: http://trialsjournal.biomedcentral.com/articles/10.1186/s13063-017-
1871-1 
52.  
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of 
disease classification system. Crit Care Med 1985;13(10):818–29.  
53.  
Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure 
Assessment) score to describe organ dysfunction/failure. On behalf of the Working 
Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. 
Intensive Care Med 1996;22(7):707–10.  
54.  
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A 
practical scale. Lancet Lond Engl 1974;2(7872):81–4.  
55.  
Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use 
with administrative data. Med Care 1998;36(1):8–27.  
56.  
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute 
respiratory distress syndrome: the Berlin Definition. JAMA J Am Med Assoc 
2012;307(23):2526–33.  
57.  
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury 
Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter 
2012;2(Suppl):1–138.  
58.  
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research 
electronic data capture (REDCap)--a metadata-driven methodology and workflow 
process for providing translational research informatics support. J Biomed Inform 
2009;42(2):377–81.  
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
1 
 
 
 
 
 
  
 
 
Pragmatic Investigation of optimaL Oxygen Targets 
(PILOT) trial 
 
Version 1.5 
 
 
Principal Investigator 
Matthew W. Semler, MD, MSc 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
Mentors 
Gordon R. Bernard, MD, Wesley H. Self, MD, MPH, & 
Todd W. Rice, MD, MSc 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
 
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
2 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Study Summary 
2.0 
Background 
3.0 
Rationale, Aims, and Hypotheses 
4.0 
Study Description 
5.0 
Inclusion/Exclusion Criteria 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Risks and Benefits 
9.0 
Adverse Events 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Privacy/Confidentiality Issues 
13.0 
Follow-up and Record Retention 
14.0 
References 
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
3 
 
 
1.0 
Study Summary 
 
Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial 
 
Background:  Mechanical ventilation of ICU patients universally involves titration of the 
fraction of inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2).  Despite 
decades of ICU practice, however, the optimal SpO2 target remains unknown.  Higher 
SpO2 targets (96-100%) provide a margin of safety against hypoxia but increase 
exposure to hyperoxia.  Lower SpO2 targets (88-92%) minimize hyperoxia, but may 
increase the risk of hypoxia.  An intermediate SpO2 target (92-96%) may avoid the risks 
of both hyperoxia and hypoxia, or may expose patients intermittently to both sets of 
risks.  Current guidelines offer divergent recommendations as to the optimal SpO2 target 
and clinical safety and efficacy data are lacking.  Therefore, we propose a 2,250-patient 
cluster-randomized cluster-crossover trial comparing a lower SpO2 target (target 90% 
and goal range 88-92%), an intermediate SpO2 target (target 94% and goal range 92-
96%), and a higher SpO2 target (target 98% and goal range 96-100%) with regard to the 
outcome of days alive and free of invasive mechanical ventilation.  
 
Primary Aim: 
• To compare the effect of higher, intermediate, and lower SpO2 targets on days 
alive and free of invasive mechanical ventilation among mechanically ventilated 
critically ill adults. 
 
Primary Hypothesis: 
• Use of a lower SpO2 target (target 90% and goal range 88-92%) for mechanically 
ventilated ICU patients will result in more days alive and free of invasive 
mechanical ventilation than use of an intermediate SpO2 target (target 94% and 
goal range 92-96%) or a higher SpO2 target (target 98% and goal range 96-100%). 
 
Inclusion Criteria: 
• We will include adults (≥ 18 years old) receiving mechanical ventilation through 
an endotracheal tube or tracheostomy who are admitted to the study ICU or for 
whom admission to the study ICU from the emergency department is planned.   
 
Exclusion Criteria:  
• We will exclude patients who are pregnant or who are prisoners. 
 
Consent: Because [1] the study enrolls only patients who would have been exposed to 
oxygen therapy as a part of clinical care outside of the study, [2] all SpO2 targets 
examined are currently used in routine care in the study ICU, [3] no high-quality data 
suggest that the choice of SpO2 target affects clinical outcomes, and [4] during the trial 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
4 
 
treating clinicians retain discretion to control the SpO2 target when felt to be required 
for the safe treatment a specific patient, we feel the study qualifies as minimal risk.  
Given the minimal risk, the implementation of SpO2 targets at an ICU level, and the 
impracticability of consenting each patient during initiation of mechanical ventilation in 
the ICU or emergency department, we will request a waiver of informed consent. 
 
Randomization:  In the PILOT trial, the entire study ICU will be assigned to a single SpO2 
target (cluster-randomized) and the ICU will switch between lower, intermediate, and 
higher SpO2 targets every two months in a randomly generated sequence (cluster-
crossover). 
 
Study Interventions: 
• Lower SpO2 Target – FiO2 will be titrated to a target SpO2 of 90% with a goal 
range of 88-92%.   
• Intermediate SpO2 Target – FiO2 will be titrated to a target SpO2 of 94% with a 
goal range of 92-96%.   
• Higher SpO2 Target – FiO2 will be titrated accord to a target SpO2 of 98% with a 
goal range of 96-100%. 
 
Primary Outcome:   
• Ventilator-free days (VFDs) to study day 28, defined as the number of calendar 
days alive and free of invasive mechanical ventilation from the final receipt of 
invasive mechanical ventilation through 28 days after enrollment. 
 
Secondary Outcome:   
• 28-day in-hospital mortality, defined as death from any cause between 
enrollment and the first of hospital discharge or 28 days after enrollment. 
 
Exploratory Outcomes: 
• Exploratory Clinical Outcomes: ICU mortality, vasopressor-free days, renal 
replacement therapy-free days, ICU-free days, hospital-free days. 
• Exploratory Organ Function Outcomes: daily non-respiratory SOFA score, 
creatinine, lactate, presence of acute respiratory distress syndrome, Stage II or 
greater AKI by KDIGO criteria. 
• Exploratory Safety Outcomes: Atrial arrhythmia, ventricular arrhythmia, cardiac 
arrest with return of spontaneous circulation, pneumothorax or 
pneumomediastinum, ischemic stroke, myocardial infarction 
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
5 
 
2.0 
Background 
 
Each year 2-3 million intensive care unit (ICU) patients receive invasive mechanical 
ventilation,1–3  at a cost of more than $20 billion dollars.4,5  Despite recent advances,6 in-
hospital mortality among mechanically ventilated ICU patients remains 25-35%,7 and 
survivors often face cognitive, psychiatric, and physical dysfunction.8–11   
 
Mechanical ventilation of ICU patients universally involves titration of the fraction of 
inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2).  Despite decades of 
ICU practice, however, the optimal SpO2 target remains unknown.  Higher SpO2 targets 
(96-100%) provide a margin of safety against hypoxemia, but may increase exposure to 
excess FiO2, hyperoxemia, and tissue hyperoxia, causing oxidative damage, 12–14 
inflammation,15,16 and increased alveolar-capillary permeability.17  Lower SpO2 targets 
(88-92%) minimize hyperoxia,6,18,19 but may increase the risk of hypoxemia, tissue 
hypoxia, and organ dysfunction.20,21  An intermediate SpO2 target (92-96%) may avoid 
the risks of both hyperoxia and hypoxia, or, conversely, may expose patients 
intermittently to both sets of risks.   
 
Current guidelines offer divergent recommendations – ranging from tolerating SpO2 
values as low as 88% (ARDS Network)22,23 to pursuing SpO2 values as high as 98% (British 
Thoracic Society)24.  The relative risks and benefits of different SpO2 targets have been 
extensively examined in the setting of the neonatal ICU,25–28 but have only been 
investigated in adult ICU patients in three small trials.29–31  Targeting lower SpO2 
resulted in improved survival in one trial and trends toward improved survival in the 
other two.   
 
In clinical practice, however, hyperoxemia remains common.32,33  In our recent 
observational study of 2,200 mechanically ventilated ICU patients at 50 centers across 
the United States (see Figure), 
the majority of patients had a 
lowest PaO2 value on the first 
study day > 100 mm Hg (~SpO2 
> 97%).  The wide variation in 
current practice (frequently 
favoring higher SpO2 targets), 
conflicting guidelines, and pilot 
trial data favoring lower SpO2 
targets have led to calls for a 
large, randomized trial to 
determine the effect of SpO2 
target on patient outcomes.18 
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
6 
 
3.0 
Rationale, Aims, and Hypotheses 
 
In order to determine the effect of SpO2 targets during mechanical ventilation of 
critically ill adults on clinical outcomes, a randomized trial is needed. 
 
Study Aims: 
• Primary:  To compare the effect of higher, intermediate, and lower SpO2 targets 
on days alive and free of invasive mechanical ventilation among mechanically 
ventilated critically ill adults. 
 
• Secondary:  
o To evaluate the effect of the same intervention in the same population 
on the pre-specified Secondary Outcome and on pre-specified Exploratory 
Clinical Outcomes, Exploratory Organ Function Outcomes, and 
Exploratory Safety Outcomes. 
o To evaluate the effect of the same intervention on days alive and free of 
invasive mechanical ventilation in clinically relevant pre-specified patient 
subgroups. 
 
Study Hypotheses: 
• Primary:  Use of a lower SpO2 target (target 90% and goal range 88-92%) for 
mechanically ventilated ICU patients will result in more days alive and free of 
invasive mechanical ventilation (Primary Outcome) than use of an intermediate 
SpO2 target (target 94% and goal range 92-96%) or a higher SpO2 target (target 
98% and goal range 96-100%). 
 
• Secondary: Use of a lower SpO2 target (target 90% and goal range 88-92%) for 
mechanically ventilated ICU patients will result in lower 28-day in-hospital 
mortality (Secondary Outcome) than use of an intermediate SpO2 target (target 
94% and goal range 92-96%) or a higher SpO2 target (target 98% and goal range 
96-100%). 
 
4.0 
Study Description 
 
In order to address the aims outlined above, we propose the Pragmatic Investigation of 
optimaL Oxygen Targets (PILOT) trial.  The PILOT trial will be a prospective, un-blinded, 
cluster-randomized, cluster-crossover trial conducted between July 1, 2018 and August 
31, 2021 in the medical ICU at Vanderbilt University Medical Center examining the 
effect of SpO2 targets on days alive and free of mechanical ventilation among 
mechanically ventilated ICU patients.   For the 36 months of enrollment in the PILOT 
trial, the entire medical ICU will be assigned to a single SpO2 target and the ICU will 
switch between lower, intermediate, and higher SpO2 targets every two months in a 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
7 
 
randomly generated sequence (Figure below).  Patients who fulfill inclusion criteria 
without meeting exclusion criteria will be enrolled at the initiation of mechanical 
ventilation in the study ICU or in the emergency department when admission to the 
study ICU is planned.  The PILOT trial will control only the SpO2 target and all other 
aspects of patients’ clinical care will remain at the discretion of the treating clinicians. 
 
 
5.0 
Inclusion and Exclusion Criteria 
 
5.1  
Inclusion Criteria: 
1. Age ≥ 18 years 
2. Receiving mechanical ventilation through an endotracheal tube or tracheostomy 
3. Admitted to the study ICU or admission to the study ICU from the emergency 
department is planned 
 
5.2  
Exclusion Criteria:  
1. Known pregnancy or beta hCG level greater than the laboratory upper limit of 
normal in a patient capable of becoming pregnant 
2. Known to be a prisoner 
 
6.0 
Enrollment/Randomization 
 
6.1 
Study Sites:   
• Medical Intensive Care Unit at Vanderbilt University Medical Center 
• Emergency Department at Vanderbilt University Medical Center 
 
6.2  
Study Population:  All adults located in the study ICU (or for whom admission to 
the study ICU from the emergency department is planned) for whom the treating 
clinicians have decided invasive mechanical ventilation is required will be enrolled 
unless meeting exclusion criteria.  Patients will be included regardless of age, gender, 
race, weight or body mass index, initial oxygen saturation, or other clinical factors.  
 
6.3  
Enrollment:  All adult patients who do not meet exclusion criteria will be 
enrolled immediately upon receipt of invasive mechanical ventilation in the study ICU or 
in the emergency department when admission to the study ICU is planned.   
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
8 
 
6.4  
Consent:  
All patients receiving invasive mechanical ventilation in an intensive care unit 
receive oxygen therapy titrated to maintain SpO2 as a part of routine care.  In clinical 
practice, 98% of SpO2 values experienced by mechanically ventilated adults fall between 
88-100%.32,33  Within this range, current guidelines for oxygen therapy in mechanically 
ventilated adults outline three contrasting approaches: [1] tolerating SpO2 values as low 
as 88% (NIH/NHLBI ARDS Network),22 [2] titrating within the range 92-96% (Thoracic 
Society of Australia and New Zealand),34 or [3] pursuing SpO2 values as high as 98% 
(British Thoracic Society).24  The lower SpO2 target (target 90% and goal range 88-92%), 
intermediate SpO2 target (target 94% and goal range 92-96%), and higher SpO2 target 
(target 98% and goal range 96-100%) examined in this study are all intermittently used 
in routine care in the study ICU and within the range recommended by at least one 
international guideline.  There are currently no high-quality data to suggest that one 
SpO2 target is better than the others with regard to clinical outcomes.  Although there 
are no clear data to support the choice of SpO2 target, during the PILOT trial, treating 
clinicians in the study ICU will be allowed to change the SpO2 target at any point if it is 
felt to be required for the safe treatment a specific patient.   
Because the interventions studied [1] are used as part of routine care in the 
study ICU, [2] are interventions to which the patient would be exposed even if not 
participating in the study, [3] have no prior data to suggest the superiority of one 
approach over the other, and [4] are equivalent options from the perspective of the 
treating clinicians (otherwise the treating clinician retains control of SpO2 target), we 
feel the study presents minimal risk. 
  
Additionally, obtaining informed consent prior to participation in the study 
would be impractical.  Endotracheal intubation and initiation of mechanical ventilation 
for critically ill patients is frequently a time-sensitive procedure.  Despite the availability 
of a formal informed consent document for the endotracheal intubation and initiation 
of mechanical ventilation, time allows discussion of risks and benefits in less than 10% of 
airway management events in the study ICU.  The oxygen titration protocol used to 
target SpO2 in this trial begins immediately at the initiation of mechanical ventilation to 
capture the period of mechanical ventilation with the highest risk for hyperoxia and 
hypoxia.  Moreover, in this cluster-randomized trial, the entire ICU is assigned to a single 
SpO2 target delivered by the unit’s respiratory therapists through a unit-wide oxygen 
titration protocol.  Obtaining informed consent from every eligible patient in the ICU 
each day would be logistically infeasible and patients who declined to participate would 
need to be transferred between ICUs which might adversely impact their care. 
 
Because the study presents minimal risk, would not adversely affect the welfare 
or privacy rights of the participant, and consent would be impracticable, we will request 
a waiver of informed consent.   
 
6.5  
Information for Patients, Families, or Surrogates about the Study:   

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
9 
 
 
Although the study will be conducted with waiver of informed consent, we will 
implement a process by which patients, families, or surrogates may be made aware of 
the study and receive investigators’ contact information in order to solicit additional 
information about the study, ask questions, or express concerns.  An information sheet 
providing an IRB-approved lay language summary of the study activities and containing 
the contact information for investigators (who will remain available throughout the 
study period to provide additional information to patients and families upon request) 
will be made available in the following manner: 
1. Throughout the study period, the information sheet will be posted 
in at least two glass display cases, one near the public entrance to 
the medical ICU and one near the mid-point of the medical ICU. 
2. Throughout the study period, the information sheet will be 
included in the welcome packet of information about the medical 
ICU, which is distributed at the time of ICU admission to available 
families or surrogates by the medical receptionist or charge nurse 
as a part of routine clinical care. 
3. Throughout the study period, copies of the information sheet will 
be available in a brochure holder on the display table in the 
medical ICU family waiting room. 
4. Throughout the study period, additional copies of the information 
sheet will be available in the physician and respiratory therapy 
offices to be provided to patients, families, or surrogates with 
questions or concerns about the study. 
 
Unlike an informed consent document, the information sheet will not be 
distributed by research personnel directly to participants but will be made generally 
available in the study setting to patients, families, and surrogates.  There may be 
patients in the study who do not receive information about the study (e.g., a patient 
without family or surrogate who is admitted to the ICU with coma).  There may be 
patients who are not in the study who do receive information about the study (e.g., a 
patient admitted to the medical ICU on high-flow nasal cannula who does not require 
invasive mechanical ventilation).   
In order to ensure and record the execution of the above approach to providing 
information about the study, the primary investigator will: 
1. Throughout the study period, audit in-person at least every 
fourteen (14) days to confirm that the most recent IRB-approved 
information sheet is posted in at least two glass display cases in 
the medical ICU.  At least twice a year take a photograph of the 
most recent IRB-approved information sheet in one of the glass 
display cases in the medical ICU.  Store the photographs with the 
date and time that they were taken electronically in the study files 
and in hard copy in the study binder.  

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
10 
 
2. Throughout the study period, audit in-person at least every 
fourteen (14) days to confirm that copies of the most recent IRB-
approved information sheet are available in a brochure holder on 
the display table in the medical ICU family waiting room. At least 
twice a year, take a photograph of the most recent IRB-approved 
information sheets in a brochure holder on the display table in the 
medical ICU family waiting room.  Store the photographs with the 
date and time that they were taken electronically in the study files 
and in hard copy in the study binder. 
3. Throughout the study period, audit in-person at least every 
fourteen (14) days to confirm that additional copies of the 
information sheet are available in the physician and respiratory 
therapy offices to be provided to patients, families, or surrogates 
with questions or concerns about the study. 
4. Record and complete a case report form in the study database 
detailing contact about the study between patients, families, and 
surrogates and study personnel. 
 
 
6.6  
Randomization:   
During each two-month block of the study, the ICU will be assigned to either a 
higher SpO2 target (target 98% and goal range 96-100%), an intermediate SpO2 target 
(target 94% and goal range 92-96%), or a lower SpO2 target (target 90% and goal range 
88-92%).  The order of study group assignments will be generated by computerized 
randomization using permuted blocks of 3 to minimize the impact of seasonal variation.  
The last 7 days of each two-month block will be a washout period during which the ICU 
will continue to target the assigned SpO2 but new patients will not be included in the 
primary analysis.  Assuming a duration of mechanical ventilation similar to that 
observed for mechanically ventilated patients admitted to the study ICU in a prior year 
(median 3 [IQR 3-5] days), a 7-day washout period will ensure that 98% patients do not 
experience a “crossover” from one assigned SpO2 target to another. 
 
 
  
7.0 
Study Procedures 
 
7.1       Study Interventions 
 
Choice of SpO2 targets: In clinical practice, 98% of SpO2 values experienced by 
mechanically ventilated adults fall between 88-100%.32,33  Within this range, current 
guidelines for oxygen therapy in mechanically ventilated adults outline three contrasting 
approaches: [1] tolerating SpO2 values as low as 88% (NIH/NHLBI ARDS Network),22 [2] 
titrating within the range 92-96% (Thoracic Society of Australia and New Zealand),34 or 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
11 
 
[3] pursuing SpO2 values as high as 98% (British Thoracic Society).24  The PILOT trial will 
have three study groups, each emulating an approach to SpO2 targets represented in 
guidelines and clinical practice (Table). 
 
 
SpO2 versus PaO2:  SpO2 is measured continuously via non-invasive pulse oximetry for 
nearly all mechanically ventilated ICU patients.  In contrast, PaO2 is assessed via arterial 
puncture intermittently and selectively, particularly among more severely ill patients 
earlier in their clinical course.  Similar to prior studies of oxygen therapy during 
mechanical ventilation29, the PILOT trial will target ranges of SpO2 for all patients with 
functioning non-invasive pulse oximetry monitoring.  For patients in the PILOT trial for 
whom non-invasive pulse oximetry monitoring is unavailable (e.g., inadequate 
plethysmography signal due to hypoperfusion), PaO2 values corresponding to the 
assigned SpO2 target will be used to guide oxygen therapy (see above Table).35 
 
Oxygen Titration:  In the study ED and ICU, and in the United States generally, titration 
of FiO2 to maintain SpO2 for mechanically ventilated adults is most commonly 
performed by respiratory therapists, with input from nurses and physicians.  Other 
aspects of mechanical ventilation (selection of tidal volume, titration of positive end-
expiratory pressure, screening for spontaneous breathing trials) are governed by 
respiratory therapy protocols jointly developed by respiratory therapy and physician 
leaders.  In preparation for the PILOT trial, we collaborated with respiratory therapy 
leaders in the study ED and ICU to adapt existing ventilator management protocols to 
provide guidance for respiratory therapists in titrating FiO2 to achieve each of the three 
study SpO2 targets.   
 
Initiation of Mechanical Ventilation:  The study protocol guides respiratory therapists 
and treating clinicians to begin titrating FiO2 to the target SpO2 value within 15 minutes 
of the initiation of mechanical ventilation in the participating ED or ICU.  This initial 15-
minute window is intended to give the treating clinicians adequate time after emergent 
tracheal intubation to stabilize the patient’s hemodynamics and initiate basic ventilator 
settings, but also to intervene early enough to control the FiO2 and SpO2 during the 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
12 
 
critical early period of mechanical ventilation when exposure to excess FiO2 and 
hyperoxemia is most common.   
 
Oxygen Titration during Mechanical Ventilation:  SpO2 will be assessed by continuous 
pulse oximetry.  The respiratory therapist managing the patient’s ventilator will target 
an SpO2 value of 98% in the higher SpO2 group, 94% in the intermediate SpO2 group, and 
90% in the lower SpO2 group.  The respiratory therapist will titrate FiO2 as directed by 
the oxygen titration protocol when SpO2 values are outside of the range 96-100% in the 
higher SpO2 group, 92-96% in the intermediate SpO2 group, and 88-92% in the lower 
SpO2 group.  Respiratory therapists and other treating clinicians may also titrate FiO2 
when SpO2 values are not outside the range considered to be at goal in order to achieve 
SpO2 values closer to the assigned SpO2 target, to facilitate weaning from mechanical 
ventilation, or for other clinical reasons.  SpO2 will be reassessed 5 minutes after each 
change in FiO2 or sooner if clinically indicated.  Study protocol determines the SpO2 
target from enrollment until the first of: (1) extubation from invasive mechanical 
ventilation, (2) transfer out of a participating study location, (3) completion of an SpO2 
target modification sheet by treating clinicians, or (4) end of the two-month study 
period.  Study protocol does not determine the SpO2 target  during time-periods in 
which the patient is not physically located in a study location (e.g., during transport) or 
when FiO2 is not being titrated to achieve an SpO2 target (e.g., when an FiO2 of 1.0 is 
being administered for a procedure). 
 
Liberation from Mechanical Ventilation:  Each day of mechanical ventilation, all patients 
in the study ICU are assessed for safety of a spontaneous awakening trial (SAT) and 
spontaneous breathing trial (SBT)36 using the SAT and SBT safety criteria from the 
Awakening and Breathing Controlled trial.37  To prevent patients in the higher SpO2 
target group from experiencing delays in qualifying for an SBT based on receipt of higher 
FiO2 to achieve the higher SpO2 target, during the PILOT trial we will allow patients in all 
groups to qualify for an SAT and SBT regardless of their current FiO2 or PEEP settings, as 
long as the other SAT and SBT Safety Screen criteria are met and treating clinicians feel 
performance of an SAT and SBT is safe.  Definitions of SAT and SBT failure and the 
ventilator settings and duration of the SBT will not be changed from those used in the 
ABC trial and during usual care in the study ICU.  For patients who have passed an SAT 
and SBT, the decision to discontinue invasive mechanical ventilation will be made by the 
treating clinicians. 
 
Modification of SpO2 Targets: At any time during the course of the study, if a treating 
clinician or a patient, family member, or surrogate feels an SpO2 target other than that 
assigned by the study is required for the safe treatment of a specific patient, the SpO2 
target for that patient may be modified.  To modify the target, the supervising physician 
will complete a one-page SpO2 target modification sheet documenting the rationale for 
modifying the target.  Details of each SpO2 target modification will be collected and 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
13 
 
monitored.  In our prior cluster-crossover trial using the same approach to modification 
of therapy assignment, treating clinicians exercised the ability to modify the assigned 
therapy for < 5% of patients.38 
 
Anticipated examples of conditions for which treating clinicians may elect to override 
the assigned SpO2 target include:  
• pneumothorax 
• pneumomediastinum 
• carbon monoxide poisoning 
• decompression sickness 
• bleomycin toxicity 
• paraquat toxicity 
 
SpO2 Monitoring:  For all mechanically ventilated patients in the study ICU, SpO2 is 
continuously monitored using Nellcor™ SpO₂ Adhesive Sensors (Medtronic, Minneapolis, 
MN), which measure changes in red and infrared light absorption in an arteriolar bed 
throughout the pulse cycle to report a non-normalized real-time plethysmographic 
waveform and arterial hemoglobin saturation values averaged over the prior 6 seconds 
with a mean difference between SpO2 and SaO2 < 2% for SpO2 values 80-100%.39  
Plethysmography and SpO2 values are displayed [1] on IntelliVue MP90 bedside patient 
monitors (PHILIPS, Amsterdam, Netherlands) in each ICU room, [2] on telemetry 
monitors located at ICU nursing stations and adjacent to the respiratory therapy office, 
and [3] in real-time in the institutional EHR, available from any physical location.  SpO2 
values are archived every 60 seconds into an intuitional data warehouse.40,41  Collecting 
SpO2 values every 60 seconds will allow the PILOT trial report with far greater accuracy 
the incidence, severity, and duration of desaturation than prior trials in which SpO2 
values were collected every 4-24 hours.29,30 
 
Feedback on SpO2 Target Adherence: [1] During the study, the IntelliVue MP90 bedside 
patient monitors in each room will be set to generate an alarm for SpO2 values outside 
the range considered to be at goal for the assigned SpO2 target group.  For example, for 
patients in the intermediate SpO2 target group, SpO2 values 92-96% generate no alarm, 
whereas SpO2 values ≤ 91% or ≥ 97% generate an alarm alerting nursing staff and 
respiratory therapy to the out-of-range value.  [2] Study personnel will remotely 
monitor SpO2 values every four hours from 4 AM through 10 PM Monday through Friday 
and during a 10% sample of night and weekend hours to identify instances of lag 
between out of range SpO2 values and FiO2 titration, provide feedback and 
reinforcement to bedside nurses and respiratory therapists, and identify any barriers to 
SpO2 target compliance.  [3] Study personnel will attend respiratory therapy group 
meetings, nursing unit board meetings, and ICU physician leadership meetings to 
educate staff about the study, solicit safety concerns and adverse events, and identify 
and address barriers to SpO2 target compliance.  This approach to daily monitoring and 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
14 
 
intermittent feedback to clinical personnel successfully achieved 95% compliance with 
the assigned intervention in a prior cluster-crossover trial in the same ICU.38 
 
Co-interventions:  Institutional protocols in the study setting will ensure that 
mechanically ventilated patients in PILOT receive: [1] ventilation targeting 6 mL/kg of 
predicted body weight and plateau pressure ≤ 30 cm H2O,6 [2] PEEP titration according 
to the ARDSNet Lower PEEP/higher FiO2 table (except for patients with severe ARDS, for 
whom the Higher PEEP/lower FiO2 table is applied),42,43 [3] management of pain, 
agitation, and delirium44 targeting Critical Care Pain Observation Tool (CPOT),45 
Richmond Agitation-Sedation Scale (RASS),46,47 and Confusion Assessment Method for 
the ICU (CAM-ICU) scores,48,49 and [4] daily spontaneous awakening trials (SAT) and 
spontaneous breathing trials (SBT).36,37 
 
7.2  
Blinding:  Similar to prior SpO2 target studies among critically ill adults29,30, 
patients and clinicians will not be blinded to study group assignment.  Observer bias will 
be minimized by use of objective endpoints collected in duplicate by [1] study personnel 
blinded to group assignment and [2] automated data extraction from the EHR (see Data 
Collection below). 
 
7.3  
Data Collection:  The PILOT trial will primarily use structured data collected in 
routine clinical care, exported daily from the institution’s EHR into an Enterprise Data 
Warehouse, along with data from the patient registration, billing, and laboratory clinical 
information systems.  We have previously validated the quality of this method of data 
collection against the reference standard of two-physician manual chart review,50 and 
the planned approach to electronic dataset generation for the PILOT trial has already 
been successfully employed for the conduct of three prior pragmatic trials.38,38,51   
 
Electronically extracted data elements will include:  
Enrollment (Day 0): age; sex; race; ethnicity; height, weight; APACHE II score;52 non-
respiratory SOFA score;53 Glasgow Coma Scale score;54 Elixhauser Comorbidity Index;55 
history of present illness; vital signs (temperature, heart rate, systolic blood pressure, 
diastolic blood pressure, SpO2); mechanical ventilator settings (mode, set and exhaled 
tidal volume, set and actual respiratory rate, positive end-expiratory pressure, peak 
pressure, FiO2); serum laboratory values (white blood cell count, hemoglobin, platelet 
count, sodium, potassium, bicarbonate, creatinine, bilirubin, alanine aminotransferase, 
aspartate aminotransferase, lactate, arterial pH, PaO2, SaO2).   
 
Daily On-Study (Days 0-28): Vital signs, ventilator settings, screening for and 
performance of spontaneous awakening trials and spontaneous breathing trials, and 
serum laboratory values (as above); receipt of red cell transfusion; number of arterial 
blood gases; non-respiratory SOFA score; ARDS by Berlin criteria;56 Stage II or greater 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
15 
 
AKI by KDIGO criteria;57 atrial arrhythmia, ventricular arrhythmia, cardiac arrest, 
pneumothorax or pneumomediastinum, ischemic stroke, myocardial infarction.   
 
Termination (Days 0-28):  Vital status at 28 days; time of liberation from invasive 
mechanical ventilation; receipt and duration of vasopressors; receipt and duration of 
renal replacement therapy; duration of ICU and hospital admission.   
 
Data elements collected manually by study personnel will include: [1] all data 
elements for a randomly selected 10% of participants to ensure the quality of 
electronically extracted data, [2] all primary and secondary outcomes collected at study 
termination for 100% of participants to ensure duplicate data collection of key study 
outcomes, and [3] any data elements for which electronic data extraction has not been 
developed and validated, including etiology of respiratory failure, indication for 
mechanical ventilation, protocol violations, and adverse events.  Data will be stored, 
curated, and secured in the online database, REDCap.58 
 
 
 
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
16 
 
7.4 
 Outcome Measures 
 
Primary Outcome:   
The primary outcome is ventilator-free days (VFDs) to study day 28.  VFDs will be 
defined as the number of calendar days alive and free of invasive mechanical ventilation 
from the final receipt of invasive mechanical ventilation through 28 days after 
enrollment.  For the assessment of VFDs, the day of enrollment (defined as the day on 
which the patient first receives invasive mechanical ventilation in a participating study 
location), will be considered to be day 0.  Outcome ascertainment will cease at the time 
of hospital discharge or 28 days after enrollment, whichever occurs first.  Receipt of 
invasive mechanical ventilation will be considered to end when patients undergo the 
final tracheal extubation or disconnection of the ventilator from the endotracheal tube 
or tracheostomy tube between enrollment and 28 days after enrollment.  Patients who 
continue to receive invasive mechanical ventilation at day 28 will receive zero VFDs.  
Patient who die prior to day 28 will receive zero VFDs.  Patients who are discharged 
from the hospital prior to day 28 and are receiving invasive mechanical ventilation at the 
time of discharge will receive zero VFDs.  Patients who are removed from invasive 
mechanical ventilation and are discharged from the hospital without invasive 
mechanical ventilation prior to 28 days will be assumed to remain free of invasive 
mechanical ventilation between hospital discharge and day 28.  For patients who are 
removed from invasive mechanical ventilation, return to invasive mechanical 
ventilation, and are subsequently removed again from invasive mechanical ventilation 
prior to day 28, VFDs will be counted from the final receipt of invasive mechanical 
ventilation prior to day 28.  We chose VFDs as the primary outcome for the PILOT trial as 
choice of SpO2 target may simultaneously affect both mortality and duration of invasive 
mechanical ventilation. 
 
Secondary Outcome:   
The sole pre-specified secondary outcome is 28-day in-hospital mortality, 
defined as death from any cause between enrollment and the first of hospital discharge 
or 28 days after enrollment. 
 
Exploratory Clinical Outcomes:  
1. ICU mortality 
2. Vasopressor-free days 
3. Renal replacement therapy-free days 
4. ICU-free days 
5. Hospital-free days 
 
Exploratory Organ Function Outcomes: (All exploratory organ function outcomes will 
employ only laboratory values and imaging obtained as a part of routine clinical care)  
1. Daily non-respiratory SOFA score 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
17 
 
2. Daily creatinine 
3. Daily lactate 
4. Presence of acute respiratory distress syndrome 
5. Stage II or greater AKI by KDIGO criteria 
 
Exploratory Safety Outcomes:   
1. Atrial arrhythmia 
2. Ventricular arrhythmia 
3. Cardiac arrest 
4. Pneumothorax or pneumomediastinum 
5. Ischemic stroke 
6. Myocardial infarction 
 
Measures of Separation between Groups:   
1. SpO2 
2. SaO2 
3. FiO2 
4. PaO2 
5. Episodes of hypoxemia, including: 
a. SpO2 < 85% for ≥ 5 minutes 
b. SpO2 < 80% for ≥ 5 minutes 
c. SpO2 < 70% for ≥ 2 minutes 
6. Episodes of hyperoxemia, including: 
a. SpO2 > 98% for ≥ 5 minutes 
b. SpO2 > 98% for ≥ 30 minutes 
7. Proportion of patients with a value for PaO2 < 55 mm Hg 
8. Proportion of patients with a value for PaO2 > 120 mm Hg 
 
Exploratory Processes of Care Outcomes:   
1. Tidal volume 
2. Positive end expiratory pressure 
3. Peak airway pressure 
4. Receipt of mandatory ventilator mode 
5. Number of arterial blood gasses 
6. Hemoglobin 
7. Red cell transfusion 
 
8.0 
Risks and Benefits: 
 
Among adult patients for whom the treating clinicians have decided invasive 
mechanical ventilation is required, there are currently no established risks or benefits to 
targeting a higher, intermediate, or lower SpO2.  At this time, there is no reason to 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
18 
 
believe that participation in this study would expose patients to greater medical risks or 
benefits than those experienced by critically ill patients receiving invasive mechanical 
ventilation as a part of routine care.  The greater benefit of the study would be to 
society in the form of improved understanding of safe and effective provision of oxygen 
therapy during mechanical ventilation for critically ill patients. 
 
A potential risk to patients participating in this study involves the collection of 
protected health information (PHI).  In order to limit the associated risks, the minimum 
amount of PHI necessary for study conduct will be collected.  After collection, the data 
will be stored in a secure online database (REDCap) only accessible by the investigators.  
After publication, a de-identified database will be generated to protect participant 
privacy. 
 
9.0 
Safety Monitoring and Adverse Events: 
 
9.1 Safety Monitoring 
 
 
The PILOT trial will take place in a high-acuity clinical care environment during 
delivery of a high-acuity procedure required for routine clinical care.  During the time of 
the study intervention, the patient will have a critical care or emergency medicine nurse 
with a low patient-to-nurse staffing ratio, immediate access to a respiratory therapist, 
and a team of critical care physicians physically located on the study unit twenty-four 
hours a day.  As a part of routine care all patients will be receiving continuous invasive 
or non-invasive monitoring of heart rate, blood pressure, respiratory rate, and oxygen 
saturation.   
Study personnel will monitor compliance with the study inclusion and exclusion 
criteria, study protocol, and study safety measures daily.  Study personnel will be readily 
available to answer questions at any time from patients, legally authorized 
representatives, or treating clinicians.  If, at any point in a patient’s clinical course, the 
treating clinicians believe an SpO2 target different from the assigned target is required 
for the safe treatment of the patient, the SpO2 target will be modified to the target the 
treating clinicians judge to be safest. 
A structured plan for prospective collection of study outcomes has been 
specified, in addition to a process by which Adverse Events and Serious Adverse Events 
will be managed and reported as required to regulatory bodies. 
A Data and Safety Monitoring Board (DSMB) will be appointed to oversee the 
study. The DSMB will be available throughout the trial to monitor enrollment, protocol 
compliance, safety, and adverse events.  Additionally the DSMB will perform an interim 
analysis for safety and efficacy. 
 
9.2 Adverse Event Reporting 
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
19 
 
A system has been established to report and track clinical outcomes and adverse 
events (AEs). Study personnel will monitor the safety of subjects and follow AEs until the 
event resolves or is explained. 
 
Clinical Outcomes (not considered Adverse Events). In this study of critically ill patients 
who are at high risk for death or other adverse outcomes due to their underlying critical 
illness, clinical outcomes, including death and organ dysfunction, will be systematically 
tracked (collected in the case report form) and will be included as part of the analyses 
for this study. For the purposes of reporting, death and organ dysfunction will not be 
recorded as AEs unless the investigator believes the event may have been caused by the 
study or is more severe or prolonged than expected given the underlying critical illness. 
This approach—considering death and organ dysfunction as outcomes rather than AEs 
and systemically tracking expected outcomes for analysis rather than solely recording 
individual AEs—is common in ICU trials because these outcomes/events occur 
commonly in the ICU and this system mandates that data regarding death, organ 
dysfunction, and expected outcomes be tracked systematically for all patients and 
analyzed appropriately. Clinical outcomes will be systemically tracked throughout the 
study period. Listed below are events that will be tracked as primary, secondary, or 
exploratory clinical outcomes and will not therefore be reported as AEs during this study 
(unless believed to be study related and more severe or prolonged than expected given 
the underlying critical illness): 
 
1. Death (all deaths occurring prior to hospital discharge will be reported on the 
CRF in the vital status at hospital discharge section); 
2. Recurrence of respiratory failure, including need for re-intubation or non-
invasive mechanical ventilation, presence of acute respiratory distress 
syndrome, or presence of pneumothorax or pneumomediastinum; 
3. Circulatory failure, including cardiac arrest or shock with or without receipt of 
vasopressors; 
4. Incidence of sustained atrial and ventricular arrhythmias; 
5. Acute kidney injury, including leading to increased creatinine or receipt of renal 
replacement therapy; 
6. Hepatic injury or failure leading to increased bilirubin, AST, or ALT; 
7. Coagulation derangements leading to elevated PT/INR or PTT, DIC, 
thrombocytopenia, or thrombocytosis; 
8. Lactic acidosis; 
9. Delirium, disability, and physical or cognitive impairment believed to be newly 
acquired; 
10. All values for SpO2, SaO2, FiO2, PaO2, or PaO2/FiO2 ratio; 
11. All values for vital signs (e.g., temperature, respiratory rate, SpO2); 
12. Receipt of co-interventions (e.g., number of arterial blood gasses, red cell 
transfusion) 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
20 
 
13. Duration of ICU admission, ICU readmission; 
14. Duration of hospitalization, hospital readmission; 
15. Alterations in routine labs, including chemistries, complete blood counts, liver 
function tests, and hemostasis profiles. 
 
Adverse Event Classifications. An Adverse Event (AE) will be any untoward medical 
occurrence for a patient enrolled in the trial that is not tracked as a clinical outcome, 
regardless of whether the event is considered study related or not. All AEs occurring 
during the observational study period will be recorded on the CRF. All AEs will then be 
assessed as to whether they are (1) related to study procedures, (2) serious, and/or (3) 
unexpected according to the following definitions: 
 
I. 
Related to study procedures. AEs that the investigator suspects are related to 
the study will be classified as study related. Certainty of relatedness is not 
required as long as a reasonable possibility exists that the AE is related to a study 
procedure. 
 
II. 
Serious. AEs that meet any of the criteria below will be considered Serious 
Adverse Events (SAEs): 
a. Results in death 
b. Is life-threatening (defined as an event in which the participant was at risk of 
death at the time of the event and NOT an event that hypothetically might have 
caused death if it would have been more severe) 
c. Prolongs an existing hospitalization 
d. Results in persistent or significant disability or incapacity 
e. Results in a congenital anomaly or birth defect 
f. Important medical event that requires an intervention to prevent any of a-e 
above. 
 
III. 
Unexpected. AEs that are more severe or prolonged than expected based on the 
investigator’s discretion will be considered Unexpected.  
 
The PILOT trial will monitor, track, and report all Clinical Outcomes and AEs as required 
by regulatory bodies. 
 
Communication and Reporting of Adverse Events. In order to ensure proper and timely 
reporting of all adverse events, there will be a clear communication plan for all study 
personnel to follow. AEs will be recorded in the AE CRF in the electronic database and 
reported to the PI within 5 days of occurrence. The PI will provide a report of all AEs 
annually to the IRB and DSMB as part of the annual review process as required. All SAEs 
will be reported to the PI within 72 hours of occurrence. The PI will, in turn, report all 
SAEs to the IRB, DSMB, and funding body within 7 calendar days of occurrence. 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
21 
 
 
9.3 Frequency of Monitoring and Interim Analysis.   
Study personnel will continuously monitor enrollment, protocol compliance, and 
AEs and SAEs throughout the course of the trial.  Semi-annually, the DSMB will formally 
review enrollment, protocol compliance, and AEs and SAEs as part of a formal DSMB 
meeting.  Additionally, the DSMB will be available to convene a meeting at any point in 
the course of the trial to review urgent issues related to AEs, protocol compliance, or 
unexpected adverse events.  Study personnel and DSMB members will adhere to the 
expectations for reporting and managing AEs and unexpected adverse events outlined in 
the DSMB charter. 
Interim Analysis.  In addition to ongoing monitoring of safety throughout the 
trial, the DSMB will conduct a single interim analysis for efficacy and safety at the 
anticipated halfway point of the PILOT trial.  The interim analysis will include patients 
enrolled during the first 18 months of the trial.  The stopping boundary for efficacy will 
be met if the P value for the difference between groups is <0.001.  Use of the 
conservative Haybittle-Peto boundary (P < 0.001) will allow the final analysis to be 
performed using an unchanged level of significance (P = 0.05).  Given the minimal risk 
nature of the study and current use of all SpO2 target as a part of usual care, there will 
be no stopping boundary for futility.  The DSMB will reserve the right to stop the trial at 
any point, request additional data or interim analyses, or request modifications of the 
study protocol as required to protect patient safety. 
 
9.4 Data and Safety Monitoring Board (DSMB).  A formal independent DSMB will 
oversee the conduct of the trial and the planned interim analysis.  The DSMB will be 
composed of at least one physician outside the study institution experienced in the 
conduct of critical care clinical trials and one biostatistical expert who will assist with 
study monitoring and performance of the interim analysis. 
 
9.5 Data Monitoring Plan. To ensure data are accurately and completely collected 
during the PILOT trial, the study team will follow a specific Data Monitoring Plan. All 
clinical outcomes will be collected in duplicate by both electronic data collection and by 
the study nurse.  All study data from random sample of 10% of study records will be 
collected in duplicate by electronic data collection and by the study nurse.  Each of 
these records will also be reviewed annually by the primary investigator to ensure data 
collection is accurate, complete, and current.  The study biostatistician will run periodic 
data cleans throughout the study looking for outliers or overtly erroneous data. This 
Monitoring Plan will serve as a method for identifying and resolving systematic 
problems and therefore increase data quality. We will submit progress reports to the 
local IRB annually, or more frequently if requested. 
 
 
10.0 
Study Withdrawal/Discontinuation 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
22 
 
 
Patients can be withdrawn from study participation in the following circumstances: 
• The investigator decides that the patient should be withdrawn for safety 
considerations. 
• There is a significant protocol violation in the judgment of the PI. 
 
The reason and date of every withdrawal will be recorded in the patient study records.  
Follow-up will be performed for all patients who discontinue due to an adverse event or 
any other safety parameter.  Follow-up will also be performed for all patients who end 
participation in the protocol for another reason, but who also have an adverse event or 
other safety parameter that could have led to discontinuation.  Follow-up will be 
conducted until the condition has resolved, until diagnosis of the adverse event or 
safety parameter is deemed chronic and stable, or as long as clinically appropriate.  This 
follow-up will be documented in the patient study record as well.   
 
 
11.0 
Statistical Considerations 
 
Power calculation.   
In a prior cluster-randomized cluster-crossover trial in the same ICU,51 880 
mechanically ventilated adults were enrolled per year (73.3 per month), with a median 
of 22 VFDs [IQR 0-25 VFDs] and an intra-cluster intra-period correlation of 0.01.  During 
the planned 36-month PILOT trial, we estimate 2,640 mechanically ventilated adults will 
be admitted to the study ICU, of whom 390 will be enrolled during washout periods and 
excluded from the primary analysis and 2,250 will be included in the primary analysis.  
With a total enrollment of 2,250 patients, a standard deviation in the primary outcome 
of VFDs of 11.4 days, and a two-sided alpha of 0.05, the PILOT trial will have 92 percent 
statistical power to detect an absolute difference between groups in VFDs of 2.0 days 
(similar to the numerical difference in VFDs between SpO2 target groups reported in 
prior studies29,30). 
 
Primary analysis of the Primary Outcome.   
The primary analysis will be an intention-to-treat comparison of the primary 
outcome of VFDs between the higher, intermediate, and lower SpO2 target groups 
among all patients enrolled in the trial except [1] those admitted during one of the 7-
day washout periods and [2] those with a laboratory-confirmed diagnosis of Coronavirus 
disease 2019 (COVID-19).  We will use a proportional odds model with independent 
covariates of group assignment (higher, intermediate, or lower SpO2 target) and time.  
Time (in days) will be treated as a continuous variable with values ranging from 1 (first 
day of enrollment) to 1,097 (final day of enrollment) and will be analyzed using 
restricted cubic splines with multiple knots to allow for non-linearity resulting from 
seasonality or secular trends.  For the purposes of declaring a statistically significant 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
23 
 
difference between groups in the primary endpoint, we will consider the conditional 
effect from the proportional odds model and a two-sided P value of 0.05.  In addition to 
the overall comparison of the three study groups, we will perform pair-wise 
comparisons between the lower and intermediate groups, lower and higher groups, and 
intermediate and higher groups using the same statistical approach. 
 
Sensitivity Analyses of the Primary Outcome 
• We will repeat the primary analysis using alternative statistical approaches to 
comparing the VFDs outcome between groups.  These statistical approaches will 
include: 
o zero-inflated Poisson regression;  
o zero-inflated negative binomial regression; 
o global rank scale analysis (see Supplementary Appendix); and 
o Fine and Gray competing risk regression in which extubation from 
invasive mechanical ventilation is the event of interest and mortality is a 
competing event. 
• We will repeat the primary analysis with adjustment for pre-specified baseline 
covariates.   
• We will repeat the primary analysis replacing the continuous covariate of time 
with a categorical covariate of season defined as: winter (January, February, 
March); spring (April, May, June); summer (July, August, September); and fall 
(October, November, December). 
• We will repeat the primary analysis among all patients enrolled in the trial, 
including [1] patients initiated on invasive mechanical ventilation in a study 
location during one of the pre-specified 7-day washout periods and [2] patients 
with a diagnosis of COVID-19 (estimated sample size of 3,000 patients). 
 
Analysis of Effect Modification for the Primary Outcome. 
We will examine whether pre-specified baseline variables modify the effect of 
study group on the primary outcome using formal tests of statistical interaction in a 
proportional odds model.  Independent variables will include study group assignment, 
the potential effect modifier of interest, and the interaction between the two (e.g., 
study group * presence of sepsis or septic shock) and time.  Significance will be 
determined by the P value for the interaction term, with values less than 0.10 
considered to suggest a potential interaction and values less than 0.05 considered to 
confirm an interaction.  
We will examine whether the following baseline variables modify the effect of 
study group on the primary outcome: 
• Age (continuous variable); 
• Race and ethnicity (Hispanic, Non-Hispanic Black, Non-Hispanic White, Other); 
• Source of admission to the ICU (ED, hospital ward, another ICU in the study 
hospital, operating room, outside hospital); 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
24 
 
• Duration of invasive mechanical ventilation prior to enrollment (0 minutes; 1 to 
360 minutes; >360 minutes); 
• Chronic comorbidities (categories are not mutually exclusive) 
o Receipt of supplemental oxygen at place of residence prior to hospital 
admission (yes, no); 
o Coronary artery disease or heart failure with reduced ejection fraction 
(yes, no); 
• Acute diagnoses at enrollment (categories are not mutually exclusive) 
o cardiac arrest (yes, no); 
o acute myocardial infarction (yes, no); 
o sepsis or septic shock (yes, no); 
o acute respiratory distress syndrome (yes, no); 
• Receipt of vasopressors at enrollment (yes, no); 
• Non-respiratory SOFA score at enrollment (continuous variable); 
• Time period (before the COVID-19 pandemic [July 2018 - December 2019], 
during the COVID-19 pandemic [January 2020 – August 2021]). 
 
Analysis of the Secondary Outcome 
 
The sole pre-specified secondary outcome of 28-day in-hospital mortality will be 
compared between the three study groups in an intention-to-treat fashion in the 
primary analysis population using a logistic regression model with independent 
covariates of group assignment (higher, intermediate, or lower SpO2 target) and time.  
We also will perform pair-wise comparisons between the lower and intermediate 
groups, lower and higher groups, and intermediate and higher groups using the same 
statistical approach. 
 
Analysis of the Exploratory Outcomes 
Each of the exploratory outcomes will be compared between groups in an 
intention-to-treat fashion in the primary analysis population.  Continuous outcomes will 
be compared between groups using a proportional odds model with independent 
covariates of group assignment (higher, intermediate, or lower SpO2 target) and time.  
Categorical outcomes will be compared between groups using a logistic regression 
model with independent covariates of group assignment (higher, intermediate, or lower 
SpO2 target) and time. 
 
Corrections for multiple testing 
We have pre-specified a single primary outcome and a single secondary 
outcome.  Consistent with recommendations of the Food and Drug Administration and 
the European Medicines Association, each will be tested using a two-sided p-value with 
a significance level of 0.05.  For all other analyses, emphasis will be placed on the 
estimate of effect size with 95% confidence intervals, as recommended by the 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
25 
 
International Committee of Medical Journal Editors, and no corrections for multiple 
comparisons will be performed. 
 
Handling of missing data 
The primary outcome of VFDs is not anticipated to be missing for any patients.  Missing 
data will not be imputed for the primary outcome or any secondary or exploratory 
outcomes.  In adjusted analyses, missing data for covariates will be imputed using 
multiple imputations. 
 
Interim Analysis 
 
We will plan for the DSMB to conduct a single interim analysis for efficacy and 
safety at the anticipated halfway point of the trial.  The interim analysis will include 
patients enrolled during the first 18 months of the trial.  The stopping boundary for 
efficacy will be met if the P value for the difference between groups is <0.001 using a 
proportional odds model with independent covariates of group assignment (higher, 
intermediate, or lower SpO2 target) and time with regard to the primary outcome of 
VFDs.  Use of the conservative Haybittle-Peto boundary (P < 0.001) will allow the final 
analysis to be performed using an unchanged level of significance (P = 0.05).  Given the 
minimal risk nature of the study and current use of all SpO2 target as a part of usual 
care, there will be no stopping boundary for futility.  The DSMB will reserve the right to 
stop the trial at any point, request additional data or interim analyses, or request 
modifications of the study protocol as required to protect patient safety. 
 
If the 18-month interim analysis reveals an enrollment indicative of <80% 
statistical power at completion, we will ask the DSMB to approve extending enrollment 
of the study to ensure the trial is not underpowered to detect the planned difference 
between groups in the primary outcome. 
             
12.0 
Privacy/Confidentiality Issues 
At no time during the course of this study, its analysis, or its publication will 
patient identities be revealed in any manner.  The minimum necessary data containing 
patient or provider identities will be collected.  All patients will be assigned a unique 
study ID number for tracking.  Data collected from the medical record will be entered 
into the secure online database REDCap.  Hard copies of the treating clinician 
modification of SpO2 target sheet will be stored in a locked room until after the 
completion of enrollment and data cleaning.  Once data are verified and the database is 
locked, all hard copies of data collection forms will be destroyed.  All data will be 
maintained in the secure online database REDCap until the time of study publication.  At 
the time of publication, a de-identified version of the database will be generated. 
 
13.0 
Follow-up and Record Retention 
Patients will be followed after enrollment for 28 days or until hospital discharge, 
whichever occurs first.  Data collected from the medical record will be entered into the 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
26 
 
secure online database REDCap.  Once data are verified and the database is locked, all 
hard copies of data collection forms will be destroyed.  All data will be maintained in the 
secure online database REDCap until the time of study publication.  At the time of 
publication, a de-identified version of the database will be generated. 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
27 
 
 
14.0 
References 
1.  
Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn 
JM. The epidemiology of mechanical ventilation use in the United States. Crit Care Med 
2010;38(10):1947–53.  
2.  
Wunsch H, Angus DC, Harrison DA, Linde-Zwirble WT, Rowan KM. 
Comparison of medical admissions to intensive care units in the United States and United 
Kingdom. Am J Respir Crit Care Med 2011;183(12):1666–73.  
3.  
Adhikari NKJ, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the 
global burden of critical illness in adults. Lancet Lond Engl 2010;376(9749):1339–46.  
4.  
Dasta JF, McLaughlin TP, Mody SH, Piech CT. Daily cost of an intensive care 
unit day: the contribution of mechanical ventilation. Crit Care Med 2005;33(6):1266–71.  
5.  
Halpern NA, Pastores SM. Critical care medicine in the United States 2000-2005: 
an analysis of bed numbers, occupancy rates, payer mix, and costs. Crit Care Med 
2010;38(1):65–71.  
6.  
Ventilation with lower tidal volumes as compared with traditional tidal volumes 
for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory 
Distress Syndrome Network. N Engl J Med 2000;342(18):1301–8.  
7.  
Esteban A, Frutos-Vivar F, Muriel A, et al. Evolution of mortality over time in 
patients receiving mechanical ventilation. Am J Respir Crit Care Med 2013;188(2):220–
30.  
8.  
Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of 
the acute respiratory distress syndrome. N Engl J Med 2003;348(8):683–93.  
9.  
Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute 
respiratory distress syndrome. N Engl J Med 2011;364(14):1293–304.  
10.  
Kahn JM, Benson NM, Appleby D, Carson SS, Iwashyna TJ. Long-term acute 
care hospital utilization after critical illness. JAMA 2010;303(22):2253–9.  
11.  
Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment 
after critical illness. N Engl J Med 2013;369(14):1306–16.  
12.  
Fridovich I. Oxygen toxicity: a radical explanation. J Exp Biol 1998;201(Pt 
8):1203–9.  
13.  
Heffner JE, Repine JE. Pulmonary strategies of antioxidant defense. Am Rev 
Respir Dis 1989;140(2):531–54.  
14.  
Freeman BA, Crapo JD. Hyperoxia increases oxygen radical production in rat 
lungs and lung mitochondria. J Biol Chem 1981;256(21):10986–92.  
15.  
Waxman AB, Einarsson O, Seres T, et al. Targeted lung expression of interleukin-
11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA 
fragmentation. J Clin Invest 1998;101(9):1970–82.  
16.  
Griffith DE, Garcia JG, James HL, Callahan KS, Iriana S, Holiday D. Hyperoxic 
exposure in humans. Effects of 50 percent oxygen on alveolar macrophage leukotriene 
B4 synthesis. Chest 1992;101(2):392–7.  
17.  
Davis WB, Rennard SI, Bitterman PB, Crystal RG. Pulmonary oxygen toxicity. 
Early reversible changes in human alveolar structures induced by hyperoxia. N Engl J 
Med 1983;309(15):878–83.  

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
28 
 
18.  
Aggarwal NR, Brower RG. Targeting normoxemia in acute respiratory distress 
syndrome may cause worse short-term outcomes because of oxygen toxicity. Ann Am 
Thorac Soc 2014;11(9):1449–53.  
19.  
Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal 
volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung 
injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA J 
Am Med Assoc 2008;299(6):637–45.  
20.  
Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and mortality in 
mechanically ventilated patients. Intensive Care Med 2012;38(1):91–8.  
21.  
de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered 
oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated 
intensive care unit patients. Crit Care Lond Engl 2008;12(6):R156.  
22.  
National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome 
(ARDS) Clinical Trials Network, Rice TW, Wheeler AP, et al. Initial trophic vs full 
enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA J 
Am Med Assoc 2012;307(8):795–803.  
23.  
Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-
linolenic acid, and antioxidant supplementation in acute lung injury. JAMA J Am Med 
Assoc 2011;306(14):1574–81.  
24.  
O’Driscoll BR, Howard LS, Earis J, Mak V, British Thoracic Society Emergency 
Oxygen Guideline Group, BTS Emergency Oxygen Guideline Development Group. BTS 
guideline for oxygen use in adults in healthcare and emergency settings. Thorax 
2017;72(Suppl 1):ii1–90.  
25.  
Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity 
(STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 
2000;105(2):295–310.  
26.  
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal 
Research Network, Carlo WA, Finer NN, et al. Target ranges of oxygen saturation in 
extremely preterm infants. N Engl J Med 2010;362(21):1959–69.  
27.  
Schmidt B, Whyte RK, Asztalos EV, et al. Effects of targeting higher vs lower 
arterial oxygen saturations on death or disability in extremely preterm infants: a 
randomized clinical trial. JAMA 2013;309(20):2111–20.  
28.  
BOOST II United Kingdom Collaborative Group, BOOST II Australia 
Collaborative Group, BOOST II New Zealand Collaborative Group, et al. Oxygen 
saturation and outcomes in preterm infants. N Engl J Med 2013;368(22):2094–104.  
29.  
Panwar R, Hardie M, Bellomo R, et al. Conservative versus Liberal Oxygenation 
Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized 
Controlled Trial. Am J Respir Crit Care Med 2016;193(1):43–51.  
30.  
Girardis M, Busani S, Damiani E, et al. Effect of Conservative vs Conventional 
Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-
ICU Randomized Clinical Trial. JAMA 2016;316(15):1583–9.  
31.  
Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline 
in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, 
randomised, clinical trial. Lancet Respir Med [Internet] 2017 [cited 2017 Feb 
20];Available from: http://linkinghub.elsevier.com/retrieve/pii/S2213260017300462 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
29 
 
32.  
Panwar R, Capellier G, Schmutz N, et al. Current oxygenation practice in 
ventilated patients-an observational cohort study. Anaesth Intensive Care 
2013;41(4):505–14.  
33.  
Suzuki S, Eastwood GM, Peck L, Glassford NJ, Bellomo R. Current oxygen 
management in mechanically ventilated patients: a prospective observational cohort 
study. J Crit Care 2013;28(5):647–54.  
34.  
Beasley R, Chien J, Douglas J, et al. Thoracic Society of Australia and New 
Zealand oxygen guidelines for acute oxygen use in adults: ‘Swimming between the 
flags.’ Respirol Carlton Vic 2015;20(8):1182–91.  
35.  
Severinghaus JW. Simple, accurate equations for human blood O2 dissociation 
computations. J Appl Physiol 1979;46(3):599–602.  
36.  
Stollings JL, Foss JJ, Ely EW, et al. Pharmacist leadership in ICU quality 
improvement: coordinating spontaneous awakening and breathing trials. Ann 
Pharmacother 2015;49(8):883–91.  
37.  
Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and 
ventilator weaning protocol for mechanically ventilated patients in intensive care 
(Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet Lond 
Engl 2008;371(9607):126–34.  
38.  
Semler MW, Noto MJ, Stollings J, et al. Effect Of Saline Versus Balanced 
Crystalloids On Major Adverse Kidney Events In The Medical Intensive Care Unit: The 
Salt Randomized Trial. Am J Respir Crit Care Med 2016;193:A4290.  
39.  
Harris BU, Char DS, Feinstein JA, Verma A, Shiboski SC, Ramamoorthy C. 
Accuracy of Pulse Oximeters Intended for Hypoxemic Pediatric Patients. Pediatr Crit 
Care Med J Soc Crit Care Med World Fed Pediatr Intensive Crit Care Soc 
2016;17(4):315–20.  
40.  
Ehrenfeld JM, Funk LM, Van Schalkwyk J, Merry AF, Sandberg WS, Gawande 
A. The incidence of hypoxemia during surgery: evidence from two institutions. Can J 
Anaesth J Can Anesth 2010;57(10):888–97.  
41.  
Lopez MG, Pretorius M, Shotwell MS, et al. The Risk of Oxygen during Cardiac 
Surgery (ROCS) trial: study protocol for a randomized clinical trial. Trials 
2017;18(1):295.  
42.  
Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-
expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J 
Med 2004;351(4):327–36.  
43.  
Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory 
pressure in patients with acute lung injury and acute respiratory distress syndrome: 
systematic review and meta-analysis. JAMA J Am Med Assoc 2010;303(9):865–73.  
44.  
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the 
management of pain, agitation, and delirium in adult patients in the intensive care unit. 
Crit Care Med 2013;41(1):263–306.  
45.  
Gélinas C, Fortier M, Viens C, Fillion L, Puntillo K. Pain assessment and 
management in critically ill intubated patients: a retrospective study. Am J Crit Care Off 
Publ Am Assoc Crit-Care Nurses 2004;13(2):126–35.  
46.  
Sessler CN, Grap MJ, Brophy GM. Multidisciplinary management of sedation 
and analgesia in critical care. Semin Respir Crit Care Med 2001;22(2):211–26.  

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
30 
 
47.  
Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU 
patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). 
JAMA 2003;289(22):2983–91.  
48.  
Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill 
patients: validation of the Confusion Assessment Method for the Intensive Care Unit 
(CAM-ICU). Crit Care Med 2001;29(7):1370–9.  
49.  
Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. 
Clarifying confusion: the confusion assessment method. A new method for detection of 
delirium. Ann Intern Med 1990;113(12):941–8.  
50.  
Semler MW, Rice TW, Shaw AD, et al. Identification of Major Adverse Kidney 
Events Within the Electronic Health Record. J Med Syst 2016;40(7):167.  
51.  
Semler MW, Self WH, Wang L, et al. Balanced crystalloids versus saline in the 
intensive care unit: study protocol for a cluster-randomized, multiple-crossover trial. 
Trials 2017;18(1).  
52.  
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of 
disease classification system. Crit Care Med 1985;13(10):818–29.  
53.  
Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure 
Assessment) score to describe organ dysfunction/failure. On behalf of the Working 
Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. 
Intensive Care Med 1996;22(7):707–10.  
54.  
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A 
practical scale. Lancet Lond Engl 1974;2(7872):81–4.  
55.  
Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use 
with administrative data. Med Care 1998;36(1):8–27.  
56.  
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute 
respiratory distress syndrome: the Berlin Definition. JAMA J Am Med Assoc 
2012;307(23):2526–33.  
57.  
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury 
Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter 
2012;2(Suppl):8.  
58.  
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research 
electronic data capture (REDCap)--a metadata-driven methodology and workflow 
process for providing translational research informatics support. J Biomed Inform 
2009;42(2):377–81.  
 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
31 
 
Tracking of Protocol Versions: 
 
Version 1.0 – Initial Protocol (5/1/2018) 
 
Version 1.1 – Revisions after initial meeting with DSMB (6/8/18) 
• Updated protocol to specify that the primary analysis will use a proportional odd 
mixed effects model with a fixed effect of study group and a random effect of 
study period. 
• Added sensitivity analyses using a zero-inflated Poisson model and a state-
transitions model 
• Specified the plan for sample size re-estimation at the interim analysis as follows: 
“If the 18-month interim analysis reveals an enrollment indicative of <80% 
statistical power at completion, we will ask the DSMB to approve extending 
enrollment of the study to ensure the trial is not underpowered to detect the 
planned difference between groups in the primary outcome.” 
• Specified that “Patients will be provided with an information sheet providing an 
IRB-approved lay language summary of the study activities.  The information 
sheet will contain the contact information for the primary investigator who will 
remain available throughout the study period to provide additional information to 
patients and families upon request.  All contact between patients, families, and 
surrogates and study personnel will be tracked in a case report form and 
available to investigators and the DSMB.” 
 
Version 1.2 – Protocol revisions during implementation (11/14/18) 
• Updated protocol to remove FiO2 and PEEP criteria from the SBT Safety Screen 
to allow patients who pass other elements of the SBT Safety Screen to attempt a 
daily SBT regardless of their current FiO2 or PEEP. 
• Revised the Patient Information Sheet based on feedback from the Community-
Engaged Research Core and patients on the Community Advisory Council to 
create a structured format with headers, make the narrative more conversational, 
and decrease the reading level. 
 
Version 1.3 – Protocol revisions prior to Continuing Review (6/19/19) 
• Updated protocol to provide additional detail regarding (a) the process used to 
provide information about the study the patients, families, and surrogates in the 
study setting and (b) the documentation of this process. 
• Updated the figures to match the changes to the SAT and SBT safety screen made 
during the 11/14/18 amendment.   
 
Version 1.4 – Protocol revisions to incorporate final Statistical Analysis Plan (10/20/20) 
• Revised trial name from “Preliminary Investigation of optimaL Oxygen Targets” 
to “Pragmatic Investigation of optimaL Oxygen Targets” to reflect the design 
• Added details on the calculation of the primary outcome of VFDs to match SAP. 
• Separated out the sole pre-specified secondary outcome of 28-day in-hospital 

Principal Investigator: Matt Semler            
  
Version Date: 4/7/2021 
Study Title: Pragmatic Investigation of optimaL Oxygen Targets (PILOT) Trial  
Institution: Vanderbilt University Medical Center 
 
 
 
32 
 
mortality from the exploratory outcomes to match SAP. 
• Added details on “Primary Analysis of the Primary Outcome”, “Sensitivity 
Analyses of the Primary Outcome”, “Analysis of Effect Modification for the 
Primary Outcome”, “Analysis of the Secondary Outcome”, “Analysis of the 
Exploratory Outcomes”, “Corrections for multiple testing”, and “Handling of 
missing data” to match the SAP. 
• Updated figure with study group assignments to reflect paused enrollment in April 
and May of 2020 due to COVID-19. 
 
Version 1.5 – Protocol revisions to incorporate updates to Statistical Analysis Plan during 
peer review (4/7/2021) 
• Revise statistical analysis plan to clarify how patients with a diagnosis of COVID-
19 will be analyzed in the primary analysis, sensitivity analyses, and analyses of 
effect modification. 
• Revise statistical analysis plan to define how race and ethnicity will be defined in 
the analysis of effect modification. 

 
 
Summary of Changes to the PILOT Trial Protocol 
 
Version 1.0 – Initial Protocol (5/1/2018) 
 
Version 1.1 – Revisions after initial meeting with DSMB (6/8/18) 
• Updated protocol to specify that the primary analysis will use a proportional odd mixed effects 
model with a fixed effect of study group and a random effect of study period. 
• Added sensitivity analyses using a zero-inflated Poisson model and a state-transitions model 
• Specified the plan for sample size re-estimation at the interim analysis as follows: “If the 18-
month interim analysis reveals an enrollment indicative of <80% statistical power at 
completion, we will ask the DSMB to approve extending enrollment of the study to ensure the 
trial is not underpowered to detect the planned difference between groups in the primary 
outcome.” 
• Specified that “Patients will be provided with an information sheet providing an IRB-approved 
lay language summary of the study activities.  The information sheet will contain the contact 
information for the primary investigator who will remain available throughout the study period 
to provide additional information to patients and families upon request.  All contact between 
patients, families, and surrogates and study personnel will be tracked in a case report form 
and available to investigators and the DSMB.” 
 
Version 1.2 – Protocol revisions during implementation (11/14/18) 
• Updated protocol to remove FiO2 and PEEP criteria from the SBT Safety Screen to allow 
patients who pass other elements of the SBT Safety Screen to attempt a daily SBT regardless 
of their current FiO2 or PEEP. 
• Revised the Patient Information Sheet based on feedback from the Community-Engaged 
Research Core and patients on the Community Advisory Council to create a structured format 
with headers, make the narrative more conversational, and decrease the reading level. 
 
Version 1.3 – Protocol revisions prior to Continuing Review (6/19/19) 
• Updated protocol to provide additional detail regarding (a) the process used to provide 
information about the study the patients, families, and surrogates in the study setting and (b) 
the documentation of this process. 
• Updated the figures to match the changes to the SAT and SBT safety screen made during the 
11/14/18 amendment.   
 
Version 1.4 – Protocol revisions to incorporate final Statistical Analysis Plan (10/20/20) 
• Revised trial name from “Preliminary Investigation of optimaL Oxygen Targets” to “Pragmatic 
Investigation of optimaL Oxygen Targets” to reflect the design 
• Added details on the calculation of the primary outcome of VFDs to match SAP. 
• Separated out the sole pre-specified secondary outcome of 28-day in-hospital mortality from 
the exploratory outcomes to match SAP. 
• Added details on “Primary Analysis of the Primary Outcome”, “Sensitivity Analyses of the 
Primary Outcome”, “Analysis of Effect Modification for the Primary Outcome”, “Analysis of the 
Secondary Outcome”, “Analysis of the Exploratory Outcomes”, “Corrections for multiple 
testing”, and “Handling of missing data” to match the SAP. 
• Updated figure with study group assignments to reflect paused enrollment in April and May of 
2020 due to COVID-19. 
 
Version 1.5 – Protocol revisions to incorporate updates to Statistical Analysis Plan during peer review 
(4/7/2021) 
• Revise statistical analysis plan to clarify how patients with a diagnosis of COVID-19 will be 
analyzed in the primary analysis, sensitivity analyses, and analyses of effect modification. 
• Revise statistical analysis plan to define how race and ethnicity will be defined in the analysis 
of effect modification. 
 

1 
 
Protocol and Statistical Analysis Plan for the Pragmatic Investigation of Optimal 
Oxygen Targets (PILOT) Clinical Trial 
 
 
Matthew W. Semler, MD, MSc1, Jonathan D. Casey MD1, Bradley D. Lloyd RRT-
ACCS2, Pamela G. Hastings RRT-ACCS2, Margaret A. Hays, RN1, Megan Roth, RN1, 
Joanna L. Stollings, PharmD, FCCM, FCCP3, John H. Brems, MD4; Kevin G. Buell 
MBBS4; Li Wang, MS5, Christopher J. Lindsell, PhD5; Robert E. Freundlich, MD6; 
Jonathan P. Wanderer, MD, MPhil6; Gordon R. Bernard MD1; Wesley H. Self MD, 
MPH7; Todd W. Rice, MD, MSc1 for the PILOT Investigators* and the Pragmatic Critical 
Care Research Group. 
 
* A full list of the PILOT Investigators may be found in supplemental file 1, section 1. 
 
Affiliations: 1Division of Allergy, Pulmonary, and Critical Care Medicine; 2Division of 
Respiratory Care; 3Department of Pharmaceutical Services; 4Department of Medicine; 
5Department of Biostatistics; 6Department of Anesthesiology and Department of 
Biomedical Informatics; 7Department of Emergency Medicine – all at Vanderbilt 
University Medical Center, Nashville, TN 
 
Corresponding author:  
Matthew W. Semler, MD, MSc 
T-1210 MCN, 1161 21st Ave S., Nashville, TN 37232-2650 
Fax: (615) 343-7448 
Corresponding Author’s Email Address: matthew.w.semler@vumc.org 
 
Key words for indexing: Oxygen, Mechanical ventilation, Respiratory Failure 
Subject Descriptor Number: 4.4 Clinical Trials in Critical Care Medicine 
Manuscript Word Count (body only): 4,102 
Abstract Word Count: 225 
Version Date: April 2, 2021  
 

2 
 
ABSTRACT: 
Introduction: Mechanical ventilation of intensive care unit (ICU) patients universally 
involves titration of the fraction of inspired oxygen (FiO2) to maintain arterial oxygen 
saturation (SpO2).  However, the optimal SpO2 target remains unknown. 
Methods and Analysis: The Pragmatic Investigation of optimaL Oxygen Targets 
(PILOT) trial is a prospective, unblinded, pragmatic, cluster-crossover trial being 
conducted in the emergency department and medical ICU at Vanderbilt University 
Medical Center in Nashville, TN, USA.  PILOT compares use of a lower SpO2 target 
(target 90% and goal range 88-92%), an intermediate SpO2 target (target 94% and goal 
range 92-96%), and a higher SpO2 target (target 98% and goal range 96-100%).  The 
study units are assigned to a single SpO2 target (cluster-level allocation) for each two-
month study block, and the assigned SpO2 target switches every two months in a 
randomly generated sequence (cluster-level crossover).  The primary outcome is 
ventilator-free days to study day 28, defined as the number of days alive and free of 
invasive mechanical ventilation from the final receipt of invasive mechanical ventilation 
through 28 days after enrollment. 
Ethics and dissemination: The trial was approved by the Vanderbilt Institutional 
Review Board. The results will be submitted for publication in a peer-reviewed journal 
and presented at one or more scientific conferences.   
Trial Registration: The trial protocol was registered with ClinicalTrials.gov on May 25, 
2018 prior to initiation of patient enrollment (ClinicalTrials.gov identifier: NCT03537937). 
 
 
 

3 
 
ARTICLE SUMMARY 
Strengths and limitations of this study 
• This ongoing pragmatic trial will provide information on the optimal oxygen 
saturation target during invasive mechanical ventilation of critically ill adults – 
informing a common therapy in current clinical practice for which there is limited 
available evidence on which to base care 
• Broad inclusion criteria will increase generalizability and the sample size will 
allow examination of important patient subgroups 
• The trial is being conducted at a single center 
• The nature of the study intervention does not allow blinding 
• Decisions regarding oxygen administration before and after invasive mechanical 
ventilation are deferred to treating clinicians  
 
 
 

4 
 
INTRODUCTION 
Each year 2-3 million intensive care unit (ICU) patients receive invasive 
mechanical ventilation [1–3].  Despite recent advances in lung-protective ventilation [4], 
in-hospital mortality among mechanically ventilated ICU patients remains 25-35% [5].   
Mechanical ventilation for ICU patients universally involves titrating the fraction of 
inspired oxygen (FiO2) to maintain arterial oxygen saturation (SpO2) within a goal range.  
Despite decades of ICU practice, however, the optimal SpO2 target remains unknown.  
Higher SpO2 targets (96-100%) provide a margin of safety against hypoxemia, but may 
increase exposure to excess FiO2, hyperoxemia, and tissue hyperoxia, causing 
oxidative damage [6–8], inflammation [9,10], and increased alveolar-capillary 
permeability [11].  Lower SpO2 targets (88-92%) minimize exposure to excess FiO2, 
hyperoxemia, and tissue hyperoxia [4,12,13], but may increase the risk of hypoxemia 
and tissue hypoxia [14,15].  An intermediate SpO2 target (92-96%) may avoid the risks 
of both hyperoxia and hypoxia or, conversely, may expose patients intermittently to both 
sets of risks [16,17]. 
The relative risks and benefits of different SpO2 or PaO2 targets have been 
extensively examined in the setting of the neonatal ICU [18–21] and have been 
examined among adult ICU patients in a series of recently-published clinical trials [22–
27].  Together, these trials have suggested that both higher and lower oxygenation 
targets are safe – although some trials have potentially suggested better outcomes with 
higher targets[25] and other trials have suggested potentially better outcomes with lower 
targets[24]. 
 

5 
 
Given the still incomplete evidence from randomized trials, current guidelines 
offer divergent recommendations – ranging from tolerating SpO2 values as low as 88% 
[28–30] to pursuing SpO2 values as high as 98% [31].  In clinical practice, hyperoxemia 
remains common [32,33], even among patients cared for by clinicians who self-identify 
as avoiding high oxygen levels [34].   
The wide variation in current practice, conflicting guidelines, and conflicting data 
from some available trials indicate the need for further clinical trials to determine the 
effect of SpO2 target on patient outcomes [12,35].  We designed the Pragmatic 
Investigation of optimaL Oxygen Targets (PILOT) trial to examine the effects of higher, 
intermediate, and lower SpO2 targets on the number of days alive and free of invasive 
mechanical ventilation among mechanically ventilated ICU patients. 
 
METHODS AND ANALYSIS 
This manuscript was prepared in accordance with Standard Protocol Items: 
Recommendations for Interventional Trials (SPIRIT) guidelines (Figure 1; SPIRIT 
checklist in online supplemental file 1, section 2). [36]  This manuscript describes key 
elements of the trial protocol and statistical analysis plan.  The Supplemental Methods 
in supplemental file 1 provide additional background on prior trials (section 3), rationale 
for design decisions (sections 4-5), SpO2 monitoring and management (sections 6-8), 
institutional protocols for mechanical ventilation (sections 9-17), a complete list of data 
elements (section 18), definitions of exploratory outcomes and measures of separation 
between groups (sections 19-21), and details of the interim analysis (section 22) and 
secondary analyses (sections 23-25). 

6 
 
 
Study Design 
 
The PILOT trial is a prospective, unblinded, pragmatic, cluster-crossover trial 
being conducted in the emergency department and medical ICU at Vanderbilt University 
Medical Center in Nashville, TN, USA.  PILOT compares use of a lower SpO2 target 
(target 90% and goal range 88-92%), an intermediate SpO2 target (target 94% and goal 
range 92-96%), and a higher SpO2 target (target 98% and goal range 96-100%) with 
regard to the number of days alive and free of invasive mechanical ventilation among 
mechanically ventilated ICU patients.  Consistent with the concept of a pragmatic 
clinical trial [37], the eligibility criteria are broad, the delivery of the intervention is 
embedded in routine clinical care and executed by clinical personnel, and data 
collection prioritizes clinical outcomes over mechanistic evaluation.  The trial was 
approved by the Vanderbilt University Medical Center Institutional Review Board (IRB) 
(IRB 171272). The trial is investigator-initiated with funding provided by the National 
Heart, Lung, and Blood Institute (K23HL143053).  The trial protocol was registered with 
ClinicalTrials.gov on May 25, 2018 prior to initiation of patient enrollment on July 1, 
2018 (ClinicalTrials.gov identifier: NCT03537937). 
 
Patient and Public Involvement 
Materials used to communicate about the study with patients and families were 
developed with input from the Vanderbilt Community Engaged Research Core and the 
Vanderbilt Community Advisory Council.  
 

7 
 
Study Site and Population 
The trial is being conducted in the adult emergency department (ED) and medical 
ICU at Vanderbilt University Medical Center. 
 
The inclusion criteria are:  
1. Age ≥ 18 years 
2. Receiving mechanical ventilation through an endotracheal tube or tracheostomy 
3. Admitted to the study ICU or admission to the study ICU from the ED is planned 
 
The exclusion criteria are: 
1. Known pregnancy or beta hCG level greater than the laboratory upper limit of 
normal in a patient capable of becoming pregnant (if measured clinically) 
2. Known to be a prisoner 
 
Adults located in the study ICU or for whom admission to the study ICU from the 
ED is planned who meet inclusion criteria and do not meet exclusion criteria are 
enrolled immediately upon receipt of invasive mechanical ventilation in a study location.  
The time of enrollment for the trial (“time zero”) is the time of first receipt of invasive 
mechanical ventilation in a participating study location. 
 
Randomization and Treatment Allocation 
For each of the 18 two-month blocks during the 36 months of enrollment in the 
PILOT trial, the medical ICU is assigned to a single SpO2 target (cluster-level 

8 
 
allocation).  Every two months, the ICU will switch between use of a lower SpO2 target 
(target 90% and goal range 88-92%), use of an intermediate SpO2 target (target 94% 
and goal range 92-96%), and use of a higher SpO2 target (target 98% and goal range 
96-100%) in a randomly generated sequence (cluster-level crossover) (Figure 2).  The 
order of study group assignments for each two-month block was generated by 
computerized randomization using permuted blocks of 3 to minimize the impact of 
seasonal variation and temporal changes.  For the 36 months of enrollment in the 
PILOT trial, patients receiving invasive mechanical ventilation in the ED for whom 
admission to the medical ICU is planned will receive the same SpO2 target assigned to 
the medical ICU. The study did not enroll in April and May of 2020 due to disruptions in 
research and clinical care from the Coronavirus Infectious Disease 2019 (COVID-19) 
pandemic (Figure 2).   
 
Washout Periods 
The last 7 days of each two-month block are considered an analytic washout 
period during which the ICU continues to target the assigned SpO2 but data from new 
patients are not included in the primary analysis.  Assuming a median duration of 
mechanical ventilation of 3 [IQR 3-5] days, a 7-day washout period will ensure that 98% 
patients in the primary analysis do not experience a “crossover” from a period assigned 
to one assigned SpO2 target to a period assigned to another SpO2 target.  Data from 
patients admitted during washout periods will be included in a pre-specified sensitivity 
analysis (see Statistical Analysis section).  Any patient who does remain mechanically 
ventilated in the study ICU through a crossover from a period assigned to one SpO2 

9 
 
target to a period assigned to another SpO2 target will be analyzed in the SpO2 target 
group to which the ICU was assigned at the time of the patient’s enrollment in the trial 
(intention-to-treat analysis). 
 
Study Interventions 
Choice of SpO2 targets 
In clinical practice, 98% of SpO2 values experienced by mechanically ventilated 
adults fall between 88-100% [32,33].  Within this range, current guidelines for oxygen 
therapy in mechanically ventilated adults outline three contrasting approaches: (1) 
allowing the lower end of the range of acceptable SpO2 values to be as low as 88% 
[28,29] to avoid excess FiO2, hyperoxemia, and hyperoxia; (2) titrating within an 
intermediate range of SpO2 values, such as 92-96% [38]; or (3) targeting higher SpO2 to 
avoid the risks of hypoxemia and hypoxia [31].  The PILOT trial has three study groups, 
each emulating a different approach to SpO2 targets represented in guidelines and 
clinical practice (Table 1).   
 
Oxygen Titration 
In the study ED and ICU, titration of FiO2 to maintain SpO2 for mechanically 
ventilated adults is typically performed by respiratory therapists with input from nurses 
and physicians.  In preparation for the PILOT trial, we collaborated with respiratory 
therapy leaders in the study ED and ICU to adapt existing ventilator management 
protocols to provide guidance for respiratory therapists in titrating FiO2 to achieve each 
of the three study SpO2 targets. 

10 
 
For patients enrolled in the study, respiratory therapists are instructed to begin 
titrating FiO2 to the target SpO2 value within 15 minutes of the initiation of mechanical 
ventilation.  During the maintenance of invasive mechanical ventilation, SpO2 is 
assessed by continuous pulse oximetry.  The protocol directs the respiratory therapist 
managing the patient’s ventilator to target an SpO2 value of 90% in the lower SpO2 
target group, an SpO2 value of 94% in the intermediate SpO2 target group, and an SpO2 
value of 98% in the higher SpO2 target group (Table 1).  Respiratory therapists and 
other treating clinicians titrate FiO2 when the SpO2 out of the goal range, when the SpO2 
is within the goal range but closer alignment with the assigned SpO2 target is desired, to 
facilitate weaning from mechanical ventilation, or for other clinical indications.  SpO2 is 
reassessed 5 minutes after each change in FiO2 or sooner if clinically indicated.   
The protocol determines the SpO2 target from enrollment until the first of: (1) 
discontinuation of invasive mechanical ventilation, (2) transfer out of a participating 
study location, (3) completion of an SpO2 target modification sheet by treating clinicians, 
or (4) end of the two-month study period.  The protocol does not determine the SpO2 
target during time-periods in which the patient is not physically located in a study 
location (e.g., during transport) or when FiO2 is being administered for purposes other 
than achieving a target SpO2 (e.g., when an FiO2 of 1.0 is being administered for a 
procedure).   
At any time, if a treating clinician or a patient, family member, or surrogate feels 
that an SpO2 target other than that assigned by the study would be best for the optimal 
treatment of the patient for any reason, the SpO2 target for that patient is modified.  To 
modify the target, the respiratory therapist and supervising physician complete a one-

11 
 
page SpO2 target modification sheet documenting the new SpO2 target and the 
rationale for modifying the target.  Examples of conditions for which the assigned SpO2 
target may be modified that were specified in the initial trial protocol included: 
pneumothorax; pneumomediastinum; carbon monoxide poisoning; decompression 
sickness; bleomycin toxicity; paraquat toxicity.  Examples of conditions for which the 
assigned SpO2 target may be modified that were not explicitly specified in the initial trial 
protocol include: severe chronic obstructive pulmonary disease; severe acute 
respiratory distress syndrome; severe anemia; status post lung transplantation; and 
receipt of extracorporeal membrane oxygenation support. Trial protocol directs only the 
titration of FiO2 to the assigned SpO2 target.  Other aspects of invasive mechanical 
ventilation, such as tidal volume [4], positive end-expiratory pressure [39,40], and use of 
rescue therapies for hypoxemia, are determined by institutional protocols and treating 
clinicians (see sections 9-17 of supplemental file 1). 
 
Blinding 
Similar to prior studies of SpO2 targets among critically ill adults [22,24,26], 
patients and clinicians will not be blinded to study group assignment. 
 
Data Collection 
The PILOT trial uses data collected by two methods to minimize observer bias: 
(1) manual data collection by study personnel and (2) automated collection of structured 
data recorded in routine clinical care, exported daily from the institution’s electronic 
health record and patient registration, billing, and laboratory clinical information systems 

12 
 
into an Enterprise Data Warehouse.  We have previously validated the quality of the 
automated method of data collection against the reference standard of two-physician 
manual chart review [41] and have employed this approach for the conduct of prior 
pragmatic trials [42,43].  Data are stored, curated, and secured in REDCap [44].   
 
Outcomes 
Primary Outcome  
The primary outcome is ventilator-free days (VFDs) to study day 28.  VFDs will 
be defined as the number of whole calendar days alive and free of invasive mechanical 
ventilation beginning at midnight on the day of the final receipt of invasive mechanical 
ventilation through day 28 after enrollment [45,46].  Outcome ascertainment will cease 
at the time of hospital discharge or 28 days after enrollment, whichever occurs first.  
Receipt of invasive mechanical ventilation will be considered to end when patients 
undergo the final tracheal extubation or disconnection of the ventilator from the 
endotracheal tube or tracheostomy tube between enrollment and 28 days after 
enrollment.  Patients whose final receipt of invasive mechanical ventilation occurs on 
the day of enrollment will receive 27 VFDs.  Patients who continue to receive invasive 
mechanical ventilation 28 days after enrollment will receive 0 VFDs.  Patient who die 
prior to day 28 will receive 0 VFDs.  Patients who are discharged from the hospital prior 
to day 28 and are receiving invasive mechanical ventilation at the time of discharge will 
receive 0 VFDs.  Patients who are removed from invasive mechanical ventilation and 
are discharged from the hospital without invasive mechanical ventilation prior to 28 days 
will be assumed to remain free of invasive mechanical ventilation between hospital 

13 
 
discharge and day 28.  For patients who are removed from invasive mechanical 
ventilation, return to invasive mechanical ventilation, and are subsequently removed 
again from invasive mechanical ventilation prior to day 28, VFDs will be counted from 
the final receipt of invasive mechanical ventilation prior to day 28. 
 
Secondary Outcome 
 
The sole pre-specified secondary outcome is 28-day in-hospital mortality, defined 
as death from any cause between enrollment and the first of hospital discharge or 28 
days after enrollment. 
 
Exploratory Clinical Outcomes 
1. ICU mortality – death in the ICU between enrollment and the first of 28 days 
after enrollment or hospital discharge 
2. Free-day outcomes – defined as whole calendar days from last receipt of 
therapy until 28 days (supplemental file 1, section 19) 
a. Vasopressor-free days  
b. Renal replacement therapy-free days  
c. ICU-free days 
d. Hospital-free days 
 
Exploratory Organ Function Outcomes 
1. Daily non-respiratory SOFA score (Table S1) [47] 
2. Plasma creatinine concentration (mg/dL) 

14 
 
3. Plasma lactate concentration (mmol/L) 
4. Presence of acute respiratory distress syndrome by Berlin criteria [48] 
5. Stage II or greater AKI by Kidney Disease: Improving Global Outcomes 
(KDIGO) creatinine criteria [49] 
 
Exploratory Safety Outcomes 
1. Atrial arrhythmia 
2. Ventricular arrhythmia 
3. Cardiac arrest with return of spontaneous circulation 
4. Pneumothorax or pneumomediastinum 
5. Ischemic stroke 
6. Myocardial infarction [50] 
 
Additional Long-term Patient-Important Outcomes 
The independently-funded Cognitive Outcomes in the Pragmatic Investigation of 
Optimal Oxygen Targets (CO-PILOT) study (R21AG063126) will assess cognitive, 
physical, and psychological outcomes at 12 months after enrollment in the PILOT trial.  
The protocol and statistical analysis plan for the CO-PILOT study will be published 
separately. 
 
Statistical Analysis and Reporting 
Sample Size Estimation and Power Calculation 

15 
 
In a prior cluster-randomized cluster-crossover trial in the same ICU [51], 880 
mechanically ventilated adults were enrolled per year (73.3 per month), with a median 
of 22 VFDs [IQR 0-25 VFDs] and an intra-cluster intra-period correlation of 0.01.  We 
estimate 2,640 mechanically ventilated adults will be admitted to the study ICU during 
the 36-month PILOT trial, of whom 390 will be excluded from the primary analysis for 
initial receipt of invasive mechanical ventilation in a study location during a washout 
period and 2,250 will be enrolled and included in the primary analysis.  With a total 
enrollment of 2,250 patients, a standard deviation in the primary outcome of VFDs of 
11.4 days, and a two-sided alpha of 0.05, we calculated using a t-test that the PILOT 
trial will have 92 percent statistical power to detect an absolute reduction in VFDs of 2.0 
days (similar to the numerical difference in VFDs between SpO2 target groups reported 
in prior studies [22,24]). 
 
Data and Safety Monitoring Board and Interim Analysis 
An independent Data and Safety Monitoring Board (DSMB) oversees the trial.  
On March 23, 2020 the DSMB conducted a single, planned interim analysis at the 
anticipated halfway point of the trial and recommended the trial continue without 
modification (see DSMB charter in online supplemental file 2 and details of interim 
analysis in supplemental file 1, section 22).  The DSMB is composed of two physicians 
outside the study institution with expertise in adult pulmonary and critical care medicine 
clinical practice and clinical research, one bioethicist, and one biostatistician.   
 
Statistical Analysis Principles 

16 
 
R (R Foundation for Statistical Computing, Vienna, Austria) will be used for 
analyses. Analyses will be conducted at the level of an individual patient during an 
individual hospitalization in an intent-to-treat fashion, unless otherwise specified. 
Continuous variables will be reported as mean ± SD or median and IQR; categorical 
variables will be reported as frequencies and proportions.  
 
Main Analysis of the Primary Outcome 
The main analysis will be an intention-to-treat comparison of the primary 
outcome of VFDs between the higher, intermediate, and lower SpO2 target groups 
among all patients enrolled in the trial except [1] those admitted during one of the 7-day 
washout periods and [2] those with a laboratory-confirmed diagnosis of COVID-19.  
Patients with a diagnosis of COVID-19 will be excluded from the main analysis for two 
reasons.  First, the majority of the PILOT trial occurred prior the COVID-19 pandemic, 
with too few two-month study blocks occurring during the pandemic to ensure balance 
in the number of patients with COVID-19 between trial groups.  Second, at the study 
hospital, ICU patients diagnosed with COVID-19 are transferred to a separate, 
dedicated COVID-19 ICU that was not participating in the PILOT trial.  Thus, patients 
with COVID-19 are unlikely to have received significant exposure to the SpO2 target 
intervention in the PILOT trial.  Patients enrolled during washout periods and patients 
diagnosed with COVID-19 will be included in sensitivity analyses (see Sensitivity 
Analyses below).  
It is possible to estimate a conditional effect, which is interpreted as the effect of 
a given SpO2 target on an individual patient given the values of the covariates for that 

17 
 
patient, or a marginal effect, which is interpreted as the population effect of 
implementing a given SpO2 target as a general policy [52]. Since an SpO2 target 
intervention may be applied both at the patient level as an individual intervention and at 
the unit level as a general policy, both may be of interest.  
To estimate the conditional effect, we will use a proportional odds model with 
independent covariates of group assignment (higher, intermediate, or lower SpO2 
target) and time [53,54].  Time (in days) will be treated as a continuous variable with 
values ranging from 1 (first day of enrollment) to 1,097 (final day of enrollment) and will 
be analyzed using restricted cubic splines with multiple knots to allow for non-linearity 
resulting from seasonality or secular trends.  For the purposes of declaring a statistically 
significant difference between groups in the primary endpoint, we will consider the 
conditional effect from the proportional odds model and a two-sided P value of 0.05. 
To estimate the marginal effect, we will use generalized estimating equations 
(GEE) with study period as the cluster and an independent variable for group 
assignment (higher, intermediate, or lower SpO2 target). 
For both approaches, in addition to assessing for an overall group effect within 
the model, we will estimate the differences between each pair of SpO2 targets by 
extracting 95% confidence intervals from the model. 
 
Sensitivity Analyses of the Primary Outcome 
• We will repeat the primary analysis using alternative statistical approaches to 
comparing the VFDs outcome between groups such as zero-inflated Poisson 

18 
 
regression or zero-inflated negative binomial regression, global rank scale 
analysis [55], and Fine and Gray competing risk regression. 
• We will repeat the primary analysis with adjustment for pre-specified baseline 
covariates of age, sex, race and ethnicity, source of ICU admission, vasopressor 
receipt, and acute diagnoses at enrollment, and severity of illness as assessed 
by the non-respiratory SOFA score. 
• We will repeat the primary analysis replacing the continuous covariate of time 
with a categorical covariate of season defined as: winter (January, February, 
March); spring (April, May, June); summer (July, August, September); and fall 
(October, November, December). 
• We will repeat the primary analysis among all patients enrolled in the trial, 
including [1] patients initiated on invasive mechanical ventilation in a study 
location during one of the pre-specified 7-day washout periods and [2] patients 
with a diagnosis of COVID-19. 
 
Analysis of Effect Modification for the Primary Outcome 
We will examine whether pre-specified baseline variables modify the effect of 
study group on the primary outcome using formal tests of statistical interaction in a 
proportional odds model.  Independent variables will include study group assignment, 
the potential effect modifier of interest, and the interaction between the two (e.g., study 
group * presence of sepsis or septic shock) and time.  Significance will be determined 
by the P value for the interaction term, with values less than 0.10 considered to suggest 
a potential interaction and values less than 0.05 considered to confirm an interaction.  

19 
 
We will examine whether the following baseline variables modify the effect of 
study group on the primary outcome: 
1. Age; 
2. Race and ethnicity (Hispanic, Non-Hispanic Black, Non-Hispanic White, Other); 
3. Source of admission to the ICU (ED, hospital ward, another ICU in the study 
hospital, operating room, outside hospital); 
4. Duration of invasive mechanical ventilation prior to enrollment; 
5. Chronic comorbidities (categories are not mutually exclusive) 
a. Receipt of supplemental oxygen at place of residence prior to hospital 
admission (yes, no); 
b. Coronary artery disease or heart failure with reduced ejection fraction 
(yes, no); 
6. Acute diagnoses at enrollment (categories are not mutually exclusive) [56] 
a. cardiac arrest (yes, no); 
b. acute myocardial infarction (yes, no); 
c. sepsis or septic shock (yes, no); 
d. acute respiratory distress syndrome (yes, no); 
7. Receipt of vasopressors at enrollment (yes, no); 
8. Non-respiratory SOFA score at enrollment; 
9. Time period (before the COVID-19 pandemic [July 2018 - December 2019], 
during the COVID-19 pandemic [January 2020 – August 2021]). 
 
Analysis of the Secondary Outcome 

20 
 
 
The sole pre-specified secondary outcome of 28-day in-hospital mortality will be 
compared between the three study groups in an intention-to-treat fashion in the main 
analysis population using a logistic regression model with independent covariates of 
group assignment (higher, intermediate, or lower SpO2 target) and time.  In addition to 
assessing for an overall group effect within the model, we will estimate the differences 
between each pair of SpO2 targets by extracting 95% confidence intervals from the 
model. 
 
Analysis of the Exploratory Outcomes 
Each of the exploratory outcomes will be compared between groups in an 
intention-to-treat fashion in the main analysis population.  Exploratory outcomes will be 
compared between study groups in a similar manner as for primary and secondary 
outcomes. A logistic model will be used for binary outcomes, a multinomial model for 
categorical outcomes, and a proportional odds model will be used for ordinal and 
continuous outcomes. 
 
 
Trial Status 
PILOT is an ongoing pragmatic trial comparing higher, intermediate, and lower 
SpO2 targets for mechanically ventilated critically ill adults. Patient enrollment began on 
July 1, 2018 and is anticipated to conclude on August 31, 2021. 
 
Ethics and dissemination  
IRB Approval 

21 
 
The trial was approved by the Institutional Review Board (IRB) of Vanderbilt 
University Medical Center with a waiver of informed consent (IRB# 171272), details of 
which are provided in supplemental file 1, section 26.  Participants who regain capacity 
to provide informed consent, or legally authorized surrogate decision-makers for those 
patients who do not regain the capacity to provide informed consent, are approached to 
provide informed consent for assessment of long-term outcomes as a part of the 
independently-funded Cognitive Outcomes in the Pragmatic Investigation of Optimal 
Oxygen Targets (CO-PILOT) study (R21AG063126). 
 
Information for Patients and Families 
An information sheet providing an IRB-approved lay language summary of the 
study and containing the contact information for investigators (who remain available 
throughout the study period to provide additional information to patients and families 
upon request) is made available throughout the study period in glass display cases near 
the public entrance to the ICU and near the center of the ICU, in the ‘welcome packet’ of 
information about the ICU, which is distributed at the time of ICU admission to patients, 
families, and surrogates by the medical receptionist or charge nurse as a part of routine 
admission processes, in a brochure holder in the family waiting room for the study ICU, 
and by treating physicians and respiratory therapist to any patients, families, or 
surrogates with questions or concerns about the study. 
 
Protocol Changes 

22 
 
Any changes to the trial protocol will be recorded on ClinicalTrials.Gov as per 
SPIRIT guidelines (see section 27 of supplemental file 1). 
 
Data Handling and Sharing 
For details of privacy, data handling, and data sharing, see sections 28-29 of 
supplemental file 1. 
 
Dissemination Plan 
 Trial results will be submitted to a peer-reviewed journal for consideration of 
publication and will be presented at scientific conferences.  The results of the study will 
be disseminated to patients and the public at the completion of the trial. 
 
 
 
Contributorship statement: Study concept and design: M.W.S., J.D.C., C.J.L., G.R.B., 
W.H.S., T.W.R.; Drafting of the manuscript: M.W.S., L.W., C.J.L.; Critical revision of the 
manuscript for important intellectual content: M.W.S., J.D.C., B.D.L., P.G.H., M.A.H., 
M.R., J.L.S., J.H.B., K.G.B., L.W., C.J.L., R.E.F., J.P.W., G.R.B., W.H.S., T.W.R; 
Statistical analysis: L.W., C.J.L.; Study supervision: G.R.B., W.H.S., T.W.R. 
 
Conflicts of Interest:  All authors completed and submitted the ICMJE Form for 
Disclosure of Potential Conflicts of Interest.  R.E.F. reported receiving grant funding and 
consulting fees from Medtronic and stock from 3M outside the current work.  T.W.R. 

23 
 
reported receiving consulting fees from Cumberland Pharmaceuticals outside the 
current work.  The authors declared no potential conflicts of interest with the current 
work. 
 
Funding: This study was supported in part by a grant from the National Heart Lung and 
Blood Institute (K23HL143053). J.D.C was supported in part by the NIH 
(K23HL153584). R.E.F. was supported in part by the NIH (1KL2TR002245, 
1K23HL148640).  T.W.R. was supported in part by the NIH (U01HL123033, 
UL1TR002244). Data collection used the Research Electronic Data Capture (REDCap) 
tool developed and maintained with Vanderbilt Institute for Clinical and Translational 
Research grant support (UL1 TR000445 from the National Center for Advancing 
Translational Sciences).  The funding institutions had no role in (1) conception, design, 
or conduct of the study, (2) collection, management, analysis, interpretation, or 
presentation of the data, or (3) preparation, review, or approval of the manuscript.  
 
 
 
 
 

24 
 
REFERENCES 
1  Wunsch H, Linde-Zwirble WT, Angus DC, et al. The epidemiology of mechanical ventilation use in the 
United States. Crit Care Med 2010;38:1947–53. doi:10.1097/CCM.0b013e3181ef4460 
2  Wunsch H, Angus DC, Harrison DA, et al. Comparison of medical admissions to intensive care units 
in the United States and United Kingdom. Am J Respir Crit Care Med 2011;183:1666–73. 
doi:10.1164/rccm.201012-1961OC 
3  Adhikari NKJ, Fowler RA, Bhagwanjee S, et al. Critical care and the global burden of critical illness in 
adults. Lancet Lond Engl 2010;376:1339–46. doi:10.1016/S0140-6736(10)60446-1 
4  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury 
and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N 
Engl J Med 2000;342:1301–8. doi:10.1056/NEJM200005043421801 
5  Esteban A, Frutos-Vivar F, Muriel A, et al. Evolution of mortality over time in patients receiving 
mechanical ventilation. Am J Respir Crit Care Med 2013;188:220–30. doi:10.1164/rccm.201212-
2169OC 
6  Fridovich I. Oxygen toxicity: a radical explanation. J Exp Biol 1998;201:1203–9. 
7  Heffner JE, Repine JE. Pulmonary strategies of antioxidant defense. Am Rev Respir Dis 
1989;140:531–54. doi:10.1164/ajrccm/140.2.531 
8  Freeman BA, Crapo JD. Hyperoxia increases oxygen radical production in rat lungs and lung 
mitochondria. J Biol Chem 1981;256:10986–92. 
9  Waxman AB, Einarsson O, Seres T, et al. Targeted lung expression of interleukin-11 enhances murine 
tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. J Clin Invest 
1998;101:1970–82. doi:10.1172/JCI1337 
10  Griffith DE, Garcia JG, James HL, et al. Hyperoxic exposure in humans. Effects of 50 percent oxygen 
on alveolar macrophage leukotriene B4 synthesis. Chest 1992;101:392–7. 
11  Davis WB, Rennard SI, Bitterman PB, et al. Pulmonary oxygen toxicity. Early reversible changes in 
human alveolar structures induced by hyperoxia. N Engl J Med 1983;309:878–83. 
doi:10.1056/NEJM198310133091502 
12  Aggarwal NR, Brower RG. Targeting normoxemia in acute respiratory distress syndrome may cause 
worse short-term outcomes because of oxygen toxicity. Ann Am Thorac Soc 2014;11:1449–53. 
doi:10.1513/AnnalsATS.201407-297PS 
13  Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment 
maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory 
distress syndrome: a randomized controlled trial. JAMA J Am Med Assoc 2008;299:637–45. 
doi:10.1001/jama.299.6.637 

25 
 
14  Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and mortality in mechanically 
ventilated patients. Intensive Care Med 2012;38:91–8. doi:10.1007/s00134-011-2419-6 
15  de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered oxygen, arterial partial 
oxygen pressure and mortality in mechanically ventilated intensive care unit patients. Crit Care Lond 
Engl 2008;12:R156. doi:10.1186/cc7150 
16  Allen BS, Ilbawi MN. Hypoxia, reoxygenation and the role of systemic leukodepletion in pediatric 
heart surgery. Perfusion 2001;16 Suppl:19–29. doi:10.1177/026765910101600i104 
17  Allen BS. The reoxygenation injury: is it clinically important? J Thorac Cardiovasc Surg 2002;124:16–
9. 
18  Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP-ROP), a 
randomized, controlled trial. I: primary outcomes. Pediatrics 2000;105:295–310. 
19  SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network, Carlo WA, 
Finer NN, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 
2010;362:1959–69. doi:10.1056/NEJMoa0911781 
20  Schmidt B, Whyte RK, Asztalos EV, et al. Effects of targeting higher vs lower arterial oxygen 
saturations on death or disability in extremely preterm infants: a randomized clinical trial. JAMA 
2013;309:2111–20. doi:10.1001/jama.2013.5555 
21  BOOST II United Kingdom Collaborative Group, BOOST II Australia Collaborative Group, BOOST II 
New Zealand Collaborative Group, et al. Oxygen saturation and outcomes in preterm infants. N Engl 
J Med 2013;368:2094–104. doi:10.1056/NEJMoa1302298 
22  Panwar R, Hardie M, Bellomo R, et al. Conservative versus Liberal Oxygenation Targets for 
Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit 
Care Med 2016;193:43–51. doi:10.1164/rccm.201505-1019OC 
23  Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline in patients with septic 
shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med 
Published Online First: February 2017. doi:10.1016/S2213-2600(17)30046-2 
24  Girardis M, Busani S, Damiani E, et al. Effect of Conservative vs Conventional Oxygen Therapy on 
Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. 
JAMA 2016;316:1583–9. doi:10.1001/jama.2016.11993 
25  Barrot L, Asfar P, Mauny F, et al. Liberal or Conservative Oxygen Therapy for Acute Respiratory 
Distress Syndrome. N Engl J Med 2020;382:999–1008. doi:10.1056/NEJMoa1916431 
26  ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials 
Group, Mackle D, Bellomo R, et al. Conservative Oxygen Therapy during Mechanical Ventilation in 
the ICU. N Engl J Med Published Online First: 14 October 2019. doi:10.1056/NEJMoa1903297 

26 
 
27  Schjørring OL, Klitgaard TL, Perner A, et al. Lower or Higher Oxygenation Targets for Acute 
Hypoxemic Respiratory Failure. N Engl J Med Published Online First: 20 January 2021. 
doi:10.1056/NEJMoa2032510 
28  Siemieniuk RAC, Chu DK, Kim LH-Y, et al. Oxygen therapy for acutely ill medical patients: a clinical 
practice guideline. BMJ 2018;363:k4169. doi:10.1136/bmj.k4169 
29  National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials 
Network, Rice TW, Wheeler AP, et al. Initial trophic vs full enteral feeding in patients with acute lung 
injury: the EDEN randomized trial. JAMA J Am Med Assoc 2012;307:795–803. 
doi:10.1001/jama.2012.137 
30  Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and 
antioxidant supplementation in acute lung injury. JAMA J Am Med Assoc 2011;306:1574–81. 
doi:10.1001/jama.2011.1435 
31  O’Driscoll BR, Howard LS, Earis J, et al. BTS guideline for oxygen use in adults in healthcare and 
emergency settings. Thorax 2017;72:ii1–90. doi:10.1136/thoraxjnl-2016-209729 
32  Panwar R, Capellier G, Schmutz N, et al. Current oxygenation practice in ventilated patients-an 
observational cohort study. Anaesth Intensive Care 2013;41:505–14. 
33  Suzuki S, Eastwood GM, Peck L, et al. Current oxygen management in mechanically ventilated 
patients: a prospective observational cohort study. J Crit Care 2013;28:647–54. 
doi:10.1016/j.jcrc.2013.03.010 
34  Helmerhorst HJ, Schultz MJ, van der Voort PH, et al. Self-reported attitudes versus actual practice of 
oxygen therapy by ICU physicians and nurses. Ann Intensive Care 2014;4:23. doi:10.1186/s13613-
014-0023-y 
35  Self WH, Semler MW, Rice TW. Oxygen Targets for Patients Who Are Critically Ill: Emerging Data and 
State of Equipoise. Chest 2020;157:487–8. doi:10.1016/j.chest.2019.12.010 
36  SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. - PubMed - NCBI. 
https://www.ncbi.nlm.nih.gov/pubmed/23303884 (accessed 8 Jan 2018). 
37  Ware JH, Hamel MB. Pragmatic Trials — Guides to Better Patient Care? N Engl J Med 
2011;364:1685–7. doi:10.1056/NEJMp1103502 
38  Beasley R, Chien J, Douglas J, et al. Thoracic Society of Australia and New Zealand oxygen guidelines 
for acute oxygen use in adults: ‘Swimming between the flags.’ Respirol Carlton Vic 2015;20:1182–
91. doi:10.1111/resp.12620 
39  Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in 
patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327–36. 
doi:10.1056/NEJMoa032193 

27 
 
40  Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with 
acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. 
JAMA J Am Med Assoc 2010;303:865–73. doi:10.1001/jama.2010.218 
41  Semler MW, Rice TW, Shaw AD, et al. Identification of Major Adverse Kidney Events Within the 
Electronic Health Record. J Med Syst 2016;40:167. doi:10.1007/s10916-016-0528-z 
42  Semler MW, Noto MJ, Stollings J, et al. Effect Of Saline Versus Balanced Crystalloids On Major 
Adverse Kidney Events In The Medical Intensive Care Unit: The Salt Randomized Trial. Am J Respir 
Crit Care Med 2016;193:A4290. 
43  Semler MW, Self WH, Wang L, et al. Balanced crystalloids versus saline in the intensive care unit: 
study protocol for a cluster-randomized, multiple-crossover trial. Trials 2017;18. 
doi:10.1186/s13063-017-1871-1 
44  Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-driven 
methodology and workflow process for providing translational research informatics support. J 
Biomed Inform 2009;42:377–81. doi:10.1016/j.jbi.2008.08.010 
45  Schoenfeld DA, Bernard GR. Statistical evaluation of ventilator-free days as an efficacy measure in 
clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 2002;30:1772–7. 
46  Harhay MO, Wagner J, Ratcliffe SJ, et al. Outcomes and statistical power in adult critical care 
randomized trials. Am J Respir Crit Care Med 2014;189:1469–78. doi:10.1164/rccm.201401-0056CP 
47  Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to 
describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of 
the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707–10. 
48  ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: 
the Berlin Definition. JAMA J Am Med Assoc 2012;307:2526–33. doi:10.1001/jama.2012.5669 
49  Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO 
Clinical Practice Guideline for Acute Kidney Injury. Kidney inter 2012;2(Suppl):8. 
50  Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). J 
Am Coll Cardiol 2018;72:2231–64. doi:10.1016/j.jacc.2018.08.1038 
51  Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N 
Engl J Med 2018;378:829–39. doi:10.1056/NEJMoa1711584 
52  Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation 
approach. Biometrics 1988;44:1049–60. 
53  Turner RM, White IR, Croudace T, et al. Analysis of cluster randomized cross-over trial data: a 
comparison of methods. Stat Med 2007;26:274–89. doi:10.1002/sim.2537 

28 
 
54  Parienti J-J, Kuss O. Cluster-crossover design: a method for limiting clusters level effect in 
community-intervention studies. Contemp Clin Trials 2007;28:316–23. 
doi:10.1016/j.cct.2006.10.004 
55  Beitler JR, Sarge T, Banner-Goodspeed VM, et al. Effect of Titrating Positive End-Expiratory Pressure 
(PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on 
Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress 
Syndrome: A Randomized Clinical Trial. JAMA Published Online First: 18 2019. 
doi:10.1001/jama.2019.0555 
56  Munshi L, Ferguson ND. Evolving Issues in Oxygen Therapy in Acute Care Medicine. JAMA Published 
Online First: 24 January 2020. doi:10.1001/jama.2019.22029 
 

29 
 
FIGURES 
Figure 1.  Standard Protocol Items: Recommendations for Interventional Trials 
(SPIRIT) checklist. Enrollment, Interventions, and Assessments.  
 
Figure 2.  Group assignment during the trial. For each of the 18 two-month study 
periods, the study ICU is randomly assigned to a higher, intermediate, or lower SpO2 
target.  In this figure, the letters “A”, “B”, and “C” each correspond to one of the three 
possible SpO2 targets, the allocation sequence of which remains concealed until the 
start of each two-month study period.  The study did not enroll in April and May of 2020 
due to disruptions in research and clinical care from the Coronavirus Infectious Disease 
2019 (COVID-19) pandemic.  As a result, March and June of 2020 represent a single-
two-month block assigned to one SpO2 target. 
 
 
 
 
 

30 
 
TABLES 
Table 1.  SpO2 and PaO2 targets and goal ranges by study group.   
Study Group 
SpO2 target SpO2 goal 
range 
PaO2 target 
PaO2 goal 
range 
Lower SpO2 target 
90% 
88-92% 
60 mm Hg 55-65 mm Hg 
Intermediate SpO2 target 
94% 
92-96% 
70 mm Hg 65-80 mm Hg 
Higher SpO2target 
98% 
96-100% 
110 mm Hg 
> 80 mm Hg 
 
For each study group, the SpO2 target and goal range are displayed.  PaO2 is used to 
guide titration of FiO2 for participants without functioning pulse oximetry monitoring. 
 

1
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
Protocol and statistical analysis plan for 
the Pragmatic Investigation of optimaL 
Oxygen Targets (PILOT) clinical trial
Matthew W Semler  ‍ ‍ ,1 Jonathan D Casey,1 Bradley D. Lloyd,2 
Pamela G. Hastings,2 Margaret Hays,1 Megan Roth,1 Joanna Stollings,3 
John Brems,4 Kevin George Buell,4 Li Wang,5 Christopher J. Lindsell,5 
Robert E. Freundlich,6 Jonathan P. Wanderer,6 Gordon R. Bernard,1 Wesley H. Self,7 
Todd W. Rice,1 The PILOT Investigators and the Pragmatic Critical Care Research 
Group
To cite: Semler MW, Casey JD, 
Lloyd BD, et al.  Protocol and 
statistical analysis plan for 
the Pragmatic Investigation 
of optimaL Oxygen Targets 
(PILOT) clinical trial. BMJ Open 
2021;11:e052013. doi:10.1136/
bmjopen-2021-052013
►
►Prepublication history and 
additional supplemental material 
for this paper are available 
online. To view these files, 
please visit the journal online 
(http://​dx.​doi.​org/​10.​1136/​
bmjopen-​2021-​052013).
Received 05 April 2021
Accepted 12 October 2021
For numbered affiliations see 
end of article.
Correspondence to
Dr Matthew W Semler;  
​matthew.​w.​semler@​vumc.​org
Protocol
© Author(s) (or their 
employer(s)) 2021. Re-­use 
permitted under CC BY-­NC. No 
commercial re-­use. See rights 
and permissions. Published by 
BMJ.
ABSTRACT
Introduction  Mechanical ventilation of intensive care unit 
(ICU) patients universally involves titration of the fraction 
of inspired oxygen to maintain arterial oxygen saturation 
(SpO2). However, the optimal SpO2 target remains 
unknown.
Methods and analysis  The Pragmatic Investigation of 
optimaL Oxygen Targets (PILOT) trial is a prospective, 
unblinded, pragmatic, cluster-­crossover trial being 
conducted in the emergency department (ED) and medical 
ICU at Vanderbilt University Medical Center in Nashville, 
Tennessee, USA. PILOT compares use of a lower SpO2 
target (target 90% and goal range: 88%–92%), an 
intermediate SpO2 target (target 94% and goal range: 
92%–96%) and a higher SpO2 target (target 98% and 
goal range: 96%–100%). The study units are assigned 
to a single SpO2 target (cluster-­level allocation) for each 
2-­month study block, and the assigned SpO2 target 
switches every 2 months in a randomly generated 
sequence (cluster-­level crossover). The primary outcome 
is ventilator-­free days (VFDs) to study day 28, defined as 
the number of days alive and free of invasive mechanical 
ventilation from the final receipt of invasive mechanical 
ventilation through 28 days after enrolment.
Ethics and dissemination  The trial was approved by the 
Vanderbilt Institutional Review Board. The results will be 
submitted for publication in a peer-­reviewed journal and 
presented at one or more scientific conferences.
Trial registration number  The trial protocol was 
registered with ​ClinicalTrials.​gov on 25 May 2018 prior to 
initiation of patient enrolment (​ClinicalTrials.​gov identifier: 
NCT03537937).
INTRODUCTION
Each year 2–3 million intensive care unit 
(ICU) patients receive invasive mechan-
ical ventilation.1–3 Despite recent advances 
in lung-­protective ventilation,4 in-­hospital 
mortality among mechanically ventilated ICU 
patients remains 25%–35%.5
Mechanical ventilation for ICU patients 
universally involves titrating the fraction of 
inspired oxygen (FiO2) to maintain arterial 
oxygen saturation (SpO2) within a goal range. 
Despite decades of ICU practice, however, 
the optimal SpO2 target remains unknown. 
Higher SpO2 targets (96%–100%) provide 
a margin of safety against hypoxaemia, but 
may increase exposure to excess FiO2, hyper-
oxaemia, and tissue hyperoxia, causing 
oxidative damage,6–8 inflammation9 10 and 
increased alveolar-­capillary permeability.11 
Lower SpO2 targets (88%–92%) minimise 
exposure to excess FiO2, hyperoxaemia and 
tissue hyperoxia,4 12 13 but may increase the 
risk of hypoxaemia and tissue hypoxia.14 15 An 
intermediate SpO2 target (92%–96%) may 
avoid the risks of both hyperoxia and hypoxia 
or, conversely, may expose patients intermit-
tently to both sets of risks.16 17
The relative risks and benefits of different 
SpO2 or PaO2 targets have been extensively 
examined in the setting of the neonatal 
ICU18–21 and have been examined among 
Strengths and limitations of this study
►
►This ongoing pragmatic trial will provide information 
on the optimal oxygen saturation target during inva-
sive mechanical ventilation of critically ill adults—
informing a common therapy in current clinical 
practice for which there is limited available evidence 
on which to base care.
►
►Broad inclusion criteria will increase generalisability 
and the sample size will allow examination of im-
portant patient subgroups.
►
►The trial is being conducted at a single centre.
►
►The nature of the study intervention does not allow 
blinding.
►
►Decisions regarding oxygen administration before 
and after invasive mechanical ventilation are de-
ferred to treating clinicians.
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

2
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
adult ICU patients in a series of recently published 
clinical trials.22–27 Together, these trials have suggested 
that both higher and lower oxygenation targets are 
safe—although some trials have potentially suggested 
better outcomes with higher targets25 and other trials 
have suggested potentially better outcomes with lower 
targets.24
Given the still incomplete evidence from randomised 
trials, current guidelines offer divergent recommen-
dations—ranging from tolerating SpO2 values as low as 
88%28–30 to pursuing SpO2 values as high as 98%.31 In clin-
ical practice, hyperoxaemia remains common,32 33 even 
among patients cared for by clinicians who self-­identify as 
avoiding high oxygen levels.34
The wide variation in current practice, conflicting 
guidelines and conflicting data from some available trials 
indicate the need for further clinical trials to determine 
the effect of SpO2 target on patient outcomes.12 35 We 
designed the Pragmatic Investigation of optimaL Oxygen 
Targets (PILOT) trial to examine the effects of higher, 
intermediate and lower SpO2 targets on the number of 
days alive and free of invasive mechanical ventilation 
among mechanically ventilated ICU patients.
METHODS AND ANALYSIS
This manuscript was prepared by the PILOT investi-
gators (online supplemental file 1, section 1) in accor-
dance with Standard Protocol Items: Recommendations 
for Interventional Trials (SPIRIT) guidelines (figure  1; 
SPIRIT checklist in online supplemental file 1, section 
2).36 This manuscript describes key elements of the trial 
protocol and statistical analysis plan. The supplemental 
methods in online supplemental file 1 provide addi-
tional background on prior trials (section 3), rationale 
for design decisions (sections 4–5), SpO2 monitoring and 
management (sections 6–8), institutional protocols for 
mechanical ventilation (sections 9–17), a complete list 
of data elements (section 18), definitions of exploratory 
outcomes and measures of separation between groups 
(sections 19–21), and details of the interim analysis 
(section 22) and secondary analyses (sections 23–25).
Study design
The PILOT trial is a prospective, unblinded, pragmatic, 
cluster-­crossover trial being conducted in the ED and 
medical ICU at Vanderbilt University Medical Center in 
Nashville, Tennessee, USA. PILOT compares use of a 
Figure 1  Standard Protocol Items: Recommendations for Interventional Trials checklist. Enrolment, interventions and 
assessments. FiO2, fraction of inspired oxygen; SpO2, arterial oxygen saturation.
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

3
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
lower SpO2 target (target 90% and goal range: 88%–92%), 
an intermediate SpO2 target (target 94% and goal range: 
92%–96%) and a higher SpO2 target (target 98% and 
goal range: 96%–100%) with regard to the number of 
days alive and free of invasive mechanical ventilation 
among mechanically ventilated ICU patients. Consistent 
with the concept of a pragmatic clinical trial,37 the eligi-
bility criteria are broad, the delivery of the intervention 
is embedded in routine clinical care and executed by 
clinical personnel, and data collection prioritises clin-
ical outcomes over mechanistic evaluation. The trial was 
approved by the Vanderbilt University Medical Center 
Institutional Review Board (IRB 171272). The trial is inves-
tigator initiated with funding provided by the National 
Heart, Lung, and Blood Institute (K23HL143053). The 
trial protocol was registered with ​ClinicalTrials.​gov on 25 
May 2018 prior to initiation of patient enrolment on 1 
July 2018 (​ClinicalTrials.​gov identifier: NCT03537937).
Patient and public involvement
Materials used to communicate about the study with 
patients and families were developed with input from the 
Vanderbilt Community Engaged Research Core and the 
Vanderbilt Community Advisory Council.
Study site and population
The trial is being conducted in the adult ED and medical 
ICU at Vanderbilt University Medical Center.
The inclusion criteria are
1.	 Age ≥18 years.
2.	 Receiving mechanical ventilation through an endotra-
cheal tube or tracheostomy.
3.	 Admitted to the study ICU or admission to the study 
ICU from the ED is planned.
The exclusion criteria are
1.	 Known pregnancy or beta-­human chorionic gonado-
tropin level greater than the laboratory upper limit of 
normal in a patient capable of becoming pregnant (if 
measured clinically).
2.	 Known to be a prisoner.
Adults located in the study ICU or for whom admis-
sion to the study ICU from the ED is planned who meet 
inclusion criteria and do not meet exclusion criteria are 
enrolled immediately on receipt of invasive mechanical 
ventilation in a study location. The time of enrolment for 
the trial (‘time zero’) is the time of first receipt of invasive 
mechanical ventilation in a participating study location.
Randomisation and treatment allocation
For each of the 18 2-­month blocks during the 36 months 
of enrolment in the PILOT trial, the medical ICU is 
assigned to a single SpO2 target (cluster-­level alloca-
tion). Every 2 months, the ICU will switch between use 
of a lower SpO2 target (target 90% and goal range: 
88%–92%), use of an intermediate SpO2 target (target 
94% and goal range: 92%–96%) and use of a higher 
SpO2 target (target 98% and goal range: 96%–100%) in 
a randomly generated sequence (cluster-­level crossover) 
(figure 2). The order of study group assignments for each 
2-­month block was generated by computerised randomi-
sation using permuted blocks of three to minimise the 
impact of seasonal variation and temporal changes. For 
the 36 months of enrolment in the PILOT trial, patients 
receiving invasive mechanical ventilation in the ED for 
whom admission to the medical ICU is planned will 
receive the same SpO2 target assigned to the medical 
ICU. The study did not enrol in April and May of 2020 
due to disruptions in research and clinical care from the 
COVID-­19 pandemic (figure 2).
Washout periods
The last 7 days of each 2-­month block are considered an 
analytic washout period during which the ICU continues 
to target the assigned SpO2, but data from new patients 
are not included in the primary analysis. Assuming a 
median duration of mechanical ventilation of 3 (IQR: 
3–5) days, a 7-­day washout period will ensure that 98% 
patients in the primary analysis do not experience a 
‘crossover’ from a period assigned to one assigned SpO2 
target to a period assigned to another SpO2 target. Data 
from patients admitted during washout periods will be 
included in a prespecified sensitivity analysis (see Statis-
tical analysis section). Any patient who does remain 
mechanically ventilated in the study ICU through a 
crossover from a period assigned to one SpO2 target to a 
period assigned to another SpO2 target will be analysed in 
the SpO2 target group to which the ICU was assigned at 
the time of the patient’s enrolment in the trial (intention-­
to-­treat analysis).
Figure 2  Group assignment during the trial. For each of the 18 2-­month study periods, the study intensive care unit is 
randomly assigned to a higher, intermediate or lower SpO2 target. in this figure, The letters ‘A’, ‘B’ and ‘C’ each correspond to 
one of the three possible SpO2 targets, the allocation sequence of which remains concealed until the start of each 2-­month 
study period. The study did not enrol in April and May of 2020 due to disruptions in research and clinical care from the 
COVID-­19 pandemic. As a result, March and June of 2020 represent a single 2-­month block assigned to one SpO2 target. SpO2, 
arterial oxygen saturation.
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

4
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
Study interventions
Choice of SpO2 targets
In clinical practice, 98% of SpO2 values experienced 
by mechanically ventilated adults fall between 88% and 
100%.32 33 Within this range, current guidelines for 
oxygen therapy in mechanically ventilated adults outline 
three contrasting approaches: (1) allowing the lower end 
of the range of acceptable SpO2 values to be as low as 
88%28 29 to avoid excess FiO2, hyperoxaemia and hyper-
oxia; (2) titrating within an intermediate range of SpO2 
values, such as 92%–96%38; or (3) targeting higher SpO2 
to avoid the risks of hypoxaemia and hypoxia.31 The 
PILOT trial has three study groups, each emulating a 
different approach to SpO2 targets represented in guide-
lines and clinical practice (table 1).
Oxygen titration
In the study ED and ICU, titration of FiO2 to main-
tain SpO2 for mechanically ventilated adults is typically 
performed by respiratory therapists with input from 
nurses and physicians. In preparation for the PILOT trial, 
we collaborated with respiratory therapy leaders in the 
study ED and ICU to adapt existing ventilator manage-
ment protocols to provide guidance for respiratory ther-
apists in titrating FiO2 to achieve each of the three study 
SpO2 targets.
For patients enrolled in the study, respiratory thera-
pists are instructed to begin titrating FiO2 to the target 
SpO2 value within 15 min of the initiation of mechanical 
ventilation. During the maintenance of invasive mechan-
ical ventilation, SpO2 is assessed by continuous pulse 
oximetry. The protocol directs the respiratory therapist 
managing the patient’s ventilator to target an SpO2 value 
of 90% in the lower SpO2 target group, an SpO2 value of 
94% in the intermediate SpO2 target group and an SpO2 
value of 98% in the higher SpO2 target group (table 1). 
Respiratory therapists and other treating clinicians titrate 
FiO2 when the SpO2 is out of the goal range, when the 
SpO2 is within the goal range but closer alignment with 
the assigned SpO2 target is desired, to facilitate weaning 
from mechanical ventilation, or for other clinical indica-
tions. SpO2 is reassessed 5 min after each change in FiO2 
or sooner if clinically indicated.
The protocol determines the SpO2 target from enrol-
ment until the first of: (1) discontinuation of invasive 
mechanical ventilation, (2) transfer out of a participating 
study location, (3) completion of an SpO2 target modifica-
tion sheet by treating clinicians or (4) end of the 2-­month 
study period. The protocol does not determine the SpO2 
target during time periods in which the patient is not 
physically located in a study location (eg, during trans-
port) or when FiO2 is being administered for purposes 
other than achieving a target SpO2 (eg, when an FiO2 of 
1.0 is being administered for a procedure).
At any time, if a treating clinician or a patient, family 
member or surrogate feels that an SpO2 target other than 
that assigned by the study would be best for the optimal 
treatment of the patient for any reason, the SpO2 target 
for that patient is modified. To modify the target, the 
respiratory therapist and supervising physician complete 
a one-­page SpO2 target modification sheet documenting 
the new SpO2 target and the rationale for modifying the 
target. Examples of conditions for which the assigned 
SpO2 target may be modified that were specified in the 
initial trial protocol included pneumothorax, pneumo-
mediastinum, carbon monoxide poisoning, decompres-
sion sickness, bleomycin toxicity and paraquat toxicity. 
Examples of conditions for which the assigned SpO2 
target may be modified that were not explicitly specified 
in the initial trial protocol include severe chronic obstruc-
tive pulmonary disease, severe acute respiratory distress 
syndrome, severe anaemia, status post lung transplanta-
tion and receipt of extracorporeal membrane oxygen-
ation support. Trial protocol directs only the titration of 
FiO2 to the assigned SpO2 target. Other aspects of invasive 
mechanical ventilation, such as tidal volume,4 positive 
end-­expiratory pressure39 40 and use of rescue therapies 
for hypoxaemia, are determined by institutional proto-
cols and treating clinicians (see sections 9–17 of online 
supplemental file 1).
Blinding
Similar to prior studies of SpO2 targets among critically ill 
adults,22 24 26 patients and clinicians will not be blinded to 
study group assignment.
Data collection
The PILOT trial uses data collected by two methods to 
minimise observer bias: (1) manual data collection by 
study personnel and (2) automated collection of struc-
tured data recorded in routine clinical care, exported 
daily from the institution’s electronic health record and 
Table 1  SpO2 and PaO2 targets and goal ranges by study group
Study group
SpO2 target
SpO2 goal range
PaO2 target (mm 
Hg)
PaO2 goal range 
(mm Hg)
Lower SpO2 target
90%
88%–92%
60
55–65
Intermediate SpO2 target
94%
92%–96%
70
65–8
Higher SpO2 target
98%
96%–100%
110
>80
For each study group, the SpO2 target and goal range are displayed. PaO2 is used to guide titration of FiO2 for participants without reliable 
pulse oximetry monitoring.
FiO2, fraction of inspired oxygen; PaO2, arterial oxygen tension; SpO2, arterial oxygen saturation.
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

5
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
patient registration, billing and laboratory clinical infor-
mation systems into an Enterprise Data Warehouse. We 
have previously validated the quality of the automated 
method of data collection against the reference stan-
dard of two-­physician manual chart review41 and have 
employed this approach for the conduct of prior prag-
matic trials.42 43 Data are stored, curated and secured in 
REDCap.44
Outcomes
Primary outcome
The primary outcome is VFDs to study day 28. VFDs 
will be defined as the number of whole calendar days 
alive and free of invasive mechanical ventilation begin-
ning at midnight on the day of the final receipt of 
invasive mechanical ventilation through day 28 after 
enrolment.45 46 Outcome ascertainment will cease at the 
time of hospital discharge or 28 days after enrolment, 
whichever occurs first. Receipt of invasive mechanical 
ventilation will be considered to end when patients 
undergo the final tracheal extubation or disconnection 
of the ventilator from the endotracheal tube or trache-
ostomy tube between enrolment and 28 days after enrol-
ment. Patients whose final receipt of invasive mechanical 
ventilation occurs on the day of enrolment will receive 27 
VFDs. Patients who continue to receive invasive mechan-
ical ventilation 28 days after enrolment will receive 0 
VFDs. Patients who die prior to day 28 will receive 0 VFDs. 
Patients who are discharged from the hospital prior to 
day 28 and are receiving invasive mechanical ventilation 
at the time of discharge will receive 0 VFDs. Patients who 
are removed from invasive mechanical ventilation and are 
discharged from the hospital without invasive mechanical 
ventilation prior to 28 days will be assumed to remain 
free of invasive mechanical ventilation between hospital 
discharge and day 28. For patients who are removed 
from invasive mechanical ventilation, return to invasive 
mechanical ventilation, and are subsequently removed 
again from invasive mechanical ventilation prior to day 
28, VFDs will be counted from the final receipt of invasive 
mechanical ventilation prior to day 28.
Secondary outcome
The sole prespecified secondary outcome is 28-­day in-­hos-
pital mortality, defined as death from any cause between 
enrolment and the first of hospital discharge or 28 days 
after enrollment.
Exploratory clinical outcomes
1.	 ICU mortality—death in the ICU between enrolment 
and the first of 28 days after enrolment or hospital 
discharge
2.	 Free-­day outcomes—defined as whole calendar days 
from last receipt of therapy until 28 days (online sup-
plemental file 1, section 19)
i.	
Vasopressor-­free days
ii.	
Renal replacement therapy-­free days
iii.	 ICU-­free days
iv.	
Hospital-­free days
Exploratory organ function outcomes
1.	 Daily non-­respiratory Sequential Organ Failure 
Assessment (SOFA) score (online supplemental table 
S1)47
2.	 Plasma creatinine concentration (mg/dL)
3.	 Plasma lactate concentration (mmol/L)
4.	 Presence of acute respiratory distress syndrome by Ber-
lin criteria48
5.	 Stage II or greater acute kidney injury (AKI) by Kidney 
Disease: Improving Global Outcomes creatinine 
criteria.49
Exploratory safety outcomes
1.	 Atrial arrhythmia
2.	 Ventricular arrhythmia
3.	 Cardiac arrest with return of spontaneous circulation
4.	 Pneumothorax or pneumomediastinum
5.	 Ischaemic stroke
6.	 Myocardial infarction50
Additional long-term patientimportant outcomes
The independently funded Cognitive Outcomes in the 
Pragmatic Investigation of Optimal Oxygen Targets 
(CO-­PILOT) study (R21AG063126) will assess cognitive, 
physical and psychological outcomes at 12 months after 
enrolment in the PILOT trial. The protocol and statistical 
analysis plan for the CO-­PILOT study will be published 
separately.
Statistical analysis and reporting
Sample size estimation and power calculation
In a prior cluster-­randomised cluster-­crossover trial in 
the same ICU,51 880 mechanically ventilated adults were 
enrolled per year (73.3 per month), with a median of 
22 VFDs (IQR: 0–25 VFDs) and an intracluster intra-
period correlation of 0.01. We estimate 2640 mechani-
cally ventilated adults will be admitted to the study ICU 
during the 36-­month PILOT trial, of whom 390 will be 
excluded from the primary analysis for initial receipt 
of invasive mechanical ventilation in a study location 
during a washout period and 2250 will be enrolled and 
included in the primary analysis. With a total enrolment 
of 2250 patients, a SD in the primary outcome of VFDs 
of 11.4 days, and a two-­sided alpha of 0.05, we calculated 
using a t-­test that the PILOT trial will have 92% statistical 
power to detect an absolute reduction in VFDs of 2.0 days 
(similar to the numerical difference in VFDs between 
SpO2 target groups reported in prior studies22 24).
DSMB and interim analysis
An independent Data and Safety Monitoring Board 
(DSMB) oversees the trial. On 23 March 2020 the DSMB 
conducted a single, planned interim analysis at the antic-
ipated halfway point of the trial and recommended the 
trial to continue without modification (see DSMB charter 
in online supplemental file 2) and details of interim 
analysis in online supplemental file 1, section 22). The 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

6
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
DSMB is composed of two physicians outside the study 
institution with expertise in adult pulmonary and critical 
care medicine clinical practice and clinical research, one 
bioethicist and one biostatistician.
Statistical analysis principles
R (R Foundation for Statistical Computing, Vienna, 
Austria) will be used for analyses. Analyses will be 
conducted at the level of an individual patient during an 
individual hospitalisation in an intent-­to-­treat fashion, 
unless otherwise specified. Continuous variables will be 
reported as mean±SD or median and IQR; categorical 
variables will be reported as frequencies and proportions.
Main analysis of the primary outcome
The main analysis will be an intention-­to-­treat compar-
ison of the primary outcome of VFDs between the higher, 
intermediate and lower SpO2 target groups among all 
patients enrolled in the trial except1 those admitted 
during one of the 7-­day washout periods and2 those with 
a laboratory-­confirmed diagnosis of COVID-­19. Patients 
with a diagnosis of COVID-­19 will be excluded from the 
main analysis for two reasons. First, the majority of the 
PILOT trial occurred prior the COVID-­19 pandemic, 
with too few 2-­month study blocks occurring during the 
pandemic to ensure balance in the number of patients 
with COVID-­19 between trial groups. Second, at the study 
hospital, ICU patients diagnosed with COVID-­19 are 
transferred to a separate, dedicated COVID-­19 ICU that 
was not participating in the PILOT trial. Thus, patients 
with COVID-­19 are unlikely to have received significant 
exposure to the SpO2 target intervention in the PILOT 
trial. Patients enrolled during washout periods and 
patients diagnosed with COVID-­19 will be included in 
sensitivity analyses (see Sensitivity analyses below).
It is possible to estimate a conditional effect, which is 
interpreted as the effect of a given SpO2 target on an indi-
vidual patient given the values of the covariates for that 
patient, or a marginal effect, which is interpreted as the 
population effect of implementing a given SpO2 target as 
a general policy.52 Since an SpO2 target intervention may 
be applied both at the patient level as an individual inter-
vention and at the unit level as a general policy, both may 
be of interest.
To estimate the conditional effect, we will use a propor-
tional odds model with independent covariates of group 
assignment (higher, intermediate or lower SpO2 target) 
and time.53 54 Time (in days) will be treated as a contin-
uous variable with values ranging from 1 (first day of 
enrolment) to 1097 (final day of enrolment) and will 
be analysed using restricted cubic splines with multiple 
knots to allow for non-­linearity resulting from seasonality 
or secular trends. For the purposes of declaring a statisti-
cally significant difference between groups in the primary 
endpoint, we will consider the conditional effect from the 
proportional odds model and a two-­sided p value of 0.05.
To estimate the marginal effect, we will use generalised 
estimating equations with study period as the cluster and 
an independent variable for group assignment (higher, 
intermediate or lower SpO2 target).
For both approaches, in addition to assessing for an 
overall group effect within the model, we will estimate 
the differences between each pair of SpO2 targets by 
extracting 95% CIs from the model.
Sensitivity analyses of the primary outcome
►
►We will repeat the primary analysis using alterna-
tive statistical approaches to comparing the VFDs 
outcome between groups such as zero-­inflated Poisson 
regression or zero-­inflated negative binomial regres-
sion, global rank scale analysis55 and Fine and Gray 
competing risk regression.
►
►We will repeat the primary analysis with adjustment 
for prespecified baseline covariates of age, sex, race 
and ethnicity, source of ICU admission, vasopressor 
receipt, acute diagnoses at enrolment, and severity of 
illness as assessed by the non-­respiratory SOFA score.
►
►We will repeat the primary analysis replacing the 
continuous covariate of time with a categorical covar-
iate of season defined as: winter (January, February, 
March); spring (April, May, June); summer (July, 
August, September); and fall (October, November, 
December).
►
►We will repeat the primary analysis among all patients 
enrolled in the trial, including1 patients initiated on 
invasive mechanical ventilation in a study location 
during one of the prespecified 7-­day washout periods 
and2 patients with a diagnosis of COVID-­19.
Analysis of effect modification for the primary outcome
We will examine whether prespecified baseline variables 
modify the effect of study group on the primary outcome 
using formal tests of statistical interaction in a propor-
tional odds model. Independent variables will include 
study group assignment, the potential effect modifier of 
interest and the interaction between the two (eg, study 
group × presence of sepsis or septic shock) and time. 
Significance will be determined by the p value for the 
interaction term, with values <0.10 considered to suggest 
a potential interaction and values <0.05 considered to 
confirm an interaction.
We will examine whether the following baseline vari-
ables modify the effect of study group on the primary 
outcome:
1.	 Age;
2.	 Race and ethnicity (Hispanic, non-­Hispanic Black, 
non-­Hispanic white, Other);
3.	 Source of admission to the ICU (ED, hospital ward, 
another ICU in the study hospital, operating room, 
outside hospital);
4.	 Duration of invasive mechanical ventilation prior to 
enrollment;
5.	 Chronic comorbidities (categories are not mutually 
exclusive)
i.	
Receipt of supplemental oxygen at place of resi-
dence prior to hospital admission (yes, no);
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

7
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
ii.	
Coronary artery disease or heart failure with re-
duced ejection fraction (yes, no);
6.	 Acute diagnoses at enrollment (categories are not mu-
tually exclusive)56
i.	
cardiac arrest (yes, no);
ii.	
acute myocardial infarction (yes, no);
iii.	 sepsis or septic shock (yes, no);
iv.	
acute respiratory distress syndrome (yes, no);
7.	 Receipt of vasopressors at enrollment (yes, no);
8.	 Non-­respiratory SOFA score at enrollment;
9.	 Time period before the COVID-­19 pandemic (July 
2018 to December 2019), and during the COVID-­19 
pandemic (January 2020 to August 2021).
Analysis of the secondary outcome
The sole prespecified secondary outcome of 28-­day 
in-­hospital mortality will be compared between the three 
study groups in an intention-­to-­treat fashion in the main 
analysis population using a logistic regression model with 
independent covariates of group assignment (higher, 
intermediate or lower SpO2 target) and time. In addition 
to assessing for an overall group effect within the model, 
we will estimate the differences between each pair of SpO2 
targets by extracting 95% CIs from the model.
Analysis of the exploratory outcomes
Each of the exploratory outcomes will be compared 
between groups in an intention-­to-­treat fashion in the 
main analysis population. Exploratory outcomes will be 
compared between study groups in a similar manner as 
for primary and secondary outcomes. A logistic model 
will be used for binary outcomes, a multinomial model 
for categorical outcomes, and a proportional odds model 
will be used for ordinal and continuous outcomes.
Trial status
PILOT is an ongoing pragmatic trial comparing higher, 
intermediate and lower SpO2 targets for mechanically 
ventilated critically ill adults. Patient enrolment began on 
1 July 2018 and is anticipated to conclude on 31 August 
2021.
Ethics and dissemination
IRB approval
The trial was approved by the IRB of Vanderbilt Univer-
sity Medical Center with a waiver of informed consent 
(IRB# 171272), details of which are provided in (online 
supplemental file 1, section 26). Participants who regain 
capacity to provide informed consent, or legally autho-
rised surrogate decision-­makers for those patients who do 
not regain the capacity to provide informed consent, are 
approached to provide informed consent for assessment 
of long-­term outcomes as a part of the independently 
funded CO-­PILOT study (R21AG063126).
Information for patients and families
An information sheet providing an IRB approved lay 
language summary of the study and containing the contact 
information for investigators (who remain available 
throughout the study period to provide additional infor-
mation to patients and families on request) is made avail-
able throughout the study period in glass display cases 
near the public entrance to the ICU and near the centre 
of the ICU, in the ‘welcome packet’ of information about 
the ICU, which is distributed at the time of ICU admis-
sion to patients, families and surrogates by the medical 
receptionist or charge nurse as a part of routine admis-
sion processes, in a brochure holder in the family waiting 
room for the study ICU, and by treating physicians and 
respiratory therapist to any patients, families, or surro-
gates with questions or concerns about the study.
Protocol changes
Any changes to the trial protocol will be recorded on 
ClinicalTrials.Gov as per SPIRIT guidelines (see section 
27 of online supplemental file 1).
Data handling and sharing
For details of privacy, data handling and data sharing, see 
sections 28–29 of online supplemental file 1.
Dissemination plan
Trial results will be submitted to a peer-­reviewed journal 
for consideration of publication and will be presented 
at scientific conferences. The results of the study will be 
disseminated to patients and the public at the completion 
of the trial.
The full list of the PILOT investigators may be found in 
(online supplemental file 1, section 1).
Author affiliations
1Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, 
Vanderbilt University School of Medicine, Nashville, Tennessee, USA
2Division of Respiratory Care, Vanderbilt University Medical Center, Nashville, 
Tennessee, USA
3Department of Pharmaceutical Services, Vanderbilt University Medical Center, 
Nashville, Tennessee, USA
4Department of Medicine, Vanderbilt University Medical Center, Nashville, 
Tennessee, USA
5Department of Biostatistics, Vanderbilt University Schoool of Medicine, Nashville, 
TN, USA
6Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, 
Tennessee, USA
7Department of Emergency Medicine, Vanderbilt University Medical Center, 
Nashville, Tennessee, USA
Twitter Bradley D. Lloyd @BradLloydVFL
Collaborators  PILOT Investigators Department of Anesthesiology – Robert E 
Freundlich*, Jonathan P Wanderer* Department of Biostatistics – Christopher J 
Lindsell*, Li Wang* Department of Emergency Medicine – Jin H Han, Wesley H Self* 
Department of Internal Medicine – John H Brems*, Kevin G Buell* Department of 
Pharmaceutical Services – Sneha Patel, Joanna L Stollings *Division of Allergy, 
Pulmonary, and Critical Care Medicine – Gordon R. Bernard*, Jonathan D Casey*, 
Christina Cleveland, Margaret A Hays*, Luis E Huerta, Karen Jackson, Todd W 
Rice*, Megan Roth*, Matthew W Semler* Division of Respiratory Care – Pamela G 
Hastings*, Bradley D Lloyd*, Roger K Richardson, J Craig Rooks All at Vanderbilt 
University Medical Center in Nashville, Tennessee. Asterisk (*) denotes members of 
the writing committee.
Contributors  Study concept and design was done by MWS, JDC, CJL, GB, WHS 
and TWR. Drafting of the manuscript was done by MWS, LW and CJL. Critical 
revision of the manuscript for important intellectual content was performd by MWS, 
JDC, BDL, PH, MH, MR, JS, JB, KGB, LW, CJL, RF, JPW, GB, WHS and TWR. LW and 
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

8
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
CJL were responsible for statistical analysis. Study supervision was done by GB, 
WHS and TWR.
Funding  This study was supported in part by a grant from the National Heart 
Lung and Blood Institute (K23HL143053). JDC was supported in part by the 
NIH (K23HL153584). REF was supported in part by the NIH (1KL2TR002245, 
1K23HL148640). TWR was supported in part by the NIH (U01HL123033, 
UL1TR002244). Data collection used the Research Electronic Data Capture 
(REDCap) tool developed and maintained with Vanderbilt Institute for Clinical 
and Translational Research grant support (UL1 TR000445 from the National 
CenterCentre for Advancing Translational Sciences). The funding institutions had no 
role in (1) conception, design or conduct of the study, (2) collection, management, 
analysis, interpretation or presentation of the data or (3) preparation, review or 
approval of the manuscript.
Competing interests  All authors completed and submitted the ICMJE Form for 
Disclosure of Potential Conflicts of Interest. RF reported receiving grant funding and 
consulting fees from Medtronic and stock from 3M outside the current work. TWR 
reported receiving consulting fees from Cumberland Pharmaceuticals outside the 
current work. The authors declared no potential conflicts of interest with the current 
work.
Patient consent for publication  Not applicable.
Provenance and peer review  Not commissioned; externally peer reviewed.
Supplemental material  This content has been supplied by the author(s). It has 
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been 
peer-­reviewed. Any opinions or recommendations discussed are solely those 
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and 
responsibility arising from any reliance placed on the content. Where the content 
includes any translated material, BMJ does not warrant the accuracy and reliability 
of the translations (including but not limited to local regulations, clinical guidelines, 
terminology, drug names and drug dosages), and is not responsible for any error 
and/or omissions arising from translation and adaptation or otherwise.
Open access  This is an open access article distributed in accordance with the 
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which 
permits others to distribute, remix, adapt, build upon this work non-­commercially, 
and license their derivative works on different terms, provided the original work is 
properly cited, appropriate credit is given, any changes made indicated, and the use 
is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/.
ORCID iD
Matthew W Semler http://​orcid.​org/​0000-​0002-​7664-​8263
REFERENCES
	 1	 Wunsch H, Linde-­Zwirble WT, Angus DC, et al. The epidemiology 
of mechanical ventilation use in the United States. Crit Care Med 
2010;38:1947–53.
	 2	 Wunsch H, Angus DC, Harrison DA, et al. Comparison of medical 
admissions to intensive care units in the United States and United 
Kingdom. Am J Respir Crit Care Med 2011;183:1666–73.
	 3	 Adhikari NKJ, Fowler RA, Bhagwanjee S, et al. Critical care and the 
global burden of critical illness in adults. Lancet 2010;376:1339–46.
	 4	 , Brower RG, Matthay MA, et al, Acute Respiratory Distress 
Syndrome Network. Ventilation with lower tidal volumes as compared 
with traditional tidal volumes for acute lung injury and the acute 
respiratory distress syndrome. N Engl J Med 2000;342:1301–8.
	 5	 Esteban A, Frutos-­Vivar F, Muriel A, et al. Evolution of mortality over 
time in patients receiving mechanical ventilation. Am J Respir Crit 
Care Med 2013;188:220–30.
	 6	 Fridovich I. Oxygen toxicity: a radical explanation. J Exp Biol 
1998;201:1203–9.
	 7	 Heffner JE, Repine JE. Pulmonary strategies of antioxidant defense. 
Am Rev Respir Dis 1989;140:531–54.
	 8	 Freeman BA, Crapo JD. Hyperoxia increases oxygen radical 
production in rat lungs and lung mitochondria. J Biol Chem 
1981;256:10986–92.
	 9	 Waxman AB, Einarsson O, Seres T, et al. Targeted lung expression 
of interleukin-­11 enhances murine tolerance of 100% oxygen and 
diminishes hyperoxia-­induced DNA fragmentation. J Clin Invest 
1998;101:1970–82.
	10	 Griffith DE, Garcia JG, James HL, et al. Hyperoxic exposure in 
humans. Effects of 50 percent oxygen on alveolar macrophage 
leukotriene B4 synthesis. Chest 1992;101:392–7.
	11	 Davis WB, Rennard SI, Bitterman PB, et al. Pulmonary oxygen 
toxicity. early reversible changes in human alveolar structures 
induced by hyperoxia. N Engl J Med 1983;309:878–83.
	12	 Aggarwal NR, Brower RG. Targeting normoxemia in acute 
respiratory distress syndrome may cause worse short-­term 
outcomes because of oxygen toxicity. Ann Am Thorac Soc 
2014;11:1449–53.
	13	 Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy 
using low tidal volumes, recruitment maneuvers, and high 
positive end-­expiratory pressure for acute lung injury and acute 
respiratory distress syndrome: a randomized controlled trial. JAMA 
2008;299:637–45.
	14	 Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and 
mortality in mechanically ventilated patients. Intensive Care Med 
2012;38:91–8.
	15	 de Jonge E, Peelen L, Keijzers PJ, et al. Association between 
administered oxygen, arterial partial oxygen pressure and mortality 
in mechanically ventilated intensive care unit patients. Crit Care 
2008;12:R156.
	16	 Allen BS, Ilbawi MN. Hypoxia, reoxygenation and the role of 
systemic leukodepletion in pediatric heart surgery. Perfusion 2001;16 
Suppl:19–29.
	17	 Allen BS. The reoxygenation injury: is it clinically important? J Thorac 
Cardiovasc Surg 2002;124:16–19.
	18	 Supplemental therapeutic oxygen for prethreshold retinopathy of 
prematurity (STOP-­ROP), a randomized, controlled trial. I: primary 
outcomes. Pediatrics 2000;105:295–310.
	19	 SUPPORT Study Group of the Eunice Kennedy Shriver NICHD 
Neonatal Research Network, Carlo WA, Finer NN, et al. Target ranges 
of oxygen saturation in extremely preterm infants. N Engl J Med 
2010;362:1959–69.
	20	 Schmidt B, Whyte RK, Asztalos EV, et al. Effects of targeting 
higher vs lower arterial oxygen saturations on death or disability 
in extremely preterm infants: a randomized clinical trial. JAMA 
2013;309:2111–20.
	21	 BOOST II United Kingdom Collaborative Group, BOOST II Australia 
Collaborative Group, BOOST II New Zealand Collaborative Group, 
et al. Oxygen saturation and outcomes in preterm infants. N Engl J 
Med 2013;368:2094–104.
	22	 Panwar R, Hardie M, Bellomo R, et al. Conservative versus liberal 
oxygenation targets for mechanically ventilated patients. a pilot 
multicenter randomized controlled trial. Am J Respir Crit Care Med 
2016;193:43–51.
	23	 Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and 
hypertonic saline in patients with septic shock (HYPERS2S): a two-­
by-­two factorial, multicentre, randomised, clinical trial. Lancet Respir 
Med 2017;5:180–90.
	24	 Girardis M, Busani S, Damiani E, et al. Effect of conservative vs 
conventional oxygen therapy on mortality among patients in an 
intensive care unit: the oxygen-­ICU randomized clinical trial. JAMA 
2016;316:1583–9.
	25	 Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen 
therapy for acute respiratory distress syndrome. N Engl J Med 
2020;382:999–1008.
	26	 ICU-­ROX Investigators and the Australian and New Zealand Intensive 
Care Society Clinical Trials Group, Mackle D, Bellomo R, et al. 
Conservative oxygen therapy during mechanical ventilation in the 
ICU. N Engl J Med 2020;382:989-­998.
	27	 Schjørring OL, Klitgaard TL, Perner A, et al. Lower or higher 
oxygenation targets for acute hypoxemic respiratory failure. N Engl J 
Med Overseas Ed 2021;384:1301–11.
	28	 Siemieniuk RAC, Chu DK, Kim LH-­Y, et al. Oxygen therapy for 
acutely ill medical patients: a clinical practice guideline. BMJ 
2018;363:k4169.
	29	 National Heart, Lung, and Blood Institute Acute Respiratory 
Distress Syndrome (ARDS) Clinical Trials Network, Rice TW, 
Wheeler AP, et al. Initial trophic vs full enteral feeding in patients 
with acute lung injury: the EDEN randomized trial. JAMA 
2012;307:795–803.
	30	 Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-­3 fatty 
acid, gamma-­linolenic acid, and antioxidant supplementation in 
acute lung injury. JAMA 2011;306:1574–81.
	31	 O'Driscoll BR, Howard LS, Earis J, et al. Bts guideline for oxygen 
use in adults in healthcare and emergency settings. Thorax 
2017;72:ii1–90.
	32	 Panwar R, Capellier G, Schmutz N, et al. Current oxygenation 
practice in ventilated patients-­an observational cohort study. Anaesth 
Intensive Care 2013;41:505–14.
	33	 Suzuki S, Eastwood GM, Peck L, et al. Current oxygen management 
in mechanically ventilated patients: a prospective observational 
cohort study. J Crit Care 2013;28:647–54.
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

9
Semler MW, et al. BMJ Open 2021;11:e052013. doi:10.1136/bmjopen-2021-052013
Open access
	34	 Helmerhorst HJ, Schultz MJ, van der Voort PH, et al. Self-­reported 
attitudes versus actual practice of oxygen therapy by ICU physicians 
and nurses. Ann Intensive Care 2014;4:23.
	35	 Self WH, Semler MW, Rice TW. Oxygen targets for patients who 
are critically ill: emerging data and state of equipoise. Chest 
2020;157:487–8.
	36	 SPIRIT. Explanation and elaboration: guidance for protocols of 
clinical trials. - PubMed - NCBI, 2013. Available: https://www.​ncbi.​
nlm.​nih.​gov/​pubmed/​23303884 [Accessed 08 Jan 2018].
	37	 Ware JH, Hamel MB. Pragmatic trials--guides to better patient care? 
N Engl J Med 2011;364:1685–7.
	38	 Beasley R, Chien J, Douglas J, et al. Thoracic society of 
Australia and New Zealand oxygen guidelines for acute oxygen 
use in adults: 'swimming between the flags'. Respirology 
2015;20:1182–91.
	39	 Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower 
positive end-­expiratory pressures in patients with the acute 
respiratory distress syndrome. N Engl J Med 2004;351:327–36.
	40	 Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-­
expiratory pressure in patients with acute lung injury and acute 
respiratory distress syndrome: systematic review and meta-­analysis. 
JAMA 2010;303:865–73.
	41	 Semler MW, Rice TW, Shaw AD, et al. Identification of major adverse 
kidney events within the electronic health record. J Med Syst 
2016;40:167.
	42	 Semler MW, Noto MJ, Stollings J. Effect of saline versus balanced 
crystalloids on major adverse kidney events in the medical intensive 
care unit: the salt randomized trial. Am J Respir Crit Care Med 
2016;193:A4290.
	43	 Semler MW, Self WH, Wang L, et al. Balanced crystalloids versus 
saline in the intensive care unit: study protocol for a cluster-­
randomized, multiple-­crossover trial. Trials 2017;18.
	44	 Harris PA, Taylor R, Thielke R, et al. Research electronic data capture 
(REDCap)--a metadata-­driven methodology and workflow process 
for providing translational research informatics support. J Biomed 
Inform 2009;42:377–81.
	45	 Schoenfeld DA, Bernard GR, ARDS Network. Statistical evaluation 
of ventilator-­free days as an efficacy measure in clinical trials of 
treatments for acute respiratory distress syndrome. Crit Care Med 
2002;30:1772–7.
	46	 Harhay MO, Wagner J, Ratcliffe SJ, et al. Outcomes and statistical 
power in adult critical care randomized trials. Am J Respir Crit Care 
Med 2014;189:1469–78.
	47	 Vincent JL, Moreno R, Takala J, et al. The SOFA (sepsis-­related 
organ failure assessment) score to describe organ dysfunction/
failure. on behalf of the Working group on sepsis-­related problems of 
the European Society of intensive care medicine. Intensive Care Med 
1996;22:707–10.
	48	 , Ranieri VM, Rubenfeld GD, et al, ARDS Definition Task Force. 
Acute respiratory distress syndrome: the Berlin definition. JAMA 
2012;307:2526–33.
	49	 Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney 
Injury Work Group. KDIGO clinical practice guideline for acute kidney 
injury. Kidney inter 2012;2:8 https://​kdigo.​org/​guidelines/​acute-​
kidney-​injury/
	50	 Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of 
myocardial infarction (2018). J Am Coll Cardiol 2018;72:2231–64.
	51	 Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids 
versus saline in critically ill adults. N Engl J Med 2018;378:829–39.
	52	 Zeger SL, Liang KY, Albert PS. Models for longitudinal data: 
a generalized estimating equation approach. Biometrics 
1988;44:1049–60.
	53	 Turner RM, White IR, Croudace T, et al. Analysis of cluster 
randomized cross-­over trial data: a comparison of methods. Stat 
Med 2007;26:274–89.
	54	 Parienti J-­J, Kuss O. Cluster-­crossover design: a method for limiting 
clusters level effect in community-­intervention studies. Contemp Clin 
Trials 2007;28:316–23.
	55	 Beitler JR, Sarge T, Banner-­Goodspeed VM, et al. Effect of titrating 
positive end-­expiratory pressure (PEEP) with an esophageal 
pressure-­guided strategy vs an empirical high PEEP-­Fio2 strategy 
on death and days free from mechanical ventilation among patients 
with acute respiratory distress syndrome: a randomized clinical trial. 
JAMA 2019;321:846.
	56	 Munshi L, Ferguson ND. Evolving issues in oxygen therapy in acute 
care medicine. JAMA 2020;323:607.
Section. Protected by copyright.
 on November 1, 2021 at Eskind Biomedical Library Serials
http://bmjopen.bmj.com/
BMJ Open: first published as 10.1136/bmjopen-2021-052013 on 28 October 2021. Downloaded from 

1 
 
ONLINE SUPPLEMENT TO: 
Protocol and Statistical Analysis Plan for the Pragmatic Investigation of Optimal 
Oxygen Targets (PILOT) Clinical Trial 
 
Contents 
SUPPLEMENTAL METHODS ................................................................................................................. 3 
1. List of PILOT Investigators ............................................................................................................... 3 
2. SPIRIT 2013 Checklist ...................................................................................................................... 4 
3. Prior Clinical Trials of Oxygen Targets for Adult ICU Patients ................................................. 11 
4. Rationale for Cluster-level Allocation ............................................................................................ 13 
5. Rationale for Targeting SpO2 versus PaO2 .................................................................................. 15 
6. Approach to Monitoring SpO2 ........................................................................................................ 16 
7. Feedback on SpO2 Target Adherence ......................................................................................... 17 
8. SpO2 Targets in Patients who return to Invasive Mechanical Ventilation ............................... 18 
9. Liberation from Mechanical Ventilation ........................................................................................ 19 
10. Protocol for Ventilator Management in the Study ICU ............................................................. 20 
11. Protocol for Assessment of Pain (CPOT score) in the Study ICU ......................................... 21 
12. Protocol for Assessment of Agitation (RASS score) in the Study ICU .................................. 22 
13. Protocol for Delirium Assessment (CAM-ICU score) in the Study ICU ................................. 23 
14. Protocol for Management of Pain, Agitation, and Delirium in the Study ICU ....................... 24 
15. Protocol for Daily Spontaneous Awakening Trial (SAT) Safety Screen, SAT Performance, 
Spontaneous Breathing Trial (SBT) Safety Screen, and SBT Performance ............................... 25 
16. Protocol for Early Mobility in the Study ICU .............................................................................. 26 
17. Treatment Decisions Determined by Treating Clinicians during the Study .......................... 27 
18. Data Collected at Each Timepoint .............................................................................................. 28 
19. Definition of Days Alive and Free of a Supportive Therapy .................................................... 30 
20. Measures of Separation between Groups and Processes of Care ....................................... 31 
21. Assessment of Compliance with the Assigned SpO2 Target .................................................. 32 
22. Interim Analysis .............................................................................................................................. 33 
23. Pre-specified Baseline Co-variates ............................................................................................. 34 
24. Corrections for Multiple Testing ................................................................................................... 35 
25. Handling of Missing Data ............................................................................................................. 36 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

2 
 
26. Rationale for Waiver of Informed Consent ................................................................................ 37 
27. Plan for Communication of Protocol Changes .......................................................................... 39 
28. Patient Privacy and Data Storage ............................................................................................... 40 
29. Data Sharing Plan ......................................................................................................................... 41 
SUPPLEMENTAL TABLES .................................................................................................................... 42 
Table S1. Modified Non-respiratory SOFA Score. .......................................................................... 42 
SUPPLEMENTAL REFERENCES ........................................................................................................ 43 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

3 
 
SUPPLEMENTAL METHODS 
 
1. List of PILOT Investigators 
 
Department of Anesthesiology – Robert E. Freundlich*, Jonathan P. Wanderer* 
Department of Biostatistics – Christopher J. Lindsell*, Li Wang* 
Department of Emergency Medicine – Jin H. Han, Wesley H. Self*  
Department of Internal Medicine – John H. Brems*, Kevin G. Buell* 
Department of Pharmaceutical Services – Sneha Patel, Joanna L. Stollings* 
Division of Allergy, Pulmonary, and Critical Care Medicine – Gordon R. Bernard*, 
Jonathan D. Casey*, Christina Cleveland, Margaret A. Hays*, Luis E. Huerta, Karen 
Jackson, Todd W. Rice*, Megan Roth*, Matthew W. Semler* 
Division of Respiratory Care – Pamela G. Hastings*, Bradley D. Lloyd*, Roger K. 
Richardson, J. Craig Rooks 
All at Vanderbilt University Medical Center in Nashville, TN 
*denotes members of the writing committee 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

4 
 
2. SPIRIT 2013 Checklist 
 
 
 
 
 
SPIRIT 2013 Checklist:  
Recommended items to address in a clinical trial protocol and related documents* 
Section/item 
Item 
No 
Description 
Addressed 
on page 
number 
Administrative information 
 
Title 
1 
Descriptive title identifying the study design, population, interventions, and, if 
applicable, trial acronym 
___1___ 
Trial 
registration 
2a 
Trial identifier and registry name. If not yet registered, name of intended registry 
___3___ 
2b 
All items from the World Health Organization Trial Registration Data Set 
___3___ 
Protocol 
version 
3 
Date and version identifier 
___2____ 
Funding 
4 
Sources and types of financial, material, and other support 
___7___ 
Roles and 
responsibilities 
5a 
Names, affiliations, and roles of protocol contributors 
___1, sup 2_ 
5b 
Name and contact information for the trial sponsor 
___1___ 
 
5c 
Role of study sponsor and funders, if any, in study design; collection, 
management, analysis, and interpretation of data; writing of the report; and the 
decision to submit the report for publication, including whether they will have 
ultimate authority over any of these activities 
 
___1-2__ 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

5 
 
 
5d 
Composition, roles, and responsibilities of the coordinating center, steering 
committee, endpoint adjudication committee, data management team, and other 
individuals or groups overseeing the trial, if applicable (see Item 21a for data 
monitoring committee) 
 
 
___1___  
Introduction 
 
 
 
Background 
and rationale 
6a 
Description of research question and justification for undertaking the trial, 
including summary of relevant studies (published and unpublished) examining 
benefits and harms for each intervention 
____5-6___ 
 
6b 
Explanation for choice of comparators 
__5,6, 9____ 
Objectives 
7 
Specific objectives or hypotheses 
____6____ 
Trial design 
8 
Description of trial design including type of trial (eg, parallel group, crossover, 
factorial, single group), allocation ratio, and framework (eg, superiority, 
equivalence, noninferiority, exploratory) 
 
____6-7____ 
Methods: Participants, interventions, and outcomes 
 
Study setting 
9 
Description of study settings (eg, community clinic, academic hospital) and list of 
countries where data will be collected. Reference to where list of study sites can 
be obtained 
___7_____ 
Eligibility 
criteria 
10 
Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for 
study centers and individuals who will perform the interventions (eg, surgeons, 
psychotherapists) 
___7-8_____ 
Interventions 
11a Interventions for each group with sufficient detail to allow replication, including 
how and when they will be administered 
__9-11____ 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

6 
 
11b Criteria for discontinuing or modifying allocated interventions for a given trial 
participant (eg, drug dose change in response to harms, participant request, or 
improving/worsening disease) 
__11-12___ 
11c Strategies to improve adherence to intervention protocols, and any procedures for 
monitoring adherence (eg, drug tablet return, laboratory tests) 
__Sup 17__ 
11d Relevant concomitant care and interventions that are permitted or prohibited 
during the trial 
__12-13__ 
Outcomes 
12 
Primary, secondary, and other outcomes, including the specific measurement 
variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, 
final value, time to event), method of aggregation (eg, median, proportion), and 
time point for each outcome. Explanation of the clinical relevance of chosen 
efficacy and harm outcomes is strongly recommended 
 
__14-17__ 
Participant 
timeline 
13 
Time schedule of enrolment, interventions (including any run-ins and washouts), 
assessments, and visits for participants. A schematic diagram is highly 
recommended (see Figure) 
___Fig 1__ 
Sample size 
14 
Estimated number of participants needed to achieve study objectives and how it 
was determined, including clinical and statistical assumptions supporting any 
sample size calculations 
__15-16___ 
Recruitment 
15 
Strategies for achieving adequate participant enrollment to reach target sample 
size 
___15____ 
Methods: Assignment of interventions (for controlled trials) 
 
Allocation: 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

7 
 
Sequence 
generation 
16a Method of generating the allocation sequence (eg, computer-generated random 
numbers), and list of any factors for stratification. To reduce predictability of a 
random sequence, details of any planned restriction (eg, blocking) should be 
provided in a separate document that is unavailable to those who enroll 
participants or assign interventions 
_8-9__ 
Allocation 
concealment 
mechanism 
16b Mechanism of implementing the allocation sequence (eg, central telephone; 
sequentially numbered, opaque, sealed envelopes), describing any steps to 
conceal the sequence until interventions are assigned 
_8-9, Fig 2__ 
Implementati
on 
16c Who will generate the allocation sequence, who will enroll participants, and who 
will assign participants to interventions 
_8-10___ 
Blinding 
(masking) 
17a Who will be blinded after assignment to interventions (eg, trial participants, care 
providers, outcome assessors, data analysts), and how 
_12___ 
 
17b If blinded, circumstances under which unblinding is permissible, and procedure for 
revealing a participant’s allocated intervention during the trial 
_NA___ 
Methods: Data collection, management, and analysis 
 
Data collection 
methods 
18a Plans for assessment and collection of outcome, baseline, and other trial data, 
including any related processes to promote data quality (eg, duplicate 
measurements, training of assessors) and a description of study instruments (eg, 
questionnaires, laboratory tests) along with their reliability and validity, if known. 
Reference to where data collection forms can be found, if not in the protocol 
_13-14_ 
 
18b Plans to promote participant retention and complete follow-up, including list of any 
outcome data to be collected for participants who discontinue or deviate from 
intervention protocols 
__13__ 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

8 
 
Data 
management 
19 
Plans for data entry, coding, security, and storage, including any related 
processes to promote data quality (eg, double data entry; range checks for data 
values). Reference to where details of data management procedures can be 
found, if not in the protocol 
__13___ 
Statistical 
methods 
20a Statistical methods for analyzing primary and secondary outcomes. Reference to 
where other details of the statistical analysis plan can be found, if not in the 
protocol 
__16-21__ 
 
20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 
__16-21__ 
 
20c Definition of analysis population relating to protocol non-adherence (eg, as 
randomized analysis), and any statistical methods to handle missing data (eg, 
multiple imputation) 
 
__16,21__ 
Methods: Monitoring 
 
Data 
monitoring 
21a Composition of data monitoring committee (DMC); summary of its role and 
reporting structure; statement of whether it is independent from the sponsor and 
competing interests; and reference to where further details about its charter can 
be found, if not in the protocol. Alternatively, an explanation of why a DMC is not 
needed 
__16__ 
 
21b Description of any interim analyses and stopping guidelines, including who will 
have access to these interim results and make the final decision to terminate the 
trial 
__Sup 34_ 
Harms 
22 
Plans for collecting, assessing, reporting, and managing solicited and 
spontaneously reported adverse events and other unintended effects of trial 
interventions or trial conduct 
_Sup 17,34__ 
Auditing 
23 
Frequency and procedures for auditing trial conduct, if any, and whether the 
process will be independent from investigators and the sponsor 
__Sup 17___ 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

9 
 
Ethics and dissemination 
 
Research 
ethics approval 
24 
Plans for seeking research ethics committee/institutional review board (REC/IRB) 
approval 
___22__ 
Protocol 
amendments 
25 
Plans for communicating important protocol modifications (eg, changes to 
eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, 
REC/IRBs, trial participants, trial registries, journals, regulators) 
__Sup 40__ 
Consent or 
assent 
26a Who will obtain informed consent or assent from potential trial participants or 
authorized surrogates, and how (see Item 32) 
___22__ 
 
26b Additional consent provisions for collection and use of participant data and 
biological specimens in ancillary studies, if applicable 
___22___ 
Confidentiality 
27 
How personal information about potential and enrolled participants will be 
collected, shared, and maintained in order to protect confidentiality before, during, 
and after the trial 
__Sup 40__ 
Declaration of 
interests 
28 
Financial and other competing interests for principal investigators for the overall 
trial and each study site 
___2___ 
Access to data 29 
Statement of who will have access to the final trial dataset, and disclosure of 
contractual agreements that limit such access for investigators 
_Sup 40-42_ 
Ancillary and 
post-trial care 
30 
Provisions, if any, for ancillary and post-trial care, and for compensation to those 
who suffer harm from trial participation 
__NA___ 
Dissemination 
policy 
31a Plans for investigators and sponsor to communicate trial results to participants, 
healthcare professionals, the public, and other relevant groups (eg, via 
publication, reporting in results databases, or other data sharing arrangements), 
including any publication restrictions 
__23___ 
 
31b Authorship eligibility guidelines and any intended use of professional writers 
__Sup 2__ 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

10 
 
 
31c Plans, if any, for granting public access to the full protocol, participant-level 
dataset, and statistical code 
_ Sup 42_ 
Appendices 
 
 
 
Informed 
consent 
materials 
32 
Model consent form and other related documentation given to participants and 
authorized surrogates 
_NA_ 
Biological 
specimens 
33 
Plans for collection, laboratory evaluation, and storage of biological specimens for 
genetic or molecular analysis in the current trial and for future use in ancillary 
studies, if applicable 
__NA_ 
*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for 
important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is 
copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” 
license.
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

11 
 
3. Prior Clinical Trials of Oxygen Targets for Adult ICU Patients 
 
To date, five small-to-moderate sized clinical trials have examined SpO2 targets 
among adult ICU patients [1–6].  The first trial compared a lower SpO2 target (88-92%) 
with a higher SpO2 target (96-100%) among 103 mechanically ventilated patients [1].  
Targeting these SpO2 ranges produced adequate separation between groups in SpO2, 
PaO2, and FiO2 without any concern for safety, but the trial was not powered to detect 
differences in clinical outcomes. The second trial enrolled mechanically ventilated adults 
with septic shock and reported a numerically higher mortality for those randomized to an 
FiO2 of 1.0 compared with those randomized to an SpO2 target of 88-95% [2].  The third 
trial reported an 8% absolute reduction in mortality with use of an SpO2 target of 94-
98% compared to 97-100% among 434 patients in a single ICU [3].  These findings 
were limited by early study termination and the authors concluded that a larger trial was 
needed [3].  The fourth trial compared use of an SpO2 target of 88-92% versus 96-100% 
among 205 mechanically ventilated adults with acute respiratory distress syndrome [4].  
No statistically significant difference was observed between groups. Although outcomes 
appeared to numerically favor the higher SpO2 target group, interpretation was limited 
by early study termination.  The fifth trial enrolled 1000 ICU patients within 2 hours of 
the initiation of mechanical ventilation [5].  Patients in the intervention group received 
the lowest FiO2 that maintained SpO2 > 90%.  Patients in the control group received 
oxygen therapy at the discretion of treating clinicians targeting SpO2 values between 
91-100%.  No difference between groups in clinical outcomes was observed, although 
modest separation between groups and sample size may have limited power to detect 
differences in patient-centered outcomes.  The sixth trial randomized 2,928 adult ICU 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

12 
 
patients with acute hypoxemic respiratory failure on at least 10 liters of oxygen per 
minute or a fraction of inspired oxygen of at least 0.5 to a PaO2 target of either 60 mm 
Hg or 90 mm Hg.  The trial reported no significant differences between groups in 90-day 
mortality, ventilator-free days, or new episodes of shock, myocardial ischemia, ischemic 
stroke, or intestinal ischemia. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

13 
 
4. Rationale for Cluster-level Allocation 
 
Group assignment in the PILOT trial occurs at the level of the ICU (cluster) for 
several reasons.  In routine clinical care in the study ICU, titration of FiO2 to maintain 
SpO2 for all mechanically ventilated adults is performed by 2 to 4 respiratory therapists, 
with input from nurses and physicians.  The management of mechanical ventilation 
(selection of tidal volume, titration of positive end-expiratory pressure, screening for and 
performance of spontaneous breathing trials) is governed by unit-wide protocols 
implemented by the 2 to 4 respiratory therapists for all patients in the unit.  Assigning 
the entire unit to a single SpO2 target emulates the way mechanical ventilation is 
managed during clinical care and limits contamination that might result from a 
respiratory therapist managing multiple patients assigned to different SpO2 targets.   
Additionally, exposure to excess FiO2, hyperoxemia, and hyperoxia is most 
common in the minutes-to-hours immediately following initiation of invasive mechanical 
ventilation [7,8].  In a recent randomized trial examining tracheal intubation of critically ill 
adults, the median values for lowest SpO2 and highest FiO2 were 97% and 1.0, 
respectively, in the first hour of invasive mechanical ventilation, compared with 96% and 
0.6 between 1 hour and 6 hours and 94% and 0.5 between 6 hours and 24 hours [9].  
Even brief periods of early hyperoxia or hypoxia may affect organ function [10–12] and 
clinical outcomes [13–16].  Enrollment immediately after initiation of invasive 
mechanical ventilation minimizes pre-study exposure to excess FiO2, hyperoxemia, and 
hyperoxia and facilitates on-study separation between groups.  Multiple prior trials 
examining SpO2 targets have aimed to enroll patients shortly after the initiation of 
invasive mechanical ventilation [5,17].  In these patient-level parallel-group trials, 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

14 
 
however, the logistical challenges of performing screening, enrollment, randomization, 
and study group assignment immediately following initiation of invasive mechanical 
ventilation resulted in the exclusion of 60-90% of eligible patients – raising concern for 
systematic exclusion of important patient groups (e.g., patients with higher acuity of 
illness).  In PILOT, group assignment at the cluster level allows enrollment immediately 
on initiation of invasive mechanical ventilation in the ED or ICU.  This approach 
emulates the manner in which oxygen therapy is managed in practice, precludes 
systematic exclusion of important patient groups, decreases pre-study exposure to 
hyperoxia and hypoxia, and facilitates early separation in oxygen therapy between 
groups. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

15 
 
5. Rationale for Targeting SpO2 versus PaO2 
 
SpO2 is measured continuously via non-invasive pulse oximetry for nearly all 
mechanically ventilated ICU patients.  In contrast, PaO2 is assessed via arterial 
puncture intermittently and selectively, with most measurements occurring early in the 
admission of severely ill patients.  Similar to prior clinical trials of oxygen therapy during 
mechanical ventilation [1,5], the PILOT trial targets SpO2 rather than PaO2 for patients 
with functioning non-invasive pulse oximetry monitoring.  For patients in the PILOT trial 
for whom non-invasive pulse oximetry monitoring is unavailable or inaccurate (e.g., 
inadequate plethysmography signal due to hypoperfusion), PaO2 values corresponding 
to the assigned SpO2 target are used to guide oxygen therapy [18]. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

16 
 
6. Approach to Monitoring SpO2  
 
For all mechanically ventilated patients in the study ED and ICU, SpO2 is 
continuously monitored using Nellcor™ SpO₂ Adhesive Sensors (Medtronic, 
Minneapolis, MN), which measure changes in red and infrared light absorption in an 
arteriolar bed throughout the pulse cycle to report a non-normalized real-time 
plethysmographic waveform and arterial hemoglobin saturation values averaged over 
the prior 6 seconds with a mean difference between SpO2 and SaO2 < 2% for SpO2 
values 80-100% [19].  Plethysmography and SpO2 values are displayed [1] on IntelliVue 
MP90 bedside patient monitors (PHILIPS, Amsterdam, Netherlands) in each ED and 
ICU room, [2] on telemetry monitors located at ED and ICU nursing stations and 
adjacent to the respiratory therapy office, and [3] in real-time in the institutional 
electronic health record, available from any physical location.  SpO2 values are archived 
every 60 seconds into an Enterprise Data Warehouse [20–22]. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

17 
 
7. Feedback on SpO2 Target Adherence 
 
During the study, the IntelliVue MP90 bedside patient monitors in each room are 
set to generate an alarm for SpO2 values outside the range considered to be at goal for 
the assigned SpO2 target group.  For example, for patients in the intermediate SpO2 
target group, SpO2 values 92-96% generate no alarm, whereas SpO2 values ≤ 91% or ≥ 
97% generate an alarm alerting nursing staff and respiratory therapy to the out-of-range 
value.   
Study personnel remotely monitor SpO2 values every four hours from 4 AM 
through 10 PM Monday through Friday and during a 10% sample of night and weekend 
hours to identify instances of lag between out-of-range SpO2 values and FiO2 titration, 
provide feedback and support to respiratory therapists and bedside nurses, and identify 
barriers to achieving the assigned SpO2 target.   
Prior to the trial, all respiratory therapists, nurses, and supervising physicians 
who practice in the study ICU received formal training in the study protocol.  Throughout 
the duration of the study, study personnel attend respiratory therapy group meetings, 
nursing unit board meetings, and ICU physician leadership meetings to provide 
continuing education about the study, reinforce elements of the study protocol including 
the process for SpO2 target modification by treating clinicians, screen for safety 
concerns or potential adverse events, and identify and address barriers to achieving the 
SpO2 targets. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

18 
 
8. SpO2 Targets in Patients who return to Invasive Mechanical Ventilation 
 
Patients who discontinue invasive mechanical ventilation and return to invasive 
mechanical ventilation in a study location during the same two-month study period 
continue to be managed using the same assigned SpO2 target.  Similarly, patients who 
are transferred out from a study location and return to receiving invasive mechanical 
ventilation in a study location during the same two-month study period continue to be 
managed using the same assigned SpO2 target.  Patients who remain on invasive 
mechanical ventilation in a study location through the end of a two-month study period 
receive the SpO2 target assigned by the study until midnight on the night that the two-
month study period ends, after which time treating clinicians determine the SpO2 target 
with which the patient is managed.  Similarly, for patients who are enrolled during one 
two-month study period, discontinue invasive mechanical ventilation or transferred out 
of the study location, and return to receiving invasive mechanical ventilation during a 
subsequent two-month study period, treating clinicians determine the SpO2 target with 
which the patient is managed during the subsequent episode of invasive mechanical 
ventilation.   
 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

19 
 
9. Liberation from Mechanical Ventilation 
 
Each day of mechanical ventilation, all patients in the study ICU are assessed for 
safety of a spontaneous awakening trial (SAT) and spontaneous breathing trial (SBT) 
[23] using the SAT and SBT safety criteria from the Awakening and Breathing 
Controlled trial [24].  To prevent patients in the higher SpO2 target group from 
experiencing delays in qualifying for an SBT based on receipt of higher FiO2 to achieve 
the higher SpO2 target, patients in all groups are allowed to qualify for an SAT and SBT 
regardless of their current FiO2 or PEEP settings, as long as the other SAT and SBT 
Safety Screen criteria are met and treating clinicians feel performance of an SAT and 
SBT is safe.  Definitions of SAT and SBT failure and the ventilator settings and duration 
of the SBT are the same as those used in the ABC trial and during clinical care in the 
study ICU.  For patients who have passed an SBT, the decision to discontinue invasive 
mechanical ventilation is made by the treating clinicians. 
 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

20 
 
10. Protocol for Ventilator Management in the Study ICU 
 
Predicted Body Weight (PBW) Calculation: 
            Males:          PBW (kg) = (height in inches – 60)*2.3+50 
            Females:      PBW (kg) = (height in inches – 60)*2.3+45.5 
 
Mode: Assist Control 
 
Tidal volume: 6 ml/kg PBW 
 
Respiratory rate: Set to maintain 60-70% minute ventilation prior to tracheal intubation.  
Adjust rate to maintain pH 7.30-7.45, NOT TO EXCEED 35 bpm or PC02 < 25. 
 
I:E Ratio: Avoid inverse ratio ventilation 
 
PEEP titration: 
FiO2 
0.3-0.4 
0.4 
0.5 
0.5 
0.6 
0.7 
0.7 
0.7 
0.8 
0.9 
0.9 
0.9 
1 
PEEP 
5 
8 
8 
10 
10 
10 
12 
14 
14 
14 
16 
18 
18-25 
     Wean patient to the lowest level of FiO2 & PEEP while maintaining goal SpO2. 
 
Acidosis Management: 
1. 
If pH <7.30, increase RR to 35 as needed. 
2. 
If pH remains <7.3 with RR = 35 call House Officer 
3. 
If pH <7.15, consider bicarbonate administration, may increase TV by 1 ml/kg 
PBW increments until pH is >7.15 or TV = 8 ml/kg PBW (under these conditions 
Pplat targets [see below] may be exceeded). 
Alkalosis Management: If pH >7.45, decrease RR. 
 
Management of Tidal Volume: 
1. Titrate TV by 1ml/kg increments (minimum of 4ml/kg PBW) to maintain a Pplat 
below 30cm H2O. 
2. Measure & record Pplat (0.5 sec inspiratory pause), SpO2, Total RR, TV and pH 
(if available) at least every 4 hours AND after each change in PEEP or TV. 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

21 
 
11. Protocol for Assessment of Pain (CPOT score) in the Study ICU 
 
Indicator 
Assessment 
Score 
Description 
Facial expressions 
Relaxed, neutral    
0 
No muscle tension observed 
Tense 
1 
Presence of frowning, brow lowering, orbit 
tightening and levator contraction or any other 
change (e.g. opening eyes or tearing during 
nociceptive procedures) 
Grimacing 
2 
All previous facial movements plus eyelid tightly 
closed (the patient may present with mouth open or 
biting the endotracheal tube) 
Body movements 
Absence of 
movements or normal 
position 
0 
Does not move at all (doesn’t necessarily mean 
absence of pain) or normal position (movements not 
aimed toward the pain site or not made for the 
purpose of protection) 
Protection 
1 
Slow, cautious movements, touching or rubbing the 
pain site, seeking attention through movements 
Restlessness/Agitation 
2 
Pulling tube, attempting to sit up, moving 
limbs/thrashing, not following commands, striking 
at staff, trying to climb out of bed 
Compliance with the ventilator 
(intubated patients) 
 
 
 
OR 
 
Vocalizations (extubated patients) 
Tolerating ventilator 
or movement 
0 
Alarms not activated, easy ventilation 
Coughing but 
tolerating 
1 
Coughing, alarms may be activated but stop 
spontaneously 
Fighting ventilator 
2 
Asynchrony: blocking ventilation, alarms 
frequently activated 
Talking in normal 
tone or no sound 
0 
Talking in normal tone or no sound 
Sighing, moaning 
1 
Sighing, moaning 
Crying out, sobbing 
2 
Crying out, sobbing 
Muscle tension 
 
Evaluate by passive flexion and 
extension of the upper limbs when 
patient is at rest or evaluation when 
patient is being turned 
Relaxed 
0 
No resistance to passive movements 
Tense, rigid 
1 
Resistance to passive movements 
Very tense or rigid 
2 
Strong resistance to passive movements or 
incapacity to complete them 
TOTAL 
 
___/8 
 
Adapted from: https://www.icudelirium.org/medical-professionals/assess-prevent-and-manage-pain 
Gélinas, C. (2010). Nurses’ Evaluations of the Feasibility and the Clinical Utility of the Critical-Care Pain 
Observation Tool. Pain Management Nursing, 11(2), 115-125. 
Arbour, C., & Gélinas, C. (2011). Ask the Experts. Setting Goals for Pain Management When Using a 
Behavioral Scale: Example With the Critical-Care Pain Observation Tool. Critical Care Nurse, 31, 66-68. 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

22 
 
12. Protocol for Assessment of Agitation (RASS score) in the Study ICU 
 
 
 
Reproduced with permission from: 
https://www.icudelirium.org/medical-professionals/delirium/monitoring-delirium-in-the-icu 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

23 
 
13. Protocol for Delirium Assessment (CAM-ICU score) in the Study ICU 
 
 
 
Reproduced with permission from: 
https://www.icudelirium.org/medical-professionals/delirium/monitoring-delirium-in-the-icu 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

24 
 
14. Protocol for Management of Pain, Agitation, and Delirium in the Study ICU 
 
Reproduced with permission from: 
https://www.icudelirium.org/medical-professionals/delirium/monitoring-delirium-in-the-icu 
 
 
 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

25 
 
15. Protocol for Daily Spontaneous Awakening Trial (SAT) Safety Screen, SAT 
Performance, Spontaneous Breathing Trial (SBT) Safety Screen, and SBT 
Performance 
 
Adapted for the PILOT trial from the “Wake Up and Breathe Flowchart”, found at: 
https://www.icudelirium.org/medical-professionals/both-sat-and-sbt 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

26 
 
16. Protocol for Early Mobility in the Study ICU 
 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

27 
 
17. Treatment Decisions Determined by Treating Clinicians during the Study 
 
All treatment decisions except choice of SpO2 target during invasive mechanical 
ventilation of are made by treating clinicians, including: approach to oxygen therapy 
before invasive mechanical ventilation; use of non-invasive ventilation before invasive 
mechanical ventilation; choice of ventilator mode during invasive mechanical ventilation; 
approach to positive end-expiratory pressure during invasive mechanical ventilation; 
administration of neuromuscular blocking agents, inhaled epoprostenol, prone 
positioning, or extracorporeal membrane oxygenation; administration of vasopressors or 
ionotropes, antimicrobial medications, diuretics, intravenous fluid, or blood products; 
arterial or venous blood gas measurement, measurement of lactate concentration, 
measurement of central or mixed venous oxygen saturation. 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

28 
 
18. Data Collected at Each Timepoint 
 
Enrollment (Day 0) 
1. Data collected by both manual and automated methods: age; sex; race; ethnicity; 
height, weight; time from presentation to the study hospital to enrollment; time 
from ICU admission to enrollment; time from first receipt of invasive mechanical 
ventilation to enrollment; study location at enrollment; source of admission to the 
ICU;  
2. Data collected only by manual method: baseline comorbidities; acute illnesses at 
enrollment; indication for invasive mechanical ventilation 
3. Data collected only by automated method: non-respiratory Sequential Organ 
Failure Assessment (SOFA) score [25] (see supplemental appendix); Elixhauser 
Comorbidity Index [26]; Glasgow Coma Scale score [27]; vital signs 
(temperature, heart rate, systolic blood pressure, diastolic blood pressure, SpO2); 
mechanical ventilator settings (mode, set and exhaled tidal volume, set and 
actual respiratory rate, positive end-expiratory pressure, peak pressure, FiO2); 
serum laboratory values (white blood cell count, hemoglobin, platelet count, 
sodium, potassium, bicarbonate, creatinine, bilirubin, alanine aminotransferase, 
aspartate aminotransferase, lactate, arterial pH, PaO2, SaO2). 
 
On-Study (Days 0-28) 
1. Data collected only by manual method:  
a. For the subset of all patient enrolled during the first 12 months of the trial, 
physician manual review blinded to study group assignment will determine 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

29 
 
whether each patient experienced acute respiratory distress syndrome 
(ARDS) by Berlin criteria [28], atrial arrhythmia, ventricular arrhythmia, 
cardiac arrest, pneumothorax or pneumomediastinum, ischemic stroke, or 
myocardial infarction.   
b. For the full duration of the trial, each time treating clinicians, patients, or 
families elect to modify the assigned SpO2 target, study personnel will 
record the date and time of the modification, the SpO2 range to which the 
target was modified, and the rationale for modifying the SpO2 target. 
c. Each weekday, study personnel will record for each patient the results of 
the SAT Safety Screen, SAT, SBT Safety Screen, and SBT. 
2. Data collected only by automated method: vital signs, ventilator settings, and 
serum laboratory values (as above); receipt of extracorporeal membrane 
oxygenation; receipt of neuromuscular blockade; receipt of inhaled epoprostenol; 
receipt of red cell transfusion; number of arterial blood gases; non-respiratory 
SOFA score; Richmond Agitation and Sedation Score [29]; Confusion 
Assessment Method for the ICU (CAM-ICU) score [30]. 
 
Termination (Day 28) 
Data collected by both manual and automated methods: death prior to hospital 
discharge; time from enrollment to death; duration of ICU admission; duration of hospital 
admission; duration of invasive mechanical ventilation; receipt of vasopressors; duration 
of vasopressor receipt; receipt of renal replacement therapy; duration of renal 
replacement therapy receipt. 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

30 
 
19. Definition of Days Alive and Free of a Supportive Therapy 
 
Each of the outcomes related to the number of days alive and free of a specific 
supportive therapy (e.g., vasopressor-free days, renal replacement therapy-free days, 
ICU-free days, and hospital-free days) will be defined using the same approach as the 
primary outcome of ventilator-free days. 
Days alive and free of the supportive therapy will be defined as the number of 
calendar days alive and free of the supportive therapy from the final receipt of the 
supportive therapy through 28 days after enrollment [67,68].  The day of enrollment will 
be considered to be day 0.  Outcome ascertainment will cease at the time of hospital 
discharge or 28 days after enrollment, whichever occurs first.   
Receipt of the supportive therapy will be considered to end at the time of the 
patient’s final receipt of the supportive therapy between enrollment and 28 days after 
enrollment.  Patients who continue to receive the supportive therapy at day 28 will 
receive a value of zero.  Patients who die prior to day 28 will receive a value of zero.  
Patients who are discharged from the hospital prior to day 28 and are receiving the 
supportive therapy at the time of discharge will receive a value of zero.  Patients who 
are removed from the supportive therapy and are discharged from the hospital without 
the supportive therapy prior to 28 days will be assumed to remain free of the supportive 
therapy between hospital discharge and day 28.  For patients who are removed from 
the supportive therapy, return to receiving the supportive therapy, and are subsequently 
removed again from the supportive therapy prior to day 28, days alive and free of the 
supportive therapy will be counted from the final receipt of the supportive therapy prior 
to day 28. 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

31 
 
20. Measures of Separation between Groups and Processes of Care 
 
Measures of Separation between Groups 
1. SpO2 during invasive mechanical ventilation 
2. SaO2 during invasive mechanical ventilation 
3. FiO2 during invasive mechanical ventilation 
4. PaO2 during invasive mechanical ventilation 
5. Episodes of hypoxemia, including: 
a. SpO2 < 85% for ≥ 5 minutes 
b. SpO2 < 80% for ≥ 5 minutes 
c. SpO2 < 70% for ≥ 2 minutes 
6. Episodes of hyperoxemia, including: 
a. SpO2 > 98% for ≥ 5 minutes 
b. SpO2 > 98% for ≥ 30 minutes 
7. Proportion of patients with a value for PaO2 < 55 mm Hg 
8. Proportion of patients with a value for PaO2 > 120 mm Hg 
Measures of Processes of Care 
1. Tidal volume 
2. Positive end-expiratory pressure 
3. Peak airway pressure 
4. Receipt of mandatory ventilator mode 
5. Number of arterial blood gasses 
6. Hemoglobin 
7. Red cell transfusion 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

32 
 
21. Assessment of Compliance with the Assigned SpO2 Target 
 
All SpO2 values measured during invasive mechanical ventilation are assessed for 
compliance with the assigned SpO2 target.  An SpO2 value is considered compliant with 
the trial protocol if any of the following conditions are met: 
1. Measured SpO2 is within the target range 
2. Measured SpO2 is above the target range and the FiO2 is 21% 
3. Measured SpO2 is below the target range and the FiO2 is 100% 
4. Measured SpO2 occurs after treating clinicians have completed an SpO2 target 
modification sheet 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

33 
 
22. Interim Analysis 
 
On March 23, 2020, the DSMB conducted a single, planned interim analysis for 
efficacy and safety at the anticipated halfway point of the trial.  The interim analysis 
included data from patients enrolled during the first 18 months of the trial.  According to 
the criteria specified in the trial protocol, the stopping boundary for efficacy would have 
been met if the P value for the difference between groups was <0.001 using a 
proportional odds model with independent covariates of group assignment (higher, 
intermediate, or lower SpO2 target) and time.  A stopping boundary for futility was not 
pre-specified.  After conducting the planned interim analysis, the DSMB recommended 
the study continue without modification.   
The DSMB reserves the right to stop the trial at any point, request additional data 
or interim analyses, or request modifications of the study protocol as required to protect 
patient safety.   
Use of the conservative Haybittle-Peto boundary (P < 0.001) will allow the final 
analysis to be performed using an unchanged level of significance (P = 0.05). 
 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

34 
 
23. Pre-specified Baseline Co-variates 
 
We will repeat the primary analysis with adjustment for the following pre-specified 
baseline covariates: age (continuous), sex (male, female), race and ethnicity (Hispanic, 
Non-Hispanic Black, Non-Hispanic White, Other), source of ICU admission (ED, hospital 
ward, another ICU in the study hospital, operating room, outside hospital), vasopressor 
receipt (yes, no), and acute diagnoses at enrollment (cardiac arrest, acute myocardial 
infarction, sepsis or septic shock, acute respiratory distress syndrome), and severity of 
illness as assessed by the non-respiratory SOFA score.   
To account for non-linear relationships, continuous variables will be analyzed 
using restricted cubic splines with between 3 and 5 knots. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

35 
 
24. Corrections for Multiple Testing 
 
We have pre-specified a single primary outcome and a single secondary 
outcome.  Consistent with recommendations of the Food and Drug Administration [65] 
and the European Medicines Association [66], each will be tested using a two-sided p-
value with a significance level of 0.05.  For all other analyses, emphasis will be placed 
on the estimate of effect size with 95% confidence intervals, as recommended by the 
International Committee of Medical Journal Editors [67], and no corrections for multiple 
comparisons will be performed. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

36 
 
25. Handling of Missing Data 
 
The primary outcome of VFDs is not anticipated to be missing for any patients.  
Missing data will not be imputed for the primary outcome or any secondary or 
exploratory outcomes.  None of the covariates pre-specified for the adjusted analysis 
are anticipated to be missing for any patients.  In additional adjusted analyses, any 
missing data for covariates will be imputed using multiple imputations.   
 
 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

37 
 
26. Rationale for Waiver of Informed Consent 
 
For all mechanically ventilated ICU patients, FiO2 is titrated to maintain SpO2 as 
a part of clinical care. In current clinical care, 98% of SpO2 values experienced by 
mechanically ventilated adult ICU patients fall between 88-100% [31,32].  Within this 
range, current guidelines for oxygen therapy in mechanically ventilated adults advocate 
contrasting approaches: [1] tolerating SpO2 values as low as 88% (NIH/NHLBI ARDS 
Network) [33], [2] titrating within the range 92-96% (Thoracic Society of Australia and 
New Zealand) [34], or [3] allowing SpO2 values above 96% (British Thoracic Society) 
[35]. The lower SpO2 target, intermediate SpO2 target, and higher SpO2 target 
examined in this study are all intermittently used in routine clinical care in the study ICU 
and are all within the range recommended by at least one international guideline. No 
high-quality data suggest that one SpO2 target is better than the others for patient 
outcomes.  During the PILOT trial, whenever treating clinicians feel that the optimal 
SpO2 target for a specific patient is known, that SpO2 target is used.  Thus, the PILOT 
trial only determines the SpO2 target for patients whose treating clinicians are uncertain 
which SpO2 target would be optimal for the patient and feel all three targets represent 
comparable and reasonable approaches. 
Because the SpO2 targets being compared in the study [1] are common 
approaches to managing a universal supportive therapy to which patients would be 
exposed as a part of clinical care if not participating in the study, [2] have no high-quality 
data suggesting the superiority of one approach over the others, and [3] are all 
comparable approaches for the patient from the perspective of the treating clinician, 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

38 
 
participation in the study presents minimal incremental risk compared to clinical care for 
mechanically ventilated ICU patients outside of the study. 
Initiation of mechanical ventilation for critically ill patients is frequently a time-
sensitive procedure. Despite the availability of a formal informed consent document for 
tracheal intubation and initiation of mechanical ventilation, time allows for discussion of 
risks and benefits of these clinical procedures in less than 10% of cases during clinical 
care in the study ICU. Titration of FiO2 to target SpO2 in PILOT begins within 15 minutes 
of the initiation of mechanical ventilation with a goal of intervening during the period with 
the highest prevalence of excess FiO2, hyperoxemia, and hyperoxia. Moreover, in this 
cluster-randomized trial, the entire ICU is assigned to a single SpO2 target delivered by 
the unit’s respiratory therapists through a unit-wide oxygen titration protocol. Obtaining 
informed consent from every patient receiving invasive mechanical ventilation in the 
study ED and ICU prior to the initiation of invasive mechanical ventilation would be 
impracticable and would potentially delay delivery of a time-sensitive intervention. 
Because the study presents minimal incremental risk, the study does not 
adversely affect the welfare or privacy rights of the participants, and obtaining informed 
consent prior to enrollment is impracticable, the study is being conducted with a waiver 
of informed consent. 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

39 
 
27. Plan for Communication of Protocol Changes 
 
 
Any changes to the trial protocol (e.g., changes to eligibility criteria, outcomes, 
analyses) will require a new version of the full trial protocol which will be tracked with 
the date of the update and the version number of the trial protocol. A list summarizing 
the changes that are made with each protocol revision will be included at the end of 
each protocol. The updated protocol will be sent to the Vanderbilt IRB for approval prior 
to implementation of the protocol change. At the time of publication, the original trial 
protocol and the final trial protocol, including the summary of changes made with each 
protocol change, will be included in the supplementary material for publication. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

40 
 
28. Patient Privacy and Data Storage  
 
All patients are assigned a unique study ID number for tracking.  Data collected 
from the medical record is entered into the secure online database REDCap.  All data is 
maintained in the secure online database REDCap until the time of study publication.  
At the time of publication, a de-identified database will be generated.  
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

41 
 
29. Data Sharing Plan 
 
 
Upon reasonable request, a completely de-identified data set may be provided by 
the authors.  Request to share data from the PILOT trial should be sent to the principal 
investigator, Matthew W. Semler, at matthew.w.semler@vumc.org.  The dataset will be 
provided to researchers whose proposed use of the data has been approved by the 
PILOT steering committee and an Institutional Review Board and is accompanied by an 
executed Data Use Agreement.  
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

42 
 
SUPPLEMENTAL TABLES 
 
Table S1. Modified Non-respiratory SOFA Score.   
 
 
0 
1 
2 
3 
4 
Coagulation 
    Platelets (x103/mm3) 
> 150 
101-150 
51-100 
21-50 
≤ 20 
 
Liver 
    Bilirubin (mg/dL) 
< 1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
≥ 12 
Cardiovascular 
    Blood pressure 
Mean arterial 
pressure ≥ 70 
mmHg and no 
receipt of 
dopamine, 
dobutamine, 
epinephrine, or 
norepinephrine 
Mean arterial 
pressure < 70 
mmHg and no 
receipt of 
dopamine, 
dobutamine, 
epinephrine, or 
norepinephrine 
On dopamine 
≤ 5 
mcg/kg/min or 
any 
dobutamine 
On dopamine 
> 5 
mcg/kg/min, 
epinephrine ≤ 
0.1 
mcg/kg/min, 
or 
norepinephrine 
≤ 0.1 
mcg/kg/min 
On dopamine 
> 15 
mcg/kg/min, 
epinephrine > 
0.1 
mcg/kg/min, 
or 
norepinephrine 
> 0.1 
mcg/kg/min 
Brain 
    Glascow coma score 
15 
13-14 
10-12 
6-9 
< 6 
Kidney 
    Renal function 
Creatinine 
<1.2 mg/dL  
Creatinine 1.2-
1.9 mg/dL 
Creatinine 2.0-
3.4 mg/dL 
Creatinine 3.5-
4.9 mg/dL 
Creatinine > 5 
mg/dL 
 
The Sequential Organ Failure Assessment (SOFA) score (Vincent et al Critical Care Medicine 1998) is 
composed of scores from six organ systems, graded from 0 to 4 according to the degree of dysfunction or 
failure.  Scores range from 0 (no evidence of organ dysfunction or failure) to 24 (evidence of severe 
dysfunction failure in each of the six organ systems).  The modified non-respiratory SOFA score is 
composed of scores from five of the six organ systems included in the complete SOFA score (excluding 
the respiratory system), graded on the same scale as the complete SOFA score.  Scores range from 0 
(no evidence of organ dysfunction or failure) to 20 (evidence of severe organ dysfunction or failure in 
each of the five organ systems assessed). 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

43 
 
SUPPLEMENTAL REFERENCES 
1  
Panwar R, Hardie M, Bellomo R, et al. Conservative versus Liberal Oxygenation Targets for 
Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit 
Care Med 2016;193:43–51. doi:10.1164/rccm.201505-1019OC 
2  
Asfar P, Schortgen F, Boisramé-Helms J, et al. Hyperoxia and hypertonic saline in patients with 
septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. The Lancet 
Respiratory Medicine Published Online First: February 2017. doi:10.1016/S2213-2600(17)30046-2 
3  
Girardis M, Busani S, Damiani E, et al. Effect of Conservative vs Conventional Oxygen Therapy on 
Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. 
JAMA 2016;316:1583–9. doi:10.1001/jama.2016.11993 
4  
Barrot L, Asfar P, Mauny F, et al. Liberal or Conservative Oxygen Therapy for Acute Respiratory 
Distress Syndrome. N Engl J Med 2020;382:999–1008. doi:10.1056/NEJMoa1916431 
5  
ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials 
Group, Mackle D, Bellomo R, et al. Conservative Oxygen Therapy during Mechanical Ventilation in 
the ICU. N Engl J Med Published Online First: 14 October 2019. doi:10.1056/NEJMoa1903297 
6  
Schjørring OL, Klitgaard TL, Perner A, et al. Lower or Higher Oxygenation Targets for Acute 
Hypoxemic Respiratory Failure. N Engl J Med Published Online First: 20 January 2021. 
doi:10.1056/NEJMoa2032510 
7  
Kraft F, Andel H, Gamper J, et al. Incidence of hyperoxia and related in-hospital mortality in critically 
ill patients: a retrospective data analysis. Acta Anaesthesiol Scand 2018;62:347–56. 
doi:10.1111/aas.13047 
8  
Palmer E, Post B, Klapaukh R, et al. The Association between Supraphysiologic Arterial Oxygen 
Levels and Mortality in Critically Ill Patients. A Multicenter Observational Cohort Study. Am J Respir 
Crit Care Med 2019;200:1373–80. doi:10.1164/rccm.201904-0849OC 
9  
Casey JD, Janz DR, Russell DW, et al. Bag-Mask Ventilation during Tracheal Intubation of Critically 
Ill Adults. N Engl J Med 2019;380:811–21. doi:10.1056/NEJMoa1812405 
10  Brenner M, Stein D, Hu P, et al. Association between early hyperoxia and worse outcomes after 
traumatic brain injury. Arch Surg 2012;147:1042–6. doi:10.1001/archsurg.2012.1560 
11  Stub D, Smith K, Bernard S, et al. Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction. 
Circulation 2015;131:2143–50. doi:10.1161/CIRCULATIONAHA.114.014494 
12  Fessel JP, Flynn CR, Robinson LJ, et al. Hyperoxia synergizes with mutant bone morphogenic 
protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension. Am J 
Respir Cell Mol Biol 2013;49:778–87. doi:10.1165/rcmb.2012-0463OC 
13  Page D, Ablordeppey E, Wessman BT, et al. Emergency department hyperoxia is associated with 
increased mortality in mechanically ventilated patients: a cohort study. Critical Care 2018;22:9. 
doi:10.1186/s13054-017-1926-4 
14  Roberts BW, Kilgannon JH, Hunter BR, et al. Association Between Early Hyperoxia Exposure After 
Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-
Directed Cohort Study. Circulation 2018;137:2114–24. doi:10.1161/CIRCULATIONAHA.117.032054 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

44 
 
15  Kilgannon JH, Jones AE, Shapiro NI, et al. Association between arterial hyperoxia following 
resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010;303:2165–71. 
doi:10.1001/jama.2010.707 
16  Austin MA, Wills KE, Blizzard L, et al. Effect of high flow oxygen on mortality in chronic obstructive 
pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ 2010;341:c5462. 
doi:10.1136/bmj.c5462 
17  Young P, Bailey M, Bellomo R, et al. HyperOxic Therapy OR NormOxic Therapy after out-of-hospital 
cardiac arrest (HOT OR NOT): a randomised controlled feasibility trial. Resuscitation 2014;85:1686–
91. doi:10.1016/j.resuscitation.2014.09.011 
18  Severinghaus JW. Simple, accurate equations for human blood O2 dissociation computations. J Appl 
Physiol Respir Environ Exerc Physiol 1979;46:599–602. 
19  Harris BU, Char DS, Feinstein JA, et al. Accuracy of Pulse Oximeters Intended for Hypoxemic 
Pediatric Patients. Pediatr Crit Care Med 2016;17:315–20. doi:10.1097/PCC.0000000000000660 
20  Buell KG, Casey JD, Wang L, et al. Big Data for Clinical Trials: Automated Collection of SpO2 for a 
Trial of Oxygen Targets during Mechanical Ventilation. Journal of Medical Systems 2020;44:153. 
doi:10.1007/s10916-020-01632-4 
21  Ehrenfeld JM, Funk LM, Van Schalkwyk J, et al. The incidence of hypoxemia during surgery: 
evidence from two institutions. Can J Anaesth 2010;57:888–97. doi:10.1007/s12630-010-9366-5 
22  Lopez MG, Pretorius M, Shotwell MS, et al. The Risk of Oxygen during Cardiac Surgery (ROCS) trial: 
study protocol for a randomized clinical trial. Trials 2017;18:295. doi:10.1186/s13063-017-2021-5 
23  Stollings JL, Foss JJ, Ely EW, et al. Pharmacist leadership in ICU quality improvement: coordinating 
spontaneous awakening and breathing trials. Ann Pharmacother 2015;49:883–91. 
doi:10.1177/1060028015582050 
24  Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning 
protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled 
trial): a randomised controlled trial. Lancet 2008;371:126–34. doi:10.1016/S0140-6736(08)60105-1 
25  Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score 
to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of 
the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707–10. 
26  Elixhauser A, Steiner C, Harris DR, et al. Comorbidity measures for use with administrative data. Med 
Care 1998;36:8–27. 
27  Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 
1974;2:81–4. 
28  ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: 
the Berlin Definition. JAMA 2012;307:2526–33. doi:10.1001/jama.2012.5669 
29  Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation–Sedation Scale. Am J Respir Crit 
Care Med 2002;166:1338–44. doi:10.1164/rccm.2107138 
30  Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the 
Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001;29:1370–
9. 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

45 
 
31  Panwar R, Capellier G, Schmutz N, et al. Current oxygenation practice in ventilated patients-an 
observational cohort study. Anaesth Intensive Care 2013;41:505–14. 
32  Suzuki S, Eastwood GM, Peck L, et al. Current oxygen management in mechanically ventilated 
patients: a prospective observational cohort study. J Crit Care 2013;28:647–54. 
doi:10.1016/j.jcrc.2013.03.010 
33  National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical 
Trials Network, Rice TW, Wheeler AP, et al. Initial trophic vs full enteral feeding in patients with acute 
lung injury: the EDEN randomized trial. JAMA 2012;307:795–803. doi:10.1001/jama.2012.137 
34  Beasley R, Chien J, Douglas J, et al. Thoracic Society of Australia and New Zealand oxygen 
guidelines for acute oxygen use in adults: ‘Swimming between the flags.’ Respirology 2015;20:1182–
91. doi:10.1111/resp.12620 
35  O’Driscoll BR, Howard LS, Earis J, et al. BTS guideline for oxygen use in adults in healthcare and 
emergency settings. Thorax 2017;72:ii1–90. doi:10.1136/thoraxjnl-2016-209729 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

 
1 
DATA AND SAFETY MONITORING BOARD 
CHARTER 
 
 
 
 
 
 
Charter, Data and Safety Monitoring Board for  
“Preliminary Investigation of optimaL Oxygen Targets (PILOT) trial”   
 
Matthew W. Semler MD, MSc 
Li Wang, MS 
Jonathan D. Casey, MD 
Todd W. Rice, MD, MSc 
Wesley H. Self, MD, MPH 
Gordon R. Bernard, MD 
 
 
 
 
 
 
 
 
 
 
 
 
_____________________________________ 
DSMB Member Printed Name 
 
 
_____________________________________ 
_____________________ 
DSMB Member Signature 
 
 
 
Date 
 
 
 
 
 
Confidential Information 
The information contained within this Charter 
is confidential and intended for the use of the 
DSMB members. 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

 
2 
Charter, Data and Safety Monitoring Board for the Preliminary Investigation of optimaL 
Oxygen Targets (PILOT) trial 
 
Version 1.2 
 6/29/2018 
 
 
1. Introduction 
This Charter is for the Data and Safety Monitoring Board (DSMB) for the Preliminary 
Investigation of optimaL Oxygen Targets (PILOT) trial. 
 
The Charter is intended to be a living document. The DSMB and investigators will review it at 
regular intervals to determine whether any changes in procedure are needed. 
 
2. Responsibilities of the DSMB 
The DSMB is responsible for safeguarding the interests of study participants, assessing the 
safety and efficacy of study procedures, and for monitoring the overall conduct of the study. 
 
The DSMB is an independent group advisory to the investigators and affiliated institution, and is 
required to provide recommendations about starting, continuing, and stopping the study. The 
DSMB makes recommendations about: 
• 
Participant safety and risk/benefit ratio of study procedures and interventions, including 
whether new data from other sources affects the study 
• 
Initial approval of the protocol and subsequent amendments (with specific attention to 
study population, intervention, and study procedures) 
• 
Adherence to the protocol requirements 
• 
Completeness, quality, and planned analysis of data  
• 
Ancillary study burden on participants and main study 
 
3. Communication Plan 
 
Communication with DSMB members will be primarily through the DSMB Chair and the primary 
investigator (Dr. Semler) or study biostatistician (Ms. Wang).  Study investigators will not 
communicate about the study with DSMB members outside of DSMB meetings. The primary 
investigator may contact the DSMB Chair when needed for urgent concerns or clarifications of 
recommendations. 
 
4. DSMB Members and Research Staff 
DSMB members and their expertise are listed in Appendix A.  The DSMB Chair will perform the 
functions of the Executive Secretary (ES).  He will draft meeting summaries, compose final 
recommendations, and assure the accurate and timely transmission of the final 
recommendations to the investigators.  The primary investigator (Dr. Semler) will be responsible 
for timely notification of co-investigators of all DSMB recommendations.  Ad hoc members may 
be added to supplement expertise for single or multiple meetings. 
 
5.  Scheduling, Timing, and Organization of Meetings 
DSMB meetings will be held by teleconference.  The purpose of the first meeting is to review 
and discuss this Charter, provide an overview of study activities, review the trial protocol, review 
the DSMB data reporting template, and finalize the Data and Safety Monitoring Plan. Each 
DSMB member will sign and return this Charter to the primary investigator (Dr. Semler) to 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

 
3 
indicate recommendation for approval.  Enrollment in the trial will not begin until the DSMB has 
recommended approval and IRB approval has been obtained. 
 
• 
Meetings by teleconference will be held twice a year, with additional meetings scheduled 
as needed. Conference calls will be scheduled by the primary investigator (Dr. Semler) 
in collaboration with the DSMB members. 
 
• 
A single interim analysis will be performed in the 30 days after data on the primary 
outcome is available for patients enrolled in the first 18 months of the trial. 
  
• 
The DSMB will conclude its operations when all study procedures, follow up, analysis, 
and publication of the primary results have been completed. 
 
The agenda for DSMB meetings will be drafted by the primary investigator (Dr. Semler) and 
study biostatistician (Ms. Wang), and finalized in consultation with the DSMB Chair. The agenda 
and meeting materials will be distributed by the primary investigator (Dr. Semler) or his 
appointee, two (2) weeks before each meeting. The NHLBI Program Office will receive this 
material at the same time as DSMB members.  
 
When the agenda is distributed, DSMB members will be asked to report any new conflicts of 
interest since the last DSMB meeting. New conflicts will be reviewed by the Chair and study 
staff to determine if the conflict limits the ability of the DSMB member to participate in the 
discussion according to conflict of interest policy at the study institution.  
 
To ensure proper trial conduct, at each meeting the DSMB will review the following data:  
• 
adverse events and other safety data,  
• 
quality and completeness of study data, and  
• 
enrollment data 
 
At the single pre-planned interim analysis after 18 months of enrollment, the DSMB will review a 
formal interim analysis for efficacy by the primary endpoint (as outlined below in the stopping 
guidelines). 
 
It is expected that all DSMB members will attend every meeting.  For the purposes of voting on 
recommendations, a quorum is three (3) members of the Board.  All standing Monitoring Board 
members are voting members. The Board may also decide in advance whether ad hoc 
members can vote. 
 
6.  Organization of Meetings 
Meetings are organized into open, closed, and executive sessions. 
 
• 
Open session - information is presented to the DSMB by the study investigators, with 
time for discussion.   
 
• 
Closed session - the DSMB and blinded study staff (NHLBI program staff may be 
invited to attend at the Chair’s discretion) discuss confidential data (any study data 
grouped by treatment arm), including information on efficacy and safety. The DSMB can 
decide to be unblinded to treatment assignments by the study statistician.  The principal 
investigator and staff involved in subject enrollment and treatment may not be present or 
review grouped data.   
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

 
4 
 
• 
Executive session (optional) DSMB members (and NHLBI program staff at the Chair’s 
discretion) may elect to convene to discuss study issues independently. If the executive 
session occurs on a conference call, steps will be taken to ensure that only the 
appropriate participants are on the call, and to invite others to re-join the call only at the 
conclusion of the executive session. 
 
• 
Recommendations (optional) – Meeting attendees may be reconvened to receive the 
DSMB’s recommendations. 
 
At the conclusion of the closed and executive sessions, the participants will be re-convened so 
that the DSMB Chair can provide a summary of the DSMB’s recommendations. This provides 
an opportunity for study investigators to ask questions to clarify the recommendations. The 
meeting is then adjourned. 
 
 
7. Expedited Safety Reporting 
A system has been established to track and report adverse events (AEs). Study personnel will 
monitor the safety of subjects and follow AEs until the event resolves or is explained. 
 
Clinical Outcomes (not considered Adverse Events). In this study of critically ill patients who are 
at high risk for death or other adverse outcomes due to their underlying critical illness, clinical 
outcomes, including death and organ dysfunction, will be systematically tracked (collected in the 
case report form) and will be included as part of the analyses for this study. For the purposes of 
reporting, death and organ dysfunction will not be recorded as AEs unless the investigator 
believes the event may have been caused by the study or is more severe or prolonged than 
expected given the underlying critical illness. Listed below are events that will be tracked as 
primary or secondary clinical outcomes and will not therefore be reported as AEs (unless 
believed to be study related and more severe or prolonged than expected given the underlying 
critical illness): 
 
1. Death (all deaths occurring prior to hospital discharge will be reported on the CRF in the 
vital status at hospital discharge section); 
2. Recurrence of respiratory failure, including need for re-intubation or non-invasive 
mechanical ventilation, presence of acute respiratory distress syndrome, or presence of 
pneumothorax; 
3. Circulatory failure, including cardiac arrest or shock with or without receipt of 
vasopressors; 
4. Incidence of sustained atrial and ventricular arrhythmias; 
5. Acute kidney injury, including leading to increased creatinine or receipt of renal 
replacement therapy; 
6. Hepatic injury or failure leading to increased bilirubin, AST, or ALT; 
7. Coagulation derangements leading to elevated PT/INR or PTT, DIC, thrombocytopenia, 
or thrombocytosis; 
8. Lactic acidosis; 
9. Delirium, disability, and physical or cognitive impairment believed to be newly acquired; 
10. All values for SpO2, SaO2, FiO2, PaO2, or PaO2/FiO2 ratio; 
11. All values for vital signs (e.g., temperature, respiratory rate, SpO2); 
12. Receipt of co-interventions (e.g., net fluid balance, number of arterial blood gasses, red 
cell transfusion) 
13. Duration of ICU admission, ICU readmission; 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

 
5 
14. Duration of hospitalization, hospital readmission; 
15. Alterations in routine labs, including chemistries, complete blood counts, liver function 
tests, and hemostasis profiles. 
 
Adverse Event Classifications. An Adverse Event (AE) will be defined as any untoward medical 
occurrence for a patient enrolled in the trial that is not tracked as a clinical outcome, regardless 
of whether the event is considered study related or not. All AEs occurring during the 
observational study period will be recorded on the CRF. All AEs will then be assessed as to 
whether they are (1) related to study procedures, (2) serious, and/or (3) unexpected according 
to the following definitions: 
 
I. 
Related to study procedures. AEs that the investigator suspects are related to the study 
will be classified as study related. Certainty of relatedness is not required as long as a 
reasonable possibility exists that the AE is related to a study procedure. 
 
II. 
Serious. AEs that meet any of the criteria below will be considered Serious Adverse 
Events (SAEs): 
a. Results in death 
b. Is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event and NOT an event that hypothetically might have caused death if it 
would have been more severe) 
c. Prolongs an existing hospitalization 
d. Results in persistent or significant disability or incapacity 
e. Results in a congenital anomaly or birth defect 
f. Important medical event that requires an intervention to prevent any of a-e above. 
 
III. 
Unexpected. AEs that are more severe or prolonged than expected based on the 
investigator’s discretion will be considered Unexpected.  
 
Communication and Reporting of Adverse Events. AEs will be recorded in the AE CRF in the 
electronic database and reported to the primary investigator (Dr. Semler) within 5 calendar days 
of occurrence. The primary investigator will provide a report of all AEs annually to the IRB, and 
semi-annually to the DSMB as part of the semi-annual DSMB meetings. All SAEs will be 
reported to the primary investigator within 72 hours of occurrence. The primary investigator will, 
in turn, report all SAEs to the IRB, DSMB, and funding body within 7 calendar days of 
occurrence.  Consistent with NHLBI policy, unanticipated problems that do not qualify as an 
SAE will be reported by the investigator to the IRB, DSMB, and NHLBI within 14 calendar days 
of the investigator becoming aware of the problem.  
 
Review by the DSMB.  All AEs will be reviewed by the DSMB at the scheduled semi-annual 
DSMB meetings.  All SAEs will be reviewed by the DSMB Chair within three (3) days of 
notification.  The DSMB Chair will respond to the primary investigator (Dr. Semler) and NHLBI 
program office with recommendations within seven (7) days. 
  
 
8. Reports to the DSMB 
For each meeting, the study biostatistician (Ms. Wang) will prepare summary reports and tables 
to facilitate the oversight role of the DSMB. The DSMB will discuss at the first and subsequent 
meetings what data they wish to review and how it should be presented (Appendix B).  
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

 
6 
9. Reports of DSMB Deliberations 
 
• 
Full Summary and Recommendations: The DSMB Chair/ES is responsible for sending 
the DSMB meeting summary to the Board within seven (7) calendar days of the meeting. 
The summary should be signed by the DSMB Chair and include key topics discussed, 
the response of the investigators to previous recommendations, and the 
recommendations of the DSMB. The study statistician may receive the full summary as 
decided by the DSMB chair on a meeting by meeting basis. 
 
Voting on recommendations will follow Roberts’ Rules of Order (Robert's Rules of 
Order Newly Revised (11th Edition) RONR. 
 
• 
Board Recommendations - signed by the DSMB Chair, will be sent to the investigators 
within fourteen (14) calendar days after the meeting. Recommendations should include a 
statement as to whether the study is approved to continue as planned, should continue 
with specified changes, or should be stopped. Requests for additional data from the 
investigators or DCC/statistician should include an expected due date. In addition to 
recommendations memos issued to investigators (for review and IRB distribution), 
recommendations related to blinded data or data analysis issues may be issued 
separately for DCCs or statisticians. 
 
The recommendations will be distributed by the principal investigator to co-investigators, 
to the local IRB, and to the NHLBI Program Office. 
 
• 
Action plan: This lists the DSMB’s recommendations and the primary investigator’s 
action plan outlining the steps required to implement the DSMB recommendations. It is 
submitted to the NHLBI Program Office and DSMB within fourteen (14) calendar days 
after the DSMB meeting. 
 
10. Statistical Monitoring Guidelines  
In addition to ongoing monitoring of safety throughout the trial, the DSMB will conduct a single 
interim analysis for efficacy and safety at the anticipated halfway point of the trial.  The interim 
analysis will include patients enrolled during the first 18 months of the trial.  The stopping 
boundary for efficacy will be met if the P value for the difference between groups is <0.001 
using a proportional odds mixed effects model accounting for fixed effects (group) and random 
effects (period) with regard to the primary outcome of VFDs.  Use of the conservative Haybittle-
Peto boundary (P < 0.001) will allow the final analysis to be performed using an unchanged 
level of significance (P = 0.05).  There will be no stopping boundary for futility.  The DSMB will 
reserve the right to stop the trial at any point, request additional data or interim analyses, or 
request modifications of the study protocol as required to protect patient safety.  If the 18-month 
interim analysis reveals an enrollment indicative of <80% statistical power at completion, we will 
ask the DSMB to approve extending enrollment of the study to ensure the trial is not 
underpowered to detect the planned difference between groups in the primary outcome. 
 
 
 
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance
Supplemental material
placed on this supplemental material which has been supplied by the author(s)
BMJ Open
 doi: 10.1136/bmjopen-2021-052013
:e052013.
 11
 2021;
BMJ Open
, et al. 
Semler MW

 
 
PILOT Trial Statistical Analysis Plan Revision Sequence 
 
 
 
April 2, 2021  
Original Statistical Analysis Plan completed 
 
April 5, 2021  
Original Statistical Analysis Plan submitted for publication 
 
August 25, 2021 
Statistical Analysis Plan submission completed peer review 
 
August 31, 2021 
Final patient enrolled 
 
October 28, 2021 
Final Statistical Analysis Plan* published: 
 
Semler MW, Casey JD, Lloyd BD, Hastings PG, Hays M, Roth 
M, Stollings J, Brems J, Buell KG, Wang L, Lindsell CJ, 
Freundlich RE, Wanderer JP, Bernard GR, Self WH, Rice TW; 
PILOT Investigators and the Pragmatic Critical Care Research 
Group.  Protocol and statistical analysis plan for the Pragmatic 
Investigation of optimaL Oxygen Targets (PILOT) clinical trial.  
BMJ Open. 2021 Oct 28;11(10):e052013. PMID: 34711597 
 
*No changes to content of the statistical analysis plan occurred between 
submission of the Protocol and Statistical Analysis Plan and its publication.