Pragmatic Trial Examining Oxygenation Prior to Intubation
Phase: NA
Conditions: Acute Respiratory Failure
Sponsor: Vanderbilt University Medical Center

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Supplementary Appendix: 
Study Protocol and Statistical Analysis Plan 
 
 
Trial:  
Pragmatic Trial Examining Oxygenation Prior to Intubation 
(PREOXI) 
 
Manuscript: 
Noninvasive Ventilation for Preoxygenation during Emergency 
Intubation 
 
ClinicalTrials.gov: NCT05267652 
 
Authors:  
Kevin W. Gibbs*; Matthew W. Semler*; Brian E. Driver; Kevin P. 
Seitz; Susan B. Stempek; Caleb Taylor; Daniel Resnick-Ault; Heath 
D. White; Sheetal Gandotra; Kevin C. Doerschug; Amira Mohamed; 
Matthew E. Prekker; Akram Khan; John P. Gaillard; Luke Andrea; 
Neil R. Aggarwal; Jason C. Brainard; LuAnn H. Barnett; Stephen J. 
Halliday; Veronika Blinder; Alon Dagan; Micah R. Whitson; Steven 
G. Schauer; James E. Walker Jr.; Andrew B. Barker; Jessica A. 
Palakshappa; Amelia Muhs; Joanne M. Wozniak; Patrick J. Kramer; 
Cori Withers; Shekhar A. Ghamande; Derek W. Russell; Andrei 
Schwartz; Ari Moskowitz; Sydney J. Hansen; Gopal Allada; Jordan 
K. Goranson; Daniel G. Fein; Peter D. Sottile; Nicholas Kelly; 
Shannon M. Alwood; Micah T. Long; Rishi Malhotra; Nathan I. 
Shapiro; David B. Page; Brit J. Long; Christopher B. Thomas; Stacy 
A Trent; David R. Janz; Todd W. Rice; Wesley H. Self; Vikhyat S. 
Bebarta; Bradley D. Lloyd; Jillian Rhoads; Kelsey Womack; Brant 
Imhoff; Adit A. Ginde**; Jonathan D. Casey**, MD, MSc 2 for the 
PREOXI Investigators and the Pragmatic Critical Care Research 
Group. 
 
This Supplementary Appendix contains the following items: 
1) Initial Trial Protocol -Version 1.0 [dated 2/21/2022] 
2) Final Trial Protocol -Version 1.1 [dated 7/7/2023] 
3) Summary of changes to Trial Protocol 
4) Original Statistical Analysis Plan [posted 3/24/2023] 
5) Final Statistical Analysis Plan [published 9/1/2023] 
6) Summary of changes to Statistical Analysis Plan 
 
 
 

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PRagmatic Trial Examining OXygenation prior to Intubation (PREOXI) 
 
 
 
 
Title 
Pragmatic trial examining oxygenation prior to intubation  
 
Acronym 
PREOXI 
 
Version   
 
Version 1.0 
 
Date 
 
February 21, 2022 
 
Protocol Chairs 
 
Kevin W. Gibbs, MD 
Wake Forest School of Medicine 
 
Jonathan Casey, MD, MSc 
Vanderbilt University Medical Center 
 
Adit A. Ginde, MD, MPH 
University of Colorado School of Medicine 
 
Coordinating Center 
Vanderbilt University Medical Center 
Director: Jonathan D. Casey, MD, MSc 
 
Network 
Pragmatic Critical Care Research Group (PCCRG) 
Steering Committee Chair: Matthew W. Semler MD, MSc  
 
Military Principal 
Investigators 
 
Maj Brit J Long, MD 
US Air Force 59MDW 
 
MAJ Steven Schauer, DO, MS 
US Army Institute of Surgical Research and US Air Force 59MDW 
 
Civilian Principal 
Investigators 
Adit A. Ginde, MD, MPH 
University of Colorado School of Medicine 
 
Jonathan Casey, MD, MSc 
Vanderbilt University Medical Center 
 
 
Funding 
US Department of Defense 
 
 
 
 
 

 
 
 
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Table of Contents 
1. TRIAL SUMMARY ........................................................................................................................... 4 
2. TRIAL DESCRIPTION ..................................................................................................................... 7 
2.1 BACKGROUND....................................................................................................................................... 7 
2.1.1 Hypoxemia during Intubation of Critically Ill Patients ............................................................................ 7 
2.1.2 Role of Preoxygenation in Preventing Hypoxemia during Intubation ..................................................... 7 
2.1.3 Preoxygenation with Non-Invasive Positive Pressure Ventilation ........................................................... 7 
2.1.4 Preoxygenation with Facemask Oxygen ................................................................................................... 8 
2.1.5 Potential Advantages of Preoxygenation with Non-Invasive Positive Pressure Ventilation or 
Preoxygenation with Facemask Oxygen ............................................................................................................ 8 
2.1.6 Prior Evidence from Clinical Trials. ......................................................................................................... 9 
2.2. PRIMARY AIM AND HYPOTHESIS ........................................................................................................ 10 
2.2.1 Study Aim: ................................................................................................................................................ 10 
2.2.2 Study Hypothesis: ..................................................................................................................................... 10 
2.3 STUDY DESCRIPTION .......................................................................................................................... 10 
3. STUDY POPULATION AND ENROLLMENT .............................................................................. 10 
3.1 INCLUSION CRITERIA: ......................................................................................................................... 10 
3.2 EXCLUSION CRITERIA: ........................................................................................................................ 10 
4. CONSENT ........................................................................................................................................ 10 
4.1 PROVISION OF INFORMATION AFTER PARTICIPATION .................................................................... 12 
5. ENROLLMENT AND RANDOMIZATION ................................................................................... 12 
5.1 STUDY ENROLLMENT LOCATIONS: .................................................................................................. 12 
5.3 ENROLLMENT AND RANDOMIZATION............................................................................................... 12 
5.3.1 Pre-Procedural Time-Out to Prevent Enrollment of Ineligible Patients ................................................ 13 
5.3.2 Monitoring and Reporting of Eligibility of Enrolled Patients ................................................................ 13 
5.3.3 Handling of Patients Found to Be Prisoners after Enrollment .............................................................. 13 
6. BLINDING ....................................................................................................................................... 14 
7. STUDY INTERVENTIONS ............................................................................................................. 14 
7.1 TREATMENT OF STUDY PATIENTS .................................................................................................... 14 
7.2 PREOXYGENATION WITH NON-INVASIVE POSITIVE PRESSURE VENTILATION GROUP .................. 14 
7.3 PREOXYGENATION WITH FACEMASK OXYGEN GROUP ................................................................... 14 
8. RECORDED STUDY OUTCOMES ................................................................................................ 15 
8.1 PRIMARY OUTCOMES ........................................................................................................................ 15 
8.2 SECONDARY OUTCOMES ................................................................................................................... 15 
8.3 SAFETY OUTCOMES........................................................................................................................... 15 
8. 4 EXPLORATORY OUTCOMES ............................................................................................................. 15 
9. DATA COLLECTION ..................................................................................................................... 15 
10. RISKS AND BENEFITS ................................................................................................................ 18 
10.1 RISKS OF TRACHEAL INTUBATION IN THE ED OR ICU ...................................................................... 18 

 
 
 
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10.2 POTENTIAL RISKS OF PARTICIPATION IN THE PREOXI TRIAL .......................................................... 18 
10.3 POTENTIAL BENEFITS OF PARTICIPATION IN THE PREOXI TRIAL .................................................... 19 
10.4 MINIMIZATION OF RISK .................................................................................................................... 19 
11. STATISTICAL CONSIDERATIONS ............................................................................................ 19 
11.1 INITIAL SAMPLE SIZE DETERMINATION: ........................................................................................... 19 
11.2 STATISTICAL ANALYSIS: ................................................................................................................... 20 
11.2.1 Primary Analysis: ................................................................................................................................... 20 
11.2.2 Secondary Analysis: ............................................................................................................................... 20 
11.2.3 EFFECT MODIFICATION (SUBGROUP ANALYSES) ...................................................................................... 20 
11.3 INTERIM ANALYSIS ................................................................................................................................ 21 
11.4 CORRECTION FOR MULTIPLE TESTING ....................................................................................................... 21 
11.5 HANDLING OF MISSING DATA ................................................................................................................. 21 
12. PRIVACY AND CONFIDENTIALITY ......................................................................................... 21 
13. FOLLOW-UP AND RECORD RETENTION ............................................................................... 22 
14. SAFETY MONITORING AND ADVERSE EVENTS .................................................................. 22 
14.1 ADVERSE EVENT DEFINITIONS ......................................................................................................... 22 
14.2 MONITORING FOR ADVERSE EVENTS ................................................................................................ 23 
14.3 RECORDING AND REPORTING ADVERSE EVENTS .............................................................................. 24 
14.4 CLINICAL OUTCOMES THAT MAY BE EXEMPT FROM ADVERSE EVENT RECORDING AND REPORTING 25 
14.5 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS ........................................ 26 
15. DATA AND SAFETY MONITORING BOARD (DSMB) ............................................................. 26 
REFERENCES ..................................................................................................................................... 28 
 
 
 

 
 
 
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1. TRIAL SUMMARY 
 
Title 
Pragmatic Trial Examining Oxygenation prior to Intubation (PREOXI) 
Background 
Clinicians perform rapid sequence induction, laryngoscopy, and tracheal 
intubation for more than 5 million critically ill adults as a part of clinical 
care each year in the United States.  One-in-ten emergency tracheal 
intubations is complicated by life-threatening hypoxemia.  Administering 
supplemental oxygen prior to induction and intubation (“preoxygenation”) 
decreases the risk of life-threatening hypoxemia. In current clinical 
practice, the most common methods for preoxygenation are non-invasive 
positive pressure ventilation and facemask oxygen.  Prior trials comparing 
non-invasive positive pressure ventilation and facemask oxygen for 
preoxygenation have been small and have yielded conflicting results.  A 
better understanding of the comparative effectiveness of these two 
common, standard-of-care approaches to preoxygenation could improve 
the care clinicians deliver and patient outcomes. 
Study Design 
Multicenter, pragmatic, non-blinded, parallel-group, randomized trial 
Treatment Groups 
 
• Non-invasive positive pressure ventilation group: Patients will receive 
preoxygenation with non-invasive mechanical ventilation via a tight-
fitting mask.   
• Facemask oxygen group: Patients will receive preoxygenation via either 
a non-rebreather mask or a compressed bag-mask device without manual 
ventilation.  
Sample Size 
1,300 patients 
Inclusion Criteria 
1. Patient is located in a participating unit 
2. Planned procedure is tracheal intubation using a laryngoscope and 
sedation 
3. Planned operator is a clinician expected to routinely perform tracheal 
intubation in the participating unit. 
Exclusion Criteria 
1. Patient is receiving positive pressure ventilation by a mechanical 
ventilator, bag-mask device, or laryngeal mask airway 
2. Patient is known to be less than 18 years old 
3. Patient is known to be pregnant 
4. Patient is known to be a prisoner 
5. Immediate need for tracheal intubation precludes safe performance of 
study procedures 
6. Patient is apneic, hypopneic, or has another condition requiring 
positive pressure ventilation between enrollment and induction 
7. Operator has determined that preoxygenation with non-invasive 
positive pressure ventilation or preoxygenation with facemask oxygen 
is required or contraindicated for optimal care of the patient 
Risks 
Participation in this study involves minimal incremental risk because: 
• All patients eligible for the study are already undergoing tracheal 
intubation with preoxygenation as part of their clinical care 

 
 
 
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• Preoxygenation with non-invasive positive pressure ventilation 
and preoxygenation with facemask oxygen are the most common 
approaches to preoxygenation of critically ill adults in clinical care 
• No benefits or risks are currently known to differ between the two 
approaches 
• If clinicians determine either approach to be required or 
contraindicated for the optimal care of an individual patient, the 
patient is excluded from the study 
Benefits 
The benefits of the PREOXI trial are largely the indirect benefits to future 
patients that will result by a better understanding of whether 
preoxygenation with non-invasive positive pressure ventilation or pre-
oxygenation with facemask oxygen prevents complications during 
tracheal intubation of critically ill adults. 
Consent 
The trial will be conducted with waiver of informed consent because: 
• Participation in the study involves minimal incremental risk 
• Obtaining informed consent prior to emergency tracheal intubation 
of critically ill adults is impracticable 
Randomization 
 
Eligible patients will be randomized 1:1 to preoxygenation with non-
invasive positive pressure ventilation or pre-oxygenation with facemask 
oxygen.  Randomization will be completed in permuted blocks of variable 
size and stratified by site. 
Blinding 
Study group assignment will remain concealed to study personnel and 
clinicians until after the decision has been made to enroll the patient in the 
study. Following enrollment, the trial will not blind patients or clinicians 
to study group assignment. 
Primary Outcome  
Hypoxemia: Oxygen saturation <85% from induction to 2 minutes after 
tracheal intubation 
Secondary Outcome 
Lowest oxygen saturation from induction to 2 minutes after tracheal 
intubation 
Safety Outcomes 
• Operator-reported aspiration 
• Fraction of inspired oxygen at 24 hours after induction 
• Oxygen saturation at 24 hours after induction 
• Radiology report of new pneumothorax on chest x-ray in the 24 hours 
after induction 
Exploratory Outcomes 
• Procedural characteristics & complications 
o Severe hypoxemia (lowest oxygen saturation of <80%) between 
induction and two minutes after tracheal intubation 
o Very severe hypoxemia (lowest oxygen saturation of <70%) 
between induction and two minutes after tracheal intubation 
o Oxygen saturation at induction 
o Systolic blood pressure at induction 
o Duration from induction to successful intubation 
o Cormack-Lehane grade of glottic view on first attempt 
o Number of laryngoscopy attempts 

 
 
 
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o Number of attempts at passing bougie 
o Number of attempts at passing endotracheal tube 
o Cardiovascular collapse, defined as a composite of one or more of 
the following between induction and 2 minutes after intubation: 
1. Systolic blood pressure < 65 mmHg  
2. New or increased vasopressor  
3. Cardiac arrest not resulting in death  
4. Cardiac arrest resulting in death 
• Clinical Outcomes 
o 28-day in-hospital mortality 
o Ventilator-free days to 28 days 
o ICU-free days to 28 days 
Analysis 
The primary analysis will be an unadjusted, intention-to-treat comparison 
of patients randomized to preoxygenation with non-invasive positive 
pressure ventilation versus patients randomized to preoxygenation with 
facemask oxygen with regard to the primary outcome. The difference 
between the two study groups will be compared using a Chi-squared test.  
Sample Size 
We will plan to enroll 1300 patients, which we estimate will provide 85% 
power at a two-sided alpha level of 0.05 to detect a 6% absolute 
difference in the incidence of the primary outcome, assuming an 
incidence of hypoxemia of 17% in the facemask group and missing data 
on the primary outcome for up to 3% of patients. 
Expected Duration 
18 months 
 
 

 
 
 
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2. TRIAL DESCRIPTION 
 
2.1 Background 
Clinicians frequently perform tracheal intubation of critically ill patients in the emergency 
department (ED) or intensive care unit (ICU).  Complications of intubation, including hypoxemia 
and cardiovascular instability, occur in nearly half of intubations performed in these settings (1, 
2, 4, 5).   Preventing complications during tracheal intubation is a key focus of clinical care and 
airway management research (4, 6, 7). 
 
 
2.1.1 Hypoxemia during Intubation of Critically Ill Patients 
Life-threatening hypoxemia occurs in 1-in-10 cases of emergency tracheal intubation.(8) Severe 
hypoxemia during intubation is associated with increased risk of cardiac arrest and death.(9, 10) 
Severe hypoxemia may be associated with worse outcomes in survivors.  For example, 
neurologic recovery from traumatic brain injury may be worse after hypoxemia due to secondary 
ischemic insult.(11)  
 
2.1.2 Role of Preoxygenation in Preventing Hypoxemia during Intubation  
In current clinical practice, emergency tracheal intubation involves the nearly simultaneous 
administration of a sedative agent and a neuromuscular blocking agent to optimize the anatomic 
conditions for intubation.  Following medication administration, patients rapidly become 
hypopneic and then apneic until invasive mechanical ventilation is initiated through the newly-
placed endotracheal tube.  The oxygen contained in the lungs at the time of neuromuscular 
blockade (i.e., the patient’s functional residual capacity) is the reservoir of oxygen available to 
the patient’s body to prevent hypoxemia and tissue hypoxia during the intubation procedure.  For 
a patient breathing ambient air (i.e., room air), only 21% of the gas in the functional residual 
capacity is oxygen; 78% is nitrogen.  Administering 100% oxygen to a patient prior to induction 
of anesthesia and tracheal intubation, referred to as “preoxygenation,” can replace the nitrogen in 
the lung with oxygen, increasing up to five-fold the reservoir of oxygen available to the body 
during the procedure and prolonging the period during which intubation can be performed safely 
without encountering hypoxemia.  In current clinical practice, the two most common methods of 
providing preoxygenation are:  
1. Non-invasive positive pressure ventilation - a tight-fitting mask connected to either an 
invasive ventilator or non-invasive mechanical ventilator. 
2. Facemask oxygen - with either a non-rebreather mask or a bag-mask device. 
2.1.3 Preoxygenation with Non-Invasive Positive Pressure Ventilation 
Preoxygenation with non-invasive positive pressure ventilation is common during emergency 
tracheal intubation of critically ill adults in current clinical practice.  During preoxygenation with 
non-invasive positive pressure ventilation, a tight-fitting mask is connected to a machine capable 
of providing positive pressure ventilation. Non-invasive positive pressure ventilation delivers up 
to 95-100% oxygen and can be provided by either a conventional invasive mechanical ventilator 
or a dedicated non-invasive ventilation machine, commonly referred to as a Bilevel Positive 
Airway Pressure (BiPAP) machine.  In addition to providing high concentrations of oxygen, non-
invasive positive pressure ventilation increases mean airway pressure and delivers breaths at a 
set rate during the period of hyponea/apnea after induction. Because a mechanical ventilator is 
always required following intubation of a critically ill adult, no specialized equipment is required 

 
 
 
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to use non-invasive positive pressure ventilation for preoxygenation of critically ill adults 
undergoing tracheal intubation.  
2.1.4 Preoxygenation with Facemask Oxygen 
In current clinical practice, preoxygenation with facemask oxygen is commonly performed using 
one of the following two types of facemask: [1] a non-rebreather mask or [2] a bag-mask device 
(8, 12).  Both a types of facemask (a non-rebreather and a compressed bag-mask device) deliver 
supplemental oxygen without increasing airway pressures or providing assistance with 
ventilation.   
• A non-rebreather mask is a type of facemask with a loose-fitting mask that sits over a 
patient’s nose and mouth and is connected to an oxygen reservoir. It delivers at least 15 
liters per minute of 100% oxygen, but it may not reliably deliver flows of oxygen greater 
than 15 liters per minute and may allow entrainment of ambient air. Studies show that the 
while the oxygen content for healthy and calm volunteers may approach 100%, the 
oxygen content received by critically ill patients with tachypnea may be as low as 
50%.(14)  It does not provide positive pressure. 
• A bag mask device is a type of facemask with a mask that forms a tight seal over the 
mouth and nose when held in place by the operator, an exhalation port, and a self-
inflating bag that serves as a reservoir for oxygen and can be compressed to provide 
positive pressure ventilation.(13) If the bag of this device is compressed, this device 
delivers oxygen without providing positive pressure ventilation and can deliver more than 
90% oxygen with an ideal mask seal. However, in the setting of emergency intubation 
leaks may result in the entrainment of ambient air and reduced oxygen delivery.      
2.1.5 Potential Advantages of Preoxygenation with Non-Invasive Positive Pressure 
Ventilation or Preoxygenation with Facemask Oxygen 
 
Preoxygenation with non-invasive positive pressure ventilation has been proposed to offer the 
following potential advantages compared to preoxygenation with facemask oxygen: 
• Entrainment of ambient air: The tight-fitting mask used to deliver non-invasive 
ventilation entrains less ambient air than a non-rebreather or bag-mask device. The higher 
flow rates of oxygen gas with non-invasive ventilation may also help prevent entrainment 
of ambient air and increase the fraction of inspired oxygen. (15) 
• Atelectasis and alveolar recruitment: Preoxygenation and induction of anesthesia rapidly 
results in the development of atelectasis in both healthy patients and critically ill 
patients.(16) This atelectasis increases shunt fraction and increases the risk of peri-
procedural hypoxia.  By delivering positive pressure during both inspiration and 
expiration, non-invasive ventilation raises mean airway pressure, recruiting alveoli and 
preventing the development of atelectasis.  
• Hypopnea and Apnea. Administration of sedation and neuromuscular blocking agents 
reduces or eliminates spontaneous respiratory effort.  This hypoventilation leads to 
accumulation of alveolar carbon dioxide and reductions in alveolar oxygen, contributing 
to hypoxemia.  Use of non-invasive ventilation before induction and between induction 
and laryngoscopy provides continuous oxygen to the alveoli, increases the size of breaths 
taken in the setting of hypopnea, and delivers controlled breaths when patients are apneic.   
 

 
 
 
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Preoxygenation with facemask oxygen (via a non-rebreather or compressed bag-mask device) 
has been proposed to offer the following potential advantages compared with preoxygenation 
with non-invasive positive pressure ventilation: 
Simplicity of use: Preoxygenation with facemask oxygen (using either a non-rebreather or 
compressed bag-mask device) is simpler to set up than non-invasive positive pressure 
ventilation.   
Low risk of gastric insufflation: Although no clinical evidence exist to suggest that 
preoxygenation with non-invasive positive pressure ventilation increases the risk of 
gastric insufflation or aspiration of gastric contents,(19) use of facemask oxygen (without 
any positive pressure) avoids this hypothetical concern.   
 
2.1.6 Prior Evidence from Clinical Trials. 
Two small clinical trials have compared preoxygenation with non-invasive ventilation to 
preoxygenation with facemask oxygen during the tracheal intubation of critically ill adults.(20, 
21) The first trial compared non-invasive ventilation to a facemask among 53 critically ill ICU 
patients in two hospitals and found that non-invasive ventilation increased the lowest oxygen 
saturation (93% vs. 81%, p<0.001) with no difference in incidence of aspiration (6% vs. 8%). 
The second trial compared non-invasive ventilation to a facemask oyxgen with regard to severity 
of illness in the 7 days after intubation among 201 critically ill ICU patients.  This trial found no 
significant difference in the severity of illness between groups and no significant difference in 
the rate of severe hypoxemia (18.4% vs 27.7%, p=0.10). This trial did not have adequate 
statistical power to detect clinically important differences between groups in the risk of 
hypoxemia.  No large, multicenter trials have compared preoxygenation with non-invasive 
positive pressure ventilation to preoxygenation with facemask oxygen for critically ill adults 
undergoing tracheal intubation.  Based on the available data from these small randomized 
clinical trials, preoxygenation with non-invasive positive pressure ventilation and 
preoxygenation with facemask oxygen both represent acceptable approaches to emergency 
tracheal intubation.  Both approaches are considered standard-of-care and are used commonly in 
current clinical practice. 
 
 
2.1.7 Rationale for a Large Multicenter Trial of Preoxygenation 
Because of the imperative to optimize emergency tracheal intubation in clinical care, the 
common use of both preoxygenation with non-invasive positive pressure ventilation and 
preoxygenation with facemask oxygen in current clinical practice, and the lack of existing data 
from randomized trials to definitively inform whether preoxygenation strategy effects the rate of 
hypoxemia, examining the approach to preoxygenation during emergency tracheal intubation 
represents an urgent research priority.  To address this knowledge gap, we propose to conduct a 
large, multicenter, randomized clinical trial comparing preoxygenation with non-invasive 
positive pressure ventilation versus preoxygenation with facemask oxygen with regard to 
hypoxemic during tracheal intubation of critically ill adults in the ED or ICU. 
 
 
 
 

 
 
 
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2.2. Primary Aim and Hypothesis 
 
2.2.1 Study Aim: 
To compare the effect of preoxygenation with non-invasive positive pressure ventilation versus 
preoxygenation with facemask oxygen on hypoxemia during tracheal intubation of critically ill 
adults. 
 
2.2.2 Study Hypothesis: 
Among critically ill adults undergoing tracheal intubation, preoxygenation with non-invasive 
positive pressure ventilation will reduce the incidence of hypoxemia between induction to 2 
minutes after tracheal intubation, compared to preoxygenation with facemask oxygen. 
 
2.3 Study Description 
We will conduct an investigator-initiated, non-blinded, pragmatic, parallel-group, randomized 
trial evaluating the effect of preoxygenation with non-invasive ventilation versus preoxygenation 
with a facemask on the incidence of hypoxemia among critically ill adults undergoing tracheal 
intubation in the ED and ICU. 
 
3. STUDY POPULATION AND ENROLLMENT 
 
3.1 Inclusion Criteria: 
1. Patient is located in a participating unit 
2. Planned procedure is tracheal intubation using a laryngoscope and sedation 
3. Planned operator is a clinician expected to routinely perform tracheal intubation in the 
participating unit. 
 
3.2 Exclusion Criteria: 
1. Patient is receiving positive pressure ventilation by a mechanical ventilator, bag-mask 
device, or laryngeal mask airway 
2. Patient is known to be less than 18 years old 
3. Patient is known to be pregnant 
4. Patient is known to be a prisoner 
5. Immediate need for tracheal intubation precludes safe performance of study procedures 
6. Patient is apneic, hypopneic, or has another condition requiring positive pressure 
ventilation between enrollment and induction 
7. Operator has determined that preoxygenation with non-invasive positive pressure 
ventilation or preoxygenation with a facemask is required or contraindicated for optimal 
care of the patient 
 
4. CONSENT 
Non-invasive positive pressure ventilation and facemask oxygen are both common approaches to 
preoxygenation during emergency tracheal intubation in the ED and ICU.  Both represent 
standard of care treatments in current clinical practice.(8, 22)  Results from prior clinical trials 
are conflicting and to not demonstrate superiority of one approach over the other. Consequently, 
some guidelines recommend non-invasive positive pressure ventilation and other guidelines 
recommend facemask oxygen.(23-26)  As a result, significant variation exists in the approach to 

 
 
 
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preoxygenation in current clinical practice, with both non-invasive positive pressure ventilation 
and facemask oxygen used commonly.(8, 27, 28).  This trial will enroll patients who are 
undergoing emergency tracheal intubation as part of their clinical care for whom treating 
clinicians have determined that preoxygenation with EITHER non-invasive positive pressure 
ventilation OR facemask oxygen would be consistent with the optimal care of the patient. 
 
We will request a waiver of informed consent because the study involves minimal incremental 
risk and obtaining informed consent would be impracticable. 
 
Participation in this study involves minimal incremental risk because: 
• All patients eligible for the study are already undergoing tracheal intubation with 
preoxygenation as part of their clinical care 
• Preoxygenation with non-invasive positive pressure ventilation and preoxygenation with 
facemask oxygen are both standard-of-care interventions that are commonly used in 
current clinical care 
• No benefits or risks are currently known to differ between the two approaches 
• Both approaches have determined to be acceptable options for the optimal care of the 
patient by treating clinicians (otherwise the patient is excluded from the study) 
  
Obtaining informed consent would be impracticable because:  
• The expected medical condition of  patients requiring emergency tracheal 
intubation in the ED or ICU is critical.  Based on prior trials in the same patient 
population and setting, approximately 70% of patients eligible for the PREOXI trial will 
be experiencing encephalopathy (altered mental status) due to their critical illness. The 
anticipated median Glasgow coma scale score is 11 (equivalent to moderate brain injury).  
Among the minority of patients whose level of consciousness is not impaired, 45-55% 
will be experiencing acute delirium.  Thus, most patients eligible for PREOXI will not 
have the capacity to provide informed consent.  Further, family members or legally 
authorized representatives (LAR) are frequently unavailable when critically ill patients 
undergo intubation in the ED or ICU.   
• The time available for patients or LARs to consider participation will be 
insufficient.  Even when a patient retains capacity or a LAR is immediately available, a 
meaningful informed consent process is precluded by the rapid clinical events leading up 
to emergency tracheal intubation. No published literature has quantified the time from 
clinicians’ decision to perform emergency tracheal intubation (the inclusion criteria for 
PREOXI) until the initiation of the intubation procedure (completion of the PREOXI 
intervention). In a convenience sample of 25 consecutive intubations in the VUMC ED or 
ICU, approximately 50% of intubations occurred within 5 minutes after treating 
clinicians verbalized the decision to intubate or ordered an induction medication.  
Obtaining informed consent for research requires study personnel to assess decisional 
capacity, identify a LAR when appropriate, review the informed consent document in a 
quiet setting, and provide sufficient time for the patient or LAR to process the 
information, assess the risks and benefits of participation, and ask questions.  Meaningful 
informed consent cannot be executed in the 5 minutes between the decision to perform 
emergency tracheal intubation and initiation of the procedure.  Emergency tracheal 
intubation of critically ill adults is a time-sensitive procedure for which every minute of 

 
 
 
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delay increases the likelihood of hypoxemia, hypotension, and peri-procedural cardiac 
arrest.  Delaying emergency tracheal intubation for a critically ill adult to attempt a 
meaningful informed consent process would be unsafe, impracticable, and unethical. 
 
Because the study involves minimal incremental risk, the study would not adversely affect the 
welfare or privacy rights of the participant, and obtaining informed consent would be 
impracticable, we will request a waiver of informed consent.  Numerous previous randomized 
trials comparing two standards of care for emergency intubation have been completed under a 
waiver of informed consent [NCT 0040102, NCT 03928925, NCT 02497729, NCT 02051816, 
NCT 00441792].(7, 29-32) 
 
4.1 Provision of Information after Participation 
Information regarding the study will be made available to each patient and family following 
intubation using a patient and family information sheet.  The sheet will inform the patient of his 
or her enrollment in the PREOXI study, describe the study, and provide contact information for 
the research team for any questions or concerns. 
  
 
5. ENROLLMENT AND RANDOMIZATION 
 
5.1 Study Enrollment Locations:  
• Participating emergency departments 
• Participating intensive care units 
 
5.2 Study Sites: 
• Vanderbilt University Medical Center 
• Other locations  
 
5.3 Enrollment and Randomization 
All patients requiring emergency tracheal intubation in a participating ED or ICU will be 
screened for eligibility for the PREOXI trial using the eligibility criteria in Section 3. Patients 
who do not meet inclusion criteria will be considered ‘ineligible’. Patients who meet inclusion 
criteria but also meet at least one exclusion criterion will be considered ‘excluded.’  For patients 
who are excluded, the reason for exclusion will be recorded.  For patients who do meet eligibility 
criteria but are not enrolled, the reason will be recorded.   
 
At enrollment, patients will be randomized in a 1:1 ratio to preoxygenation with non-invasive 
positive pressure ventilation or preoxygenation with facemask oxygen using randomly permuted 
blocks of variable size.  The randomization will be stratified by study site (i.e., each participating 
ED or ICU will comprise a different stratum).  The study group assignment will be placed in in 
opaque randomization envelopes, which will be located within participating units. Study group 
assignment will remain concealed to study personnel and treating clinicians until after the 
decision has been made to enroll the patient in the study.  
 
To facilitate rapid enrollment during this time-sensitive procedure, sequentially numbered 
randomization envelopes will be located adjacent to the equipment required for emergency 

 
 
 
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tracheal intubation (i.e., airway equipment cart, ICU work room).  When the need for emergency 
tracheal intubation is recognized, envelopes will be obtained by the treating clinician performing 
the intubation (referred to as the “operator”) or by a delegate while the operator sets up the 
equipment required for intubation.  Inclusion and exclusion criteria will be posted with 
randomization envelopes and printed on the outside of enrollment envelopes.  As the operator 
sets up the equipment for emergency tracheal intubation, a verbal “pre-procedural time-out” 
(described below) will be performed. Based on the experience from our 8 prior randomized 
clinical trials using the same process to perform randomization and group assignment during 
emergency tracheal intubation, all enrollment procedures can be completed in less than one 
minute. For a small number of particularly urgent intubations (e.g., an intubation for cardiac 
arrest), the urgency of the procedure or the limited availability of clinical personnel will preclude 
obtaining and opening the randomization envelope. These cases will be excluded using the 
exclusion criterion that states “Immediate need for tracheal intubation precludes safe 
performance of study procedures” (see Section 3). 
 
As with all trials conducted to date by our investigators, we will evaluate for the possibility of 
selection bias via the systematic exclusion of a particular groups of patients.  A prospective list 
of excluded patients will be maintained by site PIs.  Data captured on excluded patients will be 
limited to date of exclusion and reason for exclusion. The number of patients excluded and 
reasons for excluded will be reported at the time of trial publication via a consort diagram.  No 
patient-level information on excluded patients will be entered into the study database.  The 
coordinating center will not receive any patient-level data on excluded participants. 
 
5.3.1 Pre-Procedural Time-Out to Prevent Enrollment of Ineligible Patients 
The enrollment materials for the trial will include instructions for a pre-procedural timeout in 
which treating clinicians or a delegate recite aloud the inclusion and exclusion criteria and 
confirm eligibility prior to enrollment. This process requires less than 10 seconds and can be 
easily completed while the equipment and medications needed for tracheal intubation are being 
obtained. This approach has been successfully used to confirm eligibility prior to enrollment in 
multiple prior trials [NCT03928925, NCT03787732]. (33) 
 
5.3.2 Monitoring and Reporting of Eligibility of Enrolled Patients 
For all enrolled patients, study personnel will independently verify eligibility criteria at the time 
of study record creation.  In the instance that a patient is enrolled who did not meet eligibility 
criteria, this will represent a protocol violation.  Site investigators will report such a protocol 
violation to the trial primary investigators and coordinating center within 24 hours of becoming 
aware of the occurrence of a protocol violation.  The primary investigators and coordinating 
center will report the details of such a protocol violation to the IRB within 7 days of becoming 
aware of the occurrence of a protocol violation. 
 
5.3.3 Handling of Patients Found to Be Prisoners after Enrollment 
Prisoners typically present with obvious physical signs such as prison uniforms, handcuffs, and 
the presence of law enforcement.  Training of treating clinicians and the enrollment procedures 
listed above (posting of inclusion and exclusion criteria alongside enrollment envelopes and a 
“pre-enrollment time-out” with verbal recitation of eligibility criteria) have proven to be 
effective in preventing the enrollment of prisoners in recent trials. 

 
 
 
14 
 
 
If a patient who presents to the ED or ICU is not known to be a prisoner at the time of enrollment 
and following enrollment is discovered to be a prisoner or becomes a prisoner between 
enrollment and the end of study follow up, all study procedures will stop immediately, the 
patient will be withdrawn from the study, and the patient’s study record will be expunged of all 
study data.  Because both study interventions are one-time, standard-of-care interventions which 
the patient was likely to receive in clinical care even if not participating in research, no further 
follow-up will occur. 
 
6. BLINDING 
Given the nature of the trial intervention, blinding of patients and treating clinicians to study 
group assignment is not possible.  
 
7. STUDY INTERVENTIONS 
 
7.1 Treatment of Study Patients 
For enrolled patients, study group assignment determines only the approach to preoxygenation.  
All other aspects of the intubation procedure will be at the discretion of the operator, including 
patient positioning, choice of sedative agent, use of a neuromuscular blocker, choice of 
laryngoscope, laryngoscope blade size, use of a bougie to intubate the trachea, use of external 
laryngeal manipulation to optimize laryngeal view, and endotracheal tube diameter.   
 
The administration of additional supplemental oxygen by nasal cannula is not controlled by the 
study and is permitted in both groups in any phase of the tracheal intubation procedure, including 
during laryngoscopy (referred to as “apneic oxygenation”).  The administration of ventilation via 
a bag-mask device will be permitted in both groups between induction and laryngoscopy.  
Operators may use a non-assigned approach to preoxygenation at any time if it is felt to be 
required for the safe management of the patient.  Use of a non-assigned preoxygenation strategy 
as the initial approach to preoxygenation will be collected and considered to represent a 
“crossover.”  For all patients in the trial, best practices in emergency tracheal intubation will be 
encouraged according to clinical protocols in the study settings.   
 
7.2 Preoxygenation with Non-Invasive Positive Pressure Ventilation Group 
Patients assigned to preoxygenation with non-invasive positive pressure ventilation will receive 
non-invasive mechanical ventilation via a tight-fitting mask from the initiation of preoxygenation 
until the initiation of laryngoscopy.  Trial protocol will not dictate the brand or type of 
mechanical ventilator that will be used to deliver non-invasive ventilation.    
 
7.3 Preoxygenation with Facemask Oxygen Group 
For patients randomized to preoxygenation with facemask oxygen, supplemental oxygen will be 
administered via a non-rebreather mask or bag-mask device without manual ventilation from the 
initiation of preoxygenation until induction.  Trial protocol will not dictate the brand or type of 
facemask. The decision between use of a non-rebreather mask and use of a bag-mask device will 
be made by treating clinicians.  The decision of whether to provide manual ventilation with a 
bag-mask device between induction and laryngoscopy will be made by treating clinicians.  
 

 
 
 
15 
 
 
8. RECORDED STUDY OUTCOMES 
 
8.1 Primary Outcomes  
• Hypoxemia, defined as a peripheral oxygen saturation < 85% during the interval between 
induction and 2 minutes after tracheal intubation 
 
8.2 Secondary Outcomes 
• Lowest oxygen saturation during the interval between induction and 2 minutes after 
tracheal intubation 
 
8.3 Safety Outcomes  
• Operator-reported aspiration 
• Fraction of inspired oxygen at 24 hours after induction 
• Oxygen saturation at 24 hours after induction 
• Radiology report of new pneumothorax on chest x-ray in the 24 hours after induction 
 
8. 4 Exploratory Outcomes 
• Procedural Characteristics & Complications 
o 
Severe hypoxemia (lowest oxygen saturation of <80%) between induction and two 
minutes after tracheal intubation 
o 
Very severe hypoxemia (lowest oxygen saturation of <70%) between induction and 
two minutes after tracheal intubation 
o 
Oxygen saturation at induction 
o 
Systolic blood pressure at induction 
o 
Duration from induction to successful intubation (duration of the intubation 
procedure) 
o 
Cormack-Lehane grade of glottic view on first attempt 
o 
Number of laryngoscopy attempts 
o 
Number of attempts at passing a bougie 
o 
Number of attempts at passing an endotracheal tube 
o 
Cardiovascular collapse, defined as a composite of one or more of the following 
between induction and 2 minutes after intubation: 
1. 
Systolic blood pressure < 65 mmHg  
2. 
New or increased vasopressor  
3. 
Cardiac arrest not resulting in death within 1 hour of induction 
4. 
Cardiac arrest resulting in death within 1 hour of induction 
• Clinical Outcomes 
o 
28-day in-hospital mortality 
o 
Ventilator-free days to 28 days 
o 
ICU-free days to 28 days 
 
9. DATA COLLECTION 
Data collected for the purposes of this study will come from three sources: [1] variables 
documented in the electronic health record as part of clinical care, [2] variables recorded by 
clinical staff’s bedside observation during the intubation procedure, and [3] variables reported by 

 
 
 
16 
 
the operator immediately following the intubation procedure. Data from the electronic medical 
record will be collected by trained study personnel (key study personnel) using a standardized 
electronic case report form.  It is infeasible to have research staff present during each emergency 
tracheal intubation.  Therefore, clinical staff not participating in the tracheal intubation procedure 
will collect data elements relevant to outcomes of emergency tracheal intubation using a 
standardized electronic case report form. These variables are readily available by bedside 
observation and do not require interaction with the patient but are not uniformly documented in 
the electronic health record (e.g., lowest oxygen saturation and lowest blood pressure from 
induction to two minutes after tracheal intubation).  Immediately following the intubation 
procedure, the operators will record data elements known only to them (e.g., glottic view 
obtained during the procedure and visualization of gastric aspiration in the oropharynx).  
Operators and clinical staff observing the procedure at the bedside will not be considered key 
study personnel. Training will be provided to clinicians who may serve as operators or bedside 
observers.  The activities of these clinicians will be limited to the reporting of data routinely 
reported as part of clinical care.   
 
The following variables will be recorded: 
 
Baseline:  
● age 
● sex 
● race and ethnicity 
● height 
● weight 
● body mass index 
● Acute Physiology and Chronic Health Evaluation (APACHE II) score  
● active medical problems at the time of enrollment 
● comorbidities  
● indication for intubation 
● vasopressor receipt in the hour prior to enrollment 
● highest FiO2 in the hour prior to enrollment 
● lowest SpO2/FIO2 ratio (or PaO2/FIO2 ratio) in the hour prior to enrollment 
● Glasgow Coma Scale score 
● oxygen delivery device at enrollment 
● assessment of the likelihood of a difficult intubation 
● presence of difficult airway characteristics 
○ limited mouth opening 
○ limited anatomic neck mobility 
○ cervical immobilization due to trauma 
○ increased neck circumference 
○ facial trauma 
○ obesity 
○ body fluids anticipated to obscure laryngeal view 
● operator’s level of training and specialty 
● operator’s prior intubation experience  
 

 
 
 
17 
 
Peri-procedural:  
 
Enrollment to induction 
● SpO2 and FiO2 at enrollment 
● oxygen saturation from enrollment to induction 
● approach to preoxygenation 
● duration of preoxygenation 
 
Induction to first laryngoscopy attempt 
● time of sedative administration (induction) 
● sedative agent and dose 
● neuromuscular blocking agent and dose 
● administration of an intravenous fluid bolus prior to induction 
● administration of a vasopressor prior to induction 
● SpO2 at induction 
● systolic blood pressure at induction 
● approach to oxygen administration and ventilation between induction and 
laryngoscopy 
 
First laryngoscopy attempt to successful intubation 
● time of start of first laryngoscopy attempt 
● laryngoscope model, blade size, blade shape on first attempt 
● use of video screen (if applicable) on first laryngoscopy attempt 
● best Cormack-Lehane grade of glottic view on the first laryngoscopy attempt 
● presences of body fluids obstructing laryngeal view 
● presence of upper airway obstruction or edema 
● receipt of chest compressions at time of first laryngoscopy attempt 
● number of intubation attempts 
○ number of times laryngoscope entered mouth 
○ number of times bougie entered mouth (if applicable) 
○ number of times endotracheal tube entered mouth 
● reason for failure of first intubation attempt (if applicable) 
● device(s) used on subsequent intubation attempts (if applicable) 
● necessity of an additional operator 
● esophageal intubation 
● injury to the teeth 
● operator-reported aspiration between induction and intubation 
● time of successful tracheal intubation 
● endotracheal tube size 
● lowest SpO2 from induction until 2 minutes after intubation 
● lowest systolic blood pressure from induction until 2 minutes after intubation 
● new or increased vasopressor use from induction until 2 minutes after intubation 
● cardiac arrest from induction until 2 minutes after intubation not resulting in death 
within 1 hour of induction 
● cardiac arrest from induction until 2 minutes after intubation resulting in death 
within 1 hour of induction 
 
In-hospital: 
 
24 hours after enrollment 

 
 
 
18 
 
● new pneumothorax detected in the first 24 hours after enrollment 
● vasopressor receipt at 24 hours after enrollment 
● SpO2 at 24 hours after enrollment 
● FiO2 at 24 hours after enrollment 
● PEEP at 24 hours after enrollment 
● systolic blood pressure at 24 hours after enrollment 
28 days after enrollment 
● 28-day in-hospital mortality 
● ventilator-free days 
● ICU-free days 
 
10. Risks and Benefits 
 
10.1 Risks of Tracheal Intubation in the ED or ICU 
Patients who are severely ill enough to require emergency tracheal intubation in the ED or ICU 
as part of their clinical care are at high risk of complications.  Many patients are undergoing 
intubation for hypoxemia or hemodynamic instability. Severe hypoxemia or cardiovascular 
instability occurs during nearly half of intubations in the ED and ICU (1, 2, 4, 5).  Hypoxemia 
and hypotension during intubation are associated with an increased risk of cardiac arrest and 
death.(9, 10) Cardiac arrest occurs in 1-in-25 cases of emergency tracheal intubation.   
 
Other complications during intubation may include aspiration (approximately 2.8% of cases), 
esophageal intubation (1.3%) injury to oral or dental structures (0.2%), and pneumothorax 
(0.1%).  The long-term consequences of complications occurring during emergency tracheal 
intubation are unclear.  Neurologic recovery from traumatic brain injury may be worse after 
hypoxemia due to secondary ischemic insult.(11)  
 
10.2 Potential Risks of Participation in the PREOXI Trial 
Participation in the PREOXI trial involves minimal incremental risk because: 
• All patients eligible for the study are already experiencing emergency tracheal intubation, 
with the accompanying risks, as part of their clinical care 
• Preoxygenation with non-invasive positive pressure ventilation and preoxygenation with 
facemask oxygen are both standard-of-care interventions that are commonly used in 
current clinical care.  All patients eligible for the study would experience an approach to 
preoxygenation as part of their clinical care 
• No benefits or risks are currently known to differ between the two approaches 
• Both approaches have determined to be acceptable options for the optimal care of the 
patient by treating clinicians (otherwise the patient is excluded from the study) 
 
Although no risks are currently known to differ between preoxygenation with non-invasive 
positive pressure ventilation and preoxygenation with facemask oxygen (both standard-of-care 
approaches in currently clinical care), it is possible that the results of the PREOXI trial will 
ultimately demonstrate a difference between the two approaches in the risk of hypoxemia, 
hypotension, cardiac arrest, aspiration, or another outcome. 
 

 
 
 
19 
 
10.3 Potential Benefits of Participation in the PREOXI Trial 
The primary benefits of the PREOXI trial will be the indirect benefits to society that would result 
if one approach to preoxygenation is found to prevent complications.  Because millions of 
critically ill adults undergo emergency tracheal intubation each year, if one of the two 
approaches were found to prevent serious complications, the findings would immediately 
improve the care provided to millions of severely ill patients. Compared to the minimal risks of 
participation in the study, the pursuit of these benefits is reasonable.   
 
10.4 Minimization of Risk 
Federal regulations 45 CFR 46.111(a)(1) require that risks to patients are minimized by using 
procedures which are consistent with sound research design. This trial meets this human subjects 
protection requirement by incorporating numerous design elements to minimize risk to patients.  
 
Both approaches to preoxygenation have been used in clinical practice for decades with an 
established safety profile in the same populations included in the PREOXI trial.  To further 
mitigate risk, we will exclude patients with specific risk factors for adverse events such as those 
already receiving non-invasive positive pressure ventilation and any patient for whom treating 
clinicians determine that a specific approach to preoxygenation is required or contraindicated for 
the optimal care of the patient.  
 
The trial protocol includes monitoring of adverse events, robust assessment of clinical outcomes, 
and an interim analysis by an independent DSMB, empowered to stop the trial or modify the trial 
protocol at any time. 
 
Finally, to limit the risks associated with the collection of protected health information (PHI), 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. 
REDCap tools will be used to ensure that the PHI that is collected is only visible to investigators 
at the healthcare system where the patient was enrolled. To protect participant privacy, REDCap 
tools will be used to ensure that only deidentified data can be exported for use during analysis.  
 
11. Statistical Considerations 
 
11.1 Initial Sample Size Determination: 
The minimum clinically important difference in hypoxemia that would be required to justify 
routine preoxygenation with non-invasive positive pressure ventilation rather than 
preoxygenation with facemask oxygen during emergency tracheal intubation of critically ill 
adults is uncertain.  The current trial will be designed to detect a 6% absolute difference between 
groups in the rate of hypoxemia.  An absolute difference of 6% in the incidence of hypoxemia is 
similar to or smaller than the difference considered to be clinically meaningful in the design of 
prior airway management trials.(19, 31) Assuming an incidence of hypoxemia of 17% in the 
facemask group based on data from two recently completed trials in the same ED and ICU 
settings, detecting a 6% absolute decrease in the incidence of hypoxemia with 85% power at a 
two-sided alpha level of 0.05 would require enrollment of 1,264 patients (632 per group). 
Anticipating missing data for up to 3% of patients, we will plan to enroll a total of 1,300 patients 
(650 per group).  This sample size calculation was performed in PS version 3.1.2. 

 
 
 
20 
 
11.2 Statistical Analysis: 
Prior to the conclusion of enrollment, we will make publicly available a complete, final statistical 
analysis plan. Analyses conducted in accordance with the statistical analysis plan will be 
identified as a priori. Any additional analyses requested by the investigators or reviewers will be 
identified as post hoc. 
 
11.2.1 Primary Analysis: 
The primary analysis will be an unadjusted, intention-to-treat comparison of patients randomized 
to preoxygenation with non-invasive positive pressure ventilation versus patients randomized to 
preoxygenation with facemask oxygen with regard to the primary outcome. The difference 
between the two study groups will be compared using a Chi-squared test. 
 
11.2.2 Secondary Analysis: 
We will perform intention-to-treat comparisons of secondary, exploratory, and safety outcomes. 
Continuous outcomes will be compared with Wilcoxon Rank Sum test and categorical variables 
with the Chi-squared test. Data on patient characteristics will be summarized as number and 
proportion for categorical variables and as median and interquartile range for continuous 
variables. 
 
We will also perform an adjusted comparison of the primary outcome between groups using a 
generalized linear mixed effects model including a random effect for site and fixed effects for 
group assignment and the following pre-specified baseline variables:  
 
1. Age; 
2. Sex; 
3. Race and Ethnicity; 
4. Oxygen saturation at enrollment; 
5. BMI; 
6. Location at enrollment (ED or ICU) 
7. Fraction of inspired oxygen at enrollment prior to initiation of preoxygenation; 
8. APACHEII score; and 
9. Indication for intubation (hypoxemic respiratory failure, other) 
 
11.2.3 Effect Modification (Subgroup Analyses) 
To evaluate whether pre-specified baseline variables modify the effect of study group assignment 
on the primary outcome, we will perform logistic regression modelling with the primary outcome 
as the dependent variable and independent variables of study group, the proposed effect 
modifier, and the interaction between the two.  Any interaction term with a p-value less than 0.1 
will be considered to identify an effect modifier.  To account for non-linear relationships, 
continuous variables will be analyzed using restricted cubic splines with between 3 and 5 knots. 
Forest plots will be used to graphically display the adjusted analyses, and locally weighted 
regression or partial effects plots will be used to portray the association between continuous 
covariates and the outcome.  A full list of prespecified subgroup analyses will be outlined in the 
detailed Statistical Analysis Plan but will include: 
 
 

 
 
 
21 
 
1. Age; 
2. Sex; 
3. Race and Ethnicity; 
4. BMI; 
5. Location (ED vs ICU); 
6. Fraction of inspired oxygen at enrollment; 
7. Indication for intubation (hypoxemic respiratory failure, other) ; 
8. APACHEII score; and 
9. Baseline risk of the primary outcome 
 
11.3 Interim Analysis 
The DSMB will conduct a single interim analysis for efficacy and safety at the anticipated 
halfway point of the trial, after enrollment of 650 patients. The pre-specified stopping boundary 
for efficacy will be a P value < 0.001 for the difference between group in the primary outcome 
using a Chi-square test. This conservative Haybittle–Peto boundary will allow the final analysis 
to be performed using an unchanged level of significance (two-sided P value < 0.05). 
Finally, after the interim analysis, the DSMB will evaluate the rate of the primary outcome in the 
facemask group. If the incidence of the primary outcome in the facemask group differs from the 
original estimate, the DSMB may suggest an increase sample size that would maintain the pre-
planned statistical power to detect the pre-planned relative risk difference in the primary 
outcome between groups. 
11.4 Correction for Multiple Testing 
We will analyze a single pre-specified primary outcome and a single pre-specified secondary 
outcome. Consistent with recommendations of the Food and Drug Administration60 and the 
European Medicines Association,61 each will be tested using a two-sided P value with a 
significance level of 0.05. For all other analyses except safety 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,62 and no corrections for multiple 
comparisons will be performed. 
11.5 Handling of Missing Data 
No patients will be lost to follow up before the measurement of the primary outcome, but oxygen 
saturation may be unavailable in some cases (equipment malfunction, observer error during a 
rapid, emergency procedure, or cardiac arrest).  Missing data will not be imputed for the primary 
outcome, or any of the secondary or exploratory outcomes. In adjusted analyses, missing data for 
baseline covariates will be imputed using multiple imputations. 
12. Privacy and Confidentiality 
All patients will be assigned a unique study ID number for use in the coded study database.  
Study personnel will access patients’ electronic health records at three planned time points: 
immediately following enrollment; when collecting baseline demographics and comorbidities 
(may occur anytime between enrollment and final data collection); and when collecting clinical 
outcomes (any time after the first of discharge or 28 days following intubation).  The electronic 

 
 
 
22 
 
health record may be accessed again, as needed, between enrollment and study publication to 
respond to queries from the coordinating center focused on ensuring data completeness and 
quality. The minimal PHI that is collected will be visible only to site investigators at the site 
where the patient was enrolled.  The dataset for analysis will contain the unique study ID and no 
other patient identifiers.  At the time of publication, a fully de-identified version of the database 
will be generated. 
 
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. Data collected from the medical record will be entered into the secure online 
database REDCap. Hard copies of the data collection sheet completed at the time of the airway 
management event will be stored in a locked room until after the completion of enrollment and 
data cleaning. Following publication of the study results, all hard copies of data collection forms 
will be destroyed and the REDCap database will be fully de-identified in accordance with 
institutional regulations.  
 
13. Follow-up and Record Retention 
Patients will be followed after enrollment up to 28 days or until hospital discharge, whichever 
occurs first.  Data collected from the medical record will be entered into the secure online 
database REDCap. Hard copies of the data collection sheet completed at the time of the airway 
management event 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. The minimal PHI that is collected will be available only to site 
investigators at the site where the patient was enrolled. At the time of publication, a fully de-
identified version of the database will be generated. 
14. Safety Monitoring and Adverse Events 
Assuring patient safety is an essential component of this protocol.  Preoxygenation with non-
invasive positive pressure ventilation and preoxygenation with facemask oxygen are both 
standard-of-care interventions that have been used in clinical practice for decades with an 
established safety profile. However, any trial conducted during a high-risk, time-sensitive 
procedure like tracheal intubation of critically ill patients raises unique safety considerations. 
This protocol addresses these considerations through: 
1. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse 
events from preoxygenation with non-invasive positive pressure ventilation or 
preoxygenation with facemask oxygen; 
2. Systematic collection of outcomes relevant to the safety of preoxygenation with non-invasive 
positive pressure ventilation and preoxygenation with facemask oxygen; 
3. Structured monitoring, assessment, recording, and reporting of adverse events. 
 
14.1 Adverse Event Definitions 
Adverse Event – An adverse event will be defined as any untoward or unfavorable medical 
occurrence in a human subject temporally associated with the subject’s participation in the 

 
 
 
23 
 
research, whether or not considered related to the subject’s participation in the research.  Any 
adverse event occurring during the research will be classified according to the following 
characteristics: 
 
• Seriousness – An adverse event will be considered “serious” if it: 
o Results in death; 
o Is life-threatening (defined as placing the patient at immediate risk of death); 
o Results in inpatient hospitalization or prolongation of existing hospitalization;  
o Results in a persistent or significant disability or incapacity; 
o Results in a congenital anomaly or birth defect; or  
o Based upon appropriate medical judgment, may jeopardize the patient’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
 
• Unexpectedness – An adverse event will be considered “unexpected” if the nature, 
severity, or frequency is neither consistent with: 
o The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in the protocol-related documents, such 
as the IRB-approved research protocol; nor 
o The expected natural progression of any underlying disease, disorder, or condition 
of the subject experiencing the adverse event and the subject’s predisposing risk 
factor profile for the adverse event. 
 
• Relatedness – The strength of the relationship of an adverse event to a study intervention 
or study procedure will be defined as follows:  
o Definitely Related: The adverse event follows (1) a reasonable, temporal 
sequence from a study procedure AND (2) cannot be explained by the known 
characteristics of the patient’s clinical state or other therapies AND (3) evaluation 
of the patient’s clinical state indicates to the investigator that the experience is 
definitely related to study procedures.  
o Probably or Possibly Related: The adverse event meets some but not all of the 
above criteria for “Definitely Related”. 
o Probably Not Related: The adverse event occurred while the patient was on the 
study but can reasonably be explained by the known characteristics of the 
patient’s clinical state or other therapies.  
o Definitely Not Related: The adverse event is definitely produced by the patient’s 
clinical state or by other modes of therapy administered to the patient.  
o Uncertain Relationship: The adverse event does not fit in any of the above 
categories. 
 
14.2 Monitoring for Adverse Events 
The time interval during which patients will be monitored for the occurrence of adverse events 
begins at randomization and ends at the first of hospital discharge or 28 days.  Adverse events 
occurring before randomization or after hospital discharge or 28 days will not be collected. The 
lead investigator at each enrolling site will have primary responsibility overseeing the 

 
 
 
24 
 
monitoring, assessment, and reporting of adverse events. Site study personnel will evaluate for 
the occurrence of adverse events by manual review of the electronic health record and by 
communication with treating clinicians.  Site study personnel will evaluate for the occurrence of 
adverse events by manual review of the electronic health record at two time points.  The first will 
occur approximately 24 hours after randomization at the time of initial data collection.  The 
second will occur at the first of hospital discharge or 28 days after enrollment at the time of final 
data collection.  Study personnel at each site will also communicate regularly with the treating 
clinicians who perform tracheal intubation in the study environments between enrollment and 28 
days after enrollment to solicit information about any potential adverse events.  If study 
personnel at a site identify a potential adverse event, the lead investigator at the site will be 
immediately notified.  The lead investigator at the site will assess the seriousness, 
unexpectedness, and relatedness of the potential adverse event.  With assistance as needed from 
the coordinating center and the trial primary investigator, the lead investigator at the site will 
determine whether the event qualifies for recording and reporting. 
 
14.3 Recording and Reporting Adverse Events 
The following types of adverse events will be recorded and reported: 
• Adverse events that are Serious and Definitely Related, Probably or Possibly Related, or 
of Uncertain Relationship. 
• Adverse events that are Unexpected and Definitely Related, Probably or Possibly 
Related, or of Uncertain Relationship. 
Adverse events that do not meet the above criteria will not be recorded or reported.  Adverse 
events that the lead investigator at a site assesses to meet the above criteria for recording and 
reporting will be entered into the adverse event electronic case report form in the trial database.  
The lead investigator at the site will record an assessment of each characteristic for the adverse 
event, including seriousness, unexpectedness, and relatedness.  For any adverse event that is 
serious AND unexpected, and definitely related, probably or possibly related, or of uncertain 
relationship, the lead investigator at the site will report the adverse event to the coordinating 
center and the trial primary investigator within 24 hours of becoming aware of the adverse 
event.  For any other adverse event requiring recording and reporting, the lead investigator at the 
study site will report the adverse event to the coordinating center and the trial principal 
investigator within 72 hours of becoming aware of the adverse event.  The coordinating center 
and the trial principal investigator will coordinate with the lead investigator at the site to obtain 
information about the adverse event regarding each characteristic for the adverse event, 
including seriousness, expectedness, and relatedness.  The lead investigator at the site will be 
responsible for making final determinations regarding seriousness and unexpectedness.  The 
coordinating center and trial principal investigator will be responsible for making final 
determinations regarding relatedness. 
 
For adverse events that meet the above criteria for recording and reporting, the coordinating 
center will notify the DSMB, the IRB, and the sponsor in accordance with the following 
reporting plan: 
Characteristics of the Adverse Event 
Reporting Period 

 
 
 
25 
 
Fatal or life-threatening (and therefore 
serious), unexpected, and definitely related, 
probably or possibility related, or of uncertain 
relationship. 
Report to the DSMB, IRB, and sponsor within 
7 days after notification of the event. 
Serious but non-fatal and non-life-
threatening, unexpected, and definitely 
related, probably or possibly related, or of 
uncertain relationship. 
Report to DSMB, IRB, and sponsor within 15 
days of notification of the event. 
All other adverse events meeting criteria for 
recording and reporting. 
Report to DSMB in regularly scheduled 
DSMB safety reports. 
The coordinating center will distribute the written summary of the DSMB’s periodic review of 
reported adverse events to the IRB in accordance with NIH guidelines: 
(http://grants.nih.gov/grants/guide/notice-files/not99-107.html).  
14.4 Clinical Outcomes that may be Exempt from Adverse Event Recording and Reporting 
In this study of critically ill patients at high risk for death and other adverse outcomes due to 
their underlying critical illness, clinical outcomes, including death and organ dysfunction, will be 
systematically collected and analyzed for all patients. The primary, secondary, safety, and 
exploratory outcomes will be recorded and reported as clinical outcomes and not as adverse 
events unless treating clinicians or site investigators believe the event is Definitely Related or 
Probably or Possibly Related to the study intervention or study procedures.  This approach – 
considering death and organ dysfunction as clinical outcomes rather than adverse events and 
systemically collecting these clinical outcomes for analysis – is common in ICU trials. This 
approach ensures comprehensive data on death and organ dysfunction for all patients, rather than 
relying on sporadic adverse event reporting to identify these important events.  The following 
events are examples of study-specific clinical outcomes that would not be recorded and reported 
as adverse events unless treating clinicians or site investigators believe the event was Definitely 
Related or Probably or Possibly Related to the study intervention or study procedures: 
• Death (all deaths occurring prior to hospital discharge or 28 days will be recorded); 
• Organ dysfunction 
o Pulmonary – hypoxemia, aspiration, acute hypoxemic respiratory failure, 
pneumothorax 
o Cardiac – hypotension, shock, vasopressor receipt, cardiac arrest; 
• Duration of mechanical ventilation; 
• Duration of ICU admission; 
• Duration of hospitalization 
 
Note: A study-specific clinical outcome may also qualify as an adverse event meeting criteria for 
recording and reporting. For example, a pneumothorax that the investigator considers Definitely 
Related to preoxygenation with non-invasive positive pressure ventilation would be both 
recorded as a study-specific clinical outcome and recorded and reported as a Serious and 
Definitely Related adverse event. 
 

 
 
 
26 
 
14.5 Unanticipated Problems involving Risks to Subjects or Others 
Investigators must also report Unanticipated Problems Involving Risks to Subjects or Others 
(“Unanticipated Problems”), regardless of severity, associated with study procedures within 24 
hours of the site investigator becoming aware of the Unanticipated Problem. An Unanticipated 
Problem is defined as any incident, experience, or outcome that meets all of the following 
criteria:  
• Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol; and (b) the characteristics of the subject population being studied; AND 
• Definitely Related or Probably or Possibly Related to participation in the research (as 
defined above in the section on characteristics of adverse events); AND  
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
If any study personnel at a site become aware of an event that may represent an Unanticipated 
problem, they will immediately contact the lead investigator for the site.  The lead investigator 
for the site will assess whether the event represents an Unanticipated Problem by applying the 
criteria described above.  If the lead investigator at a site determines that the event represents an 
Unanticipated Problem, the lead investigator at the site will record the Unanticipated Problem in 
the Unanticipated Problem electronic case report form in the trial database.  The lead investigator 
at the site will then communicate that an Unanticipated Problem has occurred to the coordinating 
center and the principal investigator within 24 hours of the lead investigator at the site 
becoming aware of the Unanticipated Problem.  The coordinating center and principal 
investigator will coordinate with the lead investigator at the site to obtain information about the 
Unanticipated Problem.  The coordinating center will report the Unanticipated Problem to the 
DSMB, IRB, and sponsor within 15 days of becoming aware of the Unanticipated Problem. 
 
15. Data and Safety Monitoring Board (DSMB) 
The principal role of the DSMB is to assure the safety of patients in the trial. They will regularly 
monitor data from this trial, review and assess the performance of its operations, and make 
recommendations to the steering committee and sponsor with respect to:  
• Participant safety and risk/benefit ratio of study procedures and interventions 
• 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  
• Possible early termination of the trial because of new external information, early 
attainment of study objectives, safety concerns, or inadequate performance 
 
The DSMB will consist of members with expertise in bioethics, emergency medicine, pulmonary 
and critical care medicine, anesthesia, biostatistics, and clinical trials. Appointment of all 
members is contingent upon the absence of any conflicts of interest. All the members of the 
DSMB are voting members. The coordinating center, principal investigators, and unblinded 
study biostatistician will be responsible for the preparation of all DSMB and adverse event 

 
 
 
27 
 
reports. The DSMB will develop a charter and review the protocol and patient notification forms 
during its first meeting. Subsequent DSMB meetings will be scheduled in accordance with the 
DSMB Charter. The DSMB will have the ability to recommend that the trial end, be modified, or 
continued unchanged. 
 
 

 
 
 
28 
 
References 
 
1. Martin LD, Mhyre JM, Shanks AM, Tremper KK, Kheterpal S. 3,423 emergency tracheal 
intubations at a university hospital: airway outcomes and complications. Anesthesiology 
2011; 114: 42-48. 
2. Simpson GD, Ross MJ, McKeown DW, Ray DC. Tracheal intubation in the critically ill: a 
multi-centre national study of practice and complications. Br J Anaesth 2012; 108: 792-
799. 
3. Leibowitz AB. Tracheal intubation in the intensive care unit: extremely hazardous even in the 
best of hands. Crit Care Med 2006; 34: 2497-2498. 
4. Jaber S, Jung B, Corne P, Sebbane M, Muller L, Chanques G, Verzilli D, Jonquet O, Eledjam 
JJ, Lefrant JY. An intervention to decrease complications related to endotracheal 
intubation in the intensive care unit: a prospective, multiple-center study. Intensive Care 
Med 2010; 36: 248-255. 
5. Griesdale DE, Bosma TL, Kurth T, Isac G, Chittock DR. Complications of endotracheal 
intubation in the critically ill. Intensive Care Med 2008; 34: 1835-1842. 
6. van Zundert A, Pieters B, Doerges V, Gatt S. Videolaryngoscopy allows a better view of the 
pharynx and larynx than classic laryngoscopy. Br J Anaesth 2012; 109: 1014-1015. 
7. Jabre P, Combes X, Lapostolle F, Dhaouadi M, Ricard-Hibon A, Vivien B, Bertrand L, 
Beltramini A, Gamand P, Albizzati S, Perdrizet D, Lebail G, Chollet-Xemard C, Maxime 
V, Brun-Buisson C, Lefrant JY, Bollaert PE, Megarbane B, Ricard JD, Anguel N, Vicaut 
E, Adnet F, Group KCS. Etomidate versus ketamine for rapid sequence intubation in 
acutely ill patients: a multicentre randomised controlled trial. Lancet 2009; 374: 293-300. 
8. Russotto V, Myatra SN, Laffey JG, Tassistro E, Antolini L, Bauer P, Lascarrou JB, 
Szuldrzynski K, Camporota L, Pelosi P, Sorbello M, Higgs A, Greif R, Putensen C, 
Agvald-Ohman C, Chalkias A, Bokums K, Brewster D, Rossi E, Fumagalli R, Pesenti A, 
Foti G, Bellani G, Investigators IS. Intubation Practices and Adverse Peri-intubation 
Events in Critically Ill Patients From 29 Countries. JAMA 2021; 325: 1164-1172. 
9. Davis DP, Dunford JV, Poste JC, Ochs M, Holbrook T, Fortlage D, Size MJ, Kennedy F, Hoyt 
DB. The impact of hypoxia and hyperventilation on outcome after paramedic rapid 
sequence intubation of severely head-injured patients. J Trauma 2004; 57: 1-8; discussion 
8-10. 
10. April MD, Arana A, Reynolds JC, Carlson JN, Davis WT, Schauer SG, Oliver JJ, Summers 
SM, Long B, Walls RM, Brown CA, 3rd, Investigators N. Peri-intubation cardiac arrest 
in the Emergency Department: A National Emergency Airway Registry (NEAR) study. 
Resuscitation 2021; 162: 403-411. 
11. Rubenson Wahlin R, Nelson DW, Bellander BM, Svensson M, Helmy A, Thelin EP. 
Prehospital Intubation and Outcome in Traumatic Brain Injury-Assessing Intervention 
Efficacy in a Modern Trauma Cohort. Front Neurol 2018; 9: 194. 
12. Janz DR, Casey JD, Semler MW, Russell DW, Dargin J, Vonderhaar DJ, Dischert KM, West 
JR, Stempek S, Wozniak J, Caputo N, Heideman BE, Zouk AN, Gulati S, Stigler WS, 
Bentov I, Joffe AM, Rice TW, Pre PI, Pragmatic Critical Care Research G. Effect of a 
fluid bolus on cardiovascular collapse among critically ill adults undergoing tracheal 
intubation (PrePARE): a randomised controlled trial. Lancet Respir Med 2019; 7: 1039-
1047. 

 
 
 
29 
 
13. Weingart SD. Preoxygenation, reoxygenation, and delayed sequence intubation in the 
emergency department. J Emerg Med 2011; 40: 661-667. 
14. Driver BE, Prekker ME, Kornas RL, Cales EK, Reardon RF. Flush Rate Oxygen for 
Emergency Airway Preoxygenation. Ann Emerg Med 2017; 69: 1-6. 
15. Delay JM, Sebbane M, Jung B, Nocca D, Verzilli D, Pouzeratte Y, Kamel ME, Fabre JM, 
Eledjam JJ, Jaber S. The effectiveness of noninvasive positive pressure ventilation to 
enhance preoxygenation in morbidly obese patients: a randomized controlled study. 
Anesth Analg 2008; 107: 1707-1713. 
16. Rusca M, Proietti S, Schnyder P, Frascarolo P, Hedenstierna G, Spahn DR, Magnusson L. 
Prevention of atelectasis formation during induction of general anesthesia. Anesth Analg 
2003; 97: 1835-1839. 
17. Grant S, Khan F, Keijzers G, Shirran M, Marneros L. Ventilator-assisted preoxygenation: 
Protocol for combining non-invasive ventilation and apnoeic oxygenation using a 
portable ventilator. Emerg Med Australas 2016; 28: 67-72. 
18. Dafilou B, Schwester D, Ruhl N, Marques-Baptista A. It's In The Bag: Tidal Volumes in 
Adult and Pediatric Bag Valve Masks. West J Emerg Med 2020; 21: 722-726. 
19. Casey JD, Janz DR, Russell DW, Vonderhaar DJ, Joffe AM, Dischert KM, Brown RM, Zouk 
AN, Gulati S, Heideman BE, Lester MG, Toporek AH, Bentov I, Self WH, Rice TW, 
Semler MW, PreVent I, the Pragmatic Critical Care Research G. Bag-Mask Ventilation 
during Tracheal Intubation of Critically Ill Adults. N Engl J Med 2019; 380: 811-821. 
20. Baillard C, Fosse JP, Sebbane M, Chanques G, Vincent F, Courouble P, Cohen Y, Eledjam 
JJ, Adnet F, Jaber S. Noninvasive ventilation improves preoxygenation before intubation 
of hypoxic patients. Am J Respir Crit Care Med 2006; 174: 171-177. 
21. Baillard C, Prat G, Jung B, Futier E, Lefrant JY, Vincent F, Hamdi A, Vicaut E, Jaber S. 
Effect of preoxygenation using non-invasive ventilation before intubation on subsequent 
organ failures in hypoxaemic patients: a randomised clinical trial. Br J Anaesth 2018; 
120: 361-367. 
22. Weingart SD, Levitan RM. Preoxygenation and prevention of desaturation during emergency 
airway management. Ann Emerg Med 2012; 59: 165-175 e161. 
23. Higgs A, McGrath BA, Goddard C, Rangasami J, Suntharalingam G, Gale R, Cook TM, 
Difficult Airway S, Intensive Care S, Faculty of Intensive Care M, Royal College of A. 
Guidelines for the management of tracheal intubation in critically ill adults. Br J Anaesth 
2018; 120: 323-352. 
24. Frerk C, Mitchell VS, McNarry AF, Mendonca C, Bhagrath R, Patel A, O'Sullivan EP, 
Woodall NM, Ahmad I, Difficult Airway Society intubation guidelines working g. 
Difficult Airway Society 2015 guidelines for management of unanticipated difficult 
intubation in adults. Br J Anaesth 2015; 115: 827-848. 
25. Quintard H, l'Her E, Pottecher J, Adnet F, Constantin JM, De Jong A, Diemunsch P, Fesseau 
R, Freynet A, Girault C, Guitton C, Hamonic Y, Maury E, Mekontso-Dessap A, Michel 
F, Nolent P, Perbet S, Prat G, Roquilly A, Tazarourte K, Terzi N, Thille AW, Alves M, 
Gayat E, Donetti L. Experts' guidelines of intubation and extubation of the ICU patient of 
French Society of Anaesthesia and Intensive Care Medicine (SFAR) and French-speaking 
Intensive Care Society (SRLF) : In collaboration with the pediatric Association of 
French-speaking Anaesthetists and Intensivists (ADARPEF), French-speaking Group of 
Intensive Care and Paediatric emergencies (GFRUP) and Intensive Care physiotherapy 
society (SKR). Ann Intensive Care 2019; 9: 13. 

 
 
 
30 
 
26. De Jong A, Jung B, Jaber S. Intubation in the ICU: we could improve our practice. Crit Care 
2014; 18: 209. 
27. Yoon U, Mojica J, Wiltshire M, Segna K, Block M, Pantoja A, Torjman M, Wolo E. 
Emergent airway management outside of the operating room - a retrospective review of 
patient characteristics, complications and ICU stay. BMC Anesthesiol 2019; 19: 220. 
28. Kajal K, Hazarika A, Reddy S, Jain K, Meena SC. Emergency Intubation outside Operating 
Room/Intensive Care Unit Settings: Are We Following the Recommendations for Safe 
Practice? Anesth Essays Res 2018; 12: 865-872. 
29. Driver BE, Prekker ME, Klein LR, Reardon RF, Miner JR, Fagerstrom ET, Cleghorn MR, 
McGill JW, Cole JB. Effect of Use of a Bougie vs Endotracheal Tube and Stylet on First-
Attempt Intubation Success Among Patients With Difficult Airways Undergoing 
Emergency Intubation: A Randomized Clinical Trial. JAMA 2018; 319: 2179-2189. 
30. Janz DR, Semler MW, Joffe AM, Casey JD, Lentz RJ, deBoisblanc BP, Khan YA, Santanilla 
JI, Bentov I, Rice TW, Check UPI, Pragmatic Critical Care Research G. A Multicenter 
Randomized Trial of a Checklist for Endotracheal Intubation of Critically Ill Adults. 
Chest 2018; 153: 816-824. 
31. Semler MW, Janz DR, Lentz RJ, Matthews DT, Norman BC, Assad TR, Keriwala RD, 
Ferrell BA, Noto MJ, McKown AC, Kocurek EG, Warren MA, Huerta LE, Rice TW, 
Investigators F, Pragmatic Critical Care Research G. Randomized Trial of Apneic 
Oxygenation during Endotracheal Intubation of the Critically Ill. Am J Respir Crit Care 
Med 2016; 193: 273-280. 
32. Tekwani KL, Watts HF, Sweis RT, Rzechula KH, Kulstad EB. A comparison of the effects 
of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a 
prospective, randomized study. Ann Emerg Med 2010; 56: 481-489. 
33. Russell DW, Casey JD, Gibbs KW, Dargin JM, Vonderhaar DJ, Joffe AM, Ghamande S, 
Khan A, Dutta S, Landsperger JS, Robison SW, Bentov I, Wozniak JM, Stempek S, 
White HD, Krol OF, Prekker ME, Driver BE, Brewer JM, Wang L, Lindsell CJ, Self 
WH, Rice TW, Semler MW, Janz D, Investigators PI. Protocol and statistical analysis 
plan for the PREventing cardiovascular collaPse with Administration of fluid 
REsuscitation during Induction and Intubation (PREPARE II) randomised clinical trial. 
BMJ Open 2020; 10: e036671. 
34. Itagaki T, Oto J, Burns SM, Jiang Y, Kacmarek RM, Mountjoy JR. The effect of head 
rotation on efficiency of face mask ventilation in anaesthetised apnoeic adults: A 
randomised, crossover study. Eur J Anaesthesiol 2017; 34: 432-440. 
  
 
 

 
 
 
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Tracking of Protocol Versions: 
Version 1.0 – Initial Submission (***) 
 

 
 
 
1 
 
 
 
PRagmatic Trial Examining OXygenation prior to Intubation (PREOXI) 
 
 
 
 
Title 
Pragmatic trial examining oxygenation prior to intubation  
 
Acronym 
PREOXI 
 
Version   
 
Version 1.1 
 
Date 
 
July 7, 2023 
 
Protocol Chairs 
 
Kevin W. Gibbs, MD 
Wake Forest School of Medicine 
 
Jonathan Casey, MD, MSc 
Vanderbilt University Medical Center 
 
Adit A. Ginde, MD, MPH 
University of Colorado School of Medicine 
 
Coordinating Center 
Vanderbilt University Medical Center 
Director: Jonathan D. Casey, MD, MSc 
 
Network 
Pragmatic Critical Care Research Group (PCCRG) 
Steering Committee Chair: Matthew W. Semler MD, MSc  
 
Military Principal 
Investigators 
 
Maj Brit J Long, MD 
US Air Force 59MDW 
 
MAJ Steven Schauer, DO, MS 
US Army Institute of Surgical Research and US Air Force 59MDW 
 
Civilian Principal 
Investigators 
Adit A. Ginde, MD, MPH 
University of Colorado School of Medicine 
 
Jonathan Casey, MD, MSc 
Vanderbilt University Medical Center 
 
 
Funding 
US Department of Defense 
 
 
 
 
 

 
 
 
2 
 
 
 
Table of Contents 
1. TRIAL SUMMARY ........................................................................................................................... 4 
2. TRIAL DESCRIPTION ..................................................................................................................... 7 
2.1 BACKGROUND....................................................................................................................................... 7 
2.1.1 Hypoxemia during Intubation of Critically Ill Patients ............................................................................ 7 
2.1.2 Role of Preoxygenation in Preventing Hypoxemia during Intubation ..................................................... 7 
2.1.3 Preoxygenation with Non-Invasive Positive Pressure Ventilation ........................................................... 7 
2.1.4 Preoxygenation with Facemask Oxygen ................................................................................................... 8 
2.1.5 Potential Advantages of Preoxygenation with Non-Invasive Positive Pressure Ventilation or 
Preoxygenation with Facemask Oxygen ............................................................................................................ 8 
2.1.6 Prior Evidence from Clinical Trials. ......................................................................................................... 9 
2.2. PRIMARY AIM AND HYPOTHESIS ........................................................................................................ 10 
2.2.1 Study Aim: ................................................................................................................................................ 10 
2.2.2 Study Hypothesis: ..................................................................................................................................... 10 
2.3 STUDY DESCRIPTION .......................................................................................................................... 10 
3. STUDY POPULATION AND ENROLLMENT .............................................................................. 10 
3.1 INCLUSION CRITERIA: ......................................................................................................................... 10 
3.2 EXCLUSION CRITERIA: ........................................................................................................................ 10 
4. CONSENT ........................................................................................................................................ 10 
4.1 PROVISION OF INFORMATION AFTER PARTICIPATION .................................................................... 12 
5. ENROLLMENT AND RANDOMIZATION ................................................................................... 12 
5.1 STUDY ENROLLMENT LOCATIONS: .................................................................................................. 12 
5.3 ENROLLMENT AND RANDOMIZATION............................................................................................... 12 
5.3.1 Pre-Procedural Time-Out to Prevent Enrollment of Ineligible Patients ................................................ 13 
5.3.2 Monitoring and Reporting of Eligibility of Enrolled Patients ................................................................ 13 
5.3.3 Handling of Patients Found to Be Prisoners after Enrollment .............................................................. 13 
6. BLINDING ....................................................................................................................................... 14 
7. STUDY INTERVENTIONS ............................................................................................................. 14 
7.1 TREATMENT OF STUDY PATIENTS .................................................................................................... 14 
7.2 PREOXYGENATION WITH NON-INVASIVE POSITIVE PRESSURE VENTILATION GROUP .................. 14 
7.3 PREOXYGENATION WITH FACEMASK OXYGEN GROUP ................................................................... 14 
8. RECORDED STUDY OUTCOMES ................................................................................................ 15 
8.1 PRIMARY OUTCOMES ........................................................................................................................ 15 
8.2 SECONDARY OUTCOMES ................................................................................................................... 15 
8.3 SAFETY OUTCOMES........................................................................................................................... 15 
8. 4 EXPLORATORY OUTCOMES ............................................................................................................. 15 
9. DATA COLLECTION ..................................................................................................................... 16 
10. RISKS AND BENEFITS ................................................................................................................ 18 
10.1 RISKS OF TRACHEAL INTUBATION IN THE ED OR ICU ...................................................................... 18 

 
 
 
3 
 
10.2 POTENTIAL RISKS OF PARTICIPATION IN THE PREOXI TRIAL .......................................................... 18 
10.3 POTENTIAL BENEFITS OF PARTICIPATION IN THE PREOXI TRIAL .................................................... 19 
10.4 MINIMIZATION OF RISK .................................................................................................................... 19 
11. STATISTICAL CONSIDERATIONS ............................................................................................ 19 
11.1 INITIAL SAMPLE SIZE DETERMINATION: ........................................................................................... 19 
11.2 STATISTICAL ANALYSIS: ................................................................................................................... 20 
11.2.1 Primary Analysis: ................................................................................................................................... 20 
11.2.2 Secondary Analysis: ............................................................................................................................... 20 
11.2.3 EFFECT MODIFICATION (SUBGROUP ANALYSES) ...................................................................................... 20 
11.3 INTERIM ANALYSIS ................................................................................................................................ 21 
11.4 CORRECTION FOR MULTIPLE TESTING ....................................................................................................... 21 
11.5 HANDLING OF MISSING DATA ................................................................................................................. 21 
12. PRIVACY AND CONFIDENTIALITY ......................................................................................... 21 
13. FOLLOW-UP AND RECORD RETENTION ............................................................................... 22 
14. SAFETY MONITORING AND ADVERSE EVENTS .................................................................. 22 
14.1 ADVERSE EVENT DEFINITIONS ......................................................................................................... 23 
14.2 MONITORING FOR ADVERSE EVENTS ................................................................................................ 23 
14.3 RECORDING AND REPORTING ADVERSE EVENTS .............................................................................. 24 
14.4 CLINICAL OUTCOMES THAT MAY BE EXEMPT FROM ADVERSE EVENT RECORDING AND REPORTING 25 
14.5 UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS ........................................ 26 
15. DATA AND SAFETY MONITORING BOARD (DSMB) ............................................................. 26 
REFERENCES ..................................................................................................................................... 28 
 
 
 

 
 
 
4 
 
1. TRIAL SUMMARY 
 
Title 
Pragmatic Trial Examining Oxygenation prior to Intubation (PREOXI) 
Background 
Clinicians perform rapid sequence induction, laryngoscopy, and tracheal 
intubation for more than 5 million critically ill adults as a part of clinical 
care each year in the United States.  One-in-ten emergency tracheal 
intubations is complicated by life-threatening hypoxemia.  Administering 
supplemental oxygen prior to induction and intubation (“preoxygenation”) 
decreases the risk of life-threatening hypoxemia. In current clinical 
practice, the most common methods for preoxygenation are non-invasive 
positive pressure ventilation and facemask oxygen.  Prior trials comparing 
non-invasive positive pressure ventilation and facemask oxygen for 
preoxygenation have been small and have yielded conflicting results.  A 
better understanding of the comparative effectiveness of these two 
common, standard-of-care approaches to preoxygenation could improve 
the care clinicians deliver and patient outcomes. 
Study Design 
Multicenter, pragmatic, non-blinded, parallel-group, randomized trial 
Treatment Groups 
 
• Non-invasive positive pressure ventilation group: Patients will receive 
preoxygenation with non-invasive mechanical ventilation via a tight-
fitting mask.   
• Facemask oxygen group: Patients will receive preoxygenation via either 
a non-rebreather mask or a compressed bag-mask device without manual 
ventilation.  
Sample Size 
1,300 patients 
Inclusion Criteria 
1. Patient is located in a participating unit 
2. Planned procedure is tracheal intubation using a laryngoscope and 
sedation 
3. Planned operator is a clinician expected to routinely perform tracheal 
intubation in the participating unit. 
Exclusion Criteria 
1. Patient is receiving positive pressure ventilation by a mechanical 
ventilator, bag-mask device, or laryngeal mask airway 
2. Patient is known to be less than 18 years old 
3. Patient is known to be pregnant 
4. Patient is known to be a prisoner 
5. Immediate need for tracheal intubation precludes safe performance of 
study procedures 
6. Patient is apneic, hypopneic, or has another condition requiring 
positive pressure ventilation between enrollment and induction 
7. Operator has determined that preoxygenation with non-invasive 
positive pressure ventilation or preoxygenation with facemask oxygen 
is required or contraindicated for optimal care of the patient 
Risks 
Participation in this study involves minimal incremental risk because: 
• All patients eligible for the study are already undergoing tracheal 
intubation with preoxygenation as part of their clinical care 

 
 
 
5 
 
• Preoxygenation with non-invasive positive pressure ventilation 
and preoxygenation with facemask oxygen are the most common 
approaches to preoxygenation of critically ill adults in clinical care 
• No benefits or risks are currently known to differ between the two 
approaches 
• If clinicians determine either approach to be required or 
contraindicated for the optimal care of an individual patient, the 
patient is excluded from the study 
Benefits 
The benefits of the PREOXI trial are largely the indirect benefits to future 
patients that will result by a better understanding of whether 
preoxygenation with non-invasive positive pressure ventilation or pre-
oxygenation with facemask oxygen prevents complications during 
tracheal intubation of critically ill adults. 
Consent 
The trial will be conducted with waiver of informed consent because: 
• Participation in the study involves minimal incremental risk 
• Obtaining informed consent prior to emergency tracheal intubation 
of critically ill adults is impracticable 
Randomization 
 
Eligible patients will be randomized 1:1 to preoxygenation with non-
invasive positive pressure ventilation or pre-oxygenation with facemask 
oxygen.  Randomization will be completed in permuted blocks of variable 
size and stratified by site. 
Blinding 
Study group assignment will remain concealed to study personnel and 
clinicians until after the decision has been made to enroll the patient in the 
study. Following enrollment, the trial will not blind patients or clinicians 
to study group assignment. 
Primary Outcome  
Hypoxemia: Oxygen saturation <85% from induction to 2 minutes after 
tracheal intubation 
Secondary Outcome 
Lowest oxygen saturation from induction to 2 minutes after tracheal 
intubation 
Safety Outcomes 
• Operator-reported aspiration 
• Fraction of inspired oxygen at 24 hours after induction 
• Oxygen saturation at 24 hours after induction 
• New pneumothorax, defined as a radiology report of new 
pneumothorax on chest x-ray in the 24 hours after induction 
• New infiltrate, defined as a radiology report of new infiltrate on chest 
imaging in the 24 hours after intubation. 
Exploratory Outcomes 
• Procedural characteristics & complications 
o Severe hypoxemia (lowest oxygen saturation of <80%) between 
induction and two minutes after tracheal intubation 
o Very severe hypoxemia (lowest oxygen saturation of <70%) 
between induction and two minutes after tracheal intubation 
o Oxygen saturation at induction 
o Systolic blood pressure at induction 
o Duration from induction to successful intubation 

 
 
 
6 
 
o Cormack-Lehane grade of glottic view on first attempt 
o Successful intubation on the first attempt 
o Number of laryngoscopy attempts 
o Number of attempts at passing bougie 
o Number of attempts at passing endotracheal tube 
o Cardiovascular collapse, defined as a composite of one or more of 
the following between induction and 2 minutes after intubation: 
1. Systolic blood pressure < 65 mmHg  
2. New or increased vasopressor  
3. Cardiac arrest not resulting in death  
4. Cardiac arrest resulting in death 
• Clinical Outcomes 
o 28-day in-hospital mortality 
o Ventilator-free days to 28 days 
o ICU-free days to 28 days 
Analysis 
The primary analysis will be an unadjusted, intention-to-treat comparison 
of patients randomized to preoxygenation with non-invasive positive 
pressure ventilation versus patients randomized to preoxygenation with 
facemask oxygen with regard to the primary outcome. The difference 
between the two study groups will be compared using a Chi-squared test.  
Sample Size 
We will plan to enroll 1300 patients, which we estimate will provide 85% 
power at a two-sided alpha level of 0.05 to detect a 6% absolute 
difference in the incidence of the primary outcome, assuming an 
incidence of hypoxemia of 17% in the facemask group and missing data 
on the primary outcome for up to 3% of patients. 
Expected Duration 
18 months 
 
 

 
 
 
7 
 
2. TRIAL DESCRIPTION 
 
2.1 Background 
Clinicians frequently perform tracheal intubation of critically ill patients in the emergency 
department (ED) or intensive care unit (ICU).  Complications of intubation, including hypoxemia 
and cardiovascular instability, occur in nearly half of intubations performed in these settings (1, 
2, 4, 5).   Preventing complications during tracheal intubation is a key focus of clinical care and 
airway management research (4, 6, 7). 
 
 
2.1.1 Hypoxemia during Intubation of Critically Ill Patients 
Life-threatening hypoxemia occurs in 1-in-10 cases of emergency tracheal intubation.(8) Severe 
hypoxemia during intubation is associated with increased risk of cardiac arrest and death.(9, 10) 
Severe hypoxemia may be associated with worse outcomes in survivors.  For example, 
neurologic recovery from traumatic brain injury may be worse after hypoxemia due to secondary 
ischemic insult.(11)  
 
2.1.2 Role of Preoxygenation in Preventing Hypoxemia during Intubation  
In current clinical practice, emergency tracheal intubation involves the nearly simultaneous 
administration of a sedative agent and a neuromuscular blocking agent to optimize the anatomic 
conditions for intubation.  Following medication administration, patients rapidly become 
hypopneic and then apneic until invasive mechanical ventilation is initiated through the newly-
placed endotracheal tube.  The oxygen contained in the lungs at the time of neuromuscular 
blockade (i.e., the patient’s functional residual capacity) is the reservoir of oxygen available to 
the patient’s body to prevent hypoxemia and tissue hypoxia during the intubation procedure.  For 
a patient breathing ambient air (i.e., room air), only 21% of the gas in the functional residual 
capacity is oxygen; 78% is nitrogen.  Administering 100% oxygen to a patient prior to induction 
of anesthesia and tracheal intubation, referred to as “preoxygenation,” can replace the nitrogen in 
the lung with oxygen, increasing up to five-fold the reservoir of oxygen available to the body 
during the procedure and prolonging the period during which intubation can be performed safely 
without encountering hypoxemia.  In current clinical practice, the two most common methods of 
providing preoxygenation are:  
1. Non-invasive positive pressure ventilation - a tight-fitting mask connected to either an 
invasive ventilator or non-invasive mechanical ventilator. 
2. Facemask oxygen - with either a non-rebreather mask or a bag-mask device. 
2.1.3 Preoxygenation with Non-Invasive Positive Pressure Ventilation 
Preoxygenation with non-invasive positive pressure ventilation is common during emergency 
tracheal intubation of critically ill adults in current clinical practice.  During preoxygenation with 
non-invasive positive pressure ventilation, a tight-fitting mask is connected to a machine capable 
of providing positive pressure ventilation. Non-invasive positive pressure ventilation delivers up 
to 95-100% oxygen and can be provided by either a conventional invasive mechanical ventilator 
or a dedicated non-invasive ventilation machine, commonly referred to as a Bilevel Positive 
Airway Pressure (BiPAP) machine.  In addition to providing high concentrations of oxygen, non-
invasive positive pressure ventilation increases mean airway pressure and delivers breaths at a 
set rate during the period of hyponea/apnea after induction. Because a mechanical ventilator is 
always required following intubation of a critically ill adult, no specialized equipment is required 

 
 
 
8 
 
to use non-invasive positive pressure ventilation for preoxygenation of critically ill adults 
undergoing tracheal intubation.  
2.1.4 Preoxygenation with Facemask Oxygen 
In current clinical practice, preoxygenation with facemask oxygen is commonly performed using 
one of the following two types of facemask: [1] a non-rebreather mask or [2] a bag-mask device 
(8, 12).  Both a types of facemask (a non-rebreather and a compressed bag-mask device) deliver 
supplemental oxygen without increasing airway pressures or providing assistance with 
ventilation.   
• A non-rebreather mask is a type of facemask with a loose-fitting mask that sits over a 
patient’s nose and mouth and is connected to an oxygen reservoir. It delivers at least 15 
liters per minute of 100% oxygen, but it may not reliably deliver flows of oxygen greater 
than 15 liters per minute and may allow entrainment of ambient air. Studies show that the 
while the oxygen content for healthy and calm volunteers may approach 100%, the 
oxygen content received by critically ill patients with tachypnea may be as low as 
50%.(14)  It does not provide positive pressure. 
• A bag mask device is a type of facemask with a mask that forms a tight seal over the 
mouth and nose when held in place by the operator, an exhalation port, and a self-
inflating bag that serves as a reservoir for oxygen and can be compressed to provide 
positive pressure ventilation.(13) If the bag of this device is compressed, this device 
delivers oxygen without providing positive pressure ventilation and can deliver more than 
90% oxygen with an ideal mask seal. However, in the setting of emergency intubation 
leaks may result in the entrainment of ambient air and reduced oxygen delivery.      
2.1.5 Potential Advantages of Preoxygenation with Non-Invasive Positive Pressure 
Ventilation or Preoxygenation with Facemask Oxygen 
 
Preoxygenation with non-invasive positive pressure ventilation has been proposed to offer the 
following potential advantages compared to preoxygenation with facemask oxygen: 
• Entrainment of ambient air: The tight-fitting mask used to deliver non-invasive 
ventilation entrains less ambient air than a non-rebreather or bag-mask device. The higher 
flow rates of oxygen gas with non-invasive ventilation may also help prevent entrainment 
of ambient air and increase the fraction of inspired oxygen. (15) 
• Atelectasis and alveolar recruitment: Preoxygenation and induction of anesthesia rapidly 
results in the development of atelectasis in both healthy patients and critically ill 
patients.(16) This atelectasis increases shunt fraction and increases the risk of peri-
procedural hypoxia.  By delivering positive pressure during both inspiration and 
expiration, non-invasive ventilation raises mean airway pressure, recruiting alveoli and 
preventing the development of atelectasis.  
• Hypopnea and Apnea. Administration of sedation and neuromuscular blocking agents 
reduces or eliminates spontaneous respiratory effort.  This hypoventilation leads to 
accumulation of alveolar carbon dioxide and reductions in alveolar oxygen, contributing 
to hypoxemia.  Use of non-invasive ventilation before induction and between induction 
and laryngoscopy provides continuous oxygen to the alveoli, increases the size of breaths 
taken in the setting of hypopnea, and delivers controlled breaths when patients are apneic.   
 

 
 
 
9 
 
Preoxygenation with facemask oxygen (via a non-rebreather or compressed bag-mask device) 
has been proposed to offer the following potential advantages compared with preoxygenation 
with non-invasive positive pressure ventilation: 
Simplicity of use: Preoxygenation with facemask oxygen (using either a non-rebreather or 
compressed bag-mask device) is simpler to set up than non-invasive positive pressure 
ventilation.   
Low risk of gastric insufflation: Although no clinical evidence exist to suggest that 
preoxygenation with non-invasive positive pressure ventilation increases the risk of 
gastric insufflation or aspiration of gastric contents,(19) use of facemask oxygen (without 
any positive pressure) avoids this hypothetical concern.   
 
2.1.6 Prior Evidence from Clinical Trials. 
Two small clinical trials have compared preoxygenation with non-invasive ventilation to 
preoxygenation with facemask oxygen during the tracheal intubation of critically ill adults.(20, 
21) The first trial compared non-invasive ventilation to a facemask among 53 critically ill ICU 
patients in two hospitals and found that non-invasive ventilation increased the lowest oxygen 
saturation (93% vs. 81%, p<0.001) with no difference in incidence of aspiration (6% vs. 8%). 
The second trial compared non-invasive ventilation to a facemask oyxgen with regard to severity 
of illness in the 7 days after intubation among 201 critically ill ICU patients.  This trial found no 
significant difference in the severity of illness between groups and no significant difference in 
the rate of severe hypoxemia (18.4% vs 27.7%, p=0.10). This trial did not have adequate 
statistical power to detect clinically important differences between groups in the risk of 
hypoxemia.  No large, multicenter trials have compared preoxygenation with non-invasive 
positive pressure ventilation to preoxygenation with facemask oxygen for critically ill adults 
undergoing tracheal intubation.  Based on the available data from these small randomized 
clinical trials, preoxygenation with non-invasive positive pressure ventilation and 
preoxygenation with facemask oxygen both represent acceptable approaches to emergency 
tracheal intubation.  Both approaches are considered standard-of-care and are used commonly in 
current clinical practice. 
 
 
2.1.7 Rationale for a Large Multicenter Trial of Preoxygenation 
Because of the imperative to optimize emergency tracheal intubation in clinical care, the 
common use of both preoxygenation with non-invasive positive pressure ventilation and 
preoxygenation with facemask oxygen in current clinical practice, and the lack of existing data 
from randomized trials to definitively inform whether preoxygenation strategy effects the rate of 
hypoxemia, examining the approach to preoxygenation during emergency tracheal intubation 
represents an urgent research priority.  To address this knowledge gap, we propose to conduct a 
large, multicenter, randomized clinical trial comparing preoxygenation with non-invasive 
positive pressure ventilation versus preoxygenation with facemask oxygen with regard to 
hypoxemic during tracheal intubation of critically ill adults in the ED or ICU. 
 
 
 
 

 
 
 
10 
 
2.2. Primary Aim and Hypothesis 
 
2.2.1 Study Aim: 
To compare the effect of preoxygenation with non-invasive positive pressure ventilation versus 
preoxygenation with facemask oxygen on hypoxemia during tracheal intubation of critically ill 
adults. 
 
2.2.2 Study Hypothesis: 
Among critically ill adults undergoing tracheal intubation, preoxygenation with non-invasive 
positive pressure ventilation will reduce the incidence of hypoxemia between induction to 2 
minutes after tracheal intubation, compared to preoxygenation with facemask oxygen. 
 
2.3 Study Description 
We will conduct an investigator-initiated, non-blinded, pragmatic, parallel-group, randomized 
trial evaluating the effect of preoxygenation with non-invasive ventilation versus preoxygenation 
with a facemask on the incidence of hypoxemia among critically ill adults undergoing tracheal 
intubation in the ED and ICU. 
 
3. STUDY POPULATION AND ENROLLMENT 
 
3.1 Inclusion Criteria: 
1. Patient is located in a participating unit 
2. Planned procedure is tracheal intubation using a laryngoscope and sedation 
3. Planned operator is a clinician expected to routinely perform tracheal intubation in the 
participating unit. 
 
3.2 Exclusion Criteria: 
1. Patient is receiving positive pressure ventilation by a mechanical ventilator, bag-mask 
device, or laryngeal mask airway 
2. Patient is known to be less than 18 years old 
3. Patient is known to be pregnant 
4. Patient is known to be a prisoner 
5. Immediate need for tracheal intubation precludes safe performance of study procedures 
6. Patient is apneic, hypopneic, or has another condition requiring positive pressure 
ventilation between enrollment and induction 
7. Operator has determined that preoxygenation with non-invasive positive pressure 
ventilation or preoxygenation with a facemask is required or contraindicated for optimal 
care of the patient 
 
4. CONSENT 
Non-invasive positive pressure ventilation and facemask oxygen are both common approaches to 
preoxygenation during emergency tracheal intubation in the ED and ICU.  Both represent 
standard of care treatments in current clinical practice.(8, 22)  Results from prior clinical trials 
are conflicting and to not demonstrate superiority of one approach over the other. Consequently, 
some guidelines recommend non-invasive positive pressure ventilation and other guidelines 
recommend facemask oxygen.(23-26)  As a result, significant variation exists in the approach to 

 
 
 
11 
 
preoxygenation in current clinical practice, with both non-invasive positive pressure ventilation 
and facemask oxygen used commonly.(8, 27, 28).  This trial will enroll patients who are 
undergoing emergency tracheal intubation as part of their clinical care for whom treating 
clinicians have determined that preoxygenation with EITHER non-invasive positive pressure 
ventilation OR facemask oxygen would be consistent with the optimal care of the patient. 
 
We will request a waiver of informed consent because the study involves minimal incremental 
risk and obtaining informed consent would be impracticable. 
 
Participation in this study involves minimal incremental risk because: 
• All patients eligible for the study are already undergoing tracheal intubation with 
preoxygenation as part of their clinical care 
• Preoxygenation with non-invasive positive pressure ventilation and preoxygenation with 
facemask oxygen are both standard-of-care interventions that are commonly used in 
current clinical care 
• No benefits or risks are currently known to differ between the two approaches 
• Both approaches have determined to be acceptable options for the optimal care of the 
patient by treating clinicians (otherwise the patient is excluded from the study) 
  
Obtaining informed consent would be impracticable because:  
• The expected medical condition of  patients requiring emergency tracheal 
intubation in the ED or ICU is critical.  Based on prior trials in the same patient 
population and setting, approximately 70% of patients eligible for the PREOXI trial will 
be experiencing encephalopathy (altered mental status) due to their critical illness. The 
anticipated median Glasgow coma scale score is 11 (equivalent to moderate brain injury).  
Among the minority of patients whose level of consciousness is not impaired, 45-55% 
will be experiencing acute delirium.  Thus, most patients eligible for PREOXI will not 
have the capacity to provide informed consent.  Further, family members or legally 
authorized representatives (LAR) are frequently unavailable when critically ill patients 
undergo intubation in the ED or ICU.   
• The time available for patients or LARs to consider participation will be 
insufficient.  Even when a patient retains capacity or a LAR is immediately available, a 
meaningful informed consent process is precluded by the rapid clinical events leading up 
to emergency tracheal intubation. No published literature has quantified the time from 
clinicians’ decision to perform emergency tracheal intubation (the inclusion criteria for 
PREOXI) until the initiation of the intubation procedure (completion of the PREOXI 
intervention). In a convenience sample of 25 consecutive intubations in the VUMC ED or 
ICU, approximately 50% of intubations occurred within 5 minutes after treating 
clinicians verbalized the decision to intubate or ordered an induction medication.  
Obtaining informed consent for research requires study personnel to assess decisional 
capacity, identify a LAR when appropriate, review the informed consent document in a 
quiet setting, and provide sufficient time for the patient or LAR to process the 
information, assess the risks and benefits of participation, and ask questions.  Meaningful 
informed consent cannot be executed in the 5 minutes between the decision to perform 
emergency tracheal intubation and initiation of the procedure.  Emergency tracheal 
intubation of critically ill adults is a time-sensitive procedure for which every minute of 

 
 
 
12 
 
delay increases the likelihood of hypoxemia, hypotension, and peri-procedural cardiac 
arrest.  Delaying emergency tracheal intubation for a critically ill adult to attempt a 
meaningful informed consent process would be unsafe, impracticable, and unethical. 
 
Because the study involves minimal incremental risk, the study would not adversely affect the 
welfare or privacy rights of the participant, and obtaining informed consent would be 
impracticable, we will request a waiver of informed consent.  Numerous previous randomized 
trials comparing two standards of care for emergency intubation have been completed under a 
waiver of informed consent [NCT 0040102, NCT 03928925, NCT 02497729, NCT 02051816, 
NCT 00441792].(7, 29-32) 
 
4.1 Provision of Information after Participation 
Information regarding the study will be made available to each patient and family following 
intubation using a patient and family information sheet.  The sheet will inform the patient of his 
or her enrollment in the PREOXI study, describe the study, and provide contact information for 
the research team for any questions or concerns. 
  
 
5. ENROLLMENT AND RANDOMIZATION 
 
5.1 Study Enrollment Locations:  
• Participating emergency departments 
• Participating intensive care units 
 
5.2 Study Sites: 
• Vanderbilt University Medical Center 
• Other locations  
 
5.3 Enrollment and Randomization 
All patients requiring emergency tracheal intubation in a participating ED or ICU will be 
screened for eligibility for the PREOXI trial using the eligibility criteria in Section 3. Patients 
who do not meet inclusion criteria will be considered ‘ineligible’. Patients who meet inclusion 
criteria but also meet at least one exclusion criterion will be considered ‘excluded.’  For patients 
who are excluded, the reason for exclusion will be recorded.  For patients who do meet eligibility 
criteria but are not enrolled, the reason will be recorded.   
 
At enrollment, patients will be randomized in a 1:1 ratio to preoxygenation with non-invasive 
positive pressure ventilation or preoxygenation with facemask oxygen using randomly permuted 
blocks of variable size.  The randomization will be stratified by study site (i.e., each participating 
ED or ICU will comprise a different stratum).  The study group assignment will be placed in in 
opaque randomization envelopes, which will be located within participating units. Study group 
assignment will remain concealed to study personnel and treating clinicians until after the 
decision has been made to enroll the patient in the study.  
 
To facilitate rapid enrollment during this time-sensitive procedure, sequentially numbered 
randomization envelopes will be located adjacent to the equipment required for emergency 

 
 
 
13 
 
tracheal intubation (i.e., airway equipment cart, ICU work room).  When the need for emergency 
tracheal intubation is recognized, envelopes will be obtained by the treating clinician performing 
the intubation (referred to as the “operator”) or by a delegate while the operator sets up the 
equipment required for intubation.  Inclusion and exclusion criteria will be posted with 
randomization envelopes and printed on the outside of enrollment envelopes.  As the operator 
sets up the equipment for emergency tracheal intubation, a verbal “pre-procedural time-out” 
(described below) will be performed. Based on the experience from our 8 prior randomized 
clinical trials using the same process to perform randomization and group assignment during 
emergency tracheal intubation, all enrollment procedures can be completed in less than one 
minute. For a small number of particularly urgent intubations (e.g., an intubation for cardiac 
arrest), the urgency of the procedure or the limited availability of clinical personnel will preclude 
obtaining and opening the randomization envelope. These cases will be excluded using the 
exclusion criterion that states “Immediate need for tracheal intubation precludes safe 
performance of study procedures” (see Section 3). 
 
As with all trials conducted to date by our investigators, we will evaluate for the possibility of 
selection bias via the systematic exclusion of a particular groups of patients.  A prospective list 
of excluded patients will be maintained by site PIs.  Data captured on excluded patients will be 
limited to date of exclusion and reason for exclusion. The number of patients excluded and 
reasons for excluded will be reported at the time of trial publication via a consort diagram.  No 
patient-level information on excluded patients will be entered into the study database.  The 
coordinating center will not receive any patient-level data on excluded participants. 
 
5.3.1 Pre-Procedural Time-Out to Prevent Enrollment of Ineligible Patients 
The enrollment materials for the trial will include instructions for a pre-procedural timeout in 
which treating clinicians or a delegate recite aloud the inclusion and exclusion criteria and 
confirm eligibility prior to enrollment. This process requires less than 10 seconds and can be 
easily completed while the equipment and medications needed for tracheal intubation are being 
obtained. This approach has been successfully used to confirm eligibility prior to enrollment in 
multiple prior trials [NCT03928925, NCT03787732]. (33) 
 
5.3.2 Monitoring and Reporting of Eligibility of Enrolled Patients 
For all enrolled patients, study personnel will independently verify eligibility criteria at the time 
of study record creation.  In the instance that a patient is enrolled who did not meet eligibility 
criteria, this will represent a protocol violation.  Site investigators will report such a protocol 
violation to the trial primary investigators and coordinating center within 24 hours of becoming 
aware of the occurrence of a protocol violation.  The primary investigators and coordinating 
center will report the details of such a protocol violation to the IRB within 7 days of becoming 
aware of the occurrence of a protocol violation. 
 
5.3.3 Handling of Patients Found to Be Prisoners after Enrollment 
Prisoners typically present with obvious physical signs such as prison uniforms, handcuffs, and 
the presence of law enforcement.  Training of treating clinicians and the enrollment procedures 
listed above (posting of inclusion and exclusion criteria alongside enrollment envelopes and a 
“pre-enrollment time-out” with verbal recitation of eligibility criteria) have proven to be 
effective in preventing the enrollment of prisoners in recent trials. 

 
 
 
14 
 
 
If a patient who presents to the ED or ICU is not known to be a prisoner at the time of enrollment 
and following enrollment is discovered to be a prisoner or becomes a prisoner between 
enrollment and the end of study follow up, all study procedures will stop immediately, the 
patient will be withdrawn from the study, and the patient’s study record will be expunged of all 
study data.  Because both study interventions are one-time, standard-of-care interventions which 
the patient was likely to receive in clinical care even if not participating in research, no further 
follow-up will occur. 
 
6. BLINDING 
Given the nature of the trial intervention, blinding of patients and treating clinicians to study 
group assignment is not possible.  
 
7. STUDY INTERVENTIONS 
 
7.1 Treatment of Study Patients 
For enrolled patients, study group assignment determines only the approach to preoxygenation.  
All other aspects of the intubation procedure will be at the discretion of the operator, including 
patient positioning, choice of sedative agent, use of a neuromuscular blocker, choice of 
laryngoscope, laryngoscope blade size, use of a bougie to intubate the trachea, use of external 
laryngeal manipulation to optimize laryngeal view, and endotracheal tube diameter.   
 
The administration of additional supplemental oxygen by nasal cannula is not controlled by the 
study and is permitted in both groups in any phase of the tracheal intubation procedure, including 
during laryngoscopy (referred to as “apneic oxygenation”).  The administration of ventilation via 
a bag-mask device will be permitted in both groups between induction and laryngoscopy.  
Operators may use a non-assigned approach to preoxygenation at any time if it is felt to be 
required for the safe management of the patient.  Use of a non-assigned preoxygenation strategy 
as the initial approach to preoxygenation will be collected and considered to represent a 
“crossover.”  For all patients in the trial, best practices in emergency tracheal intubation will be 
encouraged according to clinical protocols in the study settings.   
 
7.2 Preoxygenation with Non-Invasive Positive Pressure Ventilation Group 
Patients assigned to preoxygenation with non-invasive positive pressure ventilation will receive 
non-invasive mechanical ventilation via a tight-fitting mask from the initiation of preoxygenation 
until the initiation of laryngoscopy.  Trial protocol will not dictate the brand or type of 
mechanical ventilator that will be used to deliver non-invasive ventilation.    
 
7.3 Preoxygenation with Facemask Oxygen Group 
For patients randomized to preoxygenation with facemask oxygen, supplemental oxygen will be 
administered via a non-rebreather mask or bag-mask device without manual ventilation from the 
initiation of preoxygenation until induction.  Trial protocol will not dictate the brand or type of 
facemask. The decision between use of a non-rebreather mask and use of a bag-mask device will 
be made by treating clinicians.  The decision of whether to provide manual ventilation with a 
bag-mask device between induction and laryngoscopy will be made by treating clinicians.  
 

 
 
 
15 
 
 
8. RECORDED STUDY OUTCOMES 
 
8.1 Primary Outcomes  
• Hypoxemia, defined as a peripheral oxygen saturation < 85% during the interval between 
induction and 2 minutes after tracheal intubation 
 
8.2 Secondary Outcomes 
• Lowest oxygen saturation during the interval between induction and 2 minutes after 
tracheal intubation 
 
8.3 Safety Outcomes  
• Operator-reported aspiration 
• Fraction of inspired oxygen at 24 hours after induction 
• Oxygen saturation at 24 hours after induction 
• New pneumothorax, defined as radiology report of new pneumothorax on chest imaging 
in the 24 hours after induction.  
• New infiltrate, defined as radiology report of new infiltrate on chest imaging in the 24 
hours after intubation.  
 
8. 4 Exploratory Outcomes 
• Procedural Characteristics & Complications 
o 
Severe hypoxemia (lowest oxygen saturation of <80%) between induction and two 
minutes after tracheal intubation 
o 
Very severe hypoxemia (lowest oxygen saturation of <70%) between induction and 
two minutes after tracheal intubation 
o 
Oxygen saturation at induction 
o 
Systolic blood pressure at induction 
o 
Duration from induction to successful intubation (duration of the intubation 
procedure) 
o 
Cormack-Lehane grade of glottic view on first attempt 
o 
Successful intubation on the first attempt 
o 
Number of laryngoscopy attempts 
o 
Number of attempts at passing a bougie 
o 
Number of attempts at passing an endotracheal tube 
o 
Cardiovascular collapse, defined as a composite of one or more of the following 
between induction and 2 minutes after intubation: 
1. 
Systolic blood pressure < 65 mmHg  
2. 
New or increased vasopressor  
3. 
Cardiac arrest not resulting in death within 1 hour of induction 
4. 
Cardiac arrest resulting in death within 1 hour of induction 
• Clinical Outcomes 
o 
28-day in-hospital mortality 
o 
Ventilator-free days to 28 days 
o 
ICU-free days to 28 days 
 

 
 
 
16 
 
9. DATA COLLECTION 
Data collected for the purposes of this study will come from three sources: [1] variables 
documented in the electronic health record as part of clinical care, [2] variables recorded by 
clinical staff’s bedside observation during the intubation procedure, and [3] variables reported by 
the operator immediately following the intubation procedure. Data from the electronic medical 
record will be collected by trained study personnel (key study personnel) using a standardized 
electronic case report form.  It is infeasible to have research staff present during each emergency 
tracheal intubation.  Therefore, clinical staff not participating in the tracheal intubation procedure 
will collect data elements relevant to outcomes of emergency tracheal intubation using a 
standardized electronic case report form. These variables are readily available by bedside 
observation and do not require interaction with the patient but are not uniformly documented in 
the electronic health record (e.g., lowest oxygen saturation and lowest blood pressure from 
induction to two minutes after tracheal intubation).  Immediately following the intubation 
procedure, the operators will record data elements known only to them (e.g., glottic view 
obtained during the procedure and visualization of gastric aspiration in the oropharynx).  
Operators and clinical staff observing the procedure at the bedside will not be considered key 
study personnel. Training will be provided to clinicians who may serve as operators or bedside 
observers.  The activities of these clinicians will be limited to the reporting of data routinely 
reported as part of clinical care.   
 
The following variables will be recorded: 
 
Baseline:  
● age 
● sex 
● race and ethnicity 
● height 
● weight 
● body mass index 
● Acute Physiology and Chronic Health Evaluation (APACHE II) score  
● active medical problems at the time of enrollment 
● comorbidities  
● indication for intubation 
● vasopressor receipt in the hour prior to enrollment 
● highest FiO2 in the hour prior to enrollment 
● lowest SpO2/FIO2 ratio (or PaO2/FIO2 ratio) in the hour prior to enrollment 
● Glasgow Coma Scale score 
● oxygen delivery device at enrollment 
● assessment of the likelihood of a difficult intubation 
● presence of difficult airway characteristics 
○ limited mouth opening 
○ limited anatomic neck mobility 
○ cervical immobilization due to trauma 
○ increased neck circumference 
○ facial trauma 
○ obesity 

 
 
 
17 
 
○ body fluids anticipated to obscure laryngeal view 
● operator’s level of training and specialty 
● operator’s prior intubation experience  
 
Peri-procedural:  
 
Enrollment to induction 
● SpO2 and FiO2 at enrollment 
● oxygen saturation from enrollment to induction 
● approach to preoxygenation 
● duration of preoxygenation 
 
Induction to first laryngoscopy attempt 
● time of sedative administration (induction) 
● sedative agent and dose 
● neuromuscular blocking agent and dose 
● administration of an intravenous fluid bolus prior to induction 
● administration of a vasopressor prior to induction 
● SpO2 at induction 
● systolic blood pressure at induction 
● approach to oxygen administration and ventilation between induction and 
laryngoscopy 
 
First laryngoscopy attempt to successful intubation 
● time of start of first laryngoscopy attempt 
● laryngoscope model, blade size, blade shape on first attempt 
● use of video screen (if applicable) on first laryngoscopy attempt 
● best Cormack-Lehane grade of glottic view on the first laryngoscopy attempt 
● presences of body fluids obstructing laryngeal view 
● presence of upper airway obstruction or edema 
● receipt of chest compressions at time of first laryngoscopy attempt 
● number of intubation attempts 
○ number of times laryngoscope entered mouth 
○ number of times bougie entered mouth (if applicable) 
○ number of times endotracheal tube entered mouth 
● reason for failure of first intubation attempt (if applicable) 
● device(s) used on subsequent intubation attempts (if applicable) 
● necessity of an additional operator 
● esophageal intubation 
● injury to the teeth 
● operator-reported aspiration between induction and intubation 
● time of successful tracheal intubation 
● endotracheal tube size 
● lowest SpO2 from induction until 2 minutes after intubation 
● lowest systolic blood pressure from induction until 2 minutes after intubation 
● new or increased vasopressor use from induction until 2 minutes after intubation 
● cardiac arrest from induction until 2 minutes after intubation not resulting in death 
within 1 hour of induction 

 
 
 
18 
 
● cardiac arrest from induction until 2 minutes after intubation resulting in death 
within 1 hour of induction 
 
In-hospital: 
 
24 hours after enrollment 
● new pneumothorax detected in the first 24 hours after enrollment 
● vasopressor receipt at 24 hours after enrollment 
● SpO2 at 24 hours after enrollment 
● FiO2 at 24 hours after enrollment 
● PEEP at 24 hours after enrollment 
● systolic blood pressure at 24 hours after enrollment 
28 days after enrollment 
● 28-day in-hospital mortality 
● ventilator-free days 
● ICU-free days 
 
10. Risks and Benefits 
 
10.1 Risks of Tracheal Intubation in the ED or ICU 
Patients who are severely ill enough to require emergency tracheal intubation in the ED or ICU 
as part of their clinical care are at high risk of complications.  Many patients are undergoing 
intubation for hypoxemia or hemodynamic instability. Severe hypoxemia or cardiovascular 
instability occurs during nearly half of intubations in the ED and ICU (1, 2, 4, 5).  Hypoxemia 
and hypotension during intubation are associated with an increased risk of cardiac arrest and 
death.(9, 10) Cardiac arrest occurs in 1-in-25 cases of emergency tracheal intubation.   
 
Other complications during intubation may include aspiration (approximately 2.8% of cases), 
esophageal intubation (1.3%) injury to oral or dental structures (0.2%), and pneumothorax 
(0.1%).  The long-term consequences of complications occurring during emergency tracheal 
intubation are unclear.  Neurologic recovery from traumatic brain injury may be worse after 
hypoxemia due to secondary ischemic insult.(11)  
 
10.2 Potential Risks of Participation in the PREOXI Trial 
Participation in the PREOXI trial involves minimal incremental risk because: 
• All patients eligible for the study are already experiencing emergency tracheal intubation, 
with the accompanying risks, as part of their clinical care 
• Preoxygenation with non-invasive positive pressure ventilation and preoxygenation with 
facemask oxygen are both standard-of-care interventions that are commonly used in 
current clinical care.  All patients eligible for the study would experience an approach to 
preoxygenation as part of their clinical care 
• No benefits or risks are currently known to differ between the two approaches 
• Both approaches have determined to be acceptable options for the optimal care of the 
patient by treating clinicians (otherwise the patient is excluded from the study) 
 
Although no risks are currently known to differ between preoxygenation with non-invasive 
positive pressure ventilation and preoxygenation with facemask oxygen (both standard-of-care 

 
 
 
19 
 
approaches in currently clinical care), it is possible that the results of the PREOXI trial will 
ultimately demonstrate a difference between the two approaches in the risk of hypoxemia, 
hypotension, cardiac arrest, aspiration, or another outcome. 
 
10.3 Potential Benefits of Participation in the PREOXI Trial 
The primary benefits of the PREOXI trial will be the indirect benefits to society that would result 
if one approach to preoxygenation is found to prevent complications.  Because millions of 
critically ill adults undergo emergency tracheal intubation each year, if one of the two 
approaches were found to prevent serious complications, the findings would immediately 
improve the care provided to millions of severely ill patients. Compared to the minimal risks of 
participation in the study, the pursuit of these benefits is reasonable.   
 
10.4 Minimization of Risk 
Federal regulations 45 CFR 46.111(a)(1) require that risks to patients are minimized by using 
procedures which are consistent with sound research design. This trial meets this human subjects 
protection requirement by incorporating numerous design elements to minimize risk to patients.  
 
Both approaches to preoxygenation have been used in clinical practice for decades with an 
established safety profile in the same populations included in the PREOXI trial.  To further 
mitigate risk, we will exclude patients with specific risk factors for adverse events such as those 
already receiving non-invasive positive pressure ventilation and any patient for whom treating 
clinicians determine that a specific approach to preoxygenation is required or contraindicated for 
the optimal care of the patient.  
 
The trial protocol includes monitoring of adverse events, robust assessment of clinical outcomes, 
and an interim analysis by an independent DSMB, empowered to stop the trial or modify the trial 
protocol at any time. 
 
Finally, to limit the risks associated with the collection of protected health information (PHI), 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. 
REDCap tools will be used to ensure that the PHI that is collected is only visible to investigators 
at the healthcare system where the patient was enrolled. To protect participant privacy, REDCap 
tools will be used to ensure that only deidentified data can be exported for use during analysis.  
 
11. Statistical Considerations 
 
11.1 Initial Sample Size Determination: 
The minimum clinically important difference in hypoxemia that would be required to justify 
routine preoxygenation with non-invasive positive pressure ventilation rather than 
preoxygenation with facemask oxygen during emergency tracheal intubation of critically ill 
adults is uncertain.  The current trial will be designed to detect a 6% absolute difference between 
groups in the rate of hypoxemia.  An absolute difference of 6% in the incidence of hypoxemia is 
similar to or smaller than the difference considered to be clinically meaningful in the design of 
prior airway management trials.(19, 31) Assuming an incidence of hypoxemia of 17% in the 
facemask group based on data from two recently completed trials in the same ED and ICU 

 
 
 
20 
 
settings, detecting a 6% absolute decrease in the incidence of hypoxemia with 85% power at a 
two-sided alpha level of 0.05 would require enrollment of 1,264 patients (632 per group). 
Anticipating missing data for up to 3% of patients, we will plan to enroll a total of 1,300 patients 
(650 per group).  This sample size calculation was performed in PS version 3.1.2. 
11.2 Statistical Analysis: 
Prior to the conclusion of enrollment, we will make publicly available a complete, final statistical 
analysis plan. Analyses conducted in accordance with the statistical analysis plan will be 
identified as a priori. Any additional analyses requested by the investigators or reviewers will be 
identified as post hoc. 
 
11.2.1 Primary Analysis: 
The primary analysis will be an unadjusted, intention-to-treat comparison of patients randomized 
to preoxygenation with non-invasive positive pressure ventilation versus patients randomized to 
preoxygenation with facemask oxygen with regard to the primary outcome. The difference 
between the two study groups will be compared using a Chi-squared test. 
 
11.2.2 Secondary Analysis: 
We will perform intention-to-treat comparisons of secondary, exploratory, and safety outcomes. 
Continuous outcomes will be compared with Wilcoxon Rank Sum test and categorical variables 
with the Chi-squared test. Data on patient characteristics will be summarized as number and 
proportion for categorical variables and as median and interquartile range for continuous 
variables. 
 
We will also perform an adjusted comparison of the primary outcome between groups using a 
generalized linear mixed effects model including a random effect for site and fixed effects for 
group assignment and the following pre-specified baseline variables:  
 
1. Age; 
2. Sex; 
3. Race and Ethnicity; 
4. BMI; 
5. Location at enrollment (ED or ICU) 
6. Highest fraction of inspired oxygen in the hour prior to initiation of preoxygenation; 
7. APACHEII score; and 
8. Indication for intubation (hypoxemic respiratory failure: Yes vs No) 
9. Operator experience (number of previous intubations the operator has performed) 
 
11.2.3 Effect Modification (Subgroup Analyses) 
To evaluate whether pre-specified baseline variables modify the effect of study group assignment 
on the primary outcome, we will perform logistic regression modelling with the primary outcome 
as the dependent variable and independent variables of study group, the proposed effect 
modifier, and the interaction between the two.  Any interaction term with a p-value less than 0.1 
will be considered to identify an effect modifier.  To account for non-linear relationships, 
continuous variables will be analyzed using restricted cubic splines with between 3 and 5 knots. 
Forest plots will be used to graphically display the adjusted analyses, and locally weighted 
regression or partial effects plots will be used to portray the association between continuous 

 
 
 
21 
 
covariates and the outcome.  A full list of prespecified subgroup analyses will be outlined in the 
detailed Statistical Analysis Plan but will include: 
 
 
1. BMI; 
2. Location (ED vs ICU); 
3. Highest fraction of inspired oxygen in the hour prior to initiation of preoxygenation) 
4. Indication for intubation (hypoxemic respiratory failure, other) ; 
5. APACHEII score; and 
6.  
 
11.3 Interim Analysis 
The DSMB will conduct a single interim analysis for efficacy and safety at the anticipated 
halfway point of the trial, after enrollment of 650 patients. The pre-specified stopping boundary 
for efficacy will be a P value < 0.001 for the difference between group in the primary outcome 
using a Chi-square test. This conservative Haybittle–Peto boundary will allow the final analysis 
to be performed using an unchanged level of significance (two-sided P value < 0.05). 
Finally, after the interim analysis, the DSMB will evaluate the rate of the primary outcome in the 
facemask group. If the incidence of the primary outcome in the facemask group differs from the 
original estimate, the DSMB may suggest an increase sample size that would maintain the pre-
planned statistical power to detect the pre-planned relative risk difference in the primary 
outcome between groups. 
11.4 Correction for Multiple Testing 
We will analyze a single pre-specified primary outcome and a single pre-specified secondary 
outcome. Consistent with recommendations of the Food and Drug Administration60 and the 
European Medicines Association,61 each will be tested using a two-sided P value with a 
significance level of 0.05. For all other analyses except safety 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,62 and no corrections for multiple 
comparisons will be performed. 
11.5 Handling of Missing Data 
No patients will be lost to follow up before the measurement of the primary outcome, but oxygen 
saturation may be unavailable in some cases (equipment malfunction, observer error during a 
rapid, emergency procedure, or cardiac arrest).  Missing data will not be imputed for the primary 
outcome, or any of the secondary or exploratory outcomes. In adjusted analyses, missing data for 
baseline covariates will be imputed using multiple imputations. 
12. Privacy and Confidentiality 
All patients will be assigned a unique study ID number for use in the coded study database.  
Study personnel will access patients’ electronic health records at three planned time points: 
immediately following enrollment; when collecting baseline demographics and comorbidities 
(may occur anytime between enrollment and final data collection); and when collecting clinical 

 
 
 
22 
 
outcomes (any time after the first of discharge or 28 days following intubation).  The electronic 
health record may be accessed again, as needed, between enrollment and study publication to 
respond to queries from the coordinating center focused on ensuring data completeness and 
quality. The minimal PHI that is collected will be visible only to site investigators at the site 
where the patient was enrolled.  The dataset for analysis will contain the unique study ID and no 
other patient identifiers.  At the time of publication, a fully de-identified version of the database 
will be generated. 
 
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. Data collected from the medical record will be entered into the secure online 
database REDCap. Hard copies of the data collection sheet completed at the time of the airway 
management event will be stored in a locked room until after the completion of enrollment and 
data cleaning. Following publication of the study results, all hard copies of data collection forms 
will be destroyed and the REDCap database will be fully de-identified in accordance with 
institutional regulations.  
 
13. Follow-up and Record Retention 
Patients will be followed after enrollment up to 28 days or until hospital discharge, whichever 
occurs first.  Data collected from the medical record will be entered into the secure online 
database REDCap. Hard copies of the data collection sheet completed at the time of the airway 
management event 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. The minimal PHI that is collected will be available only to site 
investigators at the site where the patient was enrolled. At the time of publication, a fully de-
identified version of the database will be generated. 
14. Safety Monitoring and Adverse Events 
Assuring patient safety is an essential component of this protocol.  Preoxygenation with non-
invasive positive pressure ventilation and preoxygenation with facemask oxygen are both 
standard-of-care interventions that have been used in clinical practice for decades with an 
established safety profile. However, any trial conducted during a high-risk, time-sensitive 
procedure like tracheal intubation of critically ill patients raises unique safety considerations. 
This protocol addresses these considerations through: 
1. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse 
events from preoxygenation with non-invasive positive pressure ventilation or 
preoxygenation with facemask oxygen; 
2. Systematic collection of outcomes relevant to the safety of preoxygenation with non-invasive 
positive pressure ventilation and preoxygenation with facemask oxygen; 
3. Structured monitoring, assessment, recording, and reporting of adverse events. 
 

 
 
 
23 
 
14.1 Adverse Event Definitions 
Adverse Event – An adverse event will be defined as any untoward or unfavorable medical 
occurrence in a human subject temporally associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research.  Any 
adverse event occurring during the research will be classified according to the following 
characteristics: 
 
• Seriousness – An adverse event will be considered “serious” if it: 
o Results in death; 
o Is life-threatening (defined as placing the patient at immediate risk of death); 
o Results in inpatient hospitalization or prolongation of existing hospitalization;  
o Results in a persistent or significant disability or incapacity; 
o Results in a congenital anomaly or birth defect; or  
o Based upon appropriate medical judgment, may jeopardize the patient’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
 
• Unexpectedness – An adverse event will be considered “unexpected” if the nature, 
severity, or frequency is neither consistent with: 
o The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in the protocol-related documents, such 
as the IRB-approved research protocol; nor 
o The expected natural progression of any underlying disease, disorder, or condition 
of the subject experiencing the adverse event and the subject’s predisposing risk 
factor profile for the adverse event. 
 
• Relatedness – The strength of the relationship of an adverse event to a study intervention 
or study procedure will be defined as follows:  
o Definitely Related: The adverse event follows (1) a reasonable, temporal 
sequence from a study procedure AND (2) cannot be explained by the known 
characteristics of the patient’s clinical state or other therapies AND (3) evaluation 
of the patient’s clinical state indicates to the investigator that the experience is 
definitely related to study procedures.  
o Probably or Possibly Related: The adverse event meets some but not all of the 
above criteria for “Definitely Related”. 
o Probably Not Related: The adverse event occurred while the patient was on the 
study but can reasonably be explained by the known characteristics of the 
patient’s clinical state or other therapies.  
o Definitely Not Related: The adverse event is definitely produced by the patient’s 
clinical state or by other modes of therapy administered to the patient.  
o Uncertain Relationship: The adverse event does not fit in any of the above 
categories. 
 
14.2 Monitoring for Adverse Events 
The time interval during which patients will be monitored for the occurrence of adverse events 

 
 
 
24 
 
begins at randomization and ends at the first of hospital discharge or 28 days.  Adverse events 
occurring before randomization or after hospital discharge or 28 days will not be collected. The 
lead investigator at each enrolling site will have primary responsibility overseeing the 
monitoring, assessment, and reporting of adverse events. Site study personnel will evaluate for 
the occurrence of adverse events by manual review of the electronic health record and by 
communication with treating clinicians.  Site study personnel will evaluate for the occurrence of 
adverse events by manual review of the electronic health record at two time points.  The first will 
occur approximately 24 hours after randomization at the time of initial data collection.  The 
second will occur at the first of hospital discharge or 28 days after enrollment at the time of final 
data collection.  Study personnel at each site will also communicate regularly with the treating 
clinicians who perform tracheal intubation in the study environments between enrollment and 28 
days after enrollment to solicit information about any potential adverse events.  If study 
personnel at a site identify a potential adverse event, the lead investigator at the site will be 
immediately notified.  The lead investigator at the site will assess the seriousness, 
unexpectedness, and relatedness of the potential adverse event.  With assistance as needed from 
the coordinating center and the trial primary investigator, the lead investigator at the site will 
determine whether the event qualifies for recording and reporting. 
 
14.3 Recording and Reporting Adverse Events 
The following types of adverse events will be recorded and reported: 
• Adverse events that are Serious and Definitely Related, Probably or Possibly Related, or 
of Uncertain Relationship. 
• Adverse events that are Unexpected and Definitely Related, Probably or Possibly 
Related, or of Uncertain Relationship. 
Adverse events that do not meet the above criteria will not be recorded or reported.  Adverse 
events that the lead investigator at a site assesses to meet the above criteria for recording and 
reporting will be entered into the adverse event electronic case report form in the trial database.  
The lead investigator at the site will record an assessment of each characteristic for the adverse 
event, including seriousness, unexpectedness, and relatedness.  For any adverse event that is 
serious AND unexpected, and definitely related, probably or possibly related, or of uncertain 
relationship, the lead investigator at the site will report the adverse event to the coordinating 
center and the trial primary investigator within 24 hours of becoming aware of the adverse 
event.  For any other adverse event requiring recording and reporting, the lead investigator at the 
study site will report the adverse event to the coordinating center and the trial principal 
investigator within 72 hours of becoming aware of the adverse event.  The coordinating center 
and the trial principal investigator will coordinate with the lead investigator at the site to obtain 
information about the adverse event regarding each characteristic for the adverse event, 
including seriousness, expectedness, and relatedness.  The lead investigator at the site will be 
responsible for making final determinations regarding seriousness and unexpectedness.  The 
coordinating center and trial principal investigator will be responsible for making final 
determinations regarding relatedness. 
 
For adverse events that meet the above criteria for recording and reporting, the coordinating 
center will notify the DSMB, the IRB, and the sponsor in accordance with the following 
reporting plan: 

 
 
 
25 
 
Characteristics of the Adverse Event 
Reporting Period 
Fatal or life-threatening (and therefore 
serious), unexpected, and definitely related, 
probably or possibility related, or of uncertain 
relationship. 
Report to the DSMB, IRB, and sponsor within 
7 days after notification of the event. 
Serious but non-fatal and non-life-
threatening, unexpected, and definitely 
related, probably or possibly related, or of 
uncertain relationship. 
Report to DSMB, IRB, and sponsor within 15 
days of notification of the event. 
All other adverse events meeting criteria for 
recording and reporting. 
Report to DSMB in regularly scheduled 
DSMB safety reports. 
The coordinating center will distribute the written summary of the DSMB’s periodic review of 
reported adverse events to the IRB in accordance with NIH guidelines: 
(http://grants.nih.gov/grants/guide/notice-files/not99-107.html).  
14.4 Clinical Outcomes that may be Exempt from Adverse Event Recording and Reporting 
In this study of critically ill patients at high risk for death and other adverse outcomes due to 
their underlying critical illness, clinical outcomes, including death and organ dysfunction, will be 
systematically collected and analyzed for all patients. The primary, secondary, safety, and 
exploratory outcomes will be recorded and reported as clinical outcomes and not as adverse 
events unless treating clinicians or site investigators believe the event is Definitely Related or 
Probably or Possibly Related to the study intervention or study procedures.  This approach – 
considering death and organ dysfunction as clinical outcomes rather than adverse events and 
systemically collecting these clinical outcomes for analysis – is common in ICU trials. This 
approach ensures comprehensive data on death and organ dysfunction for all patients, rather than 
relying on sporadic adverse event reporting to identify these important events.  The following 
events are examples of study-specific clinical outcomes that would not be recorded and reported 
as adverse events unless treating clinicians or site investigators believe the event was Definitely 
Related or Probably or Possibly Related to the study intervention or study procedures: 
• Death (all deaths occurring prior to hospital discharge or 28 days will be recorded); 
• Organ dysfunction 
o Pulmonary – hypoxemia, aspiration, acute hypoxemic respiratory failure, 
pneumothorax 
o Cardiac – hypotension, shock, vasopressor receipt, cardiac arrest; 
• Duration of mechanical ventilation; 
• Duration of ICU admission; 
• Duration of hospitalization 
 
Note: A study-specific clinical outcome may also qualify as an adverse event meeting criteria for 
recording and reporting. For example, a pneumothorax that the investigator considers Definitely 
Related to preoxygenation with non-invasive positive pressure ventilation would be both 
recorded as a study-specific clinical outcome and recorded and reported as a Serious and 
Definitely Related adverse event. 
 

 
 
 
26 
 
14.5 Unanticipated Problems involving Risks to Subjects or Others 
Investigators must also report Unanticipated Problems Involving Risks to Subjects or Others 
(“Unanticipated Problems”), regardless of severity, associated with study procedures within 24 
hours of the site investigator becoming aware of the Unanticipated Problem. An Unanticipated 
Problem is defined as any incident, experience, or outcome that meets all of the following 
criteria:  
• Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol; and (b) the characteristics of the subject population being studied; AND 
• Definitely Related or Probably or Possibly Related to participation in the research (as 
defined above in the section on characteristics of adverse events); AND  
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
If any study personnel at a site become aware of an event that may represent an Unanticipated 
problem, they will immediately contact the lead investigator for the site.  The lead investigator 
for the site will assess whether the event represents an Unanticipated Problem by applying the 
criteria described above.  If the lead investigator at a site determines that the event represents an 
Unanticipated Problem, the lead investigator at the site will record the Unanticipated Problem in 
the Unanticipated Problem electronic case report form in the trial database.  The lead investigator 
at the site will then communicate that an Unanticipated Problem has occurred to the coordinating 
center and the principal investigator within 24 hours of the lead investigator at the site 
becoming aware of the Unanticipated Problem.  The coordinating center and principal 
investigator will coordinate with the lead investigator at the site to obtain information about the 
Unanticipated Problem.  The coordinating center will report the Unanticipated Problem to the 
DSMB, IRB, and sponsor within 15 days of becoming aware of the Unanticipated Problem. 
 
15. Data and Safety Monitoring Board (DSMB) 
The principal role of the DSMB is to assure the safety of patients in the trial. They will regularly 
monitor data from this trial, review and assess the performance of its operations, and make 
recommendations to the steering committee and sponsor with respect to:  
• Participant safety and risk/benefit ratio of study procedures and interventions 
• 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  
• Possible early termination of the trial because of new external information, early 
attainment of study objectives, safety concerns, or inadequate performance 
 
The DSMB will consist of members with expertise in bioethics, emergency medicine, pulmonary 
and critical care medicine, anesthesia, biostatistics, and clinical trials. Appointment of all 
members is contingent upon the absence of any conflicts of interest. All the members of the 
DSMB are voting members. The coordinating center, principal investigators, and unblinded 
study biostatistician will be responsible for the preparation of all DSMB and adverse event 

 
 
 
27 
 
reports. The DSMB will develop a charter and review the protocol and patient notification forms 
during its first meeting. Subsequent DSMB meetings will be scheduled in accordance with the 
DSMB Charter. The DSMB will have the ability to recommend that the trial end, be modified, or 
continued unchanged. 
 
 

 
 
 
28 
 
References 
 
1. Martin LD, Mhyre JM, Shanks AM, Tremper KK, Kheterpal S. 3,423 emergency tracheal 
intubations at a university hospital: airway outcomes and complications. Anesthesiology 
2011; 114: 42-48. 
2. Simpson GD, Ross MJ, McKeown DW, Ray DC. Tracheal intubation in the critically ill: a 
multi-centre national study of practice and complications. Br J Anaesth 2012; 108: 792-
799. 
3. Leibowitz AB. Tracheal intubation in the intensive care unit: extremely hazardous even in the 
best of hands. Crit Care Med 2006; 34: 2497-2498. 
4. Jaber S, Jung B, Corne P, Sebbane M, Muller L, Chanques G, Verzilli D, Jonquet O, Eledjam 
JJ, Lefrant JY. An intervention to decrease complications related to endotracheal 
intubation in the intensive care unit: a prospective, multiple-center study. Intensive Care 
Med 2010; 36: 248-255. 
5. Griesdale DE, Bosma TL, Kurth T, Isac G, Chittock DR. Complications of endotracheal 
intubation in the critically ill. Intensive Care Med 2008; 34: 1835-1842. 
6. van Zundert A, Pieters B, Doerges V, Gatt S. Videolaryngoscopy allows a better view of the 
pharynx and larynx than classic laryngoscopy. Br J Anaesth 2012; 109: 1014-1015. 
7. Jabre P, Combes X, Lapostolle F, Dhaouadi M, Ricard-Hibon A, Vivien B, Bertrand L, 
Beltramini A, Gamand P, Albizzati S, Perdrizet D, Lebail G, Chollet-Xemard C, Maxime 
V, Brun-Buisson C, Lefrant JY, Bollaert PE, Megarbane B, Ricard JD, Anguel N, Vicaut 
E, Adnet F, Group KCS. Etomidate versus ketamine for rapid sequence intubation in 
acutely ill patients: a multicentre randomised controlled trial. Lancet 2009; 374: 293-300. 
8. Russotto V, Myatra SN, Laffey JG, Tassistro E, Antolini L, Bauer P, Lascarrou JB, 
Szuldrzynski K, Camporota L, Pelosi P, Sorbello M, Higgs A, Greif R, Putensen C, 
Agvald-Ohman C, Chalkias A, Bokums K, Brewster D, Rossi E, Fumagalli R, Pesenti A, 
Foti G, Bellani G, Investigators IS. Intubation Practices and Adverse Peri-intubation 
Events in Critically Ill Patients From 29 Countries. JAMA 2021; 325: 1164-1172. 
9. Davis DP, Dunford JV, Poste JC, Ochs M, Holbrook T, Fortlage D, Size MJ, Kennedy F, Hoyt 
DB. The impact of hypoxia and hyperventilation on outcome after paramedic rapid 
sequence intubation of severely head-injured patients. J Trauma 2004; 57: 1-8; discussion 
8-10. 
10. April MD, Arana A, Reynolds JC, Carlson JN, Davis WT, Schauer SG, Oliver JJ, Summers 
SM, Long B, Walls RM, Brown CA, 3rd, Investigators N. Peri-intubation cardiac arrest 
in the Emergency Department: A National Emergency Airway Registry (NEAR) study. 
Resuscitation 2021; 162: 403-411. 
11. Rubenson Wahlin R, Nelson DW, Bellander BM, Svensson M, Helmy A, Thelin EP. 
Prehospital Intubation and Outcome in Traumatic Brain Injury-Assessing Intervention 
Efficacy in a Modern Trauma Cohort. Front Neurol 2018; 9: 194. 
12. Janz DR, Casey JD, Semler MW, Russell DW, Dargin J, Vonderhaar DJ, Dischert KM, West 
JR, Stempek S, Wozniak J, Caputo N, Heideman BE, Zouk AN, Gulati S, Stigler WS, 
Bentov I, Joffe AM, Rice TW, Pre PI, Pragmatic Critical Care Research G. Effect of a 
fluid bolus on cardiovascular collapse among critically ill adults undergoing tracheal 
intubation (PrePARE): a randomised controlled trial. Lancet Respir Med 2019; 7: 1039-
1047. 

 
 
 
29 
 
13. Weingart SD. Preoxygenation, reoxygenation, and delayed sequence intubation in the 
emergency department. J Emerg Med 2011; 40: 661-667. 
14. Driver BE, Prekker ME, Kornas RL, Cales EK, Reardon RF. Flush Rate Oxygen for 
Emergency Airway Preoxygenation. Ann Emerg Med 2017; 69: 1-6. 
15. Delay JM, Sebbane M, Jung B, Nocca D, Verzilli D, Pouzeratte Y, Kamel ME, Fabre JM, 
Eledjam JJ, Jaber S. The effectiveness of noninvasive positive pressure ventilation to 
enhance preoxygenation in morbidly obese patients: a randomized controlled study. 
Anesth Analg 2008; 107: 1707-1713. 
16. Rusca M, Proietti S, Schnyder P, Frascarolo P, Hedenstierna G, Spahn DR, Magnusson L. 
Prevention of atelectasis formation during induction of general anesthesia. Anesth Analg 
2003; 97: 1835-1839. 
17. Grant S, Khan F, Keijzers G, Shirran M, Marneros L. Ventilator-assisted preoxygenation: 
Protocol for combining non-invasive ventilation and apnoeic oxygenation using a 
portable ventilator. Emerg Med Australas 2016; 28: 67-72. 
18. Dafilou B, Schwester D, Ruhl N, Marques-Baptista A. It's In The Bag: Tidal Volumes in 
Adult and Pediatric Bag Valve Masks. West J Emerg Med 2020; 21: 722-726. 
19. Casey JD, Janz DR, Russell DW, Vonderhaar DJ, Joffe AM, Dischert KM, Brown RM, Zouk 
AN, Gulati S, Heideman BE, Lester MG, Toporek AH, Bentov I, Self WH, Rice TW, 
Semler MW, PreVent I, the Pragmatic Critical Care Research G. Bag-Mask Ventilation 
during Tracheal Intubation of Critically Ill Adults. N Engl J Med 2019; 380: 811-821. 
20. Baillard C, Fosse JP, Sebbane M, Chanques G, Vincent F, Courouble P, Cohen Y, Eledjam 
JJ, Adnet F, Jaber S. Noninvasive ventilation improves preoxygenation before intubation 
of hypoxic patients. Am J Respir Crit Care Med 2006; 174: 171-177. 
21. Baillard C, Prat G, Jung B, Futier E, Lefrant JY, Vincent F, Hamdi A, Vicaut E, Jaber S. 
Effect of preoxygenation using non-invasive ventilation before intubation on subsequent 
organ failures in hypoxaemic patients: a randomised clinical trial. Br J Anaesth 2018; 
120: 361-367. 
22. Weingart SD, Levitan RM. Preoxygenation and prevention of desaturation during emergency 
airway management. Ann Emerg Med 2012; 59: 165-175 e161. 
23. Higgs A, McGrath BA, Goddard C, Rangasami J, Suntharalingam G, Gale R, Cook TM, 
Difficult Airway S, Intensive Care S, Faculty of Intensive Care M, Royal College of A. 
Guidelines for the management of tracheal intubation in critically ill adults. Br J Anaesth 
2018; 120: 323-352. 
24. Frerk C, Mitchell VS, McNarry AF, Mendonca C, Bhagrath R, Patel A, O'Sullivan EP, 
Woodall NM, Ahmad I, Difficult Airway Society intubation guidelines working g. 
Difficult Airway Society 2015 guidelines for management of unanticipated difficult 
intubation in adults. Br J Anaesth 2015; 115: 827-848. 
25. Quintard H, l'Her E, Pottecher J, Adnet F, Constantin JM, De Jong A, Diemunsch P, Fesseau 
R, Freynet A, Girault C, Guitton C, Hamonic Y, Maury E, Mekontso-Dessap A, Michel 
F, Nolent P, Perbet S, Prat G, Roquilly A, Tazarourte K, Terzi N, Thille AW, Alves M, 
Gayat E, Donetti L. Experts' guidelines of intubation and extubation of the ICU patient of 
French Society of Anaesthesia and Intensive Care Medicine (SFAR) and French-speaking 
Intensive Care Society (SRLF) : In collaboration with the pediatric Association of 
French-speaking Anaesthetists and Intensivists (ADARPEF), French-speaking Group of 
Intensive Care and Paediatric emergencies (GFRUP) and Intensive Care physiotherapy 
society (SKR). Ann Intensive Care 2019; 9: 13. 

 
 
 
30 
 
26. De Jong A, Jung B, Jaber S. Intubation in the ICU: we could improve our practice. Crit Care 
2014; 18: 209. 
27. Yoon U, Mojica J, Wiltshire M, Segna K, Block M, Pantoja A, Torjman M, Wolo E. 
Emergent airway management outside of the operating room - a retrospective review of 
patient characteristics, complications and ICU stay. BMC Anesthesiol 2019; 19: 220. 
28. Kajal K, Hazarika A, Reddy S, Jain K, Meena SC. Emergency Intubation outside Operating 
Room/Intensive Care Unit Settings: Are We Following the Recommendations for Safe 
Practice? Anesth Essays Res 2018; 12: 865-872. 
29. Driver BE, Prekker ME, Klein LR, Reardon RF, Miner JR, Fagerstrom ET, Cleghorn MR, 
McGill JW, Cole JB. Effect of Use of a Bougie vs Endotracheal Tube and Stylet on First-
Attempt Intubation Success Among Patients With Difficult Airways Undergoing 
Emergency Intubation: A Randomized Clinical Trial. JAMA 2018; 319: 2179-2189. 
30. Janz DR, Semler MW, Joffe AM, Casey JD, Lentz RJ, deBoisblanc BP, Khan YA, Santanilla 
JI, Bentov I, Rice TW, Check UPI, Pragmatic Critical Care Research G. A Multicenter 
Randomized Trial of a Checklist for Endotracheal Intubation of Critically Ill Adults. 
Chest 2018; 153: 816-824. 
31. Semler MW, Janz DR, Lentz RJ, Matthews DT, Norman BC, Assad TR, Keriwala RD, 
Ferrell BA, Noto MJ, McKown AC, Kocurek EG, Warren MA, Huerta LE, Rice TW, 
Investigators F, Pragmatic Critical Care Research G. Randomized Trial of Apneic 
Oxygenation during Endotracheal Intubation of the Critically Ill. Am J Respir Crit Care 
Med 2016; 193: 273-280. 
32. Tekwani KL, Watts HF, Sweis RT, Rzechula KH, Kulstad EB. A comparison of the effects 
of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a 
prospective, randomized study. Ann Emerg Med 2010; 56: 481-489. 
33. Russell DW, Casey JD, Gibbs KW, Dargin JM, Vonderhaar DJ, Joffe AM, Ghamande S, 
Khan A, Dutta S, Landsperger JS, Robison SW, Bentov I, Wozniak JM, Stempek S, 
White HD, Krol OF, Prekker ME, Driver BE, Brewer JM, Wang L, Lindsell CJ, Self 
WH, Rice TW, Semler MW, Janz D, Investigators PI. Protocol and statistical analysis 
plan for the PREventing cardiovascular collaPse with Administration of fluid 
REsuscitation during Induction and Intubation (PREPARE II) randomised clinical trial. 
BMJ Open 2020; 10: e036671. 
34. Itagaki T, Oto J, Burns SM, Jiang Y, Kacmarek RM, Mountjoy JR. The effect of head 
rotation on efficiency of face mask ventilation in anaesthetised apnoeic adults: A 
randomised, crossover study. Eur J Anaesthesiol 2017; 34: 432-440. 
  
 
 

 
 
 
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Tracking of Protocol Versions: 
Version 1.0 – Initial Submission  
Version 1.1: July 7, 2023:  
• Minor protocol revisions to align with prespecified statistical analysis plan: 
o Addition of new “New infiltrate” as a safety outcome and “Successful intubation 
on the first attempt” as an exploratory procedural outcome 
o Updated covariables in adjusted analysis of the primary outcome (a secondary 
analysis) to match prespecified statistical analysis plan 
o Updated prespecified variables to be evaluated in effect modification (subgroup 
analysis) to match prespecified statistical analysis plan 

 
Summary of Changes to the PREOXI Trial Protocol 
 
Tracking of Protocol Versions: 
Version 1.0 – Initial Protocol (February 21, 2022) 
Version 1.1: Final Trial Protocol (July 7, 2023):  
• Changes in this version: Minor protocol revisions to align with prespecified statistical 
analysis plan: 
o Addition of new “New infiltrate” as a safety outcome and “Successful intubation 
on the first attempt” as an exploratory procedural outcome; 
o Updated covariables in adjusted analysis of the primary outcome (a secondary 
analysis) to match prespecified statistical analysis plan; 
o Updated prespecified variables to be evaluated in effect modification (subgroup 
analysis) to match prespecified statistical analysis plan. 
 

Protocol and statistical analysis plan for the PREOXI trial of preoxygenation with 
noninvasive ventilation vs oxygen mask. 
 
Short Title: Protocol and Analysis Plan for the PREOXI Trial 
 
Kevin W. Gibbs MD*1, Adit A. Ginde MD MPH*2, Matthew E. Prekker MD MPH3,17, Kevin 
P. Seitz MD MSc4, Susan B. Stempek PA MBA5, Caleb Taylor MD MPH6, Sheetal 
Gandotra MD7, Heath White DO MS8, Daniel Resnick-Ault MD2, Akram Khan MD9, 
Amira Mohmed MD10, Jason C. Brainard MD11, Daniel G. Fein MD12, Neil R. Aggarwal 
MD13, Micah R. Whitson MD7,26, Stephen J. Halliday MD MSc14, John P. Gaillard 
MD15,16, Veronika Blinder DO10, Brian E. Driver MD17, Jessica A. Palakshappa MD MS1, 
Bradley D. Lloyd RRT RRT-ACCS18, Joanne M. Wozniak PA MS5, Matthew C. Exline 
MD MPH6, Derek W. Russell MD7,25, Shekhar Ghamande MD8, Cori Withers BS2, 
Kinsley A. Hubel MD9, Ari Moskowitz MD MPH10, Jill Bastman BSN2, Luke Andrea 
MD10, Peter D. Sottile MD13, David B. Page MD MSPH7, Micah T. Long MD19, Jordan 
Kugler Goranson MD16, Rishi Malhotra MD10, Brit J. Long MD20, Steven G. Schauer DO 
MS21, Andrew Connor DO9, Erin Anderson RN2, Kristin Maestas2, Jillian P. Rhoads 
PhD4, Kelsey Womack PhD4, Brant Imhoff MS22, David R. Janz MD MSc23,Stacy A. 
Trent, MD MSPH 2,24 Wesley H. Self MD MPH18, Todd W. Rice MD MSc4, Matthew W. 
Semler MD MSc**4, Jonathan D. Casey MD MSc**4 for the PREOXI investigators and 
the Pragmatic Critical Care Research Group 
 
*Authors contributed equally 
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

** Authors contributed equally 
*** A full list of PREOXI investigators is provided in the Supplemental file 
 
1. Section on Pulmonary, Critical Care, Allergy, and immunology, Wake Forest School 
of Medicine, Winston-Salem, NC, USA 
2. Department of Emergency Medicine, University of Colorado School of Medicine 
Aurora, CO, USA 
3, Division of Pulmonary and Critical Care Medicine, Hennepin County Medical Center, 
Minneapolis, MN, USA 
4. Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, 
Vanderbilt University Medical Center, Nashville, TN, USA 
5. Department of Medicine, Division of Pulmonary & Critical Care Medicine, Lahey 
Hospital & Medical Center, Burlington, MA, USA 
6. Pulmonary, Critical Care and Sleep Medicine, The Ohio State University, Columbus, 
OH, USA 
7.Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine 
University of Alabama at Birmingham, Birmingham, AL, USA 
8. Department of Medicine, Division of pulmonary & Critical Care Medicine, Baylor Scott 
& White Medical Center, Temple, TX, USA 
9. Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, 
Oregon Health & Science University, Portland, OR, USA 
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10. Division of Critical Care Medicine  Montefiore Medical Center  Bronx, NY, USA 
11. Department of Anesthesiology  University of Colorado School of Medicine  Aurora, 
CO, USA 
12. Division of Pulmonary Medicine  Montefiore Medical Center   Bronx, NY, USA 
13. Department of Medicine, Division of Pulmonary Sciences and Critical Care 
Medicine, University of Colorado School of Medicine, Aurora, CO, USA 
14. Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, 
University of Wisconsin School of Medicine and Public Health, Madison, Wi, USA 
15. Department of Anesthesiology, Section on Critical Care ,Wake Forest School of 
Medicine, Winston-Salem, NC, USA 
16. Department of Emergency Medicine, Wake Forest School of Medicine, Winston-
Salem, NC, USA 
17. Department of Emergency Medicine, Hennepin County Medical Center, 
Minneapolis, MN, USA 
18. Vanderbilt Institute for Clinical and Translational Research, and Department of 
Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA 
19. Department of Anesthesiology, University of Wisconsin School of Medicine & Public 
Health, Madison, WI, USA 
20. 59th Medical Wing, United States Air Force, Fort Sam Houston, San Antonio, TX, 
USA 
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21. United States Army Institute of Surgical Research, Joint Base San Antonio-Fort 
Sam Houston, San Antoni, TX, USA 
22. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 
USA 
23. University Medical Center New Orleans and the Department of Medicine, Section of 
Pulmonary/Critical Care Medicine and Allergy/Immunology, Louisiana State University 
School of Medicine, New Orleans, LA, USA 
24. Department of Emergency Medicine, Denver Health Medical Center, Denver, CO, 
USA 
25. Pulmonary Section, Birmingham VA medical Center, Birmingham, AL, USA 
26. Department of Emergency Medicine, University of Alabama at Birmingham, 
Birmingham, AL, USA 
 
 
 
 
 
Corresponding Author:  
Kevin W. Gibbs, MD 
 
Email:  
kgibbs@wakehealth.edu 
 
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Address: 
2nd Floor Watlington Hall 
1 Medical Center Blvd 
Winston-Salem, NC. 27157 
 
Author contributions: Study concept and design: KWG, AAG, MWS, JDC; Acquisition 
of data: all authors; Drafting of the manuscript KWG, AAG, MWS, JDC; Critical revision 
of the manuscript for important intellectual content: all authors; Study supervision: KWG, 
AAG, MWS, JDC.  
 
Sources of Funding: The research was funded primarily by the Department of 
Defense, Defense Health Agency, J9 Office, RESTORAL program. Kevin P. Seitz was 
supported in part by the NIH (T32HL087738).  Jessica A. Palakshappa was supported 
in part by the NIA (K23AG073529) Matthew W. Semler was supported in part by the 
NHLBI (K23HL143053). Jonathan D. Casey was supported in part by the NHLBI 
(K23HL153584).  Derek Russell was supported in part by the NHLBI (K08HL148514-
01A1). Data collection utilized the Research Electronic Data Capture (REDCap) tool 
developed and maintained with Vanderbilt Institute for Clinical and Translational 
Research grant support (UL1 TR000445 from NCATS/NIH). 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. The views expressed are those of 
the author and do not reflect the official views or policy of the Department of Defense, 
its Components. The authors do not have any financial interest in the companies whose 
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materials are discussed in this publication, and no federal endorsement of the 
companies and materials is intended. 
  
 
Conflicts of Interest and Financial Disclosures: Kevin W. Gibbs MD reports financial 
support and travel were provided by US Department of Defense. Adit. A. Ginde MD 
MPH reports financial support was provided by US Department of Defense. Matthew E. 
Prekker MD MPH reports financial support was provided by US Department of Defense. 
Kevin P. Seitz MD MSc reports financial support was provided by National Heart Lung 
and Blood Institute. Susan B. Stempek PA MBA reports financial support was provided 
by American College of Chest Physicians. Akram Khan MD reports financial support 
was provided by United Therapeutics Corporation. Akram Khan MD reports financial 
support was provided by 4D Medicine Ltd. Akram Khan MD reports financial support 
was provided by Regeneron Pharmaceuticals Inc. Akram Khan MD reports financial 
support was provided by Roche. Akram Khan MD reports financial support was 
provided by Dompé pharmaceutical. Jessica A. Palakshappa MD MS reports financial 
support was provided by National Institute on Aging. Joanne M. Wozniak PA MS reports 
was provided by American College of Chest Physicians. Matthew C. Exline MD, MPH 
reports financial support was provided by Abbott Laboratories. Derek W. Russell MD 
reports financial support was provided by National Heart Lung and Blood Institute. 
Shekar Ghamande MD reports financial support was provided by US Department of 
Defense. Ari Moskowitz MD MPH reports financial support was provided by National 
Heart Lung and Blood Institute. Jill Bastman BSN reports financial support was provided 
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by US Department of Defense. Micah T. Long MD reports financial support was 
provided by pocket cards. Steven G. Schauer DO MS reports was provided by US 
Department of Defense. David Janz MD MSc reports financial support was provided by 
US Department of Defense. Matthew W. Semler MD MSc reports financial support was 
provided by US Department of Defense. Matthew W. Semler MD MSc reports financial 
support was provided by National Heart Lung and Blood Institute. Jonathan D. Casey 
MD MSc reports was provided by US Department of Defense. Jonathan D. Casey MD 
MSc reports was provided by National Heart Lung and Blood Institute. Jonathan D. 
Casey MD MSc reports travel was provided by Fisher & Paykel Healthcare Inc. Todd W 
Rice MD MSc reports a relationship with Cumberland Pharmaceuticals Inc that includes: 
consulting or advisory and equity or stocks. Derek W. Russell MD reports a relationship 
with Achieve Life Science Inc that includes: equity or stocks. Matthew W. Semler MD 
MSc reports a relationship with Baxter International Inc that includes: consulting or 
advisory. 
 
Keywords for indexing: Endotracheal intubation, non-invasive positive pressure 
ventilation, critical illness, respiratory failure, oxygen 
 
Subject Descriptor Number: 4.4 Clinical Trials in Critical Care Medicine 
Manuscript Word Count (body only): 4060 
Abstract Word Count: 243 
 
Supplemental digital content is available for this article. 
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HIGHLIGHTS 
• Hypoxemia is common during emergency tracheal intubation 
• Supplemental oxygen prior to intubation (preoxygenation) reduces risk of 
hypoxemia 
• The PREOXI trial compares noninvasive ventilation vs oxygen mask 
preoxygenation 
• This protocol describes the design, methods, and planned analyses  
• PREOXI is the largest trial of preoxygenation for emergency intubation to date 
 
 
 
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ABSTRACT 
Background: Hypoxemia is a common and life-threatening complication during 
emergency tracheal intubation of critically ill adults. The administration of supplemental 
oxygen prior to the procedure (“preoxygenation”) decreases the risk of hypoxemia 
during intubation.  
Research Question: Whether preoxygenation with noninvasive ventilation prevents 
hypoxemia during tracheal intubation of critically ill adults, compared to preoxygenation 
with oxygen mask, remains uncertain. 
Study Design and Methods: The PRagmatic trial Examining OXygenation prior to 
Intubation (PREOXI) is a prospective, multicenter, non-blinded randomized comparative 
effectiveness trial being conducted in 7 emergency departments and 17 intensive care 
units across the United States.  The trial compares preoxygenation with noninvasive 
ventilation versus oxygen mask among 1300 critically ill adults undergoing emergency 
tracheal intubation. Eligible patients are randomized in a 1:1 ratio to receive either 
noninvasive ventilation or an oxygen mask prior to induction. The primary outcome is 
the incidence of hypoxemia, defined as a peripheral oxygen saturation <85% between 
induction and 2 minutes after intubation.  The secondary outcome is the lowest oxygen 
saturation between induction and 2 minutes after intubation. Enrollment began on 10 
March 2022 and is expected to conclude in 2023. 
Interpretation: The PREOXI trial will provide important data on the effectiveness of 
noninvasive ventilation and oxygen mask preoxygenation for the prevention of 
hypoxemia during emergency tracheal intubation.  Specifying the protocol and statistical 
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analysis plan prior to the conclusion of enrollment increases the rigor, reproducibility, 
and interpretability of the trial. 
Clinical trial registration number:  NCT05267652 
 
 
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INTRODUCTION 
Life-threatening hypoxemia occurs in 10-20% of emergency tracheal intubations 
in the Emergency Department (ED) and Intensive Care Unit (ICU).1,2  Hypoxemia during 
intubation is associated with an increased risk of cardiac arrest and death.3,4  Identifying 
interventions to prevent hypoxemia during emergency tracheal intubation is a high 
priority for clinicians and researchers.5,6  Because patients are typically apneic between 
induction of anesthesia and intubation but continue to consume oxygen, the oxygen 
content in the lungs at the time of induction is a primary determinant of whether the 
patient will experience hypoxemia.  Preoxygenation, the administration of supplemental 
oxygen prior to induction of anesthesia, increases the oxygen content in the lung at 
induction and decreases the risk of hypoxemia.7,8  In current clinical practice, 
preoxygenation for emergency tracheal intubation of critically ill adults is most 
commonly administered using either an oxygen mask or noninvasive ventilation.1   
Preoxygenation with an oxygen mask is typically performed using either a non-
rebreather mask or a bag-mask device.  A non-rebreather mask is a loose-fitting mask 
with an oxygen reservoir connected to an oxygen source.  A bag-mask device is a mask 
capable of forming a tight seal over the mouth when held in place by a clinician and can 
be used to provide supplemental oxygenation alone, or both supplemental oxygen and 
manual ventilation.9 Both types of oxygen mask can deliver up to 100% oxygen, are 
simple to set up, and have low potential for gastric insufflation. However, oxygen masks 
may deliver oxygen less effectively in critically ill patients when tachypnea, high minute 
ventilation, and poor mask seal allow the entrainment of ambient air with resulting 
alveolar oxygen concentrations as low as 50%.7,10  
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Preoxygenation is also routinely administered via noninvasive ventilation, in 
which a tight-fitting mask is connected to a machine capable of providing both 100% 
oxygen and positive pressure ventilation. Compared to an oxygen mask, noninvasive 
ventilation may reduce air entrainment by delivering a higher inspiratory flow rate of 
oxygen and by minimizing leaks. Additionally, noninvasive ventilation increases the 
mean airway pressure and recruits atelectatic lung, potentially reducing shunting.  
Compared with an oxygen mask, noninvasive ventilation may take longer to initiate and 
may potentially increase the risk of gastric insufflation and aspiration.  
 
Two small, randomized trials have compared these two approaches to 
preoxygenation. The first trial found that, among 53 ICU patients undergoing tracheal 
intubation in two hospitals in France, noninvasive ventilation increased the lowest 
oxygen saturation compared to an oxygen mask (mean lowest oxygen saturation 93% 
vs. 81%, respectively, P<0.001) with no difference between groups in the incidence of 
aspiration (6% vs. 8%).11 Among 201 ICU patients in 6 hospitals in France, the second 
trial found no difference in the severity of illness in the 7 days after intubation and an 
incidence of hypoxemia during intubation of 18.4% in the noninvasive ventilation group 
versus 27.7% in the oxygen mask group (P = 0.10).12 Thus, whether noninvasive 
ventilation for preoxygenation in critically ill adults undergoing emergency tracheal 
intubation decreases the incidence of hypoxemia compared to an oxygen mask remains 
unknown.  Therefore, we designed the PRagmatic trial Examining OXygenation prior to 
Intubation (PREOXI) to test the hypothesis that, among critically ill adults undergoing 
emergency tracheal intubation in the ED and ICU, preoxygenation with noninvasive 
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ventilation will decrease the incidence of hypoxemia compared to preoxygenation with 
an oxygen mask.   
 
METHODS AND ANALYSIS 
This manuscript was written in accordance with Standard Protocol Items: 
Recommendations for Interventional Trials (SPIRIT) guidelines (see Table 1 and online 
supplement file 1, section 1). 13 
 
Funding: 
Funding for this trial was provided by the Department of Defense, Defense 
Health Agency, J9 Office, RESTORAL program. The funder has no role in study design 
or conduct, data collection or analysis.  
 
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, which 
includes input from patients and community members. Study authors will disseminate 
the results of this study online and via social media in forms suitable for public 
understanding. 
 
 
 
Study Design: 
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PREOXI is a pragmatic, multicenter, non-blinded, parallel-group, randomized trial 
comparing preoxygenation with noninvasive ventilation to preoxygenation with an 
oxygen mask among critically ill adults undergoing emergency tracheal intubation in the 
ED and ICU.  The primary outcome is the incidence of hypoxemia, defined as a 
peripheral oxygen saturation < 85% between induction of anesthesia and two minutes 
after intubation. The trial is conducted by the Pragmatic Critical Care Research Group 
(www.pragmaticcriticalcare.org). An independent data and safety monitoring board 
(DSMB) is monitoring the progress and safety of the trial. The trial was registered prior 
to initiation of enrollment (ClinicalTrials.gov identifier: NCT05267652).  
 
Study Population:  
Patients located in a participating ED or ICU who are undergoing tracheal intubation 
using a laryngoscope and sedation are eligible. Patients are excluded if they are known 
to be less than 18 years old, are known to be pregnant or a prisoner, require positive 
pressure ventilation for apnea or hypopnea, or have an immediate need for tracheal 
intubation that precludes performance of study procedures, or if the clinician performing 
the procedure (referred to as the “operator”) determines that preoxygenation with 
noninvasive ventilaton or an oxygen mask is either required or contraindicated. 
Complete lists of inclusion and exclusion criteria are provided in Table 2. 
 
Randomization and treatment allocation: 
 
Patients are randomized in a 1:1 ratio to undergo preoxygenation with 
noninvasive ventilaton vs oxygen mask in permuted blocks of variable size, stratified by 
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study site.  Study-group assignments are generated using a computerized 
randomization sequence, placed in sequentially numbered opaque envelopes, and 
distributed to enrolling sites. Before opening the envelope, the operator determines that 
the patient meets eligibility criteria.  Study group assignment remains concealed to 
study personnel and treating clinicians until after the decision has been made to enroll 
the patient and the envelope is opened.  Patients are considered to be enrolled once 
the operator opens the opaque trial envelope to reveal study group assignment. After 
randomization, patients, treating clinicians, and study personnel are not blinded to study 
group assignment due to the nature of the study intervention. 
 
STUDY INTERVENTIONS 
Training: 
Before beginning enrollment at each site, study investigators provide training on 
study procedures including instructional videos with consensus best practice 
recommendations for preoxygenation with noninvasive ventilation and preoxygenation 
with an oxygen mask.  Observers receive in-person training on the collection of data 
during the intubation procedure using example data collection sheets. Descriptions of 
the training videos and website links can be found in the supplementary appendix.  
 
Noninvasive ventilation group: 
 
For patients assigned to the noninvasive ventilation group, operators are 
instructed to administer noninvasive ventilation via a tight-fitting mask covering the nose 
and mouth connected to either a conventional mechanical ventilator or a dedicated 
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noninvasive ventilator (i.e., BiPAP machine) from the initiation of preoxygenation until 
the initiation of laryngoscopy.  The trial protocol does not dictate brand or type of 
ventilator, ventilator settings, or duration of preoxygenation.  Operators receive the 
following best practice recommendations for the administration of preoxygenation using 
noninvasive ventilation: 
1. Preoxygenate ≥ 3 minutes (if feasible) 
2. Continue noninvasive ventilation until initiation of laryngoscopy 
3. Fraction of Inspired Oxygen (FiO2) of 100% 
4. Expiratory pressure ≥ 5 cm of water 
5. Inspiratory pressure ≥ 10 cm of water  
6. Respiratory rate of ≥ 10  
 
Oxygen mask group: 
For patients assigned to the oxygen mask group, clinicians are instructed to 
administer supplemental oxygen via a non-rebreather mask or bag-mask device without 
manual ventilation from the initiation of preoxygenation until the induction of anesthesia.   
The operator determines whether to use a non-rebreather mask or a bag-mask device 
without manual ventilation.  The trial protocol does not dictate the brand or type of non-
rebreather or bag-mask device or duration of preoxygenation.  Between induction of 
anesthesia and initiation of laryngoscopy, the operator determines whether to provide 
oxygen with a non-rebreather mask, oxygen with a bag-mask device without manual 
ventilation, or oxygen with a bag-mask device with manual ventilation.2  Operators 
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receive the following best practice recommendations for the administration of 
preoxygenation using an oxygen mask: 
1. Preoxygenate ≥ 3 minutes (if feasible) 
2. Maximal oxygen flow rate possible (≥ 15 liters per minute) 
3. Continue oxygenation from induction to laryngoscopy 
 
Cointerventions: 
 
Study group assignment determines only the initial method of preoxygenation.  
Treating clinicians determine all other aspects of the intubation procedure including: [1] 
the co-administration of supplemental oxygen by nasal cannula (either standard nasal 
cannula, large bore nasal cannula, or heated high flow nasal cannula) before induction, 
between induction an initiation of laryngoscopy, and between initiation of laryngoscopy 
and intubation of the trachea; [2] choice of induction medication and timing of 
administration; [3] use of neuromuscular blockade; [4] choice of laryngoscope; [5] use of 
additional airway management equipment and adjuncts; and [6] post-intubation 
ventilator settings.  
 
Data Collection 
An observer not directly involved with the intubation procedure collects data for 
key periprocedural outcomes, including oxygen saturation at induction and the lowest 
value for oxygen saturation between induction and two minutes after successful 
intubation.  Observers may be clinical personnel on the enrolling unit (e.g., physicians or 
nurses) or research personnel. Immediately after the intubation procedure, the operator 
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completes a paper data collection form to record the device used for preoxygenation, 
the duration of preoxygenation, the devices used for oxygenation and ventilation 
between induction and laryngoscopy, and complications of intubation.14 Study personnel 
at each site review the medical record to collect data on baseline characteristics, pre- 
and post-laryngoscopy management, and clinical outcomes. A complete list of baseline, 
peri-procedural, and in-hospital variables are provided in Supplemental Table 1. 
Data on pneumothorax and new pulmonary infiltrates are collected by study staff 
from clinical radiology reports using a structured case report form.  The clinical 
radiologist who interprets the chest imaging is unaware of study group assignment.  A 
lung infiltrate is considered to be present if the clinical radiologist identifies on the chest 
imaging the presence of air bronchograms, centrilobular nodules, consolidation, ground-
glass opacity, infiltrate, opacity, parenchymal opacification, pneumonia, pneumonitis 
pulmonary edema, or a tree-in-bud pattern.  A pneumothorax or lung infiltrate present 
on chest imaging in the 24 hours after intubation will be assumed to be new if it was not 
present on chest imaging in the 24 hours prior to intubation. If no chest imaging is 
available in the 24 hours prior to intubation, any pneumothorax or lung infiltrate on chest 
imaging will be assumed to be new. 
 
 
 
 
Primary Outcome 
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The primary outcome is the incidence of hypoxemia, defined as a peripheral 
oxygen saturation <85% during the interval between induction and 2 minutes after 
intubation.   
We selected hypoxemia (as a binary variable) rather than lowest oxygen 
saturation (a continuous variable) as the primary outcome for the trial for several 
reasons. First, experiencing hypoxemia in the range associated with an increased risk 
of adverse clinical outcomes (e.g., cardiac arrest) may be more clinically relevant than 
changes in oxygen saturation within the normal range.  For example a change in 
oxygen saturation of 5 percentage points from 87% to 82% may be more closely 
associated with adverse outcomes than a change in oxygen saturation of 10 percentage 
points from 100% to 90%. Second, values for oxygen saturation are “right-censored” 
because oxygen saturation reaches 100% with a partial pressure of oxygen in arterial 
blood (PaO2) of approximately 100 mmHg but patients may have a higher PaO2 
following preoxygenation. The approach of analyzing hypoxemia as a binary variable 
rather than lowest oxygen saturation has been used by many prior trials and endorsed 
by airway experts.15-20 
We selected an oxygen saturation of <85% as the threshold for the primary 
outcome based on several physiologic and procedural factors. First, an oxygen 
saturation of 85% corresponds with the inflection point on the oxyhemoglobin 
dissociation curve, at which further decrements in arterial oxygen concentrations result 
in rapid and critical desaturation.9 Second, an oxygen saturation <85% has been 
associated with an increased risk of cardiac arrest during tracheal intubation21 and may 
be associated with increased mortality.5  
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Secondary Outcome: 
The sole secondary outcome is the lowest oxygen saturation during the interval 
between induction and 2 minutes after tracheal intubation.  
 
Additional Outcomes: 
Table 3 reports the safety outcomes, exploratory outcomes, and clinical 
outcomes.  
 
Sample Size Estimation 
 
The minimum clinically important difference in the incidence of hypoxemia that 
would be required to justify routine preoxygenation with noninvasive ventilation rather 
than preoxygenation with an oxygen mask during the emergency tracheal intubation of 
critically ill adults is uncertain.  The current trial is designed to detect a 6% absolute 
difference between groups in the incidence of hypoxemia, a difference that is similar to 
or smaller than the difference considered to be clinically meaningful in the design of 
prior trials of oxygenation strategies during tracheal intubation.2,24 Assuming an 
incidence of hypoxemia of 17% in the oxygen mask group based on data from two 
recently completed trials by this network in similar ED and ICU settings, detecting a 6% 
absolute decrease in the incidence of hypoxemia with 85% power at a two-sided alpha 
level of 0.05 would require enrollment of 1,264 patients (632 per group).25,26 Anticipating 
missing data for up to 3% of patients, we will plan to enroll a maximum of 1,300 total 
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patients (650 per group).  This sample size calculation was performed in PS version 
3.1.2 (Nashville, Tennessee). 
 
Data and Safety Monitoring Board and Interim Analysis 
 
A data and safety monitoring board (DSMB) consisting of members with 
expertise in bioethics, emergency medicine, pulmonary and critical care medicine, 
anesthesiology, biostatistics, and clinical trial methodology has overseen the design of 
the trial and is monitoring its conduct.  The DSMB will review a single interim analysis, 
prepared by the study biostatistician at the anticipated halfway point of the trial after 
enrolment of 650 patients.  The pre-specified stopping boundary for efficacy is a P value 
< 0.001 using a Chi-square test for the difference between groups in the primary 
outcome. This conservative Haybittle–Peto boundary will allow the final analysis to be 
performed using an unchanged level of significance (two-sided P value < 0.05). 
The DSMB has the authority to recommend that the trial stop at any point, 
request additional data, request additional interim analyses, or request modifications to 
the study protocol.   
 
Statistical Analysis Principles 
 
Analyses will be conducted following reproducible research principles using R (R 
Foundation for Statistical Computing, Vienna, Austria). Categorical variables will be 
presented as number and percentage and compared between groups using a Chi-
square text.  Continuous variables will be presented as mean ± SD or median and IQR 
and compared between groups using a Wilcoxon Rank Sum test. We will also present 
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absolute between-group differences with associated 95% confidence intervals. A two-
sided P-value of < 0.05 will define a statistically significant between-group difference in 
the primary outcome. With a single primary outcome, no adjustment for multiplicity will 
be made. For secondary, safety, and exploratory analyses, emphasis will be placed on 
the magnitude of differences between groups with 95% confidence intervals rather than 
statistical significance. 
 
Main Analysis of the Primary Outcome 
 
The main analysis will be an unadjusted, intention-to-treat comparison of the 
primary outcome of hypoxemia between patients randomized to the noninvasive 
ventilation group versus patients randomized to the oxygen mask group, using a chi-
square test.  The absolute difference in proportions, associated 95% confidence 
interval, and a P value for the comparison will be presented. The primary analysis will 
be conducted among patients for whom the primary outcome is available without 
imputation of missing data. 
 
Additional Analyses of the Primary Outcome 
Multivariable analysis 
 
To account for relevant baseline covariates, we will fit a generalized linear mixed 
effects model using a logit link function with the primary outcome as the dependent 
variable, study site as a random effect, and fixed effects of study group and the 
following prespecified baseline covariates: age, sex, race and ethnicity, body mass 
index (BMI), location at enrollment (ED or ICU), highest fraction of inspired oxygen in 
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the hour prior to initiation of preoxygenation, Acute Physiology and Chronic Health 
Evaluation (APACHE) II score27, and indication for intubation (hypoxemic respiratory 
failure: Yes vs No). All continuous variables will be modelled assuming a non-linear 
relationship to the outcome using restricted cubic splines with between 3 and 5 knots. 
 
Effect modification 
 
We will examine whether prespecified baseline variables modify the effect of 
study group assignment (noninvasive ventilation vs oxygen mask) on the primary 
outcome using a formal test of statistical interaction in a generalized linear mixed-effects 
model with the primary outcome as the dependent variable, study site as a random 
effect and fixed effects of study group, the prespecified proposed effect modifier and the 
interaction between the two.  For categorical variables, we will present the OR and 95% 
CIs within each prespecified subgroup. Continuous variables will not be dichotomized 
for analysis of effect modification but may be dichotomized for data presentation.  In 
accordance with the Instrument for assessing the Credibility of effect Modification 
Analyses (ICEMAN) recommendations, we have prespecified the following baseline 
variables as potential effect modifiers and hypothesized the direction of effect 
modification for each: 
1. Patient location (ED vs ICU). We hypothesize that patient location will not modify 
the effect of study group assignment on the primary outcome.  
2. Body Mass Index (kg/m2). We hypothesize that Body Mass Index (BMI) will 
modify the effect of study group assignment on the primary outcome, with a 
greater decrease in the incidence of hypoxemia with preoxygenation within the 
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noninvasive ventilation group compared to the oxygen mask group among 
patients with higher BMIs, as compared to patients with lower BMIs.  This 
hypothesis of effect modification is supported by evidence from multiple prior 
studies that patients with obesity are more likely to have early airway closure and 
atelectasis-dependent shunting that is likely to improve with positive pressure 
ventilation. 28,29 
3. Fraction of inspired oxygen in the hour prior to intubation.  We hypothesize that 
the fraction of inspired oxygen received in the hour prior to intubation will modify 
the effect of study group assignment on the primary outcome, with a greater 
decrease in the incidence of hypoxemia in the noninvasive ventilation group 
compared to the oxygen mask group among patients with higher fractions of 
inspired oxygen in the hour prior to intubation, compared to patients with lower 
fractions of inspired oxygen.  This hypothesis of effect modification is supported 
by evidence from multiple prior studies that patients requiring higher fractions of 
inspired oxygen have more atelectasis-dependent shunting that is likely to 
improve with positive pressure ventilation.5,11,30 
4. APACHE II score. We hypothesize that APACHE II score will not modify the 
effect of study group assignment on the primary outcome. 
5. Hypoxemic respiratory failure as the indication for intubation (Yes vs No).  We 
hypothesize that hypoxemic respiratory failure as the indication for intubation will 
modify the effect of study group assignment on the primary outcome, with a 
greater decrease in the incidence of hypoxemia in the noninvasive ventilation 
group compared to the oxygen mask group among patients with hypoxemic 
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respiratory failure, compared to patients without.  This hypothesis of effect 
modification is supported by evidence from two prior randomized trials 
suggesting a potential benefit for noninvasive ventilation among patients with 
acute hypoxemic respiratory failure.11,12  
 
Analysis of the Secondary Outcome  
We will perform an unadjusted, intention-to-treat comparison of patients 
randomized to the noninvasive ventilation group versus the oxygen mask group with 
regard to the secondary outcome of lowest oxygen saturation between induction and 2 
minutes after intubation using the Wilcoxon rank sum test.  
 
Analyses of Additional Outcomes: 
 
We will conduct unadjusted, intention-to-treat analyses comparing patients 
randomized to the noninvasive ventilation group versus the oxygen mask group with 
regard to all pre-specified safety, clinical, and exploratory outcomes.  Continuous 
outcomes will be compared with the Wilcoxon rank sum test and categorical variables 
with the chi-square test. Between-group differences in continuous and categorical 
variables and the associated 95% confidence intervals will be presented. 
 
Handling of missing data: 
 
We anticipate that no patients will be lost to follow up before assessment of the 
primary outcome.  In some cases, the oxygen saturation between induction and 2 
minutes after intubation will be unmeasurable (e.g., poor plethysmography of pulse 
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oximetry, shock, cardiac arrest, peripheral arterial disease, or other reasons) or 
unavailable. We anticipate that data will be missing in less than 3% of cases based on 
the rates of missing data in prior trials in similar settings.25,26  Missing data will  
not be imputed for the primary outcome or for any of the secondary or exploratory 
outcomes. In adjusted analyses, missing data for baseline covariates will be imputed 
using multiple imputations. 
 
Trial status: 
PREOXI is a pragmatic, multi-center, non-blinded randomized clinical trial 
comparing preoxygenation with noninvasive ventilation to preoxygenation with an 
oxygen mask during the tracheal intubation of critically ill adults. Enrollment began on 
10 March 2022 and is expected to conclude in 2023. 
 
ETHICS AND DISSEMINATION 
 
Waiver of Informed Consent: 
Critically ill patients undergoing tracheal intubation in the ED or ICU are at 
significant risk for morbidity and mortality from their underlying illness. Most patients 
undergoing tracheal intubation in routine clinical care receive preoxygenation with either 
noninvasive ventilation or an oxygen mask.  Any benefits or risks of these two 
approaches are experienced by patients undergoing tracheal intubation in clinical care, 
outside the context of research. As a requirement for enrollment in PREOXI, the 
patient’s treating clinician must determine that either preoxygenation with noninvasive 
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ventilation or preoxygenation with an oxygen mask would be a safe and reasonable 
approach for the patient (otherwise the patient is excluded). Therefore, making the 
decision between the two approaches randomly in the context of a pragmatic trial, 
rather than by a clinician who thinks either approach is safe and reasonable for the 
patient, is expected to pose no more than minimal additional risk. 
 
Obtaining informed consent from potential study participants or their legally 
authorized representatives would be impracticable. The majority of critically ill patients 
undergoing emergency tracheal intubation lack decisional capacity due to their critical 
illness and surrogate decision makers are frequently unavailable. Further, emergency 
tracheal intubation is a time-sensitive procedure with only minutes between the decision 
to intubate and the completion of the procedure. Meaningful informed consent could not 
be executed in this brief window. Attempting to obtain informed consent could lead to 
potentially deleterious delays in intubation which would increase the risk of hypoxemia, 
hypotension, and cardiac arrest.   
Because the study involves minimal incremental risk, the study would not 
adversely affect the welfare or privacy rights of the participant, and obtaining informed 
consent would be impracticable, a waiver of informed consent was requested from and 
approved by the single institutional review board at Vanderbilt University Medical Center 
(reference number VUMC IRB# 211271). Conduct of this trial with waiver of informed 
consent is consistent with previous randomized trials comparing alternative approaches 
to tracheal intubation in widespread clinical use.2,24-26,31,32 This approach was 
secondarily approved by the US Department of Defense Health Agency Human 
Research Protection Office).  IRBs at participating sites reviewed the protocol, 
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addressed any local contextual factors with the site principal investigator, and ceded 
responsibility for ethics approval and study oversight to the single IRB. 
 
Information for Patients and Families 
Information regarding the study is made available to patients and families 
following intubation using a patient and family information sheet.  The patient and family 
information sheet contains information on the purpose of the PREOXI trial, study 
procedures, risks and discomforts, benefits, use of protected health information, 
confidentiality, and investigator contact information. The Defense Health Agency Human 
Research Protection Office determined that this procedure meets the requirement of 32 
CFR 219 and DODI 3216.02_AFI40-402.  At centers with a significant population of 
non-English speaking patients, the patient and family information sheet has been 
translated into Spanish and Somali languages. 
 
Protocol Changes 
In accordance with SPIRIT guidelines, changes to the study protocol will be 
documented on clinicaltrials.gov (see online supplementary file) and submitted to the 
sIRB for approval. 
 
Data Handling 
Privacy protocols and data handling are reported in the online supplement. 
 
Dissemination Plan 
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We will submit the trial results to a peer-reviewed journal for publication.  Trial 
results will also be presented at scientific conferences and disseminated online and via 
social media in forms suitable for public understanding. 
 
Conclusion 
The PREOXI trial will provide important data on the effectiveness of common 
preoxygenation strategies for the prevention of hypoxemia during emergency tracheal 
intubation with a goal of improving outcomes for critically ill adults. To aid in the 
transparency and interpretation of trial results, this protocol and statistical analysis plan 
for the PREOXI trial has been finalized prior to the conclusion of patient enrollment. 
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REFERENCES 
1. 
Russotto V, Myatra SN, Laffey JG, et al. Intubation Practices and Adverse Peri-intubation Events 
in Critically Ill Patients From 29 Countries. JAMA. Mar 23 2021;325(12):1164-1172. 
doi:10.1001/jama.2021.1727 
2. 
Casey JD, Janz DR, Russell DW, et al. Bag-Mask Ventilation during Tracheal Intubation of 
Critically Ill Adults. N Engl J Med. Feb 28 2019;380(9):811-821. doi:10.1056/NEJMoa1812405 
3. 
Davis DP, Dunford JV, Poste JC, et al. The impact of hypoxia and hyperventilation on outcome 
after paramedic rapid sequence intubation of severely head-injured patients. J Trauma. Jul 2004;57(1):1-
8; discussion 8-10. doi:10.1097/01.ta.0000135503.71684.c8 
4. 
April MD, Arana A, Reynolds JC, et al. Peri-intubation cardiac arrest in the Emergency 
Department: A National Emergency Airway Registry (NEAR) study. Resuscitation. May 2021;162:403-
411. doi:10.1016/j.resuscitation.2021.02.039 
5. 
Smischney NJ, Khanna AK, Brauer E, et al. Risk Factors for and Outcomes Associated With Peri-
Intubation Hypoxemia: A Multicenter Prospective Cohort Study. J Intensive Care Med. Dec 
2021;36(12):1466-1474. doi:10.1177/0885066620962445 
6. 
Meier NM, Gibbs KW. Evolving Tracheal Intubation Practice Patterns in the Pandemic Era. Chest. 
Dec 2021;160(6):1993-1994. doi:10.1016/j.chest.2021.07.002 
7. 
Mosier JM, Hypes CD, Sakles JC. Understanding preoxygenation and apneic oxygenation during 
intubation in the critically ill. Intensive Care Med. Feb 2017;43(2):226-228. doi:10.1007/s00134-016-
4426-0 
8. 
Berthoud M, Read DH, Norman J. Pre-oxygenation--how long? Anaesthesia. Feb 1983;38(2):96-
102. doi:10.1111/j.1365-2044.1983.tb13925.x 
9. 
Weingart SD. Preoxygenation, reoxygenation, and delayed sequence intubation in the 
emergency department. J Emerg Med. Jun 2011;40(6):661-7. doi:10.1016/j.jemermed.2010.02.014 
10. 
Driver BE, Prekker ME, Kornas RL, Cales EK, Reardon RF. Flush Rate Oxygen for Emergency 
Airway Preoxygenation. Ann Emerg Med. Jan 2017;69(1):1-6. doi:10.1016/j.annemergmed.2016.06.018 
11. 
Baillard C, Fosse JP, Sebbane M, et al. Noninvasive ventilation improves preoxygenation before 
intubation of hypoxic patients. Am J Respir Crit Care Med. Jul 15 2006;174(2):171-7. 
doi:10.1164/rccm.200509-1507OC 
12. 
Baillard C, Prat G, Jung B, et al. Effect of preoxygenation using non-invasive ventilation before 
intubation on subsequent organ failures in hypoxaemic patients: a randomised clinical trial. Br J Anaesth. 
Feb 2018;120(2):361-367. doi:10.1016/j.bja.2017.11.067 
13. 
Chan AW, Tetzlaff JM, Gotzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for 
protocols of clinical trials. BMJ. Jan 8 2013;346:e7586. doi:10.1136/bmj.e7586 
14. 
Cormack RS, Lehane J. Difficult tracheal intubation in obstetrics. Anaesthesia. Nov 
1984;39(11):1105-11.  
15. 
Writing C, Steering Committee for the RCG, Algera AG, et al. Effect of a Lower vs Higher Positive 
End-Expiratory Pressure Strategy on Ventilator-Free Days in ICU Patients Without ARDS: A Randomized 
Clinical Trial. JAMA. Dec 22 2020;324(24):2509-2520. doi:10.1001/jama.2020.23517 
16. 
Franklin D, Babl FE, Schlapbach LJ, et al. A Randomized Trial of High-Flow Oxygen Therapy in 
Infants with Bronchiolitis. N Engl J Med. Mar 22 2018;378(12):1121-1131. doi:10.1056/NEJMoa1714855 
17. 
Driver BE, Semler MW, Self WH, et al. Effect of Use of a Bougie vs Endotracheal Tube With Stylet 
on Successful Intubation on the First Attempt Among Critically Ill Patients Undergoing Tracheal 
Intubation: A Randomized Clinical Trial. JAMA. Dec 28 2021;326(24):2488-2497. 
doi:10.1001/jama.2021.22002 
 . 
CC-BY-NC-ND 4.0 International license
It is made available under a 
 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
(which was not certified by peer review)
The copyright holder for this preprint 
this version posted March 24, 2023. 
; 
https://doi.org/10.1101/2023.03.23.23287539
doi: 
medRxiv preprint 

18. 
De Jong A, Rolle A, Molinari N, et al. Cardiac Arrest and Mortality Related to Intubation 
Procedure in Critically Ill Adult Patients: A Multicenter Cohort Study. Crit Care Med. Apr 2018;46(4):532-
539. doi:10.1097/CCM.0000000000002925 
19. 
Zhang C, Xu F, Li W, et al. Driving Pressure-Guided Individualized Positive End-Expiratory 
Pressure in Abdominal Surgery: A Randomized Controlled Trial. Anesth Analg. Nov 1 2021;133(5):1197-
1205. doi:10.1213/ANE.0000000000005575 
20. 
Kritek PA, Luks AM. Preventing Dogma from Driving Practice. N Engl J Med. Feb 28 
2019;380(9):870-871. doi:10.1056/NEJMe1900708 
21. 
Mort TC. The incidence and risk factors for cardiac arrest during emergency tracheal intubation: 
a justification for incorporating the ASA Guidelines in the remote location. J Clin Anesth. Nov 
2004;16(7):508-16. doi:10.1016/j.jclinane.2004.01.007 
22. 
Higgs A, McGrath BA, Goddard C, et al. Guidelines for the management of tracheal intubation in 
critically ill adults. Br J Anaesth. Feb 2018;120(2):323-352. doi:10.1016/j.bja.2017.10.021 
23. 
Brown CA, 3rd, Mosier JM, Carlson JN, Gibbs MA. Pragmatic recommendations for intubating 
critically ill patients with suspected COVID-19. J Am Coll Emerg Physicians Open. Apr 2020;1(2):80-84. 
doi:10.1002/emp2.12063 
24. 
Semler MW, Janz DR, Lentz RJ, et al. Randomized Trial of Apneic Oxygenation during 
Endotracheal Intubation of the Critically Ill. Am J Respir Crit Care Med. Feb 1 2016;193(3):273-80. 
doi:10.1164/rccm.201507-1294OC 
25. 
Driver BE, Prekker ME, Casey JD. Use of a Bougie vs Endotracheal Tube With Stylet and 
Successful Intubation on the First Attempt Among Critically Ill Patients Undergoing Tracheal Intubation-
Reply. JAMA. Apr 19 2022;327(15):1503-1504. doi:10.1001/jama.2022.2716 
26. 
Russell DW, Casey JD, Gibbs KW, et al. Effect of Fluid Bolus Administration on Cardiovascular 
Collapse Among Critically Ill Patients Undergoing Tracheal Intubation: A Randomized Clinical Trial. JAMA. 
Jul 19 2022;328(3):270-279. doi:10.1001/jama.2022.9792 
27. 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification 
system. Crit Care Med. Oct 1985;13(10):818-29.  
28. 
Delay JM, Sebbane M, Jung B, et al. The effectiveness of noninvasive positive pressure 
ventilation to enhance preoxygenation in morbidly obese patients: a randomized controlled study. 
Anesth Analg. Nov 2008;107(5):1707-13. doi:10.1213/ane.0b013e318183909b 
29. 
Grieco DL, Anzellotti GM, Russo A, et al. Airway Closure during Surgical Pneumoperitoneum in 
Obese Patients. Anesthesiology. Jul 2019;131(1):58-73. doi:10.1097/ALN.0000000000002662 
30. 
Coussa M, Proietti S, Schnyder P, et al. Prevention of atelectasis formation during the induction 
of general anesthesia in morbidly obese patients. Anesth Analg. May 2004;98(5):1491-5, table of 
contents. doi:10.1213/01.ane.0000111743.61132.99 
31. 
Janz DR, Casey JD, Semler MW, et al. Effect of a fluid bolus on cardiovascular collapse among 
critically ill adults undergoing tracheal intubation (PrePARE): a randomised controlled trial. Lancet Respir 
Med. Dec 2019;7(12):1039-1047. doi:10.1016/S2213-2600(19)30246-2 
32. 
Janz DR, Semler MW, Lentz RJ, et al. Randomized Trial of Video Laryngoscopy for Endotracheal 
Intubation of Critically Ill Adults. Crit Care Med. Nov 2016;44(11):1980-1987. 
doi:10.1097/CCM.0000000000001841 
 
  
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Table 1: Schedule of Enrollment, Interventions, and Assessments in PREOXI 
 
Eligibility 
Screen 
Randomization 
and Allocation 
Peri-Procedural 
Final 
Outcome 
Assessment 
Timepoint 
Decision to 
perform 
tracheal 
intubation 
Before tracheal 
intubation 
Induction 
Tracheal 
intubation 
0-2 min 
after 
tracheal 
intubation 
0-24 hours 
after 
tracheal 
intubation 
Discharge or 
28 days after 
enrollment 
Enrollment: 
 
X 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
 
 
Allocation 
 
X 
 
 
 
 
 
Interventions: 
 
 
 
 
 
 
 
Preoxygenation with 
NIPPV 
 
X 
X 
 
 
 
 
Preoxygenation with 
facemask oxygen 
 
X 
X 
 
 
 
 
Screening for 
contraindications 
X 
X 
 
 
 
 
 
Assessments: 
 
 
 
 
 
 
 
Baseline variables 
X 
X 
 
 
 
 
 
Peri-procedural 
variables 
 
X 
X 
X 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Clinical outcomes 
 
 
 
 
X 
X 
X 
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Table 2: Inclusion/Exclusion Criteria 
Inclusion Criteria 
Patient is located in a participating unit. 
Planned procedure is tracheal intubation using a laryngoscope and sedation. 
Planned operator is a clinician expected to routinely perform tracheal intubation in 
the participating unit. 
 
Exclusion Criteria 
Patient is receiving positive pressure ventilation by a mechanical ventilator, bag-mask 
device, or laryngeal mask airway. 
Patient is known to be less than 18 years old. 
Patient is known to be pregnant. 
Patient is known to be a prisoner. 
Immediate need for tracheal intubation precludes safe performance of study 
procedures. 
Patient is apneic, hypopneic, or has another condition requiring positive pressure 
ventilation between enrollment and induction. 
Operator has determined that preoxygenation with noninvasive ventilation or 
preoxygenation with an oxygen mask is required or contraindicated for optimal care 
of the patient. 
 
 
Table 3: Study outcomes 
Primary Outcome 
Incidence of hypoxemia, defined as a peripheral oxygen saturation <85% 
during the interval between induction and 2 minutes after tracheal 
intubation. 
Secondary Outcome 
Lowest oxygen saturation during the interval between induction and 2 
minutes after tracheal intubation. 
Safety Outcomes 
Incidence of operator-reported aspiration. 
Fraction of inspired oxygen at 24 hours after induction. 
Oxygen saturation at 24 hours after induction. 
Incidence of pneumothorax, defined as radiology report of new 
pneumothorax on chest imaging in the 24 hours after induction. If no chest 
imaging available pre-induction, any pneumothorax in the 24 hours after 
induction will be assumed to be new. 
New infiltrate, defined as radiology report of new infiltrate on chest imaging 
in the 24 hours after intubation. If no chest imaging available pre-induction, 
any infiltrate in the 24 hours after induction will be assumed to be new. 
Exploratory 
Outcomes 
Incidence of severe hypoxemia, defined as the lowest oxygen saturation of 
<80% between induction and 2 minutes after tracheal intubation. 
 . 
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(which was not certified by peer review)
The copyright holder for this preprint 
this version posted March 24, 2023. 
; 
https://doi.org/10.1101/2023.03.23.23287539
doi: 
medRxiv preprint 

 
Incidence of very severe hypoxemia, defined as the lowest oxygen saturation 
of <70% between induction and 2 minutes after tracheal intubation. 
 
Oxygen saturation at induction. 
 
Systolic blood pressure at induction. 
 
Duration from induction to successful intubation (duration of the intubation 
procedure). 
 
Cormack-Lehane grade of glottic view on first attempt. 
 
Number of laryngoscopy attempts. 
 
Number of attempts at passing a bougie. 
 
Number of attempts at passing an endotracheal tube. 
 
Incidence of cardiovascular collapse, defined as a composite of one or more 
of the following between induction and 2 minutes after intubation: Systolic 
blood pressure <65 mmHg, new or increased vasopressor, cardiac arrest not 
resulting in death within 1 hour of induction, cardiac arrest resulting in death 
within 1 hour of induction. 
 
28 day in-hospital mortality. 
 
Ventilator-free days to 28 days. 
 
ICU-free days to 28 days. 
 
 . 
CC-BY-NC-ND 4.0 International license
It is made available under a 
 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
(which was not certified by peer review)
The copyright holder for this preprint 
this version posted March 24, 2023. 
; 
https://doi.org/10.1101/2023.03.23.23287539
doi: 
medRxiv preprint 

Protocol and Statistical Analysis Plan for the
Pragmatic Trial Examining Oxygenation Prior to
Intubation of Preoxygenation With Noninvasive
Ventilation vs Oxygen Mask in Critically Ill Adults
Kevin W. Gibbs, MD; Adit A. Ginde, MD, MPH; Matthew E. Prekker, MD, MPH; Kevin P. Seitz, MD, MSc;
Susan B. Stempek, PA, MBA; Caleb Taylor, MD, MPH; Sheetal Gandotra, MD; Heath White, DO, MS;
Daniel Resnick-Ault, MD; Akram Khan, MD; Amira Mohmed, MD; Jason C. Brainard, MD; Daniel G. Fein, MD;
Neil R. Aggarwal, MD; Micah R. Whitson, MD; Stephen J. Halliday, MD, MSc; John P. Gaillard, MD; Veronika Blinder, DO;
Brian E. Driver, MD; Jessica A. Palakshappa, MD, MS; Bradley D. Lloyd, RRT, RRT-ACCS; Joanne M. Wozniak, PA, MS;
Matthew C. Exline, MD, MPH; Derek W. Russell, MD; Shekhar Ghamande, MD; Cori Withers, BS; Kinsley A. Hubel, MD;
Ari Moskowitz, MD, MPH; Jill Bastman, BSN; Luke Andrea, MD; Peter D. Sottile, MD; David B. Page, MD, MSPH;
Micah T. Long, MD; Jordan Kugler Goranson, MD; Rishi Malhotra, MD; Brit J. Long, MD; Steven G. Schauer, DO, MS;
Andrew Connor, DO; Erin Anderson, RN; Kristin Maestas; Jillian P. Rhoads, PhD; Kelsey Womack, PhD; Brant Imhoff, MS;
David R. Janz, MD, MSc; Stacy A. Trent, MD, MSPH; Wesley H. Self, MD, MPH; Todd W. Rice, MD, MSc;
Matthew W. Semler, MD, MSc; and Jonathan D. Casey, MD, MSc; for the PREOXI Investigators and the Pragmatic Critical
Care Research Group*
BACKGROUND: Hypoxemia is a common and life-threatening complication during emergency
tracheal intubation of critically ill adults. The administration of supplemental oxygen before
the procedure (ie, preoxygenation) decreases the risk of hypoxemia during intubation.
RESEARCH QUESTION: Does preoxygenation with noninvasive ventilation prevent hypoxemia
during tracheal intubation of critically ill adults compared with preoxygenation with an
oxygen mask?
STUDY DESIGN AND METHODS: The Pragmatic Trial Examining Oxygenation Prior to Intu-
bation (PREOXI) is a prospective, multicenter, nonmasked randomized comparative effec-
tiveness trial being conducted in seven EDs and 17 ICUs across the United States. The trial
compares preoxygenation with noninvasive ventilation vs oxygen mask among 1,300 criti-
cally ill adults undergoing emergency tracheal intubation. Eligible patients are randomized in
a 1:1 ratio to receive either noninvasive ventilation or an oxygen mask before induction. The
primary outcome is the incidence of hypoxemia, deﬁned as a peripheral oxygen saturation
of < 85% between induction and 2 min after intubation. The secondary outcome is the lowest
oxygen saturation between induction and 2 min after intubation. Enrollment began on
March 10, 2022, and is expected to conclude in 2023.
INTERPRETATION: The PREOXI investigation will provide important data on the comparative
effectiveness of preoxygenation with noninvasive ventilation vs oxygen mask for the prevention
of hypoxemia during emergency tracheal intubation. Specifying the protocol and statistical
analysis plan before the conclusion of enrollment increases the rigor, reproducibility, and
interpretability of the trial.
TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT05267652; URL: www.clinicaltrials.gov
CHEST Critical Care 2023; 1(2):100014
KEY
WORDS:
critical
illness;
endotracheal
intubation;
noninvasive
positive-pressure
ventilation; oxygen; respiratory failure
[
Mechanical Ventilation and ECMO Original Research ]
chestcc.org
1

Life-threatening hypoxemia occurs in 10% to 20% of
emergency tracheal intubations in the ED and ICU.1,2
Hypoxemia during intubation is associated with an
increased risk of cardiac arrest and death.3,4 Identifying
interventions to prevent hypoxemia during emergency
tracheal intubation is a high priority for clinicians and
researchers.5,6 Because patients typically are apneic
between induction of anesthesia and intubation, but
continue to consume oxygen, the oxygen content in the
lungs at the time of induction is a primary determinant
of whether the patient will experience hypoxemia.
Preoxygenation, the administration of supplemental
oxygen before induction of anesthesia, increases lung
oxygen content at induction and decreases the risk of
hypoxemia.7,8 In clinical practice, preoxygenation for
emergency tracheal intubation of critically ill adults is
most commonly administered using either an oxygen
mask or noninvasive ventilation.1
Preoxygenation with an oxygen mask typically is
performed using either a non-rebreather mask or a bag-
mask device. A non-rebreather mask is a loose-ﬁtting
mask with an oxygen reservoir connected to an oxygen
source. A bag-mask device is a mask capable of forming
a tight seal over the mouth when held in place by a
clinician and can be used to provide supplemental
oxygenation alone, or both supplemental oxygen and
ventilation.9 Both types of oxygen mask can deliver up
to 100% oxygen, are simple to set up, and have low
potential for gastric insufﬂation. However, oxygen
masks may deliver oxygen less effectively in critically ill
patients when high minute ventilation and poor mask
seal allow the entrainment of ambient air, with resulting
alveolar oxygen concentrations as low as 50%.7,10
Preoxygenation also is administered routinely via
noninvasive ventilation, in which a tight-ﬁtting mask is
connected to a machine capable of providing both
100% oxygen and positive-pressure ventilation.
Compared with an oxygen mask, noninvasive
Take-home Points
Study Question: Does preoxygenation with nonin-
vasive ventilation prevent hypoxemia during tracheal
intubation of critically ill adults compared with pre-
oxygenation with an oxygen mask?
Results: This article describes the protocol and sta-
tistical analysis plan for the Pragmatic Trial Exam-
ining Oxygenation Prior to Intubation investigation
of
preoxygenation
with
noninvasive
ventilation
vs with oxygen mask.
Interpretation:
Prespecifying
the
full
statistical
analysis plan before completion of enrollment in-
creases rigor, reproducibility, and transparency of the
trial results.
ABBREVIATIONS: PREOXI = Pragmatic Trial Examining Oxygenation
Prior to Intubation
AFFILIATIONS: From the Section on Pulmonary, Critical Care, Al-
lergy, and Immunology (K. W. G. and J. A. P.), the Section on Critical
Care (J. P. G.,), Department of Anesthesiology, the Department of
Emergency Medicine (J. P. G. and J. K. G.), Wake Forest School of
Medicine, Winston-Salem, NC; the Department of Emergency Medi-
cine (A. A. G., D. R.-A., C. W., J. B., E. A., K. M., and S. A. T.), the
Department of Anesthesiology (J. C. B.), the Division of Pulmonary
Sciences and Critical Care Medicine (N. R. A. and P. D. S.), Depart-
ment of Medicine, University of Colorado School of Medicine, Aurora;
the Department of Emergency Medicine (S. A. T.), Denver Health
Medical Center, Denver, CO; the Division of Pulmonary and Critical
Care Medicine (M. E. P.), the Department of Emergency Medicine (M.
E. P. and B. E. D.), Hennepin County Medical Center, Minneapolis,
MN, the Division of Pulmonary, Allergy, and Critical Care Medicine
(K. P. S., J. P. R., K. W., T. W. R., M. W. S., and J. D. C.), Department of
Medicine, the Vanderbilt Institute for Clinical and Translational
Research (B. D. L. and W. H. S.), the Department of Emergency
Medicine (B. D. L. and W. H. S.), the Department of Biostatistics (B.
I.), Vanderbilt University Medical Center, Nashville, TN; the Division
of Pulmonary & Critical Care Medicine (S. B. S. and J. M. W.),
Department of Medicine, Lahey Hospital & Medical Center, Burling-
ton, MA, Pulmonary, Critical Care and Sleep Medicine (C. T. and M.
C. E.), The Ohio State University, Columbus, OH; the Division of
Pulmonary, Allergy and Critical Care Medicine (S. G., M. R. W., D. W.
R., D. B. P.), Department of Medicine, the Department of Emergency
Medicine (M. R. W.), University of Alabama at Birmingham, the
Pulmonary Section (D. W. R.), Birmingham VA Medical Center, Bir-
mingham, AL; the Division of Pulmonary & Critical Care Medicine (H.
W. and S. G.), Department of Medicine, Baylor Scott & White Medical
Center, Temple, the 59th Medical Wing (B. J. L.), United States Air
Force, Fort Sam Houston; the United States Army Institute of Surgical
Research (S. G. S.), Joint Base San Antonio-Fort Sam Houston, San
Antonio, TX; the Division of Pulmonary, Allergy, and Critical Care
Medicine (A. K., K. A. H., and A. C.), Department of Medicine, Oregon
Health & Science University, Portland, OR; the Division of Critical
Care Medicine (A. M., V. B., A. M., L. A., and R. M.), the Division of
Pulmonary Medicine (D. G. F.), Monteﬁore Medical Center Bronx,
NY; the Division of Allergy, Pulmonary, and Critical Care Medicine (S.
J. H.), Department of Medicine, the Department of Anesthesiology (M.
T. L.), University of Wisconsin School of Medicine and Public Health,
Madison, WI; and the University Medical Center New Orleans and the
Section of Pulmonary/Critical Care Medicine and Allergy/Immunology
(D. R. J.), Department of Medicine, Louisiana State University School
of Medicine, New Orleans, LA.
Drs Gibbs and Ginde contributed equally to this manuscript as ﬁrst
authors.
Drs Semler and Casey contributed equally to this manuscript as senior
authors.
Collaborators for the PREOXI Investigators and the Pragmatic Critical
Care Research Group are listed in section 2 of e-Appendix 1 (section 2).
CORRESPONDENCE
TO: Kevin
W.
Gibbs,
MD;
email:
kgibbs@
wakehealth.edu
Copyright  2023 The Authors. Published by Elsevier Inc under li-
cense from the American College of Chest Physicians. This is an open
access
article
under
the
CC
BY-NC-ND
license
(http://
creativecommons.org/licenses/by-nc-nd/4.0/).
DOI: https://doi.org/10.1016/j.chstcc.2023.100014
2
Original Research
[ 1 # 2 C H E S T C r i t i c a l C a r e S E P T E M B E R 2 0 2 3 ]

ventilation may reduce air entrainment by delivering a
higher inspiratory ﬂow rate of oxygen and by
minimizing leaks. Additionally, noninvasive ventilation
increases the mean airway pressure and recruits
atelectatic lung, potentially reducing shunting.
Compared with an oxygen mask, noninvasive
ventilation may take longer to initiate and potentially
may increase the risk of gastric insufﬂation and
aspiration.
Two small randomized trials have compared these two
approaches to preoxygenation. The ﬁrst trial found that,
among 53 patients in the ICU undergoing tracheal
intubation in two hospitals, noninvasive ventilation
increased the lowest oxygen saturation compared with
the effects of an oxygen mask (mean lowest oxygen
saturation, 93% vs 81%, respectively; P < .001) with no
difference between groups in the incidence of aspiration
(6% vs 8%).11 Among 201 patients in the ICUs of six
hospitals, the second trial found no difference in the
severity of illness in the 7 days after intubation and an
incidence of hypoxemia during intubation of 18.4% in
the noninvasive ventilation group vs 27.7% in the
oxygen mask group (P ¼ .10).12 Thus, whether
noninvasive ventilation for preoxygenation in critically
ill adults undergoing emergency tracheal intubation
decreases the incidence of hypoxemia compared with an
oxygen mask remains unknown. We designed the
Pragmatic Trial Examining Oxygenation Prior to
Intubation (PREOXI) to test the hypothesis that, among
critically ill adults undergoing emergency tracheal
intubation in the ED and ICU, preoxygenation with
noninvasive ventilation decreases the incidence of
hypoxemia compared with preoxygenation with an
oxygen mask.
Study Design and Methods
This article was written in accordance with Standard Protocol Items:
Recommendations for Interventional Trials guidelines (Table 1,
e-Appendix 1).13
Study Design
PREOXI is a pragmatic, multicenter, nonmasked, parallel-group
randomized
trial
comparing
preoxygenation
using
noninvasive
ventilation with preoxygenation using an oxygen mask among
critically ill adults undergoing emergency tracheal intubation in
TABLE 1 ] Schedule of Enrollment, Interventions, and Assessments in PREOXI
Time Point
Eligibility
Screening,
Decision to
Perform Tracheal
Intubation
Randomization
and Allocation,
Before Tracheal
Intubation
During the Procedure
Final Outcome
Assessment,
Discharge or 28
d After Enrollment
Induction
Tracheal
Intubation
0-2 min
After
Tracheal
Intubation
0-24 h
After
Tracheal
Intubation
Enrollment
Eligibility screen
X
. . .
. . .
. . .
. . .
. . .
. . .
Enrollment
. . .
X
. . .
. . .
. . .
. . .
. . .
Allocation
. . .
X
. . .
. . .
. . .
. . .
. . .
Interventions
Preoxygenation
with NIPPV
. . .
X
X
. . .
. . .
. . .
. . .
Preoxygenation
with face mask
oxygen
. . .
X
X
. . .
. . .
. . .
. . .
Screening for
contraindications
X
X
X
. . .
. . .
. . .
. . .
Assessments
Baseline variables
X
X
. . .
. . .
. . .
. . .
. . .
Periprocedural
variables
. . .
X
X
X
X
. . .
. . .
Adverse events
. . .
X
X
X
X
X
X
Clinical outcomes
. . .
. . .
. . .
. . .
X
X
X
Table entries without data mean that data elements were not collected at that time. NIPPV ¼ noninvasive positive-pressure ventilation; PREOXI ¼
Pragmatic Trial Examining Oxygenation Prior to Intubation.
chestcc.org
3

the ED and ICU. The primary outcome is the incidence of
hypoxemia,
deﬁned
as
a
peripheral
oxygen
saturation
of
<
85% between induction of anesthesia and 2 min after intubation.
The trial is conducted by the Pragmatic Critical Care Research
Group
(www.pragmaticcriticalcare.org).
The
trial
was
registered
before
initiation
of
enrollment
(ClinicalTrials.gov
Identiﬁer:
NCT05267652).
Study Population
Patients located in a participating ED or ICU who are undergoing
tracheal intubation using a laryngoscope and sedation are eligible.
Complete lists of inclusion and exclusion criteria are provided in
Table 2.
Randomization and Treatment Allocation
Patients are randomized in a 1:1 ratio to undergo preoxygenation with
noninvasive ventilaton vs oxygen mask in permuted blocks of variable
size, stratiﬁed by study site. Study-group assignments are generated
using a computerized randomization sequence, placed in sequentially
numbered opaque envelopes and distributed to enrolling sites. Before
opening the envelope, the operator determines that the patient meets
eligibility criteria. Study group assignment remains concealed to study
personnel and clinicians until after the decision has been made to enroll
the patient and the envelope is opened. Patients are enrolled as soon as
the operator opens the trial envelope to reveal study group assignment.
After randomization, patients, clinicians, and study personnel are not
masked to group assignment because of the nature of the intervention.
Study Interventions
Training
Before beginning enrollment at each site, study
investigators provide training on study procedures
including instructional videos with consensus best
practice recommendations for preoxygenation.
Descriptions of the training videos and website links can
be found in e-Appendix 1.
Noninvasive Ventilation Group
For patients assigned to the noninvasive ventilation
group, operators are instructed to administer noninvasive
ventilation using either a conventional mechanical
ventilator or a dedicated noninvasive ventilator (ie, a
bilevel positive airway pressure machine). The operator
determines the ventilator type, ventilator mode,
inspiratory and expiratory pressures, and mandatory
respiratory rate. Operators receive the following best
practice recommendations for the administration of
preoxygenation using noninvasive ventilation: (1)
preoxygenate $ 3 min (if feasible); (2) continue
noninvasive ventilation until initiation of laryngoscopy,
(3) FIO2 of 100%, (4) expiratory pressure of $ 5 cm H2O;
(5) use an inspiratory pressure of $ 10 cm H2O, and (6)
respiratory rate of $ 10 breaths per minute.
Oxygen Mask Group
For patients assigned to the oxygen mask group,
clinicians are instructed to administer supplemental
oxygen via a non-rebreather mask or bag-mask device
without bag-mask ventilation from the initiation of
preoxygenation until the induction of anesthesia. The
operator determines whether to use a non-rebreather
mask or a bag-mask device (without ventilation).
Operators receive the following best practice
recommendations for the administration of
preoxygenation using an oxygen mask: (1)
preoxygenate $ 3 min (if feasible), (2) use the maximum
oxygen ﬂow rate possible ($ 15 L/min), and (3)
continue oxygenation from induction to laryngoscopy.
Cointerventions
In both trial groups, trial protocol allows the
administration of supplemental oxygen by standard
nasal cannula or high-ﬂow nasal cannula during
preoxygenation, between induction of anesthesia and
initiation of laryngoscopy, and between initiation of
laryngoscopy and intubation of the trachea. Bag-mask
ventilation between induction and laryngoscopy also
may be provided at the discretion of the operator in both
groups. Figure 1 shows the interventions,
cointerventions, and phases of the intubation process
during which these interventions are applied.
TABLE 2 ] Inclusion and Exclusion Criteria
Inclusion criteria
Patient is located in a participating unit.
Planned procedure is tracheal intubation using a
laryngoscope and sedation.
Planned operator is a clinician expected to perform
tracheal intubation routinely in the participating unit.
Exclusion criteria
Patient is receiving positive-pressure ventilation by a
mechanical ventilator, bag-mask device, or laryngeal
mask airway.
Patient is known to be younger than 18 years.
Patient is known to be pregnant.
Patient is known to be in prison.
Immediate need for tracheal intubation precludes safe
performance of study procedures.
Patient is apneic, is hypopneic, or has another
condition requiring positive-pressure ventilation
between enrollment and induction.
Operator has determined that preoxygenation with
noninvasive ventilation or preoxygenation with an
oxygen mask is required or contraindicated for
optimal care of the patient.
4
Original Research
[ 1 # 2 C H E S T C r i t i c a l C a r e S E P T E M B E R 2 0 2 3 ]

Data Collection
An observer not directly involved with the intubation
procedure collects data for key periprocedural outcomes,
including oxygen saturation at induction and the lowest
value for oxygen saturation between induction and 2 min
after successful intubation. Observers may be trained
clinical personnel (eg, physicians or nurses) or research
personnel. Immediately after the intubation procedure,
the operator completes a paper data collection form to
record the device used for preoxygenation, the duration
of preoxygenation, the devices used for oxygenation and
ventilation between induction and laryngoscopy, and
complications of intubation (eg, aspiration).14 Study
personnel at each site review the medical record to collect
data on baseline characteristics, management before and
after laryngoscopy, and clinical outcomes. A complete list
of baseline, periprocedural, and in-hospital variables are
provided in e-Table 1.
Primary Outcome
The primary outcome is the incidence of hypoxemia,
deﬁned as a peripheral oxygen saturation of
< 85% during the interval between induction and 2 min
after intubation.
Secondary Outcome
The sole secondary outcome is the lowest oxygen
saturation during the interval between induction and
2 min after tracheal intubation.
Additional Outcomes
Table 3 reports the safety outcomes, exploratory
procedural outcomes, and exploratory clinical outcomes.
3-5 min
45-90 s
45-90 s
Duration
Initiation of
Preoxygenation
Induction of
Anesthesia
Initiation of
Laryngoscopy
Intubation of
the Trachea
Respiratory effort
Recommend
noninvasive ventilation
Allow
bag-mask ventilation
Supplemental oxygen via standard nasal cannula or high-flow nasal cannula allowed
Oxygenation and Ventilation
Oxygenation alone
Mandated by trial protocol
Recommended by trial protocol
Allowed by trial protocol
bag-mask with ventilation
Recommend providing
oxygen via non-rebreather,
bag-mask without
ventilation, or
or
Noninvasive ventilation mandated
Non-rebreather or bag-mask
device without ventilation
mandated
Either Group
NIV Group
Oxygen Mask Group
Preoxygenation
Figure 1 – Diagram showing oxygenation and ventilation interventions in each trial group. The methods of oxygen delivery and ventilation allowed,
recommended, and mandated during each phase of the tracheal intubation procedure are displayed for the noninvasive ventilation group and the
oxygen mask group. For patients assigned to the noninvasive ventilation group, clinicians are instructed to administer noninvasive ventilation via either
a dedicated noninvasive ventilator or an invasive ventilator connected to a tight-ﬁtting mask from the initiation of preoxygenation until induction of
anesthesia. Trial protocol recommends that noninvasive ventilation be continued between induction of anesthesia and the initiation of laryngoscopy.
For patients assigned to the oxygen mask group, clinicians are instructed to administer supplemental oxygen without ventilation via either a non-
rebreather mask or a bag-mask device from the initiation of preoxygenation until induction of anesthesia. Trial protocol recommends that the
administration of supplemental oxygen by mask be continued between induction of anesthesia and the initiation of laryngoscopy. In either trial group,
trial protocol allows the administration of supplemental oxygen by high-ﬂow nasal cannula or standard nasal cannula in any phase of the intubation
procedure, including under a mask during preoxygenation. In either trial group, trial protocol allows ventilation using a bag-mask device between
induction and the initiation of laryngoscopy in place of noninvasive ventilation or an oxygen mask. NIV ¼ noninvasive ventilation.
chestcc.org
5

Sample Size Estimation
The current trial is designed to detect a 6% absolute
difference between groups in the incidence of
hypoxemia, a difference that is similar to or smaller than
the difference considered to be clinically meaningful in
the design of prior trials of oxygenation strategies during
tracheal intubation.2,15 Assuming an incidence of
hypoxemia of 17% in the oxygen mask group based on
data from two recently completed trials by this network
in similar ED and ICU settings, detecting a 6% absolute
decrease in the incidence of hypoxemia with 85% power
at a two-sided a level of .05 would require enrollment of
1,264 patients (632 per group).16,17 Anticipating missing
data for up to 3% of patients, we plan to enroll a
maximum of 1,300 total patients (650 per group). This
sample size calculation was performed in PS version
3.1.2 software (Vanderbilt University Medical Center).
Data and Safety Monitoring Board and Interim
Analysis
The data and safety monitoring board and interim
analysis are described in e-Appendix 1.
Statistical Analysis Principles
Analyses will be conducted following reproducible
research principles using R software (R Foundation for
Statistical Computing). Categorical variables will be
presented as number and percentage and will be
compared between groups using a c2 test. Continuous
variables will be presented as mean  SD or median
TABLE 3 ] Study Outcomes
Outcome Type
Description
Primary
Incidence of hypoxemia, deﬁned as a peripheral oxygen saturation of < 85% during the interval
between induction and 2 min after tracheal intubation.
Secondary
Lowest oxygen saturation during the interval between induction and 2 min after tracheal
intubation.
Safety
Incidence of operator-reported aspiration.
FIO2 at 24 h after induction.
Oxygen saturation at 24 h after induction.
Incidence of pneumothorax, deﬁned as radiology report of new pneumothorax on chest imaging
in the 24 h after induction. If no chest imaging is available before induction, any pneumothorax
in the 24 h after induction will be assumed to be new.
New inﬁltrate, deﬁned as radiology report of new inﬁltrate on chest imaging in the 24 h after
intubation. If no chest imaging is available before induction, any inﬁltrate in the 24 h after
induction will be assumed to be new.
Exploratory procedural
Incidence of severe hypoxemia, deﬁned as the lowest oxygen saturation of < 80% between
induction and 2 min after tracheal intubation.
Incidence of very severe hypoxemia, deﬁned as the lowest oxygen saturation of < 70% between
induction and 2 min after tracheal intubation.
Oxygen saturation at induction.
Systolic BP at induction.
Duration from induction to successful intubation (duration of the intubation procedure).
Cormack-Lehane grade of glottic view on ﬁrst attempt.
Successful intubation on the ﬁrst attempt
No. of laryngoscopy attempts.
No. of attempts at passing a bougie.
No. of attempts at passing an endotracheal tube.
Incidence of cardiovascular collapse, deﬁned as a composite of $ 1 of the following between
induction and 2 min after intubation: systolic BP < 65 mm Hg, new or increased vasopressor
administration, cardiac arrest not resulting in death within 1 h of induction, cardiac arrest
resulting in death within 1 h of induction.
Exploratory clinical
28-d in-hospital mortality.
Ventilator-free days to 28 d.
ICU-free days to 28 d.
6
Original Research
[ 1 # 2 C H E S T C r i t i c a l C a r e S E P T E M B E R 2 0 2 3 ]

(interquartile range) and will be compared between
groups using a Wilcoxon rank-sum test. We will present
absolute between-group differences with associated
95% CIs. A two-sided P value of < .05 will deﬁne a
statistically signiﬁcant between-group difference in the
primary outcome. With a single primary outcome, no
adjustment for multiplicity will be made. For secondary,
safety, and exploratory analyses, emphasis will be placed
on the magnitude of differences between groups with
95% CIs, rather than statistical signiﬁcance.
Main Analysis of the Primary Outcome
The main analysis will be an unadjusted intention-to-
treat comparison of the primary outcome of hypoxemia
between patients randomized to the noninvasive
ventilation group vs patients randomized to the oxygen
mask group using a c2 test. The absolute difference in
proportions, associated 95% CI, and a P value for the
comparison will be presented. The primary analysis will
be conducted among patients for whom the primary
outcome is available without imputation of missing data.
Planned tables of baseline characteristics, procedural
characteristics, and outcomes are presented in e-Tables 2
and 3.
Additional Analyses of the Primary Outcome
Multivariable Analysis: To account for relevant baseline
covariates, we will ﬁt a generalized linear mixed effects
model using a logit link function with the primary
outcome as the dependent variable, study site as a
random effect, and ﬁxed effects of study group and the
following prespeciﬁed baseline covariates: age, sex, race
and ethnicity, BMI, location at enrollment (ED or ICU),
highest FIO2 1 h before initiation of preoxygenation,
Acute Physiology and Chronic Health Evaluation II
score,18 indication for intubation (hypoxemic
respiratory failure: yes vs no), and operator experience
(number of previous intubations the operator has
performed). All continuous variables will be modelled
assuming a nonlinear relationship to the outcome using
restricted cubic splines with between 3 and 5 knots.
Effect Modiﬁcation: We will examine whether
prespeciﬁed baseline variables modify the effect of study
group assignment on the primary outcome using a
formal test of statistical interaction in a logistic regression
model with the primary outcome as the dependent
variable and independent variables of study group, the
proposed effect modiﬁer, and the interaction between the
two. For categorical variables, we will present the OR and
95% CIs within each prespeciﬁed subgroup. Continuous
variables will not be dichotomized for analysis of effect
modiﬁcation, but may be dichotomized for data
presentation. In accordance with the Instrument for
Assessing the Credibility of Effect Modiﬁcation Analyses
recommendations, we have prespeciﬁed the following
baseline variables as potential effect modiﬁers and
hypothesized the direction of effect modiﬁcation for
each.
Patient Location (ED vs ICU): We hypothesize that
patient location will not modify the effect of study group
assignment on the primary outcome.
BMI (kg/m2): We hypothesize that BMI will modify the
effect of study group assignment on the primary
outcome, with a greater decrease in the incidence of
hypoxemia in the noninvasive ventilation group
compared with the oxygen mask group among patients
with higher BMIs, as compared with patients with lower
BMIs. This hypothesis is supported by evidence from
multiple prior studies that patients with obesity are more
likely to have early airway closure and atelectasis-
dependent shunting that is likely to improve with
positive-pressure ventilation.19,20
FIO2 1 h Before Intubation: We hypothesize that FIO2
1 h before intubation will modify the effect of study
group assignment on the primary outcome, with a
greater decrease in the incidence of hypoxemia in the
noninvasive ventilation group compared with the
oxygen mask group among patients with higher FIO2 1 h
before intubation compared with patients with lower
FIO2. This hypothesis is supported by evidence from
multiple prior studies that patients requiring higher FIO2
have more atelectasis-dependent shunting that is likely
to improve with positive-pressure ventilation.5,11,21
Acute Physiology and Chronic Health Evaluation II
Score: We hypothesize that Acute Physiology and
Chronic Health Evaluation II score will not modify the
effect of study group assignment on the primary
outcome.
Hypoxemic Respiratory Failure as the Indication for
Intubation (Yes vs No): We hypothesize that
hypoxemic respiratory failure as the indication for
intubation will modify the effect of study group
assignment on the primary outcome, with a greater
decrease in the incidence of hypoxemia in the
noninvasive ventilation group compared with the
oxygen mask group among patients with hypoxemic
respiratory failure compared with patients without. This
hypothesis is supported by evidence from two prior
chestcc.org
7

randomized trials suggesting a potential beneﬁt for
noninvasive ventilation among patients with acute
hypoxemic respiratory failure.11,12
Analysis of the Secondary Outcome
We will perform an unadjusted intention-to-treat
comparison of patients randomized to the noninvasive
ventilation group vs the oxygen mask group regarding
the secondary outcome of lowest oxygen saturation
between induction and 2 min after intubation using the
Wilcoxon rank-sum test.
Analyses of Additional Outcomes
The analysis plan for additional outcomes is described in
e-Appendix 1.
Handling of Missing Data
The plan for handling of missing data is described in
e-Appendix 1.
Ethics and Dissemination
Critically ill patients undergoing tracheal intubation are
at signiﬁcant risk for morbidity and mortality from the
underlying illness. Most patients undergoing tracheal
intubation in routine clinical care receive
preoxygenation with either noninvasive ventilation or an
oxygen mask. Any beneﬁts or risks of these two
approaches are experienced by patients undergoing
tracheal intubation in clinical care, outside the context of
research. As a requirement for enrollment in PREOXI,
the patient’s treating clinician must determine that
either preoxygenation with noninvasive ventilation or
preoxygenation with an oxygen mask would be a safe
and reasonable approach for the patient. Otherwise, the
patient is excluded. Therefore, making the decision
between the two approaches randomly in the context of
a trial, rather than by a clinician who thinks either
approach is safe, is expected to pose no more than
minimal additional risk.
Obtaining informed consent from potential study
participants or their legally authorized representatives
would be impracticable. Most critically ill patients
undergoing emergency tracheal intubation lack
decisional capacity because of the critical illness and
surrogate decision-makers frequently are unavailable.
Further, emergency tracheal intubation is a time-
sensitive procedure with only minutes between the
decision to intubate and the completion of the
procedure. Meaningful informed consent could not be
executed in this brief window.
Because the study involves minimal incremental risk, the
study would not adversely affect the welfare or privacy
rights of the participant, and because obtaining
informed consent would be impracticable, a waiver of
informed consent was requested from and approved by
the single institutional review board at Vanderbilt
University Medical Center (Identiﬁer: 211271). Conduct
of this trial with waiver of informed consent is consistent
with previous randomized trials comparing alternative
approaches to tracheal intubation in widespread clinical
use.2,15-17,22,23 This approach was approved secondarily
by the US Department of Defense Health Agency
Human Research Protection Ofﬁce. Institutional review
boards at participating sites reviewed the protocol,
addressed any local contextual factors, and ceded
responsibility for ethics approval and study oversight to
the single institutional review board.
Discussion
Herein, we report the rationale, design, and analysis plan
for PREOXI, a 1,300-patient randomized trial of
preoxygenation with noninvasive ventilation
vs preoxygenation with oxygen mask among critically ill
adults undergoing emergency tracheal intubation in the
ED or ICU. Several important trial design elements bear
additional consideration.
We selected hypoxemia (as a binary variable), rather
than lowest oxygen saturation (a continuous variable), as
the primary outcome for the trial for several reasons.
First, experiencing hypoxemia in the range associated
with an increased risk of adverse clinical outcomes (eg,
cardiac arrest) may be more clinically relevant than
changes in oxygen saturation within the normal range.
For example, a change in oxygen saturation of 5
percentage points from 87% to 82% may be associated
more closely with adverse outcomes than a change in
oxygen saturation of 10 percentage points from 100% to
90%. Second, values for oxygen saturation are right-
censored because oxygen saturation reaches 100% with a
PaO2 of approximately 100 mm Hg, but patients may
have a higher PaO2 after preoxygenation. The approach
of analyzing hypoxemia as a binary variable, rather than
lowest oxygen saturation, has been used by many prior
trials and has been endorsed by airway experts.24-29
We selected an oxygen saturation of < 85% as the
threshold for the primary outcome based on several
physiologic and procedural factors. First, an oxygen
saturation of 85% corresponds with the inﬂection point
on the oxyhemoglobin dissociation curve, at which
8
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[ 1 # 2 C H E S T C r i t i c a l C a r e S E P T E M B E R 2 0 2 3 ]

further decrements in arterial oxygen concentrations
result in rapid and critical desaturation.9 Second, an
oxygen saturation of < 85% has been associated with an
increased risk of cardiac arrest during tracheal
intubation30 and may be associated with increased
mortality.5
Another trial design element that warrants consideration
is the decision to allow the use of either a non-rebreather
mask or a bag-mask device to provide preoxygenation in
the oxygen mask group. Both devices can be used to
provide supplemental oxygen without positive-pressure
ventilation, but differ in some respects. A non-
rebreather mask uses a loose-ﬁtting interface and
requires no provider involvement, whereas a bag-mask
device requires a provider to hold the mask in place and
can provide a tight mask seal. A bag-mask device also
can be used to provide positive-pressure ventilation,
which in the oxygen mask group of the current trial was
allowed only after induction of anesthesia. Although
these differences theoretically could affect
preoxygenation, available evidence suggests that the two
devices perform similarly.31 Any theoretical difference in
preoxygenation between two devices providing oxygen is
likely to be much smaller than the difference between
these devices, which provide supplemental oxygen alone,
and devices that provide both supplemental oxygen and
positive-pressure ventilation (ie, the noninvasive
ventilation group in PREOXI). Allowing both types of
oxygen masks routinely used in clinical care also
increases the generalizability of trial results.
The use of positive-pressure ventilation after induction
of anesthesia (the end of preoxygenation) is allowed in
both trial groups. Evidence from a prior randomized
trial conducted among patients in the ICU suggests that
bag-mask ventilation between induction and
laryngoscopy reduces the risk of hypoxemia.2 However,
the safety and efﬁcacy of bag-mask ventilation has not
been evaluated among patients in the ED. Some experts
have advocated avoiding bag-mask ventilation among
patients in the ED who are less likely to have fasted than
patients in the ICU and therefore may be at higher risk
of aspiration.32 Because PREOXI enrolls patients in both
the ED and ICU and focuses on preoxygenation and not
management between induction and laryngoscopy, trial
protocol allows bag-mask ventilation after induction of
anesthesia, but does not mandate it.
The ﬁnal design consideration is the administration of
supplemental oxygen via standard nasal cannula and
high-ﬂow nasal cannula. Because oxygen facemasks
and facemasks for noninvasive ventilation must be
removed during laryngoscopy, some experts advocate
for the administration of supplemental oxygen via
standard nasal cannula oxygen or high-ﬂow nasal
cannula during laryngoscopy. The randomized trials
available to date have not demonstrated consistently a
beneﬁt from administration of supplemental oxygen
via standard nasal cannula or high-ﬂow nasal cannula
during tracheal intubation.15,33-38 Therefore, the trial
protocol for PREOXI allows, but does not require, the
administration of supplemental oxygen via standard
nasal cannula and high-ﬂow nasal cannula in both
trial groups.
Interpretation
PREOXI will provide important evidence regarding the
effectiveness of common preoxygenation strategies for
the prevention of hypoxemia during emergency tracheal
intubation. To aid in the transparency and
interpretation of trial results, this article detailing the
protocol and statistical analysis plan for PREOXI has
been ﬁnalized before the conclusion of patient
enrollment.
Funding/Support
The research was funded primarily by the United States
Department of Defense, Defense Health Agency, J9
Ofﬁce, Restoral program. K. P. S. was supported in part
by the National Institutes of Health [Grant
T32HL087738]. J. A. P. was supported in part by the
National Institute on Aging [Grant K23AG073529]. M.
W. S. was supported in part by the National Heart, Lung,
and Blood Institute [Grant K23HL143053]. J. D. C. was
supported in part by the National Heart, Lung, and
Blood Institute [Grant K23HL153584]. D. R. was
supported in part by the National Heart, Lung, and
Blood Institute [Grant K08HL148514-01A1]. Data
collection used the Research Electronic Data Capture
tool developed and maintained with Vanderbilt Institute
for Clinical and Translational Research grant support
[Grant UL1 TR000445 from the National Center for
Advancing Translational Sciences, National Institutes of
Health).
Financial/Nonﬁnancial Disclosures
The authors have reported to CHEST Critical Care the
following: K. W. G. reports ﬁnancial support and travel
were provided by US Department of Defense. A. A. G.
reports ﬁnancial support was provided by US
Department of Defense. M. E. P. reports ﬁnancial support
chestcc.org
9

was provided by US Department of Defense. K. P. S.
reports ﬁnancial support was provided by National
Heart, Lung, and Blood, Institute. S. B. S. reports ﬁnancial
support was provided by CHEST. A. K. reports ﬁnancial
support was provided by United Therapeutics
Corporation, 4D Medicine, Ltd., Regeneron
Pharmaceuticals, Inc., Roche, and Dompé
Pharmaceutical. J. A. P. reports ﬁnancial support was
provided by the National Institute on Aging. J. M. W.
reports ﬁnancial support was provided by CHEST. M. C.
E. reports ﬁnancial support was provided by Abbott
Laboratories. D. W. R. reports ﬁnancial support was
provided by the National Heart, Lung, and Blood
Institute and a relationship with Achieve Life Science,
Inc., that includes equity or stocks. S. G. reports ﬁnancial
support was provided by US Department of Defense. A.
M. reports ﬁnancial support was provided by the
National Heart, Lung, and Blood Institute. J. B. reports
ﬁnancial support was provided by US Department of
Defense. M. T. L. reports ﬁnancial support was provided
by pocket cards. S. G. S. reports was provided by US
Department of Defense. D. R. J. reports ﬁnancial support
was provided by US Department of Defense. M. W. S.
reports ﬁnancial support was provided by US
Department of Defense and the National Heart, Lung,
and Blood Institute and a relationship with Baxter
International, Inc., that includes consulting or advisory. J.
D. C. reports ﬁnancial support was provided by US
Department of Defense. T. W. R. reports a relationship
with Cumberland Pharmaceuticals, Inc., that includes
consulting or advisory and equity or stocks. J. D. C.
reports ﬁnancial support was provided by the National
Heart, Lung, and Blood Institute and travel was provided
by Fisher & Paykel Healthcare, Inc.
Acknowledgments
Author contributions: K. W. G. , A. A. G.,
M. W. S., and J. D. C. helped with study
concept and design, acquisition of data,
drafting and critical revision of the
manuscript, and study supervision. M. E. P.,
K. P. S., S. B. S., C. T., S. G., H. W., D. R.-A.,
N. R. A., M. R. W., S. J. H., J. P. G., V. B., B. E.
D., J. A. P., B. D. L., J. M. W., M. C. E., D. W.
R., S. G., C. W., K. A. H., A. M., J. B., L. A., P.
D. S., D. B. P., M. T. L., J. K. G., R. M., B. J. L.,
S. G. S., E. A., K. M., J. P. R., K. W., D. R. J., S.
A. T., W. H. S., and T. W. R. helped with
acquisition of data and critical revision of the
manuscript for important intellectual
content. A. C. helped with development of
training videos and critical revision of the
manuscript for important intellectual
content. B. I. helped with acquisition of data,
statistical analysis, and critical revision of the
manuscript for important intellectual
content.
Collaborators for the PREOXI Investigators
and the Pragmatic Critical Care Research
Group: Listed in e-Appendix 1.
Role of sponsors: The funding institutions
had no role in (1) conception, design, or
conduct of the study; or (2) collection,
management, analysis, interpretation, or
presentation of the data.
Disclaimer: The views expressed are those of
the authors and do not reﬂect the ofﬁcial
views or policy of the Department of Defense
or its components. The authors do not have
any ﬁnancial interest in the companies whose
materials are discussed in this publication,
and no federal endorsement of the companies
and materials is intended.
Additional information: The e-Appendix
and e-Tables are available online under
“Supplementary Data.”
References
1. Russotto V, Myatra SN, Laffey JG, et al.
Intubation practices and adverse peri-
intubation events in critically ill patients
from 29 countries. JAMA. 2021;325(12):
1164-1172.
2. Casey JD, Janz DR, Russell DW, et al. Bag-
mask ventilation during tracheal
intubation of critically ill adults. N Engl J
Med. 2019;380(9):811-821.
3. Davis DP, Dunford JV, Poste JC, et al. The
impact of hypoxia and hyperventilation
on outcome after paramedic rapid
sequence intubation of severely head-
injured patients. J Trauma. 2004;57(1):
1-8; discussion 8-10.
4. April MD, Arana A, Reynolds JC, et al.
Peri-intubation cardiac arrest in the
emergency department: a National
Emergency Airway Registry (NEAR)
study. Resuscitation. 2021;162:403-411.
5. Smischney NJ, Khanna AK, Brauer E,
et al. Risk factors for and outcomes
associated with peri-intubation
hypoxemia: a multicenter prospective
cohort study. J Intensive Care Med.
2021;36(12):1466-1474.
6. Meier NM, Gibbs KW. Evolving tracheal
intubation practice patterns in the
pandemic era. Chest. 2021;160(6):
1993-1994.
7. Mosier JM, Hypes CD, Sakles JC.
Understanding preoxygenation and
apneic oxygenation during intubation in
the critically ill. Intensive Care Med.
2017;43(2):226-228.
8. Berthoud M, Read DH, Norman J. Pre-
oxygenation—how long? Anaesthesia.
1983;38(2):96-102.
9. Weingart SD. Preoxygenation,
reoxygenation, and delayed sequence
intubation in the emergency department.
J Emerg Med. 2011;40(6):661-667.
10. Driver BE, Prekker ME, Kornas RL,
Cales EK, Reardon RF. Flush rate oxygen
for emergency airway preoxygenation.
Ann Emerg Med. 2017;69(1):1-6.
11. Baillard C, Fosse JP, Sebbane M, et al.
Noninvasive ventilation improves
preoxygenation before intubation of
hypoxic patients. Am J Respir Crit Care
Med. 2006;174(2):171-177.
12. Baillard C, Prat G, Jung B, et al. Effect of
preoxygenation using non-invasive
ventilation before intubation on
subsequent organ failures in hypoxaemic
patients: a randomised clinical trial. Br J
Anaesth. 2018;120(2):361-367.
13. Chan AW, Tetzlaff JM, Gotzsche PC, et al.
SPIRIT 2013 explanation and elaboration:
guidance for protocols of clinical trials.
BMJ. 2013;346:e7586.
14. Cormack RS, Lehane J. Difﬁcult tracheal
intubation in obstetrics. Anaesthesia.
1984;39(11):1105-1111.
15. Semler MW, Janz DR, Lentz RJ, et al.
Randomized trial of apneic oxygenation
during endotracheal intubation of the
critically ill. Am J Respir Crit Care Med.
2016;193(3):273-280.
16. Driver BE, Prekker ME, Casey JD. Use of a
bougie vs endotracheal tube with stylet
and successful intubation on the ﬁrst
attempt among critically ill patients
undergoing tracheal intubation-reply.
JAMA. 2022;327(15):1503-1504.
17. Russell DW, Casey JD, Gibbs KW, et al.
Effect of ﬂuid bolus administration on
cardiovascular collapse among critically ill
patients undergoing tracheal intubation: a
randomized clinical trial. JAMA.
2022;328(3):270-279.
18. Knaus WA, Draper EA, Wagner DP,
Zimmerman JE. APACHE II: a severity of
disease classiﬁcation system. Crit Care
Med. 1985;13(10):818-829.
10
Original Research
[ 1 # 2 C H E S T C r i t i c a l C a r e S E P T E M B E R 2 0 2 3 ]

19. Delay JM, Sebbane M, Jung B, et al. The
effectiveness of noninvasive positive
pressure ventilation to enhance
preoxygenation in morbidly obese
patients: a randomized controlled study.
Anesth Analg. 2008;107(5):1707-1713.
20. Grieco DL, Anzellotti GM, Russo A, et al.
Airway closure during surgical
pneumoperitoneum in obese patients.
Anesthesiology. 2019;131(1):58-73.
21. Coussa M, Proietti S, Schnyder P, et al.
Prevention of atelectasis formation during
the induction of general anesthesia in
morbidly obese patients. Anesth Analg.
2004;98(5):1491-1495.
22. Janz DR, Casey JD, Semler MW, et al.
Effect of a ﬂuid bolus on cardiovascular
collapse among critically ill adults
undergoing tracheal intubation
(PrePARE): a randomised controlled trial.
Lancet Respir Med. 2019;7(12):1039-1047.
23. Janz DR, Semler MW, Lentz RJ, et al.
Randomized trial of video laryngoscopy
for endotracheal intubation of critically ill
adults. Crit Care Med. 2016;44(11):
1980-1987.
24. Writing Committee and Steering
Committee for the RELAx Collaborative
Group, Algera AG, Pisani L, et al. Effect of
a lower vs higher positive end-expiratory
pressure strategy on ventilator-free days in
ICU patients without ARDS: a
randomized clinical trial. JAMA.
2020;324(24):2509-2520.
25. Franklin D, Babl FE, Schlapbach LJ, et al.
A randomized trial of high-ﬂow oxygen
therapy in infants with bronchiolitis.
N Engl J Med. 2018;378(12):1121-1131.
26. Driver BE, Semler MW, Self WH, et al.
Effect of use of a bougie vs endotracheal
tube with stylet on successful intubation
on the ﬁrst attempt among critically ill
patients undergoing tracheal intubation: a
randomized clinical trial. JAMA.
2021;326(24):2488-2497.
27. De Jong A, Rolle A, Molinari N, et al.
Cardiac arrest and mortality related to
intubation procedure in critically ill adult
patients: a multicenter cohort study. Crit
Care Med. 2018;46(4):532-539.
28. Zhang C, Xu F, Li W, et al. Driving
pressure-guided individualized positive
end-expiratory pressure in abdominal
surgery: a randomized controlled trial.
Anesth Analg. 2021;133(5):1197-1205.
29. Kritek PA, Luks AM. Preventing dogma
from driving practice. N Engl J Med.
2019;380(9):870-871.
30. Mort TC. The incidence and risk factors
for cardiac arrest during emergency
tracheal intubation: a justiﬁcation for
incorporating the ASA guidelines in the
remote location. J Clin Anesth. 2004;16(7):
508-516.
31. Driver BE, Klein LR, Carlson K,
Harrington J, Reardon RF, Prekker ME.
Preoxygenation with ﬂush rate oxygen:
comparing the nonrebreather mask with
the bag-valve mask. Ann Emerg Med.
2018;71(3):381-386.
32. Brown CA 3rd. Rapid sequence intubation
in adults for emergency medicine and
critical care. uptodate. UpToDate, Wolters
Kluwer website. Accessed July 5, 2023.
https://www.uptodate.com/contents/
rapid-sequence-intubation-in-adults-for-
emergency-medicine-and-critical-care?
search¼rapid%20sequence%20intubation
%20in%20adults%200utside%200perating
%20room&source¼search_
result&selectedTitle¼1150&usage_
type¼default&display_rank¼1
33. Caputo N, Azan B, Domingues R, et al.
emergency department use of apneic
oxygenation versus usual care during
rapid sequence intubation: a randomized
controlled trial (the ENDAO trial). Acad
Emerg Med. 2017;24(11):1387-1394.
34. Vourc’h M, Asfar P, Volteau C, et al.
High-ﬂow nasal cannula oxygen during
endotracheal intubation in hypoxemic
patients: a randomized controlled clinical
trial. Intensive Care Med. 2015;41(9):
1538-1548.
35. Vourc’h M, Huard D, Le Penndu M, et al.
High-ﬂow oxygen therapy versus
facemask preoxygenation in anticipated
difﬁcult airway management (PREOPTI-
DAM): an open-label, single-centre,
randomised controlled phase 3 trial.
EClinicalMedicine. 2023;60:101998.
36. Vourc’h M, Baud G, Feuillet F, et al. High-
ﬂow nasal cannulae versus non-invasive
ventilation for preoxygenation of obese
patients: the PREOPTIPOP randomized
trial. EClinicalMedicine. 2019;13:112-119.
37. Guitton C, Ehrmann S, Volteau C, et al.
Nasal high-ﬂow preoxygenation for
endotracheal intubation in the critically ill
patient: a randomized clinical trial.
Intensive Care Med. 2019;45(4):447-458.
38. Frat JP, Ricard JD, Quenot JP, et al.
Non-invasive ventilation versus high-
ﬂow nasal cannula oxygen therapy with
apnoeic oxygenation for preoxygenation
before intubation of patients with acute
hypoxaemic respiratory failure: a
randomised, multicentre, open-label
trial. Lancet Respir Med. 2019;7(4):
303-312.
chestcc.org
11

 
 
PREOXI Trial Statistical Analysis Plan Revision Sequence 
 
 
 
March 24, 2023 
Statistical Analysis Plan posted on preprint server 
 
April 13, 2023 
Statistical Analysis Plan submitted for publication  
 
August 11, 2023 
Statistical Analysis Plan completed peer review 
 
September 1, 2023 Statistical Analysis Plan* published: 
 
Gibbs KW, Ginde AA, Prekker ME, Seitz Kevin P, Stempek SB, 
Taylor C, Gandotra S, White H, Resnick-Ault D, Khan A, Mohmed A, 
Brainard JC, Fein DG, Aggarwal NR, Whitson MR, Halliday SJ, 
Gaillard JP, Blinder V, Driver BE, Palakshappa JA, Lloyd BD, 
Wozniak JM, Exline MC, Russell DW, Ghamande S, Withers C, Hubel 
KA, Moskowitz A, Bastman J, Andrea L, Sottile PD, Page DB, Long 
MT, Goranson JK, Malhotra R, Long BJ, Schauer SG, Connor A, 
Anderson E, Maestas K, Rhoads JP, Womack K, Imhoff B, Janz DR, 
Trent SA, Self WH, Rice TW, Semler MW, Casey JD for the PREOXI 
investigators and the Pragmatic Critical Care Research Group.  
Protocol and Statistical Analysis Plan for the Pragmatic Trial 
Examining Oxygenation Prior to Intubation of Preoxygenation With 
Noninvasive Ventilation vs Oxygen Mask in Critically Ill Adults. 
CHEST Critical Care. 2023 Sep 1;1(2):100014. 
https://doi.org/10.1016/j.chstcc.2023.100014. 
 
October 14, 2023 
Final patient enrolled 
 
*No changes to the statistical analysis plan occurred between initial posting of 
the Statistical Analysis Plan on a preprint server and its publication.