Clinical trial NCT03026777
Conditions: Acute Respiratory Failure Intubation Complication
Sponsor: Louisiana State University Health Sciences Center in New Orleans
Start date: 2017-01-01; Completion date: 2018-01-01
Enrollment: 337 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Endotracheal intubation is common in the care of critically ill patients. Complications of airway management in this setting are frequently encountered and may be associated with an increased risk of death. The prevention of complications during urgent and emergent endotracheal intubation is a key focus for airway management research. Post-intubation hypotension (PIH), a common complication of endotracheal intubation in the critically ill, may be prevented by a bolus of intravenous fluid prior to the start of the procedure, but this approach has not been examined in a prospective trial. There are no randomized trials of intravenous fluid administration to prevent PIH in critically ill adults. The investigators propose a randomized trial of fluid loading to prevent PIH in critically ill adults.

Detailed description:
The investigators propose a randomized, parallel-group trial evaluating the impact of fluid loading to decrease cardiovascular collapse during and after endotracheal intubation in critically ill adults. Patients admitted to the study sites who are deemed by their clinical team to require intubation and fulfill inclusion criteria without meeting exclusion criteria will be enrolled and randomly assigned to intravenous fluid loading versus none. All other decisions regarding airway management will remain at the discretion of the treating provider. Data will be collected at the time of intubation and prospectively from the medical record in order to determine the effect of the assigned intervention on short- and long-term outcomes. All data are collected non-invasively and are already a part of clinical data obtained in usual ICU care at the bedside or in the medical record. No additional data will be collected that is not observed at the bedside or obtained from the medical record.

Study Population: The study population will be all critically ill adults for whom the clinical team has decided to perform endotracheal intubation using sedation with or without neuromuscular blockade. Patients will be excluded only if the operator feels: 1. Additional intravenous fluids in the form of fluid loading is absolutely indicated or contraindicated, or 2. The urgency of the intubation would make performing the study procedures unsafe. Patients will be included regardless of gender, race, weight or body mass index, initial oxygen saturation, anticipated grade of view, and other clinical factors.

Study Interventions:

Fluid Loading - (1) 500 milliliters of an intravenous crystalloid solution of the operator's choosing will be (2) infused at any time after randomization and prior to the administration of procedural medications from (3) above the level of the central or peripheral intravenous or intraosseus access used and allowed to infuse by gravity and (4) stopped after 500 mL have infused. All intravenous infusions preceding the decision to perform endotracheal intubation will not be altered.

No Fluid Loading - No intravenous fluids are started after the decision is made to perform endotracheal intubation. All intravenous infusions preceding the decision to perform endotracheal intubation will not be altered.

Primary Endpoint:

Cardiovascular collapse - a composite endpoint defined as one or more of the following:

* Death within 1 hour of intubation
* Cardiac arrest within 1 hour of intubation
* New systolic blood pressure \< 65 mmHg between induction and 2 minutes after completion of intubation
* New or increased vasopressor receipt between induction and 2 minutes after completion of intubation

Arms: arm 1: (1) 500 milliliters of an intravenous crystalloid solution of the operator's choosing will be (2) infused at any time after randomization and prior to the administration of procedural medications from (3) above the level of the central or peripheral intravenous or intraosseus access used and allowed to infuse by gravity and (4) stopped after 500 mL have infused. All intravenous infusions preceding the decision to perform endotracheal intubation will not be altered. arm 2: No intravenous fluids are started after the decision is made to perform endotracheal intubation. All intravenous infusions preceding the decision to perform endotracheal intubation will not be altered.
Interventions: intervention 1: intravenous crystalloid fluid, 500 mL
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_001.pdf: 
Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
 
Preventing cardiovascular collaPse with Administration of fluid 
Resuscitation before Endotracheal intubation:  
The PrePARE Trial  
 
Version 1.2 
 
LSU Investigators 
 
David R Janz, MD, MSc 
Section of Pulmonary and Critical Care Medicine 
 
Vanderbilt Investigators 
 
      Jonathan D. Casey, MD 
Division of Allergy, Pulmonary, and Critical Care Medicine 
 
Matthew W. Semler, MD, MSc 
Division of Allergy, Pulmonary, and Critical Care Medicine 
 
Todd W. Rice, MD, MSc 
Division of Allergy, Pulmonary, and Critical Care Medicine 
 
Wesley Self, MD  
Department of Emergency Medicine 
 
University of Washington Investigators 
 
Aaron Joffee, DO 
Department of Anesthesiology 
 
University of Alabama Birmingham Investigators 
 
Derek Russel, MD 
Division of Pulmonary and Critical Care Medicine 
 
Lahey Clinic Investigators 
 
James M Dargin, MD 
Department of Pulmonary and Critical Care Medicine 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
Lincoln Medical and Mental Health Center Investigators 
 
Nicholas Caputo, MD 
Department of Emergency Medicine 
 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Study Summary 
2.0 
Background 
3.0 
Rationale, Aims, and Hypotheses 
4.0 
Study Description 
5.0 
Inclusion/Exclusion Criteria 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Risks and Benefits 
9.0 
Adverse Events 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Privacy/Confidentiality Issues 
13.0 
Follow-up and Record Retention 
14.0 
References 
 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
1.0 
Study Summary 
 
Title: Preventing cardiovascular collapse with Administration of fluid Resuscitation during 
Endotracheal intubation: The PrePARE Randomized Controlled Trial 
-  A multi-center, randomized trial of fluid loading to prevent cardiovascular collapse during 
endotracheal intubation of critically ill adults.  
 
Study Sites: LSU New Orleans/University Medical Center New Orleans ICUs, Ochsner Medical 
Center Jefferson Campus MICU, Vanderbilt Medical Center Nashville ICUs and Emergency 
Department, University of Washington Harborview Medical Center ICUs, University of Alabama 
Birmingham MICU, Lahey Medical Center MICU, Lincoln Medical Center Emergency Department 
 
Background: Severe complications are common during endotracheal intubation of critically ill 
patients.  One of the most common complications, a post-procedural decrease in blood 
pressure, is associated with increased resource utilization and poor clinical outcomes.  Fluid 
loading, a rapid infusion of 500 milliliters of a intravenous crystalloid solution beginning prior to 
the start of the procedure, may prevent a decrease in blood pressure, but effectiveness data 
are lacking.  Currently, pre-intubation fluid loading occurs sporadically, with significant provider 
practice variation.  We propose a randomized trial to compare fluid loading versus none to 
prevent cardiovascular collapse after endotracheal intubation of critically ill adults.  
 
Primary Aim: 
• To compare the effect of fluid loading versus none on cardiovascular collapse 
(composite endpoint) among critically ill adults undergoing endotracheal intubation 
 
Primary Hypothesis: 
• Fluid loading will reduce the rate of cardiovascular collapse among critically ill adults 
undergoing endotracheal intubation 
 
Inclusion Criteria: 
1. Patient is admitted to a participating study unit 
2. Planned procedure is endotracheal intubation and planned operator is a provider 
expected to routinely perform endotracheal intubation in the participating unit 
3. Administration of sedation (with or without neuromuscular blockade) is planned 
 
Exclusion Criteria: 
1. Operator feels fluid loading is absolutely indicated or contraindicated in the patient 
2. Urgency of intubation precludes safe performance of study procedures 
3. Prisoners 
4. Pregnant Patients 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
5. <18 years of age 
 
 
Consent: Given that (1) fluid loading is already an arbitrarily used approach to endotracheal 
intubation used in half of critically ill adults, (2) there no established risk or benefit with either 
approach, and (3) providers will exclude patients from this trial for whom they feel either fluid 
loading or no fluid loading is required for safe care, this trial poses no increased risk beyond 
usual ICU care to the patients.  Over 90% of patients undergoing endotracheal intubation in the 
ICU cannot consent for the procedure itself, therefore it is impractical to obtain informed 
consent for research prior to the procedure.  Given the minimal risk interventions and 
impractability of informed consent, a waiver of informed consent will be requested. 
 
Randomization: Using opaque envelopes available in the patient care areas, participants will be 
randomized 1:1 to fluid loading or none.   
 
Study Interventions: 
• Fluid Loading: 
o Fluid Loading – (1) 500 milliliters of an intravenous crystalloid solution of the 
operator’s choosing will be (2) infused at any time after randomization and prior 
to the administration of procedural medications from (3) above the level of the 
central or peripheral intravenous or intraosseus access used and allowed to 
infuse by gravity and (4) stopped after 500 mL have infused.  All intravenous 
infusions preceding the decision to perform endotracheal intubation will not be 
altered.   
o No Fluid Loading – No intravenous fluids are started after the decision is made 
to perform endotracheal intubation.  All intravenous infusions preceding the 
decision to perform endotracheal intubation will not be altered. 
 
Primary Endpoint (All endpoints are collected non-invasively and are already a part of clinical 
data obtained in usual ICU care at the bedside or in the medical record):   
o One or more of the following items indicating cardiovascular collapse: 
! Death within 1 hour of intubation 
! Cardiac arrest within 1 hour of intubation 
! New systolic blood pressure < 65 mmHg between induction and 2 
minutes following intubation  
! New or increased vasopressor between induction and 2 minutes 
following intubation  
 
Secondary Endpoints:  
! Each of the individual items in the composite primary endpoint 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
! Additional fluids given to either group and started between induction and 
2 minutes after intubation 
! Lowest systolic blood pressure between induction and 2 minutes after 
intubation 
! Lowest arterial oxygen saturation between induction and 2 minutes after 
intubation 
! Incidence of hypoxemia (oxygen saturation <90%) and severe hypoxemia 
(oxygen saturation <80%) between induction and 2 minutes after 
intubation; incidence of desaturation (defined by decrease in oxygen 
saturation of >3%); change in saturation from induction to lowest oxygen 
saturation 
! ICU-free days 
! Ventilator-free days 
! In-hospital mortality 
 
Safety Endpoints:  
! Lowest oxygen saturation in the 24 hours after intubation; highest 
fraction of inspired oxygen in the 24 hours after intubation; highest 
positive end-expiratory pressure in the 24 hours after intubation 
! Cumulative diuretic dose (in furosemide equivalents) on the day of 
enrollment and from enrollment through three days after enrollment 
! Vasopressor-free days 
! Cumulative intravenous fluid administration from enrollment through 
three days after enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
2.0 
Background 
 
Endotracheal intubation is common in the care of critically ill patients (1-3).  
Complications of airway management in this setting are frequently encountered and may be 
associated with an increased risk of death (1, 2, 4, 5).  The prevention of complications during 
urgent and emergent endotracheal intubation is a key focus for airway management research 
(4, 6, 7).  Post-intubation hypotension (PIH), a common complication of endotracheal 
intubation in the critically ill (4), may be prevented by a bolus of intravenous fluid prior to the 
start of the procedure, but this approach has not been examined in a prospective trial. 
 
2.1 
Complications of Endotracheal Intubation of the Critically Ill 
 
The emergent endotracheal intubation of critically ill patients is associated with an 
increased risk of complications compared to the intubation of patients in the OR (8).  
Approximately 30% of emergent endotracheal intubations in the ICU are associated with 
complications, including:  hypotension, hypoxia, failed intubation, esophageal intubation, 
airway trauma, aspiration, cardiac arrest, and death (4, 8, 9).  PIH, which occurs in as many as 
46% of critically ill adults during endotracheal intubation (4, 10), is associated with an increased 
risk of mortality double that of ICU patients who do not experience procedural hypotension (10, 
11).  PIH is thought to be due to three potential mechanisms, all of which may respond to an 
intervention which increases preload with intravenous fluid: 1. procedural medication-induced 
hypotension, 2.  pre-existing hemodynamic instability and increased venous capacitance due to 
decreased circulating catecholamines, and 3.  decreased venous return secondary to positive 
pressure applied to the thoracic cavity.       
 
2.2 
Potential Mechanisms of Post-intubation Hypotension in the Critically Ill 
 
 
Procedural medication-induced hypotension.  In an effort to facilitate rapid placement of 
an endotracheal tube in the trachea, sedating and neuromuscular blocking medications are 
often chosen by the operator to relax the muscles of the upper airway and perform the 
procedure in a comfortable fashion for the patient (12, 13).  Propofol and benzodiazepines, 
commonly selected sedatives to facilitate endotracheal intubation, are commonly associated 
with PIH.  The mechanism by which propofol induces hypotension is thought to be related the 
medication’s ability to venodilate and decrease preload.  In a study of adults undergoing 
intubation, propofol caused a decrease in systolic blood pressure and increase in venous 
compliance measured by forearm occlusive plethysmography compared to control patients 
(14).  Additionally, propofol may have a depressive effect on the myocardium and reduce 
cardiac index beyond an isolated decrease in preload (15).  Decreased preload due to 
venodilation and a possible decrease in myocardial contractility are contributors to propofol-
associated PIH observed in multiple studies of endotracheal intubation (15-18).  The use of 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
midazolam for procedural sedation also results in PIH in critically ill adults (19, 20).  Even newer 
sedative agents used in rapid sequence intubation, such as etomidate and ketamine, can result 
in venodilation and PIH.  Increasing preload via the administration of an intravenous crystalloid 
fluid bolus prior to the administration of procedural medications may reduce the incidence of 
PIH associated with these medications.    
 
Pre-existing Hemodynamic Instability.  Even after treatment of critical illness has begun, 
critically ill adults often experience further clinical deterioration and require endotracheal 
intubation (21-23).  In a recent randomized trial of endotracheal intubation in critically ill adults 
conducted by our group, prior to the start of the procedure patients had severe physiologic 
derangements resulting in a median APACHE II score of 22 and around 25% of patients were in 
shock (21, 22).  Specifically, an increase in the APACHE II score by 1 point is associated with a 
2% increased risk of PIH (24).  Even in the absence of pre-existing shock, in a study of critically ill 
adults undergoing endotracheal intubation, a pre-procedure shock index (heart rate divided by 
systolic blood pressure) of ≥ 0.8 was strongly predictive of the development of PIH (11).  
Additionally, increasing pre-procedure shock index is also associated with complete 
cardiovascular collapse resulting in cardiac arrest (25).  These shock and “pre-shock” states 
seen in critically ill adults are often, in part, a result of decreased preload due to hypovolemia 
and are often treated by the administration of intravenous fluids (26-29).  Patients with shock 
and “pre-shock” may be dependent on circulating catecholamines to sustain blood pressure.  
With decreased levels of catecholamines after induction, increased venous capacitance may 
decrease preload, cardiac output, and mean arterial blood pressure.  Again, increasing preload 
by the pre-procedure administration of intravenous crystalloids may improve the physiologic 
derangements commonly seen in critically ill adults and prevent PIH. 
 
The New Application of Positive Pressure to the Thoracic Cavity.  Venous return to the 
right atrium is dependent on the pressure gradient created between the predominantly 
positive pressure, extrathoracic anatomic sites and the predominantly negative pressure in the 
thoracic cavity.  The application of positive pressure to the thoracic cavity by mechanical 
ventilation reduces venous return to the right atrium and can cause PIH in hypovolemic 
patients with reduced preload.  Additionally, in one observational study of critically ill adults 
with traumatic injuries and presumed hypovolemia, intubation and positive pressure ventilation 
was independently associated with the new development of hypotension and increased 
mortality (30).  Intravenous infusion of a crystalloid fluid prior to the application of positive 
intrathoracic pressure may increase extrathoracic pressure, increase preload, and prevent PIH 
in critically ill adults.   
 
2.3 
Existing Evidence on the Use of Fluid Loading to Prevent Post-Intubation Hypotension 
 
There are no randomized trials of intravenous fluid administration to prevent PIH in critically ill 
adults.  Fluid loading has been studied indirectly in one observational study of using a pre-
procedure checklist for endotracheal intubation of critically ill adults (4).  In this “before-and-
after” study, observational data were collected both 6 months before and after the institution 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
of a pre-procedure checklist.  One item on this checklist was “fluid loading” defined as an 
intravenous infusion of 500 milliliters of isotonic saline or 250 milliliters of a starch-based fluid 
in the absence of cardiogenic pulmonary edema started prior to the procedure.  Prior to 
instituting the checklist, operators performed fluid loading in 49% of patients.  During the 
checklist phase, use of fluid loading increased to 75% and the incidence of severe 
cardiovascular collapse decreased from 26% to 15%.  These data support the hypothesis that 
fluid loading may prevent PIH; however the observational nature of this study prevents us from 
invoking a causal relationship.  Additionally, the ten-item checklist also included other 
interventions which may explain a decrease in PIH, such as using only etomidate or ketamine 
for procedural sedation and starting an intravenous norepinephrine infusion for low measured 
blood pressures.  As a result of a lack of evidence around this intervention and concerns about 
fluid loading contributing to volume overload and hypoxemia, observational studies have 
shown that operators use fluid loading arbitrarily in about 50% of critically ill adults undergoing 
endotracheal intubation (4, 31). 
 
 
 
3.0 
Rationale, Aims, and Hypotheses 
 
In order to determine the impact of fluid loading on procedural and clinical outcomes of 
endotracheal intubation of critically ill patients, a randomized trial is needed.  
 
Study Aims: 
• Primary:  
o To compare the effect of fluid loading compared with none on a composite of 
cardiovascular collapse experienced by critically ill adults undergoing 
endotracheal intubation 
• Secondary:  
o To evaluate the effect of the same intervention in the same population on 
clinical outcomes (ventilator-free days, ICU-free days, and in-hospital mortality), 
severe hypoxia, and airway management characteristics (first pass success, grade 
of view, time to completion of intubation, additional devices, additional 
operators) 
 
Study Hypotheses: 
• Primary:  
o In critically ill adults undergoing endotracheal intubation, fluid loading will 
reduce the incidence of cardiovascular collapse among critically ill adults 
undergoing endotracheal intubation 
 
• Secondary:  


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
o Fluid loading will increase the lowest systolic blood pressure measured between 
procedural medication administration and 2 minutes after endotracheal 
intubation without affecting other procedural, physiologic, and clinical outcomes 
 
 
4.0 
Study Description 
 
In order to address the aims outlined above, we propose a randomized, parallel-group 
trial evaluating the impact of fluid loading to decrease cardiovascular collapse during and after 
endotracheal intubation in critically ill adults.  Patients admitted to the study sites who are 
deemed by their clinical team to require intubation and fulfill inclusion criteria without meeting 
exclusion criteria will be enrolled and randomly assigned to fluid loading versus none.  All other 
decisions regarding airway management will remain at the discretion of the treating provider.  
Data will be collected at the time of intubation and prospectively from the medical record in 
order to determine the effect of the assigned intervention on short- and long-term outcomes.  
All data are collected non-invasively and are already a part of clinical data obtained in usual ICU 
care at the bedside or in the medical record.  No additional data will be collected that is not 
observed at the bedside or obtained from the medical record. 
 
5.0 
Inclusion and Exclusion Criteria 
 
5.1  
Inclusion Criteria: 
We will include airway management events in which: 
1. Patient is admitted to participating study unit 
2. Planned procedure is endotracheal intubation and planned operator is a provider 
expected to routinely perform endotracheal intubation in the participating unit 
3. Administration of sedation with or without neuromuscular blockade is planned 
4. Age ≥ 18 years old 
 
5.2  
Exclusion Criteria:  
We will exclude airway management events in which: 
1. Operator believes fluid loading to be absolutely indicated or contraindicated for the safe 
care of the patient 
2. Urgency of intubation precludes safe performance of study procedures 
3. Pregnancy 
4. Prisoners 
5. Age < 18 years old 
 
6.0 
Enrollment/Randomization 
 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
6.1 
Study Sites:  Intensive Care Units at University Medical Center New Orleans (UMCNO), 
Vanderbilt University Medical Center in Nashville (VUMC) MICU and Emergency Department, 
University of Washington Harborview Medical Center, University of Alabama Birmingham, 
Lahey Medical Center, Lincoln Medical Center Emergency Department 
 
6.2  
Study Population:  The study population will be all critically ill adults for whom the 
clinical team has decided to perform endotracheal intubation using sedation with or without 
neuromuscular blockade.  Patients will be excluded only if the operator feels: 1. Additional 
intravenous fluids in the form of fluid loading is absolutely indicated or contraindicated, or 2.  
The urgency of the intubation would make performing the study procedures unsafe.  Patients 
will be included regardless of gender, race, weight or body mass index, initial oxygen saturation, 
anticipated grade of view, and other clinical factors. Patients enrolled in this trial may also be 
enrolled in other ongoing clinical trials. Specifically, a trial with similar eligibility criteria 
examining the effect of ventilation between induction and laryngoscopy on per-intubation 
desaturation, the PreVent trial (Preventing Hypoxemia With Manual Ventilation During 
Endotracheal Intubation Trial; ClinicalTrials.gov Identifier: NCT03026322), may co-enroll a 
portion of patients in the PrePARE trial.  For any trial co-enrolling with the current trialthat 
focuses on outcomes of endotracheal intubation, we will formally record study group 
assignment for both trials and perform a formal statistical test for interaction. 
 
6.3  
Enrollment: All patients will be enrolled at the time the clinical team decides that 
intubation is required and the patient meets inclusion but no exclusion criteria. 
 
6.4  
Consent:  
 
 
Fluid loading or the absence of additional fluid administration are both commonly used 
approaches during endotracheal of critically ill adults in current practice (4, 32, 33).  In prior 
observational studies of critically ill adults undergoing endotracheal intubation, clinicians have 
opted to administer a fluid bolus prior to induction in approximately 50% of patients, with 
significant variability by provider and practice environment (4, 31).  Currently,  there are no 
randomized trials or evidence-based guidelines to support the choice between fluid loading or 
none for the endotracheal intubation of critically ill adults.   
 
Because both approaches to peri-intubation fluid management being studied are (1) 
commonly used as a part of routine care, (2) are interventions the patient would arbitrarily be 
exposed to even if not participating in the study, and (3) are acceptable options from the 
perspective of the clinical provider (otherwise patient is excluded), we feel the study meets 
criteria for minimal risk. 
 
Additionally, obtaining informed consent in the study would be impracticable.  
Endotracheal intubation of acutely ill patients is frequently a time-sensitive procedure.  Despite 
the availability of a formal informed consent document for the procedure itself, time allows 
discussion of risks and benefits in less than 10% of airway management events in the ICU. 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
Because the study poses minimal risk, would not adversely affect the welfare or privacy 
rights of the participant, and consent would be impracticable, we will request a waiver of 
informed consent. 
 
 
6.5  
Randomization:   
 
 
Computerized randomization using permuted blocks of two, four, or six will be 
conducted in order to generate a series of study assignments deliberately exceeding the 
planned enrollment number.  Study assignments will be stratified by study site, placed in 
opaque randomization envelopes, and will be available to operators in the ICUs.  Study group 
assignment will remain concealed to study personnel and operators until after the decision has 
been made to enroll the patient in the study.  Once it has been determined by the treating 
team that (1) intubation is required, (2) sedation with or without neuromuscular blockade will 
be used, and (3) urgency of the intubation does not preclude safe performance of study 
procedures, the operator will open the next consecutively numbered envelope and follow the 
assignment of either fluid loading or no fluid loading.   
 
 
7.0 
Study Procedures 
 
7.1       Study Interventions 
 
7.1.1  Fluid Loading 
 
The PrePARE study will affect only the initiation of fluid bolus administration for the 
prevention of cardiovascular collapse between enrollment and two minutes after completion of 
endotracheal intubation.  The study will NOT affect fluid administration initiated prior to 
enrollment, fluid administration initiated after two minutes after completion of intubation, or 
fluid bolus administration for the treatment of cardiovascular collapse.  This study will not 
protocolize any other aspect of endotracheal intubation such as choice of induction agent and 
neuromuscular blocker, patient position, choice of laryngoscopy – all of which will be 
determined by the treating clinicians.   
Once the envelope is opened and group assignment is known, the clinical team will 
either start fluid loading or not anytime prior to the administration of procedural medications.  
Although the patient must be either receiving fluid loading or not at the time of initiation of 
procedural medications, if difficulties with airway management are encountered, the provider 
may revise the fluid management strategy at any time thereafter in order to ensure safe 
performance of the procedure. 
 
In patients randomized to fluid loading, the bedside nurse will obtain 500 milliliters of a 
crystalloid fluid of the operator’s choosing, connect this volume to intravenous infusion tubing, 
and attach the tubing to any intravenous catheter or intraosseous device.  The crystalloid fluid 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
will then be placed above the level of the intravenous or intraosseous device and allowed to 
infuse by gravity.  At any time after the initiation of fluid loading, the operator can choose to 
begin the procedure by administering procedure-related medications.  Fluid loading will 
continue until all 500 milliliters are infused.  Infusions present prior to the decision to perform 
endotracheal intubation will not be altered by the current study.  
 
In patients randomized to no fluid loading, no additional intravenous crystalloid 
administration will be initiated by the study between enrollment and two minutes after 
completion of endotracheal intubation.  Infusions present prior to the decision to perform 
endotracheal intubation will not be affected by the study and their management will be 
deferred to the treating clinician.  Treating clinicians may initiate a fluid bolus at any time for 
the treatment of cardiovascular collapse (not considered a protocol violation).  Treating 
clinicians may also initiate a fluid bolus at any time if felt to be mandatory for the safe 
treatment of the patient (if between enrollment and two minutes after completion of 
intubation and in the absence of cardiovascular collapse this will be recorded as a protocol 
violation).    
 
 
8.2 Data Collection 
 
All data are collected non-invasively and are already a part of clinical data obtained in usual ICU 
care at the bedside or in the medical record.  No additional data will be obtained beyond that 
which is obtained by bedside observation and from the electronic medical record. 
 
Baseline: Age, gender, height, weight, race, APACHE II score, active medical problems 
at the time of intubation, active comorbidities complicating intubation, mean 
arterial pressure and vasopressor use prior to intubation, noninvasive ventilator 
use, highest FiO2 delivered in prior 6 hours, lowest oxygen saturation in prior six 
hours, pH, PaO2, PaCO2, indication for intubation, reintubation, preoxygenation 
technique, operator experience will be collected from the medical record. 
 
Peri-procedural: Date and time of sedative and/or neuromuscular blocker administration, 
saturation at time of sedative and/or neuromuscular blocker administration, sedative, 
neuromuscular blocker, device used for pre-oxygenation prior to medication administration, 
ventilation between induction and laryngoscopy, tube characteristics, route, laryngoscope type 
and size, total number of attempts, tube tape level, confirmation of placement technique, 
airway grade, airway difficulty, rescue device use, need for additional operators, mechanical 
complications (esophageal intubation, aspiration, airway trauma), arrhythmia requiring 
therapy, and patient positioning.  Lowest arterial oxygen saturation, lowest systolic blood 
pressure, vasopressor administration, time to intubation, presence of additional personnel, and 
other key peri-procedural outcomes will be collected by a trained, independent observer not 
affiliated with the performance of the procedure. 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
0-24 hours: Post-intubation imaging, post intubation shock or cardiac arrest, SaO2, FiO2, PEEP, 
and systolic and mean arterial pressures up to 24 hours after intubation will be collected from 
the medical record. 
 
In-Hospital Outcomes: Total cumulative fluid adminstration in the ICU after randomization, 
total cumulative furosemide dose in the ICU and during hospitalization after randomization, 
date of extubation (ventilator-free days), date of ICU discharge (ICU-free days), and date of 
death will be collected from the medical record. 
 
 
 
8.3 Outcome Measures 
 
Primary Endpoint:   
o Cardiovascular collapse – a composite endpoint defined as one or more of the 
following: 
! Death within 1 hour of intubation 
! Cardiac arrest within 1 hour of intubation 
! New systolic blood pressure < 65 mmHg between induction and 2 
minutes after completion of intubation 
! New or increased vasopressor receipt between induction and 2 minutes 
after completion of intubation 
 
Secondary and Tertiary Endpoints: 
 
Secondary Outcomes 
1. The incidence of each component of the cardiovascular collapse composite endpoint 
2. Additional fluids given to either group and started between induction and 2 minutes 
after intubation 
3. Lowest systolic blood pressure between induction and two minutes after intubation; 
change in systolic blood pressure from induction to lowest systolic blood pressure 
4. Lowest oxygen saturation between induction and 2 minutes after completion; 
Incidence of severe hypoxia between induction and 2 minutes following intubation – 
defined as new arterial oxygen saturation of <80% 
5. Time from administering induction medications to successful endotracheal 
intubation 
6. Lowest systolic blood pressure adjusting for systolic blood pressure at induction 
7. Cumulative ICU furosemide administration from enrollment to three days after 
enrollment 
8. Cumulative ICU fluid adminstration from enrollment to three days after enrollment 
9. Cormack-Lehane grade of view on first attempt 


Principal Investigator: David Janz, MD, MSc            
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10. Incidence of “first pass success” defined as “placement of an endotracheal tube in 
the trachea after the first insertion of the laryngoscope into the oral cavity without 
the use of any other devices” 
11. Number of attempts required for successful tube placement  
12. Incidence of need for additional intubating equipment, second operator 
13. Incidence of post-intubation tube malposition on CXR 
14. Incidence of fluid administration outside of the study 
15. Cumulative furosemide administration from enrollment through hospital discharge 
or death 
 
Tertiary outcomes  
1. In-hospital mortality  
2. Ventilator-free days (VFDs)  
3. ICU-free days (ICUFDs) 
4.  Vasopressor-free days 
 
 
ICU-free days to 28 days after enrollment will be defined as the number of midnights alive and 
not admitted to an intensive care unit service after the patient’s final discharge from the 
intensive care unit before 28 days. If the patient is admitted to an intensive care unit service at 
day 28 or dies prior to day 28, ICU-free days will be 0. 
 
Ventilator-free days to day 28 will be defined as the number of midnights alive and with 
unassisted breathing to day 28 after enrollment, assuming a patient survives for at least two 
consecutive calendar days after initiating unassisted breathing and remains free of assisted 
breathing.  If a patient returns to assisted breathing and subsequently achieves unassisted 
breathing prior to day 28, VFD will be counted from the end of the last period of assisted 
breathing to day 28.  If the patient is receiving assisted ventilation at day 28 or dies prior to day 
28, VFD will be 0.     
 
 
8.0 
Risks and Benefits: 
 
In patients for whom the treating team has decided endotracheal intubation is required, 
there are currently no established risks or benefits to intubation with or without fluid loading.  
Patients randomized to the fluid loading group may be at increased risk of developing 
pulmonary edema and those randomized to the no fluid loading group may be at increased risk 
of cardiovascular collapse.  However, previous studies of endotracheal intubation of critically ill 
adults suggest that in routine care, operators arbitrarily decide to use fluid loading in 
approximately 50% of patients.  Therefore, patients would be exposed to either pulmonary 
edema or procedural hypotension in routine practice.  In addition, the exclusion criteria would 


Principal Investigator: David Janz, MD, MSc            
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Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
exclude patients in whom the treating provider felt that peri-procedural fluid loading was 
needed to prevent hypotension or was contraindicated due to the risk of developing pulmonary 
edema.  At this time, there is no reason to believe that participation in this study would expose 
patients to greater medical risks or benefits than those experienced by critically ill patients 
requiring endotracheal intubation as a part of routine care.  The greater benefit of the study 
would be to society in the form of improved understanding of safe and effective airway 
management for critically ill patients. 
 
A potential risk to patients participating in this study involves the collection of protected 
health information (PHI).  In order to limit the associated risks, the minimum amount of PHI 
necessary for study conduct will be collected.  After collection, the data will be stored in a 
secure online database (REDCap) only accessible by the investigators.  After publication, a de-
identified database will be generated to protect participant privacy. 
 
 
9.0 
Safety Monitoring and Adverse Events: 
 
9.1 Safety Monitoring 
 
 
This study will take place in the environment of an intensive care unit or emergency 
department at the time of a procedure required for routine clinical care.  Thus, at the time of 
the study intervention, the patient will have in the room a critical care- or emergency medicine-
trained physician, a nurse trained in critical care, and usually a respiratory therapist in addition 
to continuous invasive or non-invasive monitoring.  Additionally, study personnel will be readily 
available to answer questions at any time during the study course.  Even after randomization, if 
any healthcare provider participating in the intubation procedure believes that the study 
interventions cannot be performed for the safe performance of the procedure, the study 
intervention is halted and the patient is intubated in the manner which the clinical team judges 
to be safest. 
 
A Data and Safety Monitoring Board (DSMB) will oversee the trial.  Interim analyses for safety 
and efficacy will be conducted as described in the Statistical Analysis section of the protocol. 
 
9.2 Adverse Events 
 
An adverse event is defined as any untoward medical occurrence in a clinical 
investigation where a participant is administered an intervention that does not necessarily have 
to have a causal relationship with the intervention.  An adverse event therefore can be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of 
an intervention, whether or not the incident is considered related to the intervention. 


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A serious adverse event (SAE) is defined as any unexpected and untoward medical 
occurrence that is probably or possibly related to the study and meets any of the following 
criteria: 
a. Results in death 
b. Is life-threatening (defined as an event in which the participant was at risk of death at 
the time of the event and NOT an event that hypothetically might have caused death if 
it would have been more severe).  Life-threatening cardiovascular complications, as 
defined as the primary endpoint of this trial, will be prospectively and systematically 
collected as the outcome.  As such, these events will not be reported as SAEs.  Similarly, 
life-threatening severe hypoxia will also be systematically collected as a secondary 
endpoint and will therefore not be reported as an SAE. 
c. Requires inpatient hospitalization 
d. Prolongs an existing hospitalization 
e. Results in persistent or significant disability or incapacity 
f. Results in a congenital anomaly or birth defect 
g. Important medical event that requires an intervention to prevent any of a-f above. 
 
 
 
The Principal Investigator will be responsible for overseeing the safety of this trial on a daily 
basis.  He will be available at any time for questions from the clinical team or bedside nurses, 
who will also be monitoring the patients continuously for adverse events and serious adverse 
events.  Serious and unexpected adverse events potentially associated with study 
interventions will be recorded in a case report form in the study record and reported to the 
IRB and DSMB within 7 calendar days in accordance with IRB policy.  As endotracheal 
intubation in the critical care setting is known to be independently associated with numerous 
adverse events including hypoxemia, aspiration, esophageal intubation, airway trauma, failed 
attempts at intubation, pneumothorax, pneumomediastinum, hypotension, severe bradycardia, 
cardiac arrest, and death, these events will be recorded as study outcomes and monitored by 
the Data and Safety Monitoring Board  at the semi-annual DSMB meetings to determine if a 
preponderance of adverse events in one study group merits consideration of stoppage of the 
trial.  However, in the absence of an imbalance of the above events between study groups, 
these events are expected in the routine performance of the airway management procedure 
and will not be individually reported to the IRB and DSMB as serious and unexpected adverse 
events, unless the investigators or clinical team believe the event was related to the study 
intervention. 
As an additional safety measure, the exclusion criteria specifically state that airway 
management events in which urgency precludes performance of study or the operator foresees 
a potential need for or contraindication to manual ventilation between induction and 
intubation will not be included in the trial so all airway management events studied will be 
those in which the treating clinical team felt equipoise between the interventions being 
examined.  Further, only the conditions at the initiation of the airway management event are 


Principal Investigator: David Janz, MD, MSc            
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Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
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proscribed by the study protocol and if at any time during the procedure the operator chooses 
to employ an alternative airway management strategy they are free to do so. 
In addition, a DSMB containing at least one clinical investigator experienced in 
monitoring and conducting clinical trials in critically ill patients will oversee the study.  In 
addition to assisting the PI with monitoring the trial for safety, the DSMB will also perform the 
interim analyses described in the statistical methods.  If the data meet the stopping rules for 
efficacy at the interim analysis, the DSMB will communicate a recommendation to stop the trial 
at that time.  In addition, the DSMB will also be available to review unexpected serious adverse 
events in a timely manner.  They will be asked to be available for rapid access by the 
investigators in the case of the need to evaluate unexpected serious adverse events or any 
other major unanticipated or safety related issues.  Furthermore, in cases of unexpected 
serious adverse events, the DSMB will have the ability to pause the trial to investigate possible 
safety issues and/or suggest changes to the design of the study to abrogate any safety issues. 
 
 
10.0 
Study Withdrawal/Discontinuation 
 
Patients can be withdrawn from study participation in the following circumstances: 
• The investigator decides that the patient should be withdrawn for safety 
considerations. 
• There is a significant protocol violation in the judgment of the PI. 
 
The reason and date of every withdrawal will be recorded in the patient study records.  Follow-
up will be performed for all patients who discontinue due to an adverse event or any other 
safety parameter.  Follow-up will also be performed for all patients who end participation in the 
protocol for another reason, but who also have an adverse event or other safety parameter 
that could have led to discontinuation.  Follow-up will be conducted until the condition has 
resolved, until diagnosis of the adverse event or safety parameter is deemed chronic and 
stable, or as long as clinically appropriate.  This follow-up will be documented in the patient 
study record as well.   
 
 
11.0 
Statistical Considerations 
 
Sample Size Determination: 
In a previous before-and-after observational study (4)  which incorporated preemptive 
intravenous fluid loading to prevent cardiovascular collapse during endotracheal intubation in 
critically ill adults, the rate of life-threatening cardiovascular collapse was approximately 25% in 
the control arm and 15% in the preemptive intravenous fluid loading arm (an absolute risk 
reduction of 10% and a relative risk reduction of 40%).  Randomization of a total of 500 patients 


Principal Investigator: David Janz, MD, MSc            
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Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
(250 patients per group) will provide 80% power to detect the same 10% difference in 
cardiovascular collapse between groups with an alpha of 0.05. 
 
Statistical Analysis: 
 
Analysis principles 
• Primary analysis will be conducted on an intention-to-treat basis (patients with protocol 
violations are analyzed per the assigned treatment arm). 
• All hypothesis tests will be two sided, with an α of 0.05 unless otherwise specified. 
• All analyses will be unadjusted unless otherwise specified. 
• Subgroup analyses will be performed irrespective of treatment efficacy. 
 
Trial profile:  
We will present a Consolidated Standards of Reporting Trials diagram as Figure 1 to 
detail the movement of patients through the study. This diagram will include total number of 
patients meeting inclusion criteria, number excluded and reason for exclusion, number enrolled 
and randomized in the study, number followed, and number analyzed. 
 
Baseline Characteristics:  
To assess randomization success, we will summarize in Table 1 the distribution of 
baseline variables across the study arms. Categorical variables will be reported as frequencies 
and percentages and continuous variables as either means with SDs or medians with 
interquartile ranges. Variables reported will include Demographics (age, gender, race, BMI, co-
morbidities); Indication for intubation; Active illnesses at the time of intubation; Severity of 
Illness (APACHE II score); Respiratory status pre-intubation; Airway management procedure 
(Preoxygenation technique, Saturation at 
time of induction, Induction medication, Neuromuscular blocker, Laryngoscope 
type). 
 
 
Primary Analyses: 
 
Unadjusted test of treatment effect.   
 
The primary endpoint will be the categorical variable of cardiovascular collapse.  The difference 
between the two groups will be compared using the Pearson χ2 test. All other comparisons will 
be considered secondary analyses.   
 
 
Secondary Analyses: 
 


Principal Investigator: David Janz, MD, MSc            
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Per-Protocol Analysis of Primary Outcome.   
 
In addition to the intention-to-treat analysis, we will conduct a per protocol analysis of the 
primary outcome comparing patients in which the enitre volume of crystalloid was infused to 
patients who received no fluid loading.  
 
Analysis of Secondary and Tertiary Outcomes. 
 
We will conduct unadjusted analyses examining the treatment effect of fluid loading on each of 
the pre-specified secondary and tertiary outcomes.  Continuous outcomes will be compared 
with the Mann-Whitney U test and categorical variables with the Fischer exact test. 
 
Subgroup Analyses. 
 
We will conduct unadjusted analyses examining the treatment effect of fluid loading on life-
threatening cardiovascular complications in each of the pre-specified subgroups.  Data will be 
presented as odds ratios and 95% confidence intervals for categorical variables and as mean 
differences and 95% confidence intervals for continuous variables. 
 
Modeling to Examine Potential Interactions 
 
We will test for heterogeneity of treatment effect across each of the prespecified subgroups 
using multivariable regression with the primary outcome as the dependent variable, study 
group and the subgroup of interest as independent variables along with relevant confounders, 
and a cross-product interaction term.  Subgroup variables which are continuous will not be 
artificially dichotomized.  Significance will be determined by p value for the interaction term.   
 
Modeling to Examine Potential Confounding Factors. 
 
We will develop a multiple regression model with the primary outcome as the dependent 
variable and study group and relevant confounders included as independent variables. 
 
 
Presentation of Statistics 
Continuous variables will be described as mean and standard deviation or median and 
25th percentile – 75th percentile or bootstrapped 95% confidence intervals as appropriate.  
Categorical variables will be given as percentage and number.  All between-group comparisons 
with continuous variables will be performed using Mann-Whitney U tests and Fisher’s exact test 
for categorical variables.  Kaplan-Meier curves and log-rank tests will be used to analyze time-
to-event comparisons between groups.   
 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
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 250 patients.  The stopping boundary for efficacy 
will be met if the P value for the difference between groups in the primary outcome is 0.003 or 
less.  Assuming a 25% event rate of life-threatening cardiovascular collapse in the control arm, 
this stopping boundary would stop the trial for any relative risk reduction greater than 58%.  
Should the trial not meet this stopping point, but still have the same relative risk reduction for 
the second half of the patients enrolled, at most 18 additional patients would be at risk for 
developing life-threatening cardiovascular collapse due to not stopping the trial early.  Use of 
this conservative stopping boundary (P ≤ 0.003) will allow the final analysis to be performed 
using an unchanged level of significance (P = 0.05).  Given the relatively large number targeted 
for enrollment, the interim analysis will also evaluate the trial for futility.  A futility stopping 
boundary of P > 0.60 will be used for stopping the trial for futility.  If the control arm has the 
anticipated 25% incidence of life-threatening cardiovascular collapse, this means the trial would 
be stopped for futility at the interim analysis if the relative risk reduction was 12% or less 
(equivalent to an absolute risk reduction less than 3%).  
 
The DSMB will be asked to formally evaluate the safety of the trial at the interim analysis.  As 
the theoretical risk of the intervention is acute pulmonary edema requiring increased 
ventilatory support, the primary determination of safety will be based on the highest fraction of 
inspired oxygen and highest positive end-expiratory pressure between 6 and 24 hours after 
intubation.  If (1) the P value for the difference between study groups in both of these 
physiologic variables is less than 0.001, (2) the difference between groups in both physiologic 
variables is concordant in direction with the point estimate for in-hospital mortality, AND (3) 
the P value for the difference between study groups in in-hospital mortality is less than 0.1, it is 
recommended that the study be stopped early for safety.  Additionally, the DSMB will reserve 
the right to stop the trial at any point, request additional data or interim analyses, or request 
modifications of the study protocol as required to protect patient safety.  Finally, the DSMB will 
have the ability to monitor the rate of the primary outcome in the control group at the interim 
analysis and can ask that the study be re-powered if the rate of the primary outcome is 
different from our original estimate of 25%.   
 
             
12.0 
Privacy/Confidentiality Issues 
At no time during the course of this study, its analysis, or its publication will patient 
identities be revealed in any manner.  The minimum necessary data containing patient or 
provider identities will be collected.  All patients will be assigned a unique study ID number for 
tracking.  Data collected from the medical record will be entered into the secure online 
database REDCap.  Hard copies of the data collection sheet completed at the time of the airway 


Principal Investigator: David Janz, MD, MSc            
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Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
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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.  At the time of publication, a de-identified version 
of the database will be generated. 
 
13.0 
Follow-up and Record Retention 
Patients will be followed after enrollment for 28 days or until hospital discharge, 
whichever occurs first.  Data collected from the medical record will be entered into the secure 
online database REDCap.  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.  At the time of publication, a de-identified 
version of the database will be generated.


Principal Investigator: David Janz, MD, MSc            
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Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
 
14.0 
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Principal Investigator: David Janz, MD, MSc            
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Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
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Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
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Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden 
D, deBoisblanc B, Connors AF, Hite RD, Harabin AL. Comparison of two fluid-management 
strategies in acute lung injury. N Engl J Med 2006;354:2564–2575. 
 


Principal Investigator: David Janz, MD, MSc            
 Version Date: 12/8/2020 
Study Title: The PrePARE Trial 
Institution/Hospital: LSU School of Medicine New Orleans - University Medical Center of New 
Orleans 
 
Tracking of Protocol Versions: 
 
Version 1.0 – Initial Submission (11/16/2016) 
 
Version 1.1 – Revisions after initial meeting with DSMB (1/25/17) 
• The planned approach to co-enrollment in other clinical trials was specified.  A plan to 
perform a test of interaction when co-enrollment occurred with another intervention 
airway management trial was specified.  Registration information was provided for the 
PreVent trial, for which there is anticipated to be co-enrollment. 
• The plan to provide all study outcomes, adverse events, and serious adverse events to the 
DSMB at each of the semi-annual DSMB meetings was clarified.  The plan to collect 
anticipated adverse events as outcomes and report to the IRB and DSMB within 7 days 
only those which are unexpected and potentially related to the study intervention was 
clarified. 
• At the request of the DSMB, the stopping criteria for safety at the interim analysis were 
clarified to eliminate the oxygen saturation criteria, specify a P value for the difference in 
mortality between groups, and eliminate the ventilator-free days criterion. 
 
Version 1.2   
• Amendment is to add Lincoln Medical Center Emergency Department as an enrolling site 
following receipt of IRB approval from their local institutional review board 
 
 

SAP_000.pdf: 
Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
Preventing cardiovascular collaPse with Administration of fluid Resuscitation 
before Endotracheal intubation: The PrePARE Trial  
 
Statistical Analysis Plan 
 
 
Background 
Severe complications are common during endotracheal intubation of critically ill 
patients.  One of the most common complications, peri-procedural decrease in blood 
pressure, is associated with increased resource utilization and worsened clinical 
outcomes.  Fluid loading, a rapid infusion of 500 milliliters of a intravenous crystalloid 
solution beginning prior to the start of the procedure, may prevent a decrease in blood 
pressure.  However, effectiveness data are lacking.  Currently, pre-intubation fluid 
loading occurs sporadically, with significant provider practice variation.  We describe 
here the statistical analysis plan for a randomized trial comparing fluid loading versus 
none to prevent cardiovascular collapse after endotracheal intubation of critically ill 
adults. 
 
Design:  Multicenter, prospective, parallel-group, open-label, randomized trial 
comparing fluid loading versus no fluid loading with regard to the development of life-
threatening cardiovascular collapse during endotracheal intubation of critically ill adults.  
The trial was registered with ClinicalTrials.gov prior to initiation of patient enrollment 
(ClinicalTrials.gov identifier: NCT03026777). 
 
Study Sites:  LSU New Orleans/University Medical Center New Orleans ICUs, Ochsner 
Medical Center Jefferson Campus MICU, Vanderbilt Medical Center Nashville MICU, 
University of Washington Harborview Medical Center ICUs, University of Alabama 
Birmingham MICU, Lahey Medical Center MICU, Lincoln Medical Center Emergency 
Department 
 
Patient Population 
Adult patients undergoing endotracheal intubation in a participating intensive care unit. 
 
Inclusion Criteria 
1. Patient is admitted to a participating study unit 
2. Planned procedure is endotracheal intubation and planned operator is a provider 
expected to routinely perform endotracheal intubation in the participating unit 
3. Administration of sedation (with or without neuromuscular blockade) is planned 
 
Exclusion Criteria 
1. Operator feels fluid loading is absolutely indicated or contraindicated  
2. Urgency of intubation precludes safe performance of study procedures 
3. Prisoners 
4. Pregnant Patients 
5. <18 years of age 
 
Specific Hypothesis 
Fluid loading will reduce the rate of cardiovascular collapse among critically ill adults 
undergoing endotracheal intubation 


Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
 
Study Interventions: 
 
Fluid Loading: 
o Fluid Loading Group – (1) an infusion of 500 milliliters of an intravenous 
crystalloid solution of the operator’s choosing will be (2) initiated at any 
time after randomization and prior to the administration of procedural 
medications from (3) above the level of the central or peripheral 
intravenous or intraosseous access used and allowed to infuse by gravity 
and (4) stopped after 500 mL have infused.  All intravenous infusions 
preceding the decision to perform endotracheal intubation will not be 
altered.   
o No Fluid Loading Group – No intravenous fluids are started after the 
decision is made to perform endotracheal intubation.  All intravenous 
infusions preceding the decision to perform endotracheal intubation will 
not be altered. 
 
 
Variable Definitions 
 
 
Primary Outcome 
o Cardiovascular collapse, defined as one or more of the following: 
 
Death within 1 hour of intubation 
 
Cardiac arrest within 1 hour of intubation 
 
New systolic blood pressure < 65 mmHg between induction and 2 
minutes following intubation  
 
New or increased vasopressor between induction and 2 minutes 
following intubation  
 
 
Secondary Outcomes 
o Each component of the cardiovascular collapse composite: 
 
Death within 1 hour of intubation 
 
Cardiac arrest within 1 hour of intubation 
 
New systolic blood pressure < 65 mmHg between induction and 2 
minutes following intubation  
 
New or increased vasopressor between induction and 2 minutes 
following intubation  
 
 
Exploratory Outcomes 
1. Cardiovascular collapse composite outcome with an alternate systolic blood 
pressure cutoff: 
i. Death within 1 hour of intubation 
ii. Cardiac arrest within 1 hour of intubation 
iii. New systolic blood pressure < 90 mmHg between induction 
and 2 minutes following intubation  
iv. New or increased vasopressor between induction and 2 
minutes following intubation  
2. Incidence of systolic blood pressure < 90 mmHg between induction and 2 
minutes after intubation 


Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
3. Lowest systolic blood pressure between induction and 2 minutes after 
intubation 
4. Change in systolic blood pressure from induction to lowest systolic blood 
pressure  
5. Lowest arterial oxygen saturation between induction and 2 minutes after 
intubation 
6. Incidence of hypoxemia (oxygen saturation <90%) between induction and 2 
minutes after intubation 
7. Incidence of severe hypoxemia (oxygen saturation <80%) between induction 
and 2 minutes after intubation 
8. Incidence of desaturation (defined by decrease in oxygen saturation of >3%) 
between induction and 2 minutes after intubation  
9. Change in saturation from induction to lowest oxygen saturation between 
induction and 2 minutes after intubation 
10. Lowest SpO2 in the 6-24 hours after intubation 
11. Highest FiO2 in the 6-24 hours after intubation 
12. Highest positive end-expiratory pressure in the 6-24 hours after intubation 
13. Cumulative diuretic dose (in furosemide equivalents) from enrollment through 
three days after intubation 
14. Cumulative intravenous fluid administration from enrollment through three 
days after intubation  
15. Vasopressor receipt in the 1 hour after intubation 
16. Composite of new or worsening shock in the 1 hour after intubation 
 
New mean arterial blood pressure < 65 mmHg  
 
New vasopressor use 
 
Increased dose of previous vasopressor 
17. In-hospital mortality 
18. Ventilator-free days (VFDs) 
19. ICU-free days (ICUFDs) 
 
Measures of Study Intervention Delivery 
Measures of study intervention will be presented for each study group but are not 
study outcomes: 
1. Estimated volume of intravenous fluids infused as part of fluid loading 
prior to induction drug administration 
 
Co-interventions 
Co-interventions are aspects of the endotracheal intubation procedure that will be 
presented for each study group but are not study outcomes: 
1. Time from administering induction medications to successful 
endotracheal intubation 
2. Cormack-Lehane grade of view on first attempt 
3. Incidence of endotracheal intubation on first attempt 
4. Number of attempts required for successful tube placement  
5. Incidence of need for additional intubating equipment, second operator 
6. Agreement between primary and secondary outcomes recorded by 
observers and study staff 
 


Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
 
 
ICU-free days to 28 days after enrollment will be defined as the number of midnights 
alive and not admitted to an intensive care unit service after the patient’s final discharge 
from the intensive care unit before 28 days. If the patient is admitted to an intensive care 
unit service at day 28 or dies prior to day 28, ICU-free days will be 0.  Censoring will 
occur at hospital discharge. 
 
Ventilator-free days to day 28 will be defined as the number of midnights alive and with 
unassisted breathing to day 28 after enrollment, assuming a patient survives for at least 
two consecutive calendar days after initiating unassisted breathing and remains free of 
assisted breathing.  If a patient returns to assisted breathing and subsequently achieves 
unassisted breathing prior to day 28, VFD will be counted from the end of the last period 
of assisted breathing to day 28.  If the patient is receiving assisted ventilation at day 28 
or dies prior to day 28, VFD will be 0.  Censoring will occur at hospital discharge. 
 
 
Data Collection and Follow Up 
 
Given the pragmatic nature of this trial, data below will be collected when 
available in the medical record of the patient. 
 
 
Baseline: Age, gender, height, weight, race, APACHE II score, active medical 
problems at the time of intubation, active comorbidities complicating intubation, lowest 
systolic blood pressure and vasopressor use prior to intubation, noninvasive ventilator 
use, highest FiO2 delivered in prior 6 hours, lowest oxygen saturation in the prior six 
hours, arterial pH, PaO2, PaCO2 in the prior six hours, indication for intubation, 
reintubation, preoxygenation technique, operator experience, baseline echocardiogram 
 
Peri-procedural: Date and time of sedative and/or neuromuscular blocker 
administration, saturation at time of sedative and/or neuromuscular blocker 
administration, pre-oxygenation devices used, sedative, neuromuscular blocker, 
ventilation between induction and laryngoscopy, laryngoscope type and size, total 
number of attempts, airway grade, airway difficulty, rescue device use, need for 
additional operators, mechanical complications (esophageal intubation, aspiration, 
airway trauma), volume of fluids infused as part of fluid loading, cardiac arrest, 
vasopressor use, and death.  Lowest systolic blood pressure, lowest arterial oxygen 
saturation, vasopressor administration, fluid administration, time to intubation and other 
key peri-procedural outcomes will be collected by a trained, independent observer not 
affiliated with the performance of the procedure. 
 
0-1 hour after intubation: Post-intubation imaging, post intubation shock, vasopressor 
use or cardiac arrest, and range of SpO2, FiO2, PEEP, and SBO in the 0 to 1 hour after 
intubation  
 
1-6 hour after intubation: Range of SpO2, FiO2, PEEP, and SBP in the 1 to 6 hours 
after intubation  
 
6-24 hours: Range of SpO2, FiO2, PEEP, and SBO in the 6 to 24 hours after intubation  
 


Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
0-72 hours: cumulative intravenous fluid administration, cumulative diuretic 
administration (in furosemide equivalents) 
 
In-Hospital Outcomes: Date of last extubation (ventilator-free days), date of last ICU 
discharge (ICU-free days), date of death 
 
 
Treatment Allocation 
Opaque randomization envelopes will be present in the ICUs and available to operators 
when it is determined endotracheal intubation will be performed.  Randomization will be 
stratified by study site and in permuted blocks of two, four, or six. Study personnel along 
with the operators will be blinded to the group assignment prior to the opening of an 
envelope.  Once it has been determined by the treating team that (1) intubation is 
required, and (2) the operator confirms the absence of exclusion criteria, the operator 
will open the envelope and follow the assignment of either fluid loading or no fluid 
loading. 
 
Power and Sample Size 
 
In a previous before-and-after observational study which incorporated preemptive 
intravenous fluid loading to prevent cardiovascular collapse during endotracheal 
intubation in critically ill adults, the rate of cardiovascular collapse was approximately 
25% in the control arm and 15% in the preemptive intravenous fluid loading arm (an 
absolute risk reduction of 10% and a relative risk reduction of 40%).  Randomization of a 
total of 500 patients (250 patients per group) will provide 80% power to detect the same 
10% difference in cardiovascular collapse between groups with an alpha of 0.05. 
 
During one scheduled interim analysis after 250 patients have been enrolled, the 
DSMB will have the ability to monitor the rate of the primary outcome overall in the study 
at the interim analysis and can ask that the study be re-powered to maintain an 80% 
power to show a 40% relative risk reduction. 
 
Consent 
Fluid loading or the absence of additional fluid administration are both commonly 
used approaches during endotracheal intubation of critically ill adults in current practice.  
In prior observational studies of critically ill adults undergoing endotracheal intubation, 
clinicians have opted to administer a fluid bolus prior to induction in approximately 50% 
of patients, with significant variability by provider and practice environment.  Currently, 
there are no randomized trials or evidence-based guidelines to support the choice 
between fluid loading or none during endotracheal intubation of critically ill adults.   
 
Because both approaches to peri-intubation fluid management being studied are 
(1) commonly used as a part of routine care, (2) are interventions the patient would 
arbitrarily be exposed to even if not participating in the study, and (3) are acceptable 
options from the perspective of the clinical provider (otherwise patient is excluded), we 
feel the study meets criteria for minimal risk. 
 
Additionally, obtaining informed consent in the study would be impracticable.  
Endotracheal intubation of acutely ill patients is frequently a time-sensitive procedure.  
Despite the availability of a formal informed consent document for the procedure itself, 
time allows for formal discussion of risks and benefits in less than 10% of airway 
management events in the ICU. 


Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
 
Because the study poses minimal risk, does not adversely affect the welfare or 
privacy rights of the participant, and consent is impracticable, the study is being 
conducted under a waiver of informed consent. 
 
 
Statistical analysis 
 
Analysis principles 
 
Primary analysis will be conducted on an intention-to-treat basis (patients with 
protocol violations are analyzed per the assigned treatment arm). 
 
All hypothesis tests will be two sided, with an α of 0.05 unless otherwise 
specified. 
 
All analyses will be unadjusted unless otherwise specified. 
 
Subgroup analyses will be performed irrespective of treatment efficacy. 
 
 
Trial profile 
We will present a Consolidated Standards of Reporting Trials diagram to detail 
the movement of patients through the study. This diagram will include total number of 
patients meeting inclusion criteria, number excluded and reason for exclusion, number 
enrolled and randomized in the study, number followed, and number analyzed. 
 
Baseline comparisons and assessment of randomization 
To assess randomization success, we will summarize in a table the distribution of 
baseline variables across the study arms. Categorical variables will be reported as 
frequencies and percentages and continuous variables as either means with SDs or 
medians with interquartile ranges. Variables reported will include Demographics (age, 
gender, race, BMI, co-morbidities); Indication for intubation; Active illnesses at the time 
of intubation; Severity of Illness (APACHE II score); Respiratory status pre-intubation; 
vasopressor use at the time of intubation; Airway management procedure 
(Preoxygenation technique, systolic blood pressure at time of induction, Induction 
medication, Neuromuscular blocker, Laryngoscope type). 
 
Primary Analysis 
 
Unadjusted test of treatment effect.  The primary analysis will be an intention-to-treat, 
unadjusted comparison of the primary outcome between patients assigned to the fluid 
loading and no fluid loading groups.  The primary endpoint will be the categorical 
variable of cardiovascular collapse.  The difference between the two groups will be 
compared using the χ2 test.  
 
 
Secondary Analyses 
 
Analysis of Secondary and Exploratory Outcomes.  We will conduct unadjusted analyses 
examining the treatment effect of fluid loading on each of the pre-specified secondary 
and exploratory outcomes.  Continuous outcomes will be compared with the Mann-
Whitney U test and categorical variables with the χ2 test.  Kaplan-Meier curves and log-
rank tests will be used to analyze time-to-event comparisons between groups.   


Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
 
Per-Protocol Analyses.  In addition to the intention-to-treat analysis, we will conduct a 
per protocol analysis of the primary outcome comparing patients who received fluid 
loading prior to induction compared to patients who received no fluid loading prior to 
induction.  
 
 
 
Effect Modification (Subgroup analyses).  We will determine whether pre-specified 
baseline variables modify the effect of treatment group on the primary outcome.  We will 
evaluate for effect modification by fitting a logistic regression model for the composite 
primary outcome of cardiovascular collapse; independent variables will include study 
group assignment, the potential modifier variable of interest, and the interaction between 
the two (e.g., study_group*vasopressors at enrollment).  Significance will be determined 
by the P value for the interaction term, with values less than 0.10 considered suggestive 
of a potential interaction and values less than 0.05 considered to confirm an interaction.  
Subgroups derived from categorical variables will be displayed as a forest plot.  
Continuous variables will be analyzed using restricted cubic splines with 3-5 knots and 
preferentially displayed as continuous variables with predicted probabilities of the 
categorical outcome.  If the presentation of data requires it, dichotomization of 
continuous variables for inclusion in the forest plot will be performed. 
 
Pre-specified subgroups that may modify the physiologic impact of fluid loading: 
1.  Vasopressor receipt at enrollment (Yes/No) 
2.  Baseline left ventricular ejection fraction (continuous variable) 
 
3.  Sepsis diagnosis in the ICU (Yes/No) 
 
4.  Congestive heart failure diagnosis at baseline (Yes/No) 
5.  Chronic kidney disease, including end-stage renal disease, diagnosis at    
baseline (Yes/No) 
6.  Cirrhosis diagnosis at baseline (Yes/No) 
7.  Non-invasive ventilation for preoxygenation (Yes/No) 
8.  Bag-valve-mask ventilation after induction (Yes/No) 
 
Subgroups related to risk for the primary outcome: 
 
1. APACHE II score at enrollment (continuous variable) 
2. Reason for intubation (Hypoxic or Hypercarbic Respiratory Failure / Altered     
mental status or seizure / Procedure / Other) 
3. Lowest systolic blood pressure in the 6 hours prior to the procedure 
4. Lowest SpO2 in the 6 hours prior to the procedure and at induction 
5. BMI 
6.  Re-intubation 
7.  Induction agent (Etomidate / Propofol / Other) 
 
Modeling to Examine Potential Confounding Factors.  We will develop a logistic 
regression model with the primary outcome as the dependent variable and study group 
and relevant confounders included as independent variables (age, APACHE II score, 
vasopressor receipt at induction, systolic blood pressure at induction). 
 


Principal Investigator: David R. Janz 
 
 Version Date: 1/8/18 
Study Title: The PrePARE Trial 
Institutions: LSU New Orleans, Vanderbilt, Ochsner, University of Alabama Birmingham, 
University of Washington, Lahey Medical Center, Lincoln Medical Center  
 
Missing Data.  In the initial analysis, missing data will not be imputed.  As sensitivity 
analyses, the primary analysis will be repeated with missing data imputed by (1) 
assigning a value of “No, primary endpoint did not occur” to data missing from the fluid 
loading group and a value of “Yes, primary endpoint did occur” to data missing from the 
no fluid loading, and (2) assigning a value of “No” to data missing from the fluid loading 
group and a value of “Yes” to data missing from the no fluid loading group. 
 
 
Corrections for multiple testing 
We have pre-specified a single primary analysis of a single primary outcome.  All 
additional analyses will be considered hypothesis-generating, and no corrections for 
multiple comparisons will be performed. 
 
Conclusion 
We describe, before the conclusion of enrollment or data unblinding, our approach to 
analyzing the data from the PrePARE trial of fluid loading versus none to prevent life-
threatening cardiovascular collapse.  We anticipate that this pre-specified framework will 
enhance the utility of the reported result and allow readers to better judge the impact.