The Randomized Trial of Sedative Choice for Intubation
Phase: PHASE4
Conditions: Acute Respiratory Failure
Sponsor: Vanderbilt University Medical Center

Randomized Trial of Sedative Choice for Intubation 
Protocol and Statistical Analysis Plan 
Clinicaltrials.gov: NCT 05277896 
This Supplementary Appendix contains the following items: 
1) Initial Trial Protocol -Version 1.0 [dated March 9, 2022]
2) Final Trial Protocol -Version 2.2 [dated March 7, 2025]
3) Summary of changes to Trial Protocol
4) Original Statistical Analysis Plan [posted January 18, 2025]
5) Final Statistical Analysis Plan [published May 21, 2025]
6) RSI Trial Statistical Analysis Plan Revision Sequence

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Randomized Trial of Sedative Choice for Intubation (“RSI”) Trial Protocol 
The Pragmatic Critical Care Research Group Investigators 
 
 
 
Title:  
Randomized Trial of Sedative Choice for Intubation  
Acronym:  
RSI 
Funder:  
The National Heart, Lung, and Blood Institute (NHLBI) 
Network:  
Pragmatic Critical Care Research Group 
Protocol:  
Version 1.0 
Date: 
 
March 9, 2022 
Study Chair:  
Jonathan Casey MD, MSc, Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 

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RSI Trial Leadership 
 
 
Protocol Committee Chair 
Jonathan Casey, MD, MSc 
Vanderbilt University Medical Center 
Email: Jonathan.D.Casey@vumc.org 
 
Protocol Committee Members 
Matthew Semler MD, MSc 
Todd Rice MD, MSc 
Wesley Self MD, MSc 
 
 
NHLBI Officers 
Lora Reineck MD 
 
Consultants to the Protocol 
Brian Driver MD 
 
 
 

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Table of Contents 
 
REVISIONS TO THE PROTOCOL ............................................................................................................. 7 
ABBREVIATIONS ...................................................................................................................................... 8 
1. STUDY SUMMARY ................................................................................................................................ 9 
2. TRIAL DESCRIPTION .......................................................................................................................... 12 
2.1 Background ............................................................................................................................... 12 
2.1.1 Cardiovascular Collapse during Intubation .................................................................................... 12 
2.1.2 Sedative Medications Contribute to the Risk of Cardiovascular Collapse ..................................... 12 
2.1.3 Ketamine as a Sedative during Tracheal Intubation. ...................................................................... 13 
2.1.4 Etomidate as a Sedative during Tracheal Intubation. ..................................................................... 13 
2.1.5 Prior Evidence from Clinical Trials. ............................................................................................... 14 
2.1.6 Rationale for a Trial of Ketamine vs Etomidate in Non-Traumatic Critical Illness. ...................... 14 
2.1.7 Rationale for Two Stages of the RSI trial. ...................................................................................... 14 
2.2 Study Aims and Hypotheses ..................................................................................................... 15 
2.2.1 Study aims ...................................................................................................................................... 15 
2.2.2 Study hypothesis ............................................................................................................................. 15 
2.3 Study Design .............................................................................................................................. 16 
3. STUDY POPULATION AND ENROLLMENT ................................................................................... 16 
3.1 Inclusion Criteria ...................................................................................................................... 16 
3.2 Exclusion Criteria ..................................................................................................................... 16 
3.3 Justification of Exclusion Criteria ........................................................................................... 16 
4.0 Process of Obtaining Informed Consent ............................................................................................... 17 
5.0 Enrollment and Randomization ............................................................................................................ 18 
6.0 Blinding ................................................................................................................................................ 19 
7.0 STUDY INTERVENTIONS................................................................................................................. 19 
7.1 Treatment of Study Patients .................................................................................................... 19 
7.2 Ketamine Group ........................................................................................................................ 19 
7.3 Etomidate Group ...................................................................................................................... 20 
7.4 Co-Interventions ....................................................................................................................... 20 
7.5 Packaging and Labeling ........................................................................................................... 20 
7.6 Storage and Accountability ...................................................................................................... 20 
7.7 On-Study Monitoring ............................................................................................................... 21 

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8. OUTCOMES........................................................................................................................................... 21 
8.1 Stage 1 Primary Outcome ........................................................................................................ 21 
8.2 Stage 1 Secondary Outcomes ................................................................................................... 21 
8.3 Stage 2 Primary Outcome ........................................................................................................ 22 
8.4 Stage 2 Secondary Outcome ..................................................................................................... 22 
8.5 Exploratory Outcomes (for both Stage 1 and Stage 2) .......................................................... 22 
8.6 Safety outcomes (for both Stage 1 and Stage 2) ..................................................................... 22 
9. DATA COLLECTION ........................................................................................................................... 22 
9.1 Baseline Variable Collection .................................................................................................... 23 
9.2 Peri-Procedural Variables ........................................................................................................ 23 
9.3 Assessments between Hospital Presentation and Hospital Discharge .................................. 24 
9.4 REDCap Clinical Data Interoperability Services .................................................................. 24 
10. STATISTICAL CONSIDERATIONS .................................................................................................. 25 
10.1 Stage 1 Sample Size Calculation ............................................................................................ 25 
10.2 Stage 2 Sample Size Calculation ............................................................................................ 25 
10.3 Progression from Stage 1 to Stage 2 of RSI .......................................................................... 25 
10.4 Primary Analysis ..................................................................................................................... 26 
10.5 Secondary Analyses ................................................................................................................ 26 
10.6 Effect Modification (Subgroup Analyses) ............................................................................. 27 
10.7 Interim Analysis ...................................................................................................................... 27 
10.8 Correction for Multiple Testing ............................................................................................. 27 
10.9 Handling of Missing Data ....................................................................................................... 27 
11. DATA QUALITY MONITORING AND STORAGE ......................................................................... 28 
11.1 Data Quality Monitoring ........................................................................................................ 28 
11.2 Data Storage ............................................................................................................................ 28 
12. RISK ASSESSMENT ........................................................................................................................... 28 
12.1 Potential Risks of Receiving Ketamine ................................................................................. 28 
12.2 Potential Risks of Receiving Etomidate ................................................................................ 29 
12.3 Potential Risk of Participation in the RSI Trial ................................................................... 30 
12.4 Minimization of Risk .............................................................................................................. 31 
12.5 Potential Benefit ...................................................................................................................... 31 
12.6 Risk in Relation to Anticipated Benefit ................................................................................. 31 
13. HUMAN SUBJECTS PROTECTIONS ............................................................................................... 32 

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13.1 Length of Therapeutic Window ............................................................................................. 32 
13.2 Inability to Conduct Trial without EFIC .............................................................................. 32 
13.3 Opportunity to Decline Participation .................................................................................... 33 
13.4 Notification of Enrollment ...................................................................................................... 33 
13.5 Documentation and Tracking of Notification Process ......................................................... 34 
13.6 Selection of Subjects................................................................................................................ 34 
13.7 Justification of Including Vulnerable Subjects .................................................................... 34 
13.8 Investigational New Drug Application .................................................................................. 35 
13.9 Additional Safeguards for Vulnerable Patients ................................................................... 35 
13.10 Confidentiality ....................................................................................................................... 35 
14. ADVERSE EVENTS ............................................................................................................................ 35 
14.1 Adverse Event Definitions ...................................................................................................... 36 
14.2 Safety Monitoring ................................................................................................................... 36 
14.3 Serious Adverse Events .......................................................................................................... 37 
15. Data and Safety Monitoring Board (DSMB) ........................................................................................ 37 
16. REFERENCES. .................................................................................................................................... 39 
17. APPENDICES ...................................................................................................................................... 44 
Appendix A. Schedule of Events .................................................................................................... 44 
Appendix B: Compliance with Criteria and Processes Required for EFIC .............................. 45 
APPENDIX C. Script to Provide an Opportunity to Opt-Out of Participation ........................ 54 
APPENDIX D. Notification of Enrollment Form ......................................................................... 55 
Appendix E: Letter to be Mailed if Unable to Notify Patient prior to Discharge ..................... 61 
Appendix F: Letter to Mailed if Patient Dies before Notification .............................................. 62 
Appendix G: Adverse Event Reporting and Unanticipated Events ........................................... 63 
H.1. Expedited Adverse Event Review and DSMB Notification Process ............................................... 63 
H.2. Unanticipated Problems (UP) .......................................................................................................... 63 
H.3. Determining Relationship of Adverse Events to Study Medication or Study Procedures ............... 64 
H.4. Clinical Outcomes that may be Exempt from Adverse Event Reporting ........................................ 64 
 
 
 

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REVISIONS TO THE PROTOCOL 
 
Protocol Version 1 
Date: March 9, 2022 
Initial protocol 
 
 

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ABBREVIATIONS 
 
AE 
Adverse event 
SOFA score 
Sequential Organ Failure Assessment score 
DSMB 
Data safety monitoring board 
ED 
Emergency department 
EFIC 
Exception from Informed Consent (21 CFR 50.24.7) 
ICU 
Intensive care unit 
IV 
Intravenous 
LAR 
Legally authorized representative 
PI 
Principal investigator (the clinician leading the study across all sites) 
RCT 
Randomized control trial 
SAE 
Serious adverse events 
S/F 
SpO2/FiO2 ratio 
SOP 
Standard operating procedure 
 
 
 
 
 
 
 

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1. STUDY SUMMARY 
 
Title 
Randomized Trial of Sedative Choice for Intubation (RSI) 
Background 
Among critically ill adults undergoing emergency tracheal intubation, one in five 
experience hypotension, cardiac arrest, or death. The sedatives used to rapidly 
induce anesthesia for emergency tracheal intubation have been hypothesized to 
effect cardiovascular complications and patient outcomes, but the optimal 
sedative medication for intubation of critically ill adults remains unknown. 
Ketamine and etomidate are the two most commonly used sedatives during 
intubation of critically ill adults.  Data from a randomized clinical trial are 
urgently needed to determine the effect of ketamine versus etomidate on 
cardiovascular complications and clinical outcomes of emergency tracheal 
intubation.  
 
Study Design 
Multi-center non-blinded, parallel-group, randomized clinical trial 
Treatment Groups 
 
Ketamine group: Patients will receive intravenous ketamine at a recommended 
dose of 2 mg/kg for induction of anesthesia for emergency tracheal intubation. 
 
Etomidate group: Patients will receive intravenous etomidate at a recommended 
dose of 0.3 mg/kg for the induction of anesthesia for emergency tracheal 
intubation. 
 
In this investigator-initiated, multi-center, non-blinded, randomized trial 
comparing two commonly used medications within their approved indications, 
the assigned sedative medication will be dispensed from the clinical pharmacy 
and administered by clinical personnel as would occur in clinical care. 
 
Sample Size 
Stage 1 (feasibility): 464 patients 
Stage 2 (effectiveness): 1,900 patients 
 
Inclusion Criteria 
1. Patient is critically ill and undergoing emergency tracheal intubation with 
sedation in an enrolling unit 
2. Planned procedure is orotracheal intubation using a laryngoscope 
3. Planned operator is a clinician expected to routinely perform tracheal  
intubation in the participating unit 
 
Exclusion Criteria 
1. Patient is known to be less than 18 years old 
2. Patient is known to be pregnant 
3. Patient is known to be a prisoner 
4. Patient is known to have an allergy to ketamine or etomidate 
5. Patient is presenting to the emergency department with a primary diagnosis 
of trauma  
6. Patient or LAR declines participation during pre-enrollment opt-out 
conversation or by wearing opt-out bracelet for the RSI trial 
7. Clinician feels ketamine is required or contraindicated for the optimal care 
of the patient 

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8. Clinician feels etomidate is required or contraindicated for the optimal care 
of the patient 
9. Clinician feels an induction medication other than ketamine or etomidate is 
required for the optimal care of the patient 
10. Immediate need for tracheal intubation precludes safe performance of 
study procedures 
Consent 
Emergency tracheal intubation of critically ill patients is a time-sensitive 
procedure with a brief therapeutic window between the decision to perform 
intubation and the completion of the procedure. A written informed consent is 
available and will be used when feasible in RSI. However, it is expected that 
written consent will be infeasible in most, if not all, cases because delaying the 
emergency tracheal intubation of critically ill adults would cause irreparable 
harm to patients. Therefore, it is expected that most, if not all, patients will be 
enrolled under “Exception from informed consent required for emergency 
research” (EFIC).  
 
In conformance with EFIC requirements, measures to protect the rights and 
welfare of subjects will include: a) community consultation, b) public disclosure 
of plans to conduct the trial, c) public disclosure of trial results, d) independent 
data monitoring, and e) opportunity for pre-randomization opt-out (when 
feasible) and notification of the patient, legally authorized representative, or a 
family member of a patient’s enrollment in the trial with an opportunity to 
discontinue trial participation. 
Randomization 
 
Eligible patients will be randomized 1:1 to ketamine versus etomidate. 
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 operators 
until after the decision has been made to enroll the patient in the study. 
Following enrollment, the trial will not blind patients or treating clinicians to 
study group assignment. 
Primary Outcome  
Stage 1 (if trial terminates during or at the end of the feasibility stage):  
• Cardiovascular Collapse, a composite of any of the following between 
induction and 2 minutes after intubation:  
o Systolic blood pressure < 65 mmHg 
o New or increased vasopressors  
o Cardiac arrest not resulting in death within 1 hour of induction 
o Cardiac arrest resulting in death within 1 hour of induction 
Stage 2: 28-day in-hospital mortality 
 
Secondary Outcome 
Stage 1 (if trial terminates during or at the end of the feasibility stage): 28-day 
in-hospital mortality 
 
Stage 2:  
• Cardiovascular Collapse, a composite of any of the following between 
induction and 2 minutes after intubation:  
o Systolic blood pressure < 65 mmHg 

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o New or increased vasopressors  
o Cardiac arrest not resulting in death within 1 hour of induction 
o Cardiac arrest resulting in death within 1 hour of induction 
Exploratory Outcomes 
• 
Procedural Characteristics & Complications 
o 
Cormack-Lehane Grade of glottic view 
o 
Number of attempts at tracheal intubation 
o 
Time from induction to successful tracheal intubation 
o 
Operator-assessed difficulty of intubation 
o 
Lowest oxygen saturation between induction and two minutes after 
intubation 
o 
Lowest oxygen saturation < 80% between induction to two minutes 
after intubation  
o 
Highest and lowest systolic blood pressure from induction to two 
minutes after intubation 
o 
Systolic blood pressure > 180 between induction and two minutes 
after intubation 
o 
Systolic blood pressure < 65 mmHg between induction and 2 
minutes after intubation 
o 
New or increased vasopressor between induction and 2 minutes 
after intubation 
o 
Cardiac arrest within 2 minutes of intubation not resulting in death 
o 
Cardiac arrest within 2 minutes of intubation resulting in death 
• 
Short-term Clinical Outcomes 
o 
Ventilator-free days to study day 28 
o 
Vasopressor-free days to study day 28 
o 
ICU-free days to study day 28 
Safety Outcomes 
• 
Systolic blood pressure at 24 hours after induction 
• 
Receipt of vasopressors at 24 hours after induction 
• 
Cardiac arrest receiving cardiopulmonary resuscitation between 
induction and hospital discharge 
Analysis 
The primary analysis will be an unadjusted, intention-to-treat comparison of 
patients randomized to ketamine versus patients randomized to etomidate with 
regard to the primary outcome. The difference between the two study groups will 
be compared using a Chi-squared test. 
 
 
 

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2. TRIAL DESCRIPTION 
2.1 Background 
Each year more than 1.5 million critically ill adults receive invasive mechanical ventilation in the United 
States,1–3 at a cost of nearly $30 billion dollars annually.1,2 Recent research has dramatically improved 
patient safety during the maintenance, weaning, and liberation stages of invasive mechanical 
ventilation.4,5 In contrast, the optimal approach to the initiation of mechanical ventilation remains an 
important knowledge gap in the care of adults with respiratory failure. Among critically ill adults, life-
threatening complications during tracheal intubation and initiation of invasive mechanical ventilation 
remain common. One in five patients experiences hypotension and one-in-forty experiences cardiac arrest 
during the two-minute tracheal intubation procedure.6–10  
2.1.1 Cardiovascular Collapse during Intubation 
Cardiovascular collapse is a peri-procedural outcome defined as severe hypotension, new or increased 
vasopressors, cardiac arrest or death. The occurrence of cardiovascular collapse during tracheal intubation 
of critically ill adults increases patients’ risk of in-hospital mortality.11 Randomized trials examining 
intubation technique commonly target cardiovascular collapse as an outcome.12–14 Adherence to 
recommended best-practices for tracheal intubation (e.g., preoxygenation,15,16 optimization of patient 
positioning,9 and procedural checklists8) are insufficient to prevent 20-40% of critically ill adults from 
experiencing cardiovascular collapse during tracheal intubation.12,14,17–19  
2.1.2 Sedative Medications Contribute to the Risk of Cardiovascular Collapse 
Rapid sequence induction and tracheal intubation, the most common method of intubation for critically ill 
patients, is the nearly simultaneous administration of a sedative medication and neuromuscular blocking 
medication. The ideal sedative agent for rapid sequence intubation would rapidly provide a deep state of 
unconsciousness and analgesia without causing hemodynamic side effects. No available agent meets all of 
these criteria.20  The administration of any of the available sedative agents at a dose large enough to 
rapidly induce unconsciousness contributes to cardiovascular collapse through vasodilation, decreased 
cardiac filling pressures from sedation-induced venodilation, and decreased endogenous 
catecholamines.21–24 While all sedatives commonly used during emergency tracheal intubation of 
critically ill patients have been associated with unsatisfactory hypotension (21 CFR 50.24(a)(1)), 
ketamine and etomidate are the medications used most commonly in clinical practice due to their rapid 
onset and favorable hemodynamic profiles relative to the other available sedatives.25,26 Other sedatives 
that have been used in some settings during rapid sequence intubation include benzodiazepines, propofol, 
and barbiturates.  Benzodiazepines do not provide any analgesia and are associated with an unsatisfactory 
degree of hypotension, with a drop in mean arterial blood pressure of 10 to 25 percent, even among 
healthy patients.27–29  At present, barbiturates are rarely used for tracheal intubation in the US because of 
unsatisfactorily high rates of post-intubation hypotension and evidence of negative cardiac ionotropy.30  
While propofol is commonly used to induce anesthesia among healthy patients, and is commonly 
administered as a continuous infusion to maintain sedation for critically ill patients, it is used less 
commonly as a bolus during tracheal intubation of critically ill patients because it has been suggested to 
cause unsatisfactorily high rates of hypotension and cardiac depression, compared to ketamine or 
etomidate.31,32 

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2.1.3 Ketamine as a Sedative during Tracheal Intubation.  
Ketamine is a phencyclidine derivative that provides anesthesia via its effect at the NMDA receptors. 
Ketamine has been approved by the United States Food and Drug Administration (FDA) with approved 
indications including “use as the sole anesthetic agent for diagnostic and surgical procedures that do not 
require skeletal muscle relaxation” and “induction of anesthesia prior to the administration of other 
general anesthetic agents.” In addition to sedation, ketamine provides significant amnesia and analgesia 
via action at the opioid receptors, and is commonly used for procedural sedation and as a continuous 
infusion to control pain.33  
Ketamine activates the sympathetic nervous system, stimulating the release of catecholamines,34 which 
may increase heart rate and blood pressure during intubation and prevent peri-procedural cardiovascular 
collapse.33 Conversely ketamine has direct negative ionotropic effects, leading to myocardial 
depression.30,35,36 While the myocardial depression may be counteracted by increased catecholamine 
release, ketamine could cause cardiovascular collapse among patients with depleted catecholamine stores, 
and case reports of unexpected cardiac arrest during intubations with ketamine have been published.37 
Despite stimulating the release of catecholamines, using ketamine as the induction agent during 
emergency tracheal intubation does not appear to frequently cause or worsen hypertensive urgency or 
emergency; however, the literature on this topic is limited to case reports.38 
Historically, concerns have been raised that ketamine might increase intracranial pressure and cause 
deleterious decreases in cranial perfusion pressure. Recent studies have suggested, however, that 
ketamine may be associated with a beneficial increase in cranial perfusion pressure as a result of 
increased mean arterial pressure,39,40 and a recent, large before-after study showed no significant 
differences in clinical outcomes for trauma patients intubated with ketamine versus etomidate.41  
2.1.4 Etomidate as a Sedative during Tracheal Intubation.  
Etomidate is an imidazole derivative that acts at gamma-aminobutyric acid “A” (GABA) receptors. 
Etomidate has been approved by the FDA with an indication for “induction of general anesthesia.” In a 
recent review of more than 19,000 intubations by a large, multicenter emergency medicine registry, 
etomidate was the most commonly used sedative during emergency tracheal intubation.26  
Etomidate causes less hemodynamic instability than propofol42 and midazolam,27 but the data regarding 
the relative risk of hemodynamical instability with etomidate, compared to ketamine, is unclear.  It was 
initially suggested that ketamine might cause less hypotension than etomidate, given ketamine’s ability to 
stimulate the release of catecholamines,43,44 but a recent observational study comparing ketamine and 
etomidate among nearly 7,000 critically ill adults undergoing tracheal intubation in emergency 
departments suggested that ketamine was independently associated with an increased risk of peri-
intubation hypotension.26 
Etomidate was initially used both for induction of anesthesia and as a continuous drip for maintenance of 
anesthesia. Its use as a continuous drip for maintenance of anesthesia was halted after it was discovered 
that prolonged use of etomidate causes inhibition of adrenal cortisol production by blockade of 11-β-
hydroxylase, leading to adrenal insufficiency, and increased mortality.45–47 Etomidate use as a single bolus 
for induction of anesthesia has continued, but numerous studies have demonstrated that even a single dose 
of etomidate can cause transient adrenal insufficiency.48–53 The clinical significance of this relative 

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adrenal insufficiency, however, remains unclear. Contrasting observational studies have suggested that 
etomidate may have positive,41,54 negative 47,52,55–57 or neutral impacts41,48,49,51,58,59 on mortality.  
2.1.5 Prior Evidence from Clinical Trials.  
Two randomized trials have directly compared ketamine to etomidate for RSI among critically ill 
adults.60,61  
The Ketased trial, published in 2009, was a 469-patient trial conducted across 12 emergency medical 
services and emergency departments in France.60 Because many patients were enrolled in the pre-hospital 
setting without continuous blood pressure monitoring, peri-procedural outcomes such as cardiovascular 
collapse were not collected, and the results were indeterminate, in regards to the primary outcome, 
average Sequential Organ Failure Assessment (SOFA) scores in the 72 hours after intubation. The results, 
however, demonstrated significant heterogeneity. Patients with trauma (for whom increased intracranial 
pressure from ketamine may be important) experienced a non-significant 4% absolute increase in 
mortality when intubated with ketamine compared to etomidate. All other patients experienced a non-
significantly lower mortality when intubated with ketamine, particularly patients with sepsis who 
experienced a non-significant 7% absolute mortality benefit (and in whom adrenal insufficiency from 
etomidate may be particularly important). 
The EvK trial, published in January 2022, was a single-center, 801-patient trial conducted among 
hospitalized patients at a single hospital in Texas.61  Survival at 7 days, the primary outcome of the EvK 
trial, was higher in the ketamine group, compared to the etomidate group (85.1% vs 77.3%; p=0.005), but 
this difference was attenuated by day 28, at which point it was no longer significant (66.8% vs 64.1%, 
p=0.294).  The conclusion of this single-center trial was that “there was no significant difference in 
survival by Day 28”, however it was noted that this “could represent a small but durable long-term 
survival effect, one which our trial was under-powered to detect.”61 
2.1.6 Rationale for a Trial of Ketamine vs Etomidate in Non-Traumatic Critical Illness.  
Experts have pointed out that the currently available data on sedative choice during tracheal intubation of 
critically ill patients are inadequate and have called for additional randomized clinical trials.48,49,62 
Because (1) cardiovascular collapse is common during tracheal intubation of critically ill adults (2) 
sedatives are a driver of cardiovascular collapse, (3) use of ketamine or etomidate varies between centers, 
specialties, and operators, and (4) prior data suggests the potential for ketamine to significantly decrease 
mortality for patients without trauma, a large, multicenter trial is needed to determine the effects of 
ketamine and etomidate on mortality in non-traumatic critical illness.  
2.1.7 Rationale for Two Stages of the RSI trial. 
Stage 1 of the RSI trial will focus on feasibility and short-term, peri-procedural outcomes.  This stage is 
required to demonstrate the feasibility of performing a pragmatic trial comparing ketamine to etomidate 
during emergency tracheal intubation of critically ill adults under exception from informed-consent 
(EFIC) requirements for emergency research (under FDA code of regulations 21 CFR 50.24.7).99,100   
Stage 1 of the RSI trial (funded by the National Heart, Lung, and Blood Institute; grant number, 
K23HL153584) is designed to be of sufficient size to inform the effects of ketamine and etomidate on the 
short-term, peri-procedural outcome of cardiovascular collapse. 

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Stage 2 of the RSI trial will focus on the effect of ketamine vs etomidate on in-hospital mortality. Data on 
the effects of ketamine and etomidate on the short-term, peri-procedural outcome of cardiovascular 
collapse (the primary outcome of stage 1) could make an immediate impact on the use of these 
medications in clinical practice. However, the effects of ketamine and etomidate on in-hospital mortality 
may be mediated by mechanisms presenting after the peri-procedural period (e.g. adrenal insufficiency or 
increased intracranial pressure), and the effects of ketamine and etomidate on cardiovascular collapse 
may, therefore, be discordant with their effects on in-hospital mortality. A finding in stage 1 of the RSI 
trial that ketamine decreases, increases, or has no impact on cardiovascular collapse would in no way 
detract from the need for definitive data on the effect of ketamine and etomidate on in-hospital mortality.  
Completing a feasibility trial, closing enrollment, and subsequently initiating a separate, new, definitive 
trial using the same study design is inefficient.  Such an approach introduces delays in enrollment 
between the stages and fails to make use of data on clinical outcomes from patients enrolled during the 
feasibility stage.  This increases the total number of patients who must experience the potential risks of 
trial participation to obtain a definitive answer to the research question. The RSI trial is, therefore, 
planned as a single, adaptive trial with two stages.  
To increase efficiency and minimize the number of patients exposed to the potential risks of trial 
participation, the RSI trial is designed to allow progress from the stage assessing feasibility (Stage 1) to 
the stage assessing effectiveness (Stage 2) if the following criteria are met: (1) the data and safety 
monitoring board (DSMB) determines that the feasibility and safety of conducting the trial have been 
demonstrated; (2) the investigators determine that the observed enrollment rate, protocol compliance, 
separation between groups in receipt of the assigned therapy, and data completeness and quality permit 
progression to Stage 2; and (3) funding for a multicenter trial is available. Additional details regarding the 
progression from Stage 1 to Stage 2 are providing in section 10.3 of the protocol.   
2.2 Study Aims and Hypotheses 
2.2.1 Study aims 
Stage 1: To compare the effects of ketamine versus etomidate on cardiovascular collapse during tracheal 
intubation of critically ill adults.  To evaluate the feasibility of conducting a pragmatic trial of ketamine 
versus etomidate during tracheal intubation of critically ill adults in the ED or ICU using EFIC. 
Stage 2: To compare the effects of ketamine versus etomidate on in-hospital mortality among non-
traumatic critically ill adults undergoing tracheal intubation in the ED or ICU 
2.2.2 Study hypothesis 
Stage 1: Conducting a pragmatic trial comparing ketamine versus etomidate during tracheal intubation of 
non-traumatic critically ill adults in the ED or ICU using EFIC will be feasible. Ketamine will decrease 
the incidence of cardiovascular collapse.    
Stage 2: Ketamine will decrease the incidence of in-hospital mortality among non-traumatic critically ill 
adults undergoing intubation in the ED or ICU. 

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2.3 Study Design 
We will conduct an investigator-initiated non-blinded, pragmatic, parallel-group, randomized clinical trial 
evaluating the effect of ketamine versus etomidate on clinical outcomes of non-traumatic critically ill 
adults undergoing tracheal intubation in the ED and ICU. 
 
3. STUDY POPULATION AND ENROLLMENT 
 
3.1 Inclusion Criteria 
1. Patient is critically ill and undergoing emergency tracheal intubation with sedation in an enrolling 
unit 
2. Planned procedure is orotracheal intubation using a laryngoscope 
3. Planned operator is a clinician expected to routinely perform tracheal intubation in the 
participating unit 
3.2 Exclusion Criteria 
1. Patient is known to be less than 18 years old 
2. Patient is known to be pregnant 
3. Patient is known to be a prisoner 
4. Patient is known to have an allergy to ketamine or etomidate 
5. Patient is presenting to the emergency department with a primary diagnosis of trauma  
6. Patient or LAR declines participation during pre-enrollment opt-out conversation or by wearing 
opt-out bracelet for the RSI trial 
7. Clinician feels ketamine is required or contraindicated for the optimal care of the patient 
8. Clinician feels etomidate is required or contraindicated for the optimal care of the patient 
9. Clinician feels an induction medication other than ketamine or etomidate is required for the 
optimal care of the patient 
10. Immediate need for intubation precludes safe performance of study procedures 
 
3.3 Justification of Exclusion Criteria 
The RSI trial is intended to be broadly inclusive of critically ill patients who would receive ketamine or 
etomidate during intubation in usual care. The purpose of the exclusion criteria is to prevent the 
enrollment of patients who should not be enrolled under EFIC, patients who have a contraindication to 
study medications, or patients who have an indication for an alternative treatment. Pregnant women and 
prisoners are explicitly excluded from studies performed under EFIC. Patients with trauma are excluded 
from the RSI trial given the concern that ketamine may cause increased intracranial pressure among 
patients with head trauma.  No patients will be excluded on the basis of race, ethnicity, or sex.  
 

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4.0 Process of Obtaining Informed Consent  
Respect for human subjects and their safety is paramount in clinical research. Clinical research aiming to 
evaluate optimal care for critically ill adults during an emergency procedure presents unique ethical 
challenges. Protecting patient autonomy through the informed consent process is an ethical cornerstone of 
human subjects research.   
An informed consent document is available and will be used to obtain written informed consent from the 
patient or legally authorized representative for participation in the trial, when feasible. However, it is 
expected that obtaining written informed consent will be infeasible in most, if not all, cases due to:  
1. The expected medical condition of the patient. Based on prior trials in the same patient 
population and setting, approximately 70% of patients eligible for the trial will be experiencing 
encephalopathy (altered mental status) and the median Glasgow coma scale score will be 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 the trial will not have the capacity to provide informed consent.   
2. Sufficient time for the patient or legally authorized representative to consider participation 
& circumstances for consent that minimize the possibility of undue influence.  Even in 
instances in which a patient retains decisional capacity, or a legally authorized representative 
(LAR) is immediately available, the rapidity with which emergency tracheal intubation is 
clinically required (and the accompanying distress of the patient or LAR from the critical illness 
and need for emergency tracheal intubation) precludes execution of a meaningful informed 
consent process.  Although no published literature quantifies the time from the decision to 
perform emergency tracheal intubation (the inclusion criteria for the trial) until the initiation of 
intubation (the trial intervention), among a convenience sample of 25 consecutive critically ill 
adults undergoing emergency tracheal intubation in the VUMC ED or ICU, approximately 50% 
of intubations occurred within 5 minutes, 75% of intubations occurred within 10 minutes, and no 
intubations occurred longer than 30 minutes after treating clinicians verbalized the decision to 
intubate (or placed a written order for an induction medication).  Obtaining informed consent for 
research requires research personnel to assess decisional capacity, identify an 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 for cannot be executed in the 5 minutes before 
emergency tracheal intubation of a critically ill adult or their LAR in the ED or ICU.  Moreover, 
obtaining informed consent for participation in research in the minutes before emergency tracheal 
intubation from a distressed patient or LAR places the informed consent process for research 
adjacent to the receipt of life-saving care and risks blurring the distinction between treatment and 
research.  Emergency tracheal intubation of critically ill adults is, definitionally, a time-sensitive 
procedure for which every minute of 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. 
 

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The RSI trial comparing ketamine versus etomidate during tracheal intubation of critically ill adults can, 
therefore, only be conducted with exception from informed consent (EFIC) for emergency research, and it 
is expected that most, if not all, patients will be enrolled under “Exception from informed consent 
required for emergency research” (EFIC).  
Complete details of the plan for conducting the RSI trial in compliance with FDA regulation for EFIC are 
provided in Appendix B.  In coordination with the IRB, investigators for the RSI trial will conduct 
community consultation and public disclosure prior to beginning enrollment (see Community 
Consultation and Public Disclosure Plan).  The trial will be overseen by the IRB and an independent data 
and safety monitoring board.   
 
While the nature of emergency tracheal intubation precludes a full, written, informed consent process in 
most, if not all, cases, the RSI trial will provide an opportunity for patients, LARs, or family members to 
object to participation based on more limited information whenever feasible using a pre-enrollment opt-
out script (details in section 13.3).  
 
After enrollment of each patient, study personnel will attempt to notify the patients, LAR, or family 
members of enrollment in the trial in person. Notification of enrollment will be performed by research 
team members trained in informed consent processes, HIPAA laws, and the trial protocol. Patients or 
family members will be provided with a notification document approved by the Institutional Review 
Board (IRB). In the event that the patient, LAR, or family member cannot be contacted in person (for 
example, if they are outside of the state), study personnel will notify by telephone or by registered mail. 
There is no single timeline that is appropriate for all patients or families who are dealing with issues 
surrounding emergency tracheal intubation in the setting of critical illness. Study personnel will 
coordinate with treating clinicians to incorporate the judgement of treating clinicians as to the appropriate 
timing of notification for a given patient.  For cases in which a LAR or family member cannot be reached 
and the patient does not survive their critical illness, study personnel will send a letter approved by the 
IRB. Study personnel will keep a log that reflects the required steps for contacting the LAR or family 
member. The notification tracking log will be completed for each patient enrolled and included in the 
patient’s research records. 
 
Patients or their LARs may decline follow-up or access to medical record review, as stated in the 
notification document. If a patient or LAR declines follow up or access to medical record review, this 
information will be documented in the patient’s research record, along with the date and reason for 
withdrawal. As suggested in federal regulations for EFIC, the study investigators may examine data 
collected prior to patient withdrawal as this is necessary to maximize understanding of the safety of the 
study intervention. 
5.0 Enrollment and Randomization  
Patients will be enrolled at the time that treating clinicians have decided to pursue tracheal intubation and 
confirmed that the patient meets eligibility criteria. The enrollment materials for the RSI trial will include 
instructions for a pre-procedural timeout to review the inclusion and exclusion criteria prior to enrollment. 

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This process requires less than 10 seconds and can be easily completed during the 2-minute 
preoxygenation period. This approach has been successfully used in multiple prior trials.7–10  
Patients who are enrolled will be randomized 1:1 to ketamine or etomidate using random permuted blocks 
of two, four, and six.  Study group assignment will be stored and concealed prior to enrollment using 
opaque envelopes or the Randomization Module in the online database REDCap.  
 
6.0 Blinding  
The trial will not blind patients or treating clinicians to study group assignment. Obscuring treatment 
assignment in a controlled trial is particularly important when the outcomes are subjective, such as 
alleviation of pain, but less important for objective criteria, such as hypotension, cardiac arrest, or death.63 
Treating clinician’s awareness of study group assignment in the current trial may predispose to 
differential administration of co-interventions. For example, patients in the etomidate group may be more 
likely to be treated by clinicians with corticosteroid replacement therapy. In an explanatory trial focused 
on the mechanistic effects of a medication, such a difference in co-intervention could be viewed as 
confounding. In a pragmatic trial, the intent is to compare the manner in which the two interventions of 
interest would be administered as a part of routine clinical practice. Therefore, if patients in the etomidate 
group are administered corticosteroids at a higher rate than in the ketamine group, but the clinical 
outcomes in such circumstances are not different between groups, this provides the most robust answer to 
the question of the comparative effectiveness of ketamine versus etomidate for RSI as a part of routine 
clinical care.  
 
7.0 STUDY INTERVENTIONS 
7.1 Treatment of Study Patients 
Timing of study procedures is based on the time of the administration of sedative medication (e.g., 
ketamine or etomidate), which is the first step of rapid sequence induction and tracheal intubation and 
will be defined as “Time 0.”.  
Study medications will be administered by the same treating clinicians (e.g., registered nurse, physician, 
pharmacist) who would administer those medications as part of routine clinical care. 
7.2 Ketamine Group 
Patients in the ketamine group will be assigned to receive intravenous ketamine for induction of 
anesthesia during tracheal intubation. A dose of 2 mg/kg will be recommended, and the group assignment 
sheet will contain a nomogram providing the recommended dose for a range of patient weights (in pounds 
and kg). In this pragmatic trial, treating clinicians will be able elect to give a lesser or greater dose of 
ketamine than recommended if felt to be required for optimal patient care.      

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7.3 Etomidate Group 
Patients in the etomidate group will be assigned to receive intravenous etomidate for induction of 
anesthesia during tracheal intubation. A dose of 0.3 mg/kg will be recommended, and the group 
assignment sheet will contain a nomogram providing the recommended dose for a range of patient 
weights (in pounds and kg). In this pragmatic trial, treating clinicians will be able elect to give a lesser or 
greater dose of etomidate than recommended if felt to be required for optimal patient care.      
7.4 Co-Interventions 
The RSI trial will control only the first sedative medication administered during the intubation procedure. 
Subsequent sedative boluses or drips will be determined by treating clinicians. Other aspects of tracheal 
intubation (e.g., pre-intubation fluid management, pre-oxygenation, choice of neuromuscular blocking 
medication, choice of laryngoscopy device) will be performed by treating clinicians according to 
standardized clinical protocols already in place in the study units. Co-interventions that could modify the 
effect of ketamine or etomidate on cardiovascular collapse or clinical outcomes (e.g., vasopressors, 
corticosteroids) will be prospectively recorded. 
7.5 Packaging and Labeling 
Ketamine and etomidate will be packaged and labeled by the manufacturers of the medications. The 
labeling will not be altered. As the study is unblinded, concealment of the study medication after 
randomization is not necessary. 
Ketamine has been approved by the United States Food and Drug Administration (FDA) and is 
commercially available with approved indications including “use as the sole anesthetic agent for 
diagnostic and surgical procedures that do not require skeletal muscle relaxation” and “induction of 
anesthesia prior to the administration of other general anesthetic agents.” Etomidate has been approved by 
the FDA and is commercially available with an indication for “induction of general anesthesia.” 
Because both agents are FDA-approved and will be used in a manner consistent with FDA-labeling and 
standard of care for tracheal intubation in the ED and ICU, labeling ketamine and etomidate as 
investigational drugs is unnecessary. At all times and all study sites, study medications will already 
include standard labeling applied by the manufacturer.  
The IND application for the RSI trial will, therefore, request a waiver of 21 CFR 312.6, which requires 
labeling of investigational new drugs with the statement: “Caution: New Drug—Limited by Federal (or 
United States) law to investigational use.” Given ED and ICU staff familiarity with the current labeling 
applied by the manufacturer, lack of investigational labeling will not pose a significant or unreasonable 
risk for any patient. In fact, investigational labeling could introduce increased risk to patients by 
introducing a new and unfamiliar label to a commonly used medication during a high-risk, time-sensitive 
procedure.  
7.6 Storage and Accountability 
The medications administered in this investigation will be stored and handled as they are in routine 
clinical care in the study units, in accordance with institutional policies for each medication. This will 

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include secure storage in pharmacy and in study units with the use of a password-protected secure 
medication storage devices (e.g. Omnicell machine). When treatment allocation is revealed at the time of 
enrollment, the assigned medication will be ordered, procured, prepared, and administered by clinical 
pharmacists, registered nurses, or physicians as it would be as part of routine clinical care. 
7.7 On-Study Monitoring 
This study will take place in high-acuity clinical care environments (EDs and ICUs) at the time of a 
procedure routinely performed as part of usual care. Thus, at the time of the study intervention, the patient 
will have in the room: a physician trained in the care of critically ill adults, a critical care or emergency 
medicine nurse, and usually a respiratory therapist and pharmacist. The patient will be receiving 
continuous invasive or non-invasive monitoring.  
 
The intravenous injection of either ketamine or etomidate produces anesthetic effects that last for less 
than 10 minutes. Therefore, patients will be intensely monitored, with treating clinicians at the bedside for 
the duration of the primary effects of the study agents. Following intubation, no additional monitoring is 
planned beyond what occurs in the usual care of critically ill patients who have received these 
medications. 
8. OUTCOMES 
8.1 Stage 1 Primary Outcome  
• Cardiovascular Collapse, a composite of any of the following between induction and 2 minutes 
after intubation:  
o Systolic blood pressure < 65 mmHg 
o New or increased vasopressors  
o Cardiac arrest not resulting in death within 1 hour of induction 
o Cardiac arrest resulting in death within 1 hour of induction 
 
8.2 Stage 1 Secondary Outcomes 
• 
All-cause 28-day in-hospital mortality 
• 
Feasibility, defined as meeting all the following: 
o Enrollment of at least 16 patients per month 
o Appropriate documentation of patient eligibility and adherence to EFIC requirements for 
notification of enrollment for all patients 
o Greater than 95% of enrolled patients receiving the induction medication assigned by the 
trial 
o Appropriate mechanisms for ongoing monitoring of EFIC compliance, tracking of 
excluded patients, and protocol adherence 
o Adequate completeness and timeliness of data entry 
 

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8.3 Stage 2 Primary Outcome  
• 
All-cause, 28-day, in-hospital mortality 
 
8.4 Stage 2 Secondary Outcome  
• Cardiovascular Collapse, a composite of any of the following between induction and 2 minutes 
after intubation:  
o Systolic blood pressure < 65 mmHg 
o New or increased vasopressors  
o Cardiac arrest not resulting in death within 1 hour of induction 
o Cardiac arrest resulting in death within 1 hour of induction 
 
 
 
8.5 Exploratory Outcomes (for both Stage 1 and Stage 2) 
• 
Procedural Characteristics & Complications 
o Cormack-Lehane Grade of glottic view 
o Number of attempts at tracheal intubation 
o Time from induction to successful tracheal intubation 
o Operator-assessed difficulty of intubation 
o Lowest oxygen saturation between induction and two minutes after intubation 
o Lowest oxygen saturation < 80% between induction to two minutes after intubation  
o Highest and lowest systolic blood pressure from induction to two minutes after intubation 
o Systolic blood pressure > 180 between induction and two minutes after intubation 
o Systolic blood pressure < 65 mmHg between induction and 2 minutes after intubation 
o New or increased vasopressor between induction and 2 minutes after intubation 
o Cardiac arrest within 2 minutes of intubation not resulting in death within 1 hour of 
induction 
o Cardiac arrest within 2 minutes of intubation resulting in death within 1 hour of induction 
• 
Short-term Clinical Outcomes 
o Ventilator-free days to study day 28 
o Vasopressor-free days to study day 28 
o ICU-free days to study day 28 
8.6 Safety outcomes (for both Stage 1 and Stage 2) 
• 
Systolic blood pressure at 24 hours after induction 
• 
Receipt of vasopressors at 24 hours after induction 
• 
Cardiac arrest receiving cardiopulmonary resuscitation between induction and hospital discharge 
 
9. DATA COLLECTION 
Data will be stored in the secure, online database REDCap. A trained independent observer, not involved 
in the performance of the procedure, will collect peri-procedural outcomes, including oxygen saturation 

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and systolic blood pressure at the time of induction, lowest oxygen saturation and lowest systolic blood 
pressure between induction and two minutes after tracheal intubation, peri-procedural cardiac arrest, and 
time from induction to intubation. This process for outcome collection has been used by the primary 
investigator during multiple prior trials with nearly perfect agreement with the reference standard of direct 
observation by research staff (Spearman's rho rank correlation coefficient = 0.998).9 Immediately after 
each intubation, the operator will report approach to preoxygenation, pre-intubation fluid boluses or 
vasopressors, Cormack-Lehane grade of glottic view,64 subjective difficulty of tracheal intubation, airway 
complications during the procedure, and the level of operator experience.  Study personnel will manually 
collect data from the medical record on baseline characteristics, pre- and post-laryngoscopy management, 
and clinical outcomes.  
 
9.1 Baseline Variable Collection 
• Presence or absence of inclusion and exclusion criteria 
• Date and time of induction 
• Admission data: date and time of presentation, location at enrollment (ED, hospital ward, ICU) 
• Demographics (age, sex, race, ethnicity, height, weight) 
• Severity of illness score prior to induction 
• Active medical problems at the time of induction 
• Active comorbidities complicating induction 
• Vasopressor use in the hour prior to induction 
• Noninvasive ventilator use in the 1 hour prior to induction 
• High flow nasal cannula use in the 1 hour prior to induction 
• Highest FiO2 delivered in the 1 hour prior to induction 
• Indication for intubation 
• Preoxygenation technique 
• Operator experience (number of prior intubations performed) 
• Receipt of corticosteroids in the 48 hours prior to induction 
• Vasopressor administration prior to or with induction 
• Oxygen saturation by pulse oximetry at time of induction  
• Systolic blood pressure at time of induction 
9.2 Peri-Procedural Variables 
• Lowest arterial oxygen saturation from induction to two minutes after intubation 
• Lowest systolic blood pressure from induction to two minutes after intubation 
• Highest systolic blood pressure from induction to two minutes after intubation 
• Vasopressor administration from induction to two minutes after intubation 
• Cardiac arrest from induction to one hour after intubation 
• Time from induction to tracheal intubation  
• Total number of attempts at intubation 
• Sedative agent and dose 

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• Neuromuscular blocking agent and dose 
• Use of nasal cannula, high flow nasal cannula, oxygen by bag-valve-mask, ventilation by bag mask, 
non-invasive ventilation, or ventilation by laryngeal mask airway between sedative administration 
and intubation  
• Laryngoscope type 
• Use of a bougie 
• Presence of aspiration between induction and intubation 
• Cormack-Lehane grade of glottic view 
• Rescue device use 
• Need for additional operators 
• Mechanical complications (esophageal intubation) 
• Self-reported difficulty of the intubation 
9.3 Assessments between Hospital Presentation and Hospital Discharge 
• Cardiac arrest between one hour after intubation and hospital discharge  
• Oxygen saturation at 24 hours after intubation 
• FiO2 at 24 hours after intubation 
• PEEP at 24 hours after intubation 
• Systolic blood pressure at 24 hours after intubation 
• Vasopressor receipt at 24 hours after intubation 
• Receipt of corticosteroids between induction and hospital discharge 
• Clinically recorded Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scores 
on days 1-7 
• SOFA Score on days 1-7 
• Clinically recorded Glasgow Coma Scale on days 1-7 
• Date and time of final receipt of invasive mechanical ventilation  
• Date and time of first and final receipt of vasopressors following sedative administration (if 
applicable)  
• Date and time of final ICU discharge (if applicable) 
• Date and time of hospital discharge (if applicable) 
• Date of death (if applicable) 
9.4 REDCap Clinical Data Interoperability Services 
This project will utilize the REDCap platform for data collection and management.  Project team 
members listed as Key Study Personnel with existing electronic health record (EHR) system access rights 
may also be granted use of REDCap Clinical Data Interoperability Services (CDIS) tools.  These tools are 
designed to enable transfer of relevant study-related data from the Vanderbilt Research Derivative (or 
local equivalents) and/or directly from the EHR into REDCap. 
 

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10. STATISTICAL CONSIDERATIONS 
10.1 Stage 1 Sample Size Calculation 
Stage 1 of the RSI trial is primarily focused on feasibility. However, stage 1 will be of sufficient size to 
provide critical data on the short-term periprocedural outcome of cardiovascular collapse. Assuming that 
cardiovascular collapse will occur in 19% of patients in the etomidate group (a similar incidence as 
observed in a prior trial of airway management in which etomidate was the primary sedative),12 we 
calculate that enrolling 464 patients will provide 80% statistical power (at a two-sided alpha of 0.05) to 
demonstrate a relative risk reduction of 50% in the primary outcome of cardiovascular collapse in the 
ketamine group, compared to the etomidate group.  
10.2 Stage 2 Sample Size Calculation 
To estimate the incidence of in-hospital mortality in the etomidate group of stage 2 of the RSI trial, we 
used data from 656 adults undergoing tracheal intubation for non-traumatic critical illness who were 
recently enrolled from EDs and ICUs in two recent randomized trials in the ED and ICU. Among these 
patients, the incidence of 28-day in-hospital mortality was 31%. The minimum clinically important 
difference (MCID) in mortality used in the design of prior critical care RCTs has been an absolute risk 
reduction of a median of 8 percent (IQR, 6-10).65 We powered the RSI trial to detect a more conservative 
absolute risk reduction of 6 percent. This equates to an incidence of the primary outcome of 25% in the 
ketamine group and a relative risk of mortality with ketamine compared to etomidate of 0.81 – 
comparable to the relative risk of 0.827 among adults with non-traumatic critical illness observed in the 
only prior RCT comparing ketamine vs etomidate.60 Achieving 80% statistical power at a two-sided alpha 
of 0.05 to detect a 6 percent absolute difference between groups in the primary outcome would require 
enrolling 911 patients per group (1,822 overall). Anticipating that, like prior EFIC trials, less than 5% of 
patients will discontinue participation after enrollment, we aim to enroll a total of 1,900 patients. 
10.3 Progression from Stage 1 to Stage 2 of RSI 
If, between initiation of enrollment in Stage 1 and enrollment of 464 patients in Stage 1, funding becomes 
available for Stage 2, the DSMB will perform a formal assessment of feasibility and issue a 
recommendation of whether the trial should progress from Stage 1 to Stage 2. To perform this assessment 
of feasibility, the DSMB will meet to review data from at least 100 patients enrolled in Stage 1.  The 
DSMB will review: 1) the rate of enrollment, 2) the number, proportion, and reasons for exclusion, 3) 
protocol adherence, 4) data quality, 5) compliance with the requirements of EFIC (under FDA code of 
regulations 21 CFR 50.24.7) including a review of the timeliness and success of patient or LAR 
notification,99,100 and 6) adverse events. Metrics upon which the DSMB may base their recommendation to 
progress to Stage 2 will include: 
1. Enrollment of at least 16 patients per month. 
2. Appropriate documentation of patient eligibility and adherence to EFIC requirements for 
notification of enrollment for all patients. 
3. Greater than 95% of enrolled patients receiving the induction medication assigned by the trial 
4. Appropriate mechanisms for ongoing monitoring of EFIC compliance, tracking of excluded 
patients, and protocol adherence. 
5. Adequate completeness and timeliness of data entry. 

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If the DSMB recommends the trial progress to Stage 2 and the investigators accept the DSMB’s 
recommendation, no analysis of Stage 1 outcomes (primary outcome of cardiovascular collapse) will be 
performed.  At the end of enrollment in Stage 2, all patients enrolled in the trial will be included in a 
single planned analysis of the Stage 2 outcomes (primary outcome of 28-day in-hospital mortality). If the 
trial does not progress to Stage 2 for any reason, the planned analysis of Stage 1 outcomes (primary 
outcome of cardiovascular collapse) will be performed and reported. 
 Figure 1. Flow diagram for Adaptation from Stage 1 to Stage 2 of RSI 
10.4 Primary Analysis  
Whether the trial stops at the end of stage 1 or progresses to the completion of stage 2, the approach to 
analysis will be the same. The primary analysis will be an unadjusted, intention-to-treat comparison of 
patients randomized to ketamine versus patients randomized to etomidate with regard to the primary 
outcome. The difference between the two study groups will be compared using a Chi-squared test. 
10.5 Secondary Analyses  
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 (e.g., Vanderbilt University ED, Vanderbilt 
University Medical ICU) and fixed effects for group assignment and the following pre-specified baseline 
variables:  
1. Age; 
2. Sex; 
3. Race; 
4. Systolic blood pressure at induction; 
5. Receipt of vasopressors in the 1 hour prior to induction; 
6. Sequential Organ Failure Assessment score prior to induction; and 
7. Diagnosis of sepsis at the time of intubation. 

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10.6 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.  Pre-specified effect modifiers will include: 
1. Age; 
2. Location (ED vs ICU); 
3. Systolic blood pressure at induction; 
4. Receipt of vasopressors in the 1 hour prior to induction; 
5. Sequential Organ Failure Assessment score prior to induction; 
6. Diagnosis of sepsis at the time of intubation; 
7. Indication for intubation; and 
8. Baseline risk of the primary outcome. 
10.7 Interim Analysis 
If the RSI trial does not progress to Stage 2, no interim analysis will be performed as Stage 1 is primarily 
focused on feasibility and a finding that ketamine or etomidate reduced the incidence of the short-term 
peri-procedural outcome of cardiovascular collapse would not negate the need for a definitive trial 
evaluating the effect of ketamine and etomidate on mortality.  If the RSI trial progresses to Stage 2, the 
DSMB will review an interim analysis performed after the enrollment of 950 patients (50% of the 
anticipated trial enrollment). 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). 
10.8 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 Administration66 and the European Medicines 
Association,67 each will be tested using a two-sided P value with a significance level of 0.05. For all other 
analyses, emphasis will be placed on the estimate of effect size with 95% confidence intervals, as 
recommended by the International Committee of Medical Journal Editors,68 and no corrections for 
multiple comparisons will be performed. 
10.9 Handling of Missing Data 
No patients will be lost to follow up before the measurement of the primary outcome, except those that 
choose to withdraw from the study. Missing data will not be imputed for the primary outcome, or any of 

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the secondary or exploratory outcomes. In adjusted analyses, missing data for baseline covariates will be 
imputed using multiple imputations. 
 
11. DATA QUALITY MONITORING AND STORAGE 
11.1 Data Quality Monitoring 
Data quality will be reviewed using front-end range and logic checks at the time of data entry and back-
end monitoring of data using application programming interface tools connecting the online database to 
statistical software to generate data reports. The coordinating center will perform remote monitoring of 
documentation of eligibility criteria, completion of EFIC requirements, and the completeness of study 
outcome collection. 
11.2 Data Storage  
Data will be entered into a secure online database. All data will be maintained in the secure online 
database until the time of study publication. At the time of publication, a de-identified version of the 
database will be generated. 
 
12. RISK ASSESSMENT 
12.1 Potential Risks of Receiving Ketamine 
Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound 
analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, 
cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory 
depression. At an intravenous dose of 2 mg/kg of body weight, the onset of ketamine is rapid, usually 
producing surgical anesthesia within 30 seconds after injection. The anesthetic effect usually lasts five to 
ten minutes and the duration of action of the medication is less than fifteen minutes.  
Potential risks of receiving ketamine can be classified based on their severity as major or minor. Major 
potential risks of receiving ketamine include: 
1) Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration of 
ketamine alone. However, hypotension and bradycardia have been observed. Arrhythmia has also 
occurred. Elevation of blood pressure begins shortly after injection, reaches a maximum within a 
few minutes, and usually returns to preanesthetic values within 15 minutes after injection. In the 
majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above 
preanesthetic levels shortly after induction of anesthesia. Regardless of which sedative is used, 
cardiovascular complications including hypotension and cardiac arrest are common during the 
tracheal intubation of critically ill adults. Determining whether or not use of ketamine for 

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induction of anesthesia during intubation of critically ill adults effects the risk of cardiovascular 
events compared to etomidate is a key objective of the RSI trial. 
 
2) Respiration: Although respiration is frequently stimulated, severe depression of respiration or 
apnea may occur following rapid intravenous administration of high doses of ketamine. 
Laryngospasm has also been reported. Given that ketamine will be used in this trial only as part 
of the process of tracheal intubation and initiation of invasive mechanical ventilation, respiratory 
suppression from ketamine is not a significant concern in the RSI trial. 
 
3) Anaphylaxis: Allergic reactions to ketamine are extremely rare and only a few cases of 
anaphylaxis have been reported. Patients with known allergy to ketamine are excluded from the 
RSI trial.69,70  
 
4) Psychological: According to the FDA package insert for ketamine, adverse psychological 
manifestations with ketamine are common, reportedly occurring in up to 12% of patients. The 
psychological manifestations vary in severity from pleasant dream-like states to hallucinations 
and emergence delirium. The duration is reported to be no more than several hours for most 
patients with rare occurrences up to 24 hours post postoperatively. Because patients in the RSI 
trial are critically ill and will receive ketamine at the time of tracheal intubation with a median 
duration of invasive mechanical ventilation and accompanying sedation and analgesia of 2-3 
days,10,12 psychological manifestations are unlikely to represent significant risk to patients in the 
RSI trial. 
 
5) Increased intracranial pressure: An increase in cerebrospinal fluid pressure has been reported 
following administration of ketamine hydrochloride and caution is recommended for patients 
with preanesthetic elevated cerebrospinal fluid pressure. However, the original evidence 
supporting this assertion is anecdotal and recent studies have contraindicated these findings, 
suggesting that ketamine may be associated with a beneficial increase in cranial perfusion 
pressure as a result of increased mean arterial pressure.39,40 Ketamine is routinely administered to 
patients with head trauma in routine clinical care in the study settings. However, to maximize 
patient safety, patients presenting with a primary diagnosis of trauma are excluded from the RSI 
trial.  
Minor potential risks of receiving ketamine include: diplopia, nystagmus, temporary increase in 
intraocular pressure, anorexia, nausea, and vomiting. Lower urinary tract and bladder symptoms have also 
been reported with chronic use. 
12.2 Potential Risks of Receiving Etomidate 
Etomidate is a rapidly acting general anesthetic without analgesic activity. At a dose of 0.3 mg/kg body 
weight, onset of action is usually within one minute with a duration of action of three to five minutes.  
Potential risks of receiving etomidate can be classified based on their severity as major or minor. Major 
potential risks of receiving etomidate include: 

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1) Endocrine: Reduced plasma cortisol and aldosterone levels have been reported following the 
induction doses of etomidate that will be recommended in the RSI trial. These reductions in 
plasma cortisol and aldosterone persist for approximately 6-8 hours and appear to be 
unresponsive to ACTH stimulation.  They are likely related to blockage of 11 beta-hydroxylation 
within the adrenal cortex. Determining whether or not these transient reduction in cortisol and 
aldosterone levels influence clinical outcomes for patients is a key objective of the RSI trial. 
 
2) Circulatory: Hypertension, hypotension, tachycardia, bradycardia, and other arrhythmias have 
occasionally been observed during induction with etomidate. Geriatric patients, particularly those 
with hypertension, may be at increased risk for the development of cardiac depression following 
etomidate administration. Regardless of which sedative is used, cardiovascular complications 
including hypotension and cardiac arrest are common during the tracheal intubation of critically 
ill adults. Determining whether or not use of etomidate for induction of anesthesia during 
intubation of critically ill adults effects the risk of cardiovascular events compared to ketamine is 
a key objective of the RSI trial. 
 
3) Respiration: Hyperventilation, hypoventilation, apnea of short duration (5 to 90 seconds with 
spontaneous recovery), laryngospasm, hiccup and snoring suggestive of partial upper airway 
obstruction have been observed in some patients. Given that etomidate will be used in this trial 
only as part of the process of tracheal intubation and initiation of invasive mechanical ventilation, 
respiratory suppression from etomidate is not a significant concern in the RSI trial. 
 
4) Anaphylaxis: Allergic reactions to etomidate are extremely rare and limited to one case of severe 
hypotension and tachycardia.  Patients with known allergy to etomidate are excluded from the 
RSI trial.  
Minor potential risks of receiving etomidate include: transient venous pain on injection (20% of the 
patients) and transient skeletal muscle movements (32% of patients) including myoclonus, nausea, or 
vomiting. 
12.3 Potential Risk of Participation in the RSI Trial 
The RSI trial will enroll critically ill adults whose treating clinicians have determined that (1) tracheal 
intubation is clinically required and (2) use of either ketamine or etomidate is consistent with optimal care 
for the patient.  Both ketamine and etomidate are FDA-approved medications being used within their 
FDA approved indications, and the only prior randomized trial reported no significant difference in 
outcome between the two medications.  More than 95% of patients undergoing tracheal intubation in the 
study sites receive either ketamine or etomidate as a part of routine clinical care.  All patients eligible for 
the RSI trial will experience the risks of emergency tracheal intubation and the risks of receipt of an 
induction medication such as ketamine or etomidate as a part of their routine clinical care, whether or not 
they are enrolled in the RSI trial.  The incremental risks of participation in the RSI trial are (1) the risk 
associated with collection of PHI and (2) the risk associated with allowing the choice between ketamine 
and etomidate to be made by trial group assignment rather than by the treating clinician.  Because the 
only patients eligible are those whose treating clinicians feel use of either ketamine or etomidate is 

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consistent with optimal care, the incremental risk of participation in the RSI trial, compared to routine 
clinical care outside the trial, is minimal. 
12.4 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 subject protection 
requirement by incorporating numerous design elements to minimize risk to patients.  
Both therapies used in the RSI trial, ketamine and etomidate, are approved by the Food and Drug 
Administration and have been used in clinical practice for decades with an established safety profile in the 
same populations included in the RSI trial. Both medications will be administered at the recommended 
dose and route. 
To further mitigate risk, we will exclude patients with specific risk factors for adverse events from 
ketamine or etomidate including patients with known allergies to ketamine or etomidate, patients with a 
primary diagnosis of trauma, and any patient for whom treating clinicians believe that ketamine or 
etomidate is required or contraindicated for the optimal care of the patient. Finally, 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.  
12.5 Potential Benefit 
Participation in the RSI trial holds the prospect of direct benefit to the subjects.  Previous animal and 
clinical studies have established several mechanisms by which either ketamine or etomidate might 
provide a direct benefit to individual critically ill subjects undergoing tracheal intubation via improved 
hemodynamics and survival. 
Determining whether ketamine or etomidate improves clinical outcomes among critically ill patients 
undergoing tracheal intubation in the ED or ICU will also benefit RSI trial patients who go on to require 
emergency tracheal intubation again in the future, as well as the millions of critically ill adults who 
undergo tracheal intubation each year.   
12.6 Risk in Relation to Anticipated Benefit 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in relation to 
anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be 
expected to result.”  The incremental risks of participation in the RSI trial, compared to routine clinical 
care outside the trial for eligible patients, are minimal as all patients enrolled in the RSI trial would have 
received a sedative as part of emergency tracheal intubation in routine clinical care, regardless of 
participation in the RSI trial.  Understanding the effect of these two commonly used medications on 
clinical outcomes will benefit RSI trial patients who go on to require emergency tracheal intubation again 
in the future, as well as the millions of critically ill adults who undergo tracheal intubation each year.  
Thus, the risks to subjects are reasonable in relation to the anticipated benefits and importance of the 
knowledge to be gained. 

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13. HUMAN SUBJECTS PROTECTIONS 
Emergency tracheal intubation of critically ill adults is a time-sensitive procedure with a brief therapeutic 
window between the decision to perform intubation and the completion of the procedure. Critically ill 
patients requiring tracheal intubation are nearly uniformly unconscious, delirious, or in states of distress 
for which it would be unsafe to delay intubation for an informed consent discussion with the patient or a 
surrogate. Legally authorized representatives are rarely available during the narrow therapeutic window. 
Even in the rare cases where the patient retains decisional capacity or the patient’s legally authorized 
representative (LAR) is present at the bedside at the moment the decision is made to intubate a critically 
ill patient, the urgency of the intubation procedure would preclude the detailed discussion of risks and 
benefits required for informed consent. 
Therefore, it is expected that all patients will be enrolled under “Exception from informed consent 
required for emergency research” (EFIC).  Additional details regarding how the RSI trial will comply 
with each of the requirements of EFIC are provided in Appendix B. 
13.1 Length of Therapeutic Window 
For an induction medication used for emergency tracheal intubation, the therapeutic window begins at the 
time treating clinicians decide to perform emergency tracheal intubation with sedation and ends at the 
time an induction medication is administered for emergency tracheal intubation.  To our knowledge, no 
published literature has quantified this therapeutic window among critically ill adults.  Among a 
convenience sample of 25 consecutive critically ill adults undergoing emergency tracheal intubation in 
the ED or ICU in the planned study sites of the RSI trial, the median time from treating clinicians 
verbalizing the decision to intubate with sedation (or placing a written order for an induction medication) 
to the administration of an induction medication was 5 minutes [interquartile range, 1 minute to 10 
minutes].  For no patient was this window longer than 30 minutes.  Tracheal intubation of critically ill 
adults is a time-sensitive procedure for which every minute of delay increases the likelihood of 
hypoxemia, hypotension, and peri-procedural cardiac arrest.  For most patients in the RSI trial, 
completion of the trial intervention (a one-time injection at the start of the emergency tracheal intubation 
procedure) is anticipated to occur less than 5 minutes after meeting trial eligibility criteria.  Thus, in the 
RSI trial, we anticipate that the therapeutic window for most patients will be less than 5 minutes.   
13.2 Inability to Conduct Trial without EFIC 
Most patients eligible for the RSI trial will be experiencing unconsciousness or delirium due to critical 
illness.  More than half of critically ill adults undergoing tracheal intubation in the ED or ICU have a 
Glasgow Coma Scale score less than 12 (equivalent to moderate brain injury) and among those whose 
level of consciousness is not impaired, most experience acute delirium.  Even in instances in which a 
patient retains capacity, or an LAR is immediately available, the rapidity with which emergency tracheal 
intubation is clinically required, and the accompanying distress of the patient or LAR from the critical 
illness and need for emergency tracheal intubation, precludes a meaningful informed consent process.  

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Delaying emergency tracheal intubation for a critically ill adults to attempt a meaningful informed 
consent process would be unsafe, impracticable, and unethical. 
One approach for obtaining prospective consent for interventions with short therapeutic window is to 
consent patients at high risk of requiring the intervention in the future.  Unfortunately, there is no 
reasonable method for prospectively identifying individuals who will develop a need for emergency 
tracheal intubation. Many different acute illnesses lead to emergency tracheal intubation in the ED or ICU 
including stroke, spontaneous intracranial hemorrhage, seizure, sepsis, drug overdose, acute coronary 
syndrome, aspiration pneumonitis, acute bacterial pneumonia, pneumothorax, and others. Any patient in 
the community or in the hospital may unexpectedly develop a need for emergency tracheal intubation 
within a period of minutes with no warning.  
For these reasons, the RSI trial could not be conducted without EFIC, and it is expected that all patients 
will be enrolled through EFIC.  
13.3 Opportunity to Decline Participation 
 
Although it is expected that in most, if not all cases, the urgency of the procedure and the nature of the 
patient’s critical illness will preclude a detailed informed consent discussion between the trained research 
staff and the patient or LAR during the brief therapeutic window, a consent form will be available and the 
RSI trial will provide two mechanisms to opt-out of participation.   
First, medical alert bracelets will be made available prior to and throughout the trial for any community 
members who become aware of the trial and desire to express their preference against participation should 
they become critically ill and require tracheal intubation (details of public notification plan and process of 
requesting opt-out bracelets are provided in the Community Consultation and Public Disclosure Plan). 
Second, when feasible, the RSI trial will provide an opportunity for patients, LARs, or family members to 
express their objection immediately prior to research enrollment.  While the nature of emergency tracheal 
intubation precludes a full, written, informed consent process in most, if not all, cases, the RSI trial will 
provide an opportunity for patients, LARs, or family members to object to participation based on more 
limited information whenever feasible using a pre-enrollment opt-out script. Because patient enrollment 
and delivery of the trial intervention are performed by treating clinicians (not research staff) and occur 
within a period of minutes after meeting eligibility, this opt-out script will be read by treating clinicians 
using a script approved by the IRB to describe the study and provide an opportunity for patients, LARs, 
or family members to decline participation before enrollment (Appendix C). The decisional capacity of 
the patient and the safety and feasibility of reading the script during the brief therapeutic window will be 
determined by the treating clinicians.  Allowing a mechanism, whenever feasible, for patients to opt out 
of participation is consistent with the respect for autonomy emphasized in the EFIC guidelines.  
13.4 Notification of Enrollment 
At the soonest feasible opportunity after study enrollment, the patient or the patient’s LAR or family 
member will be notified of the study enrollment. Details of the investigation will be provided, all 
questions will be answered, and the patient or patient’s LAR or family member will be informed of their 
right to discontinue study participation. The patient or LAR or family member will be provided with a 

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patient notification form (Appendix D) which contains study details and contact information for study 
personnel and the IRB.  
Because the study intervention is a one-time injection occurring within minutes of enrollment, all patients 
will have completed the study intervention and experienced the risks and benefits of the study 
intervention by the time notification of participation occurs.  The only remaining study activity is review 
of the patient’s medical record by study personnel until the end of the patient’s hospitalization.  For those 
who wish to discontinue participation, no further data will be collected. Data collected prior to withdrawal 
will remain in the study database as per FDA requirements and guidance. 
A minimum of three attempts will be made to discuss the study with the patient or the patient’s LAR. 
Whenever feasible, this will occur in a face-to-face discussion in the hospital between trained study 
personnel and the patient or LAR. If the patient is discharged before a face-to-face discussion occurs, 
these attempts will be made by phone, and a notification sheet will be mailed to the patient’s address 
(Appendix E). 
If a patient is enrolled in the RSI trial and dies before a face-to-face discussion with the patient or LAR, a 
reliable mailing address for the patient’s family or LAR will be obtained. After allowing a two to four-
week period of grieving, study personnel will send a letter (Appendix F) with basic information about the 
clinical investigation, the patient’s inclusion, and contact information so that families can call or write to 
obtain more information or to get questions answered if desired. 
If the patient regains decision-making capacity prior to hospital discharge, study personnel will notify the 
patient of the study and ask if the patient wants to continue participation.  
13.5 Documentation and Tracking of Notification Process 
Notification logs will be incorporated into the study case report forms and will allow tracking and 
reporting of the timeliness of these processes. This log will include the types of attempts made, the 
number and timing of those attempts, and the outcome of each attempt. Notification logs will be available 
for IRB review as requested and will be summarized for the IRB at the time of continuing review.  
13.6 Selection of Subjects 
Federal regulations 45 CFR 46(a)(3) require the equitable selection of subjects. All patients undergoing 
tracheal intubation in a participating unit who meet inclusion criteria without meeting exclusion criteria 
will be enrolled. We will not discriminate based on gender, race, or ethnicity. Study exclusion criteria 
neither unjustly exclude classes of individuals from participation in the research nor unjustly include 
classes of individuals for participation in the research. Hence, the recruitment of patients conforms to the 
principle of distributive justice. 
13.7 Justification of Including Vulnerable Subjects 
The present research aims to investigate the safety and efficacy of ketamine and etomidate during the 
tracheal intubation of critically ill patients. Due to the nature of this patient population, most patients will 
have impaired decision-making capabilities. Moreover, those with intact decision-making capacities 
probably have milder disease than those with impaired capacity. Therefore, the validity of the study and 

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its generalizability to severely ill patients would be compromised by enrolling only those patients with 
retained decision-making capacity. Hence, patients recruited for this trial are not being unfairly burdened 
with involvement in this research. 
13.8 Investigational New Drug Application 
As required by studies conducted under 21 CFR 50.24, the RSI protocol will be included as part of an 
Investigational New Drug Application to the United States Food and Drug Administration (FDA). The 
study will not proceed until the primary investigator has received written authorization from both the 
FDA and the Vanderbilt Institutional Review Board 
13.9 Additional Safeguards for Vulnerable Patients 
The present research will involve patients who might be vulnerable to coercion or undue influence. As 
required in 45CFR46.111(b), we recommend that sites utilize additional safeguards to protect the rights 
and welfare of these patients. Such safeguards might include but are not limited to: a) assessment of the 
patient’s capacity to understand notification of enrollment and b) the availability of the LAR to monitor 
the patient’s participation and withdrawal from the study. The specific nature of the additional safeguards 
will be left to the discretion of the central IRB, in conjunction with the sites. 
13.10 Confidentiality 
Federal regulations 45 CFR 46 111 (a) (7) requires that, when appropriate, there are adequate provisions 
to protect the privacy of patients and to maintain the confidentiality of data. 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. All data collected for this study will be entered into a 
secure online database. All data will be maintained in the secure online database until the time of study 
publication. At the time of publication, a de-identified version of the database will be generated. Further, 
tools within the secure online database will be used so that only the coordinating center and investigators 
from the enrolling site will have access to data from patients enrolled at that site. 
 
14. ADVERSE EVENTS 
Assuring patient safety is an essential component of this protocol. Both ketamine and etomidate have 
been approved by the Food and Drug Administration and 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 
ketamine or etomidate; 
2. Systematic collection of safety outcomes relevant to use of ketamine and etomidate in this setting; 
3. Structured reporting of adverse events. 

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14.1 Adverse Event Definitions 
Adverse Event: Any untoward medical occurrence associated with the use of a medication or a study 
procedure, whether or not considered medication related. 
Serious Adverse Event: A serious adverse event is any adverse event that results in one of the outcomes 
listed in section 14.3 below.  
Adverse Reaction: An adverse reaction means any adverse event caused by a study intervention. An 
adverse reaction is a subset of all suspected adverse events where there is a reason to conclude that the 
study intervention caused the event.  
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the 
study procedures caused the adverse event. Reasonable possibility means there is evidence to suggest a 
causal relationship between the study procedures and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction.  
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both 
unexpected (not consistent with risks outlined in the study protocol or investigator brochure), serious, and 
meets the definition of a suspected adverse reaction. 
14.2 Safety Monitoring 
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 for 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 as close as feasible to 24 hours after randomization during initial data 
collection.  The second will occur at the first of hospital discharge or 28 days after enrollment during 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. 
The following adverse events will be considered reportable and thus collected in the adverse event case 
report forms: 
 
 Serious adverse events that are considered by the investigator to be related to study 
procedures, possibly or probably related, or of uncertain relationship (Appendix G) 
 Unexpected adverse events that are considered by the investigator to be related to study 
procedures, possibly or probably related, or of uncertain relationship (Appendix G) 

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Study-specific clinical outcomes (Primary, Secondary and Safety Outcomes), including serious 
outcomes such as organ failures and death, are systematically recorded in the case report forms 
and are exempt from adverse event reporting unless the investigator deems the adverse event to 
be serious and definitely related to the administration of study medication or the conduct of study 
procedures (or of uncertain relationship) as outlined in Appendix G.  
Because ketamine and etomidate are 1) FDA-approved, 2) used within their approved indications, 
and 3) have well-established safety profiles, the RSI trial will not plan to collect non-serious 
adverse events as suggested in FDA guidelines for Investigator Reporting (21 CFR 312.64(b)) for 
post-marketing outcome trials conducted with an IND.  
Adverse events will be evaluated by the lead investigator at each enrolling site . If an adverse 
event is judged to be potentially reportable, as outlined above, then the lead investigator at each 
enrolling site will record the adverse event via electronic data entry for review. The principal 
investigator will be responsible for making final determinations regarding potential relatedness of 
adverse events, based on the criteria outlined in Section 14.3 and Appendix G. The principal 
investigators will also consider if the event is unexpected. Unexpected adverse events are events 
not listed in the study protocol or the investigator brochure for Ketamine or Etomidate. In making 
determinations, the principal investigator will determine if adverse events are unanticipated given 
the patient’s clinical course, previous medical conditions, and concomitant medications.  
14.3 Serious Adverse Events 
The lead investigator at each enrolling site must alert the primary investigator of any serious and study 
procedure related adverse event within 24 hours of investigator awareness of the event. Alerts issued via 
telephone are to be immediately followed with official notification on the adverse event case report form. 
See Appendix G for reporting timelines for serious, unexpected, study related events (SAEs) and serious, 
unexpected suspected adverse reactions (SUSARs). 
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in one of 
the following outcomes: 
• 
Death 
• 
A life-threatening experience (that is, immediate risk of dying) 
• 
Prolonged inpatient hospitalization or re-hospitalization 
• 
Persistent or significant disability/incapacity 
Reportable serious adverse events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon appropriate medical 
judgment, they may jeopardize the patient or require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
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:  
• 
Review of adverse events 
• 
Interim results of the study for evidence of efficacy or adverse events 

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• 
Possible early termination of the trial because of new external information, early attainment of 
study objectives, safety concerns, or inadequate performance 
• 
Possible modifications in the clinical trial protocol  
• 
Performance of individual centers  
The DSMB will consist of members with expertise in bioethics, emergency medicine, pulmonary critical 
care, 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 Principal 
Investigator and unblinded study biostatistician will be responsible for the preparation of all DSMB and 
adverse event 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 with the assistance of the Principal Investigator. The DSMB will have the ability to 
recommend that the trial end, be modified, or continued unchanged. 
 
 

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16. REFERENCES. 
 
1.  
Pfuntner A, Wier LM, Stocks C. Most Frequent Procedures Performed in U.S. Hospitals, 2011: 
Statistical Brief #165 [Internet]. In: Healthcare Cost and Utilization Project (HCUP) Statistical 
Briefs. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 [cited 2018 Jun 
4]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174682/ 
2.  
Wunsch H, Wagner J, Herlim M, Chong DH, Kramer AA, Halpern SD. ICU occupancy and 
mechanical ventilator use in the United States. Crit Care Med 2013;41(12):2712–9.  
3.  
Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JM. The 
epidemiology of mechanical ventilation use in the United States. Crit Care Med 2010;38(10):1947–
53.  
4.  
Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute 
Lung Injury and the Acute Respiratory Distress Syndrome. N Engl J Med 2000;342(18):1301–8.  
5.  
Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator 
weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing 
Controlled trial): a randomised controlled trial. The Lancet 2008;371(9607):126–34.  
6.  
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(5):792–9.  
7.  
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):273–80.  
8.  
Janz DR, Semler MW, Joffe AM, et al. A Multicenter Randomized Trial of a Checklist for 
Endotracheal Intubation of Critically Ill Adults. Chest 2018;153(4):816–24.  
9.  
Semler MW, Janz DR, Russell DW, et al. A Multicenter, Randomized Trial of Ramped Position 
vs Sniffing Position During Endotracheal Intubation of Critically Ill Adults. Chest 
2017;152(4):712–22.  
10.  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):811–21.  
11.  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.  
12.  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 [Internet] 2019 [cited 2019 Oct 3];0(0). Available from: 
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(19)30246-2/abstract 
13.  Russell DW, Casey JD, Gibbs KW, et al. 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(9):e036671.  

RSI Protocol Version 1.0 
March 9, 2022 
 
Page 40 of 141 
14.  Jaber S, Jung B, Corne P, et al. An intervention to decrease complications related to endotracheal 
intubation in the intensive care unit: a prospective, multiple-center study. Intensive Care Med 
2009;36(2):248–55.  
15.  Baillard C, Fosse J-P, Sebbane M, et al. Noninvasive ventilation improves preoxygenation before 
intubation of hypoxic patients. Am J Respir Crit Care Med 2006;174(2):171–7.  
16.  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):1538–48.  
17.  Green RS, Turgeon AF, McIntyre LA, et al. Postintubation hypotension in intensive care unit 
patients: A multicenter cohort study. J Crit Care 2015;30(5):1055–60.  
18.  Ishimaru T, Goto T, Takahashi J, et al. Association of ketamine use with lower risks of post-
intubation hypotension in hemodynamically-unstable patients in the emergency department. Sci Rep 
2019;9(1):17230.  
19.  Smischney NJ, Kashyap R, Khanna AK, et al. Risk factors for and prediction of post-intubation 
hypotension in critically ill adults: A multicenter prospective cohort study. PLOS ONE 
2020;15(8):e0233852.  
20.  Brown C, Sakles JC. Rapid Sequence Intubation for Adults outside the Operating Room. [cited 
2019 Feb 17];Available from: https://www.uptodate.com/contents/rapid-sequence-intubation-for-
adults-outside-the-operating-
room?sectionName=Adjunct%20strategies&topicRef=8365&anchor=H3397071694&source=see_li
nk#H3397071694 
21.  Möller Petrun A, Kamenik M. Bispectral index-guided induction of general anaesthesia in patients 
undergoing major abdominal surgery using propofol or etomidate: a double-blind, randomized, 
clinical trial. Br J Anaesth 2013;110(3):388–96.  
22.  Shah SB, Chowdhury I, Bhargava AK, Sabbharwal B. Comparison of hemodynamic effects of 
intravenous etomidate versus propofol during induction and intubation using entropy guided 
hypnosis levels. J Anaesthesiol Clin Pharmacol 2015;31(2):180–5.  
23.  Kaushal RP, Vatal A, Pathak R. Effect of etomidate and propofol induction on hemodynamic and 
endocrine response in patients undergoing coronary artery bypass grafting/mitral valve and aortic 
valve replacement surgery on cardiopulmonary bypass. Ann Card Anaesth 2015;18(2):172–8.  
24.  Perbet S, De Jong A, Delmas J, et al. Incidence of and risk factors for severe cardiovascular collapse 
after endotracheal intubation in the ICU: a multicenter observational study. Crit Care Lond Engl 
2015;19:257.  
25.  Stollings JL, Diedrich DA, Oyen LJ, Brown DR. Rapid-Sequence Intubation: A Review of the 
Process and Considerations When Choosing Medications. Ann Pharmacother 2014;48(1):62–76.  
26.  April MD, Arana A, Schauer SG, et al. Ketamine Versus Etomidate and Peri-intubation 
Hypotension: A National Emergency Airway Registry Study. Acad Emerg Med [Internet] [cited 
2020 Sep 25];n/a(n/a). Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/acem.14063 

RSI Protocol Version 1.0 
March 9, 2022 
 
Page 41 of 141 
27.  Choi YF, Wong TW, Lau CC. Midazolam is more likely to cause hypotension than etomidate in 
emergency department rapid sequence intubation. Emerg Med J EMJ 2004;21(6):700–2.  
28.  Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J Emerg Med 
1997;15(3):357–65.  
29.  Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet 
1998;35(1):37–47.  
30.  Gelissen HPMM, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, Hertog A den. Inotropic Effects 
of Propofol, Thiopental, Midazolam, Etomidate, and Ketamine on Isolated Human Atrial Muscle. 
Anesthesiology 1996;84(2):397–403.  
31.  Stowe DF, Bosnjak ZJ, Kampine JP. Comparison of etomidate, ketamine, midazolam, propofol, and 
thiopental on function and metabolism of isolated hearts. Anesth Analg 1992;74(4):547–58.  
32.  Hannam JA, Mitchell SJ, Cumin D, et al. Haemodynamic profiles of etomidate vs propofol for 
induction of anaesthesia: a randomised controlled trial in patients undergoing cardiac surgery. Br J 
Anaesth 2019;122(2):198–205.  
33.  Brown CA. The Walls Manual of Emergency Airway Management [Internet]. 5th. Wolters Kluwer 
Health; 2017 [cited 2018 May 4]. Available from: 
http://proxy.library.vanderbilt.edu/login?url=http://ovidsp.ovid.com/ovidweb.cgi?T=JS&NEWS=n
&CSC=Y&PAGE=booktext&D=books&AN=01996178$&XPATH=/PG(0)&EPUB=Y 
34.  Spotoft H, Korshin JD, Sørensen MB, Skovsted P. The cardiovascular effects of ketamine used for 
induction of anaesthesia in patients with valvular heart disease. Can Anaesth Soc J 1979;26(6):463–
7.  
35.  Pagel PS, Kampine JP, Schmeling WT, Warltier DC. Ketamine Depresses Myocardial Contractility 
as Evaluated by the Preload Recruitable Stroke Work Relationship in Chronically Instrumented 
Dogs with Autonomic Nervous System Blockade. Anesthesiology 1992;76(4):564–72.  
36.  Waxman K, Shoemaker WC, Lippmann M. Cardiovascular effects of anesthetic induction with 
ketamine. Anesth Analg 1980;59(5):355–8.  
37.  Dewhirst E, Frazier WJ, Leder M, Fraser DD, Tobias JD. Cardiac arrest following ketamine 
administration for rapid sequence intubation. J Intensive Care Med 2013;28(6):375–9.  
38.  Burmon C, Adamakos F, Filardo M, Motov S. Acute pulmonary edema associated with ketamine-
induced hypertension during procedural sedation in the ED. Am J Emerg Med 2017;35(3):522.e1-
522.e4.  
39.  Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on ICP in traumatic brain 
injury. Neurocrit Care 2014;21(1):163–73.  
40.  Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on intracranial pressure in 
nontraumatic neurological illness. J Crit Care 2014;29(6):1096–106.  

RSI Protocol Version 1.0 
March 9, 2022 
 
Page 42 of 141 
41.  Upchurch CP, Grijalva CG, Russ S, et al. Comparison of Etomidate and Ketamine for Induction 
During Rapid Sequence Intubation of Adult Trauma Patients. Ann Emerg Med 2017;69(1):24-
33.e2.  
42.  Harris CE, Murray AM, Anderson JM, Grounds RM, Morgan M. Effects of thiopentone, etomidate 
and propofol on the haemodynamic response to tracheal intubation. Anaesthesia 1988;43 Suppl:32–
6.  
43.  Myatra SN, Ahmed SM, Kundra P, et al. The All India Difficult Airway Association 2016 
guidelines for tracheal intubation in the Intensive Care Unit. Indian J Anaesth 2016;60(12):922–30.  
44.  Higgs A, McGrath BA, Goddard C, et al. Guidelines for the management of tracheal intubation in 
critically ill adults. Br J Anaesth [Internet] [cited 2018 Jan 15];Available from: 
https://www.sciencedirect.com/science/article/pii/S000709121754060X 
45.  de Jong FH, Mallios C, Jansen C, Scheck PA, Lamberts SW. Etomidate suppresses adrenocortical 
function by inhibition of 11 beta-hydroxylation. J Clin Endocrinol Metab 1984;59(6):1143–7.  
46.  Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition of adrenal steroidogenesis 
by the anesthetic etomidate. N Engl J Med 1984;310(22):1415–21.  
47.  Ledingham IMca, Watt I. INFLUENCE OF SEDATION ON MORTALITY IN CRITICALLY ILL 
MULTIPLE TRAUMA PATIENTS. The Lancet 1983;321(8336):1270.  
48.  Bruder EA, Ball IM, Ridi S, Pickett W, Hohl C. Single induction dose of etomidate versus other 
induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev 
2015;1:CD010225.  
49.  Gu W-J, Wang F, Tang L, Liu J-C. Single-dose etomidate does not increase mortality in patients 
with sepsis: a systematic review and meta-analysis of randomized controlled trials and observational 
studies. Chest 2015;147(2):335–46.  
50.  Freund Y, Jabre P, Mourad J, et al. Relative adrenal insufficiency in critically ill patient after rapid 
sequence intubation: KETASED ancillary study. J Crit Care 2014;29(3):386–9.  
51.  Mohammad Z, Afessa B, Finkielman JD. The incidence of relative adrenal insufficiency in patients 
with septic shock after the administration of etomidate. Crit Care Lond Engl 2006;10(4):R105.  
52.  Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal responsiveness 
and mortality in patients with septic shock. Intensive Care Med 2009;35(11):1868–76.  
53.  Morel J, Salard M, Castelain C, et al. Haemodynamic consequences of etomidate administration in 
elective cardiac surgery: a randomized double-blinded study. Br J Anaesth 2011;107(4):503–9.  
54.  Jung B, Clavieras N, Nougaret S, et al. Effects of etomidate on complications related to intubation 
and on mortality in septic shock patients treated with hydrocortisone: a propensity score analysis. 
Crit Care Lond Engl 2012;16(6):R224.  
55.  Chan CM, Mitchell AL, Shorr AF. Etomidate is associated with mortality and adrenal insufficiency 
in sepsis: a meta-analysis*. Crit Care Med 2012;40(11):2945–53.  

RSI Protocol Version 1.0 
March 9, 2022 
 
Page 43 of 141 
56.  Lipiner-Friedman D, Sprung CL, Laterre PF, et al. Adrenal function in sepsis: The retrospective 
Corticus cohort study: Crit Care Med 2007;35(4):1012–8.  
57.  Albert SG, Ariyan S, Rather A. The effect of etomidate on adrenal function in critical illness: a 
systematic review. Intensive Care Med 2011;37(6):901–10.  
58.  Ray DC, McKeown DW. Effect of induction agent on vasopressor and steroid use, and outcome in 
patients with septic shock. Crit Care 2007;11:R56.  
59.  Mcphee LC, Badawi O, Fraser GL, et al. Single-dose Etomidate Is Not Associated With Increased 
Mortality in Icu Patients With Sepsis: Analysis of a Large Electronic Icu Database*. Crit Care Med 
2013;41(3):774–83.  
60.  Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in 
acutely ill patients: a multicentre randomised controlled trial. The Lancet 2009;374(9686):293–300.  
61.  Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency endotracheal 
intubation: a randomized clinical trial. Intensive Care Med 2022;48(1):78–91.  
62.  Jones AE. The Etomidate Debate. Ann Emerg Med 2010;56(5):490–1.  
63.  Day SJ, Altman DG. Blinding in clinical trials and other studies. BMJ 2000;321(7259):504.  
64.  Cormack RS, Lehane J. Difficult tracheal intubation in obstetrics. Anaesthesia 1984;39(11):1105–
11.  
65.  Yarnell CJ, Abrams D, Baldwin MR, et al. Clinical trials in critical care: can a Bayesian approach 
enhance clinical and scientific decision making? Lancet Respir Med [Internet] 2020 [cited 2020 
Nov 25];Available from: http://www.sciencedirect.com/science/article/pii/S2213260020304719 
66.  Food and Drug Administration (FDA). Multiple Endpoints in Clinical Trials: Guidance for Industry. 
2017;Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm53
6750.pdf 
67.  European Medicines Agency. Guideline on multiplicity issues in clinical trials. 2016;Available 
from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-multiplicity-
issues-clinical-trials_en.pdf 
68.  Uniform requirements for manuscripts submitted to biomedical journals. International Committee of 
Medical Journal Editors. JAMA 1997;277(11):927–34.  
69.  Mathais Q, Paleiron N, Vatin L, Bordes J, Gaillard PE. Ketamine-induced anaphylactic shock 
during elective parotidectomy: A case report. Eur J Anaesthesiol EJA 2019;36(1):70–1.  
70.  Bylund W, Delahanty L, Cooper M. The Case of Ketamine Allergy. Clin Pract Cases Emerg Med 
2017;1(4):323–5.  
 
 

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17. APPENDICES  
Appendix A. Schedule of Events 
Study Activity 
Pre-
Induction 
Administration 
of Sedatives 
(Induction) 
Tracheal 
Intubation 
Day 1 
Days  
2-27 
Day 28 
Eligibility assessment 
X 
 
 
 
 
 
Opt-out conversation 
(when feasible) 
X 
 
 
 
 
 
Pre-enrollment time-out 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Recording of baseline 
blood pressure and 
oxygen saturation 
X 
 
 
 
 
 
Study medication 
delivery (Ketamine or 
Etomidate) 
 
X 
 
 
 
 
Recording of  
peri-procedural 
outcomes  
 
X 
X 
X 
 
 
Assessment for study 
medication adherence 
 
X 
X 
X 
 
 
Safety monitoring for 
adverse events 
 
X 
X 
X 
 
X 
Notification of 
Enrollment 
 
 
 
X 
X 
 
Mortality assessment 
 
 
X 
X 
X 
X 
28-day in-hospital 
outcomes  
(chart review) 
 
 
 
 
 
X 

 
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Appendix B: Compliance with Criteria and Processes Required for EFIC 
FDA regulations identify the specific circumstances in which EFIC is appropriate. RSI fulfills 
these requirements for emergency research. In the following section, the components of the 
regulations are reproduced, along with an explanation of how RSI will comply with each 
requirement. 
 
1) Critical illness requiring emergency tracheal intubation is a life-threatening situation and available 
treatments are unsatisfactory or unproven. 
 
21 CFR 50.24(a)(1) The human subjects are in a life-threatening situation, available treatments 
are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include 
evidence obtained through randomized placebo-controlled investigations, is necessary to 
determine the safety and effectiveness of particular interventions. 
 
Each year more than 1.5 million critically ill patients receive mechanical ventilation in the United 
States.1–3 Despite adherence to recommended best-practices for tracheal intubation (e.g., 
preoxygenation,15,16 optimization of patient positioning,9 and procedural checklists8), one in five critically 
ill patients experiences hypotension and one-in-forty experiences cardiac arrest during the brief, two-
minute procedure to place an endotracheal tube.6–10 Around 30% of critically ill adults undergoing 
emergency tracheal intubation die prior to hospital discharge. 
 
Rapid sequence induction and tracheal intubation, the most common method of intubation for critically ill 
patients, is the nearly simultaneous administration of a sedative medication and neuromuscular blocking 
medication. The ideal sedative agent for rapid sequence intubation would rapidly provide a deep state of 
unconsciousness and analgesia without causing hemodynamic side effects, but no available agent meets 
all criteria.20  The administration of any available sedative at a dose large enough to rapidly induce 
unconsciousness contributes to cardiovascular collapse through vasodilation, decreased cardiac filling 
pressures from sedation-induced venodilation, and decreased endogenous catecholamines.21–24 While all 
sedatives commonly used during emergency tracheal intubation of critically ill patients have been 
associated with unsatisfactory hypotension (21 CFR 50.24(a)(1)), ketamine and etomidate are the 
medications used most commonly in clinical practice due to their rapid onset and relatively favorable 
hemodynamic profiles (as described in section 2.1.2).25,26 A large multi-center trial is needed to determine 
the effects on peri-procedural hemodynamics and mortality of the two most commonly used sedatives for 
the tracheal intubation of critically ill adults.  
 
2) Obtaining prospective informed consent is not feasible during emergency tracheal intubation. 
21 CFR 50.24(a)(2) Obtaining informed consent is not feasible because: (i) the subjects will not 
be able to give their informed consent as a result of their medical condition; (ii) the intervention 
under investigation must be administered before consent from the subjects' legally authorized 
representatives is feasible; and (iii) There is no reasonable way to identify prospectively the 
individuals likely to become eligible for participation in the clinical investigation. 
 

 
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Most patients eligible for the RSI trial will be experiencing unconsciousness or delirium due to critical 
illness.  More than half of critically ill adults undergoing tracheal intubation in the ED or ICU have a 
Glasgow Coma Scale score less than 12 (equivalent to moderate brain injury) and among those whose 
level of consciousness is not impaired, most experience acute delirium.  Even in instances in which a 
patient retains capacity, or an LAR is immediately available, the rapidity with which emergency tracheal 
intubation is clinically required, and the accompanying distress of the patient or LAR from the critical 
illness and need for emergency tracheal intubation, precludes a meaningful informed consent process.  
Delaying emergency tracheal intubation for a critically ill adults to attempt a meaningful informed 
consent process would be unsafe, impracticable, and unethical. 
There is no reasonable method for prospectively identifying individuals for informed consent prior to 
developing a need for emergency tracheal intubation. Many different acute illnesses lead to emergency 
tracheal intubation in the ED or ICU including stroke, spontaneous intracranial hemorrhage, seizure, 
sepsis, drug overdose, acute coronary syndrome, aspiration pneumonitis, acute bacterial pneumonia, 
pneumothorax, and others. Any patient in the community or in the hospital may unexpectedly develop a 
need for emergency tracheal intubation within a period of minutes with no warning.  
For these reasons, the RSI trial could not be conducted without EFIC, and it is expected that most, if not 
all, patients will be enrolled through EFIC.  
3) Participation in RSI holds prospect of direct benefit to subjects 
 
21 CFR 50.24(a)(3) Participation in the research holds out the prospect of direct benefit to the 
subjects because: (i) subjects are facing a life-threatening situation that necessitates intervention; 
(ii) appropriate animal and other preclinical studies have been conducted, and the information 
derived from those studies and related evidence support the potential for the intervention to 
provide a direct benefit to the individual subjects; and (iii) risks associated with the investigation 
are reasonable in relation to what is known about the medical condition of the potential class of 
subjects, the risks and benefits of standard therapy, if any, and what is known about the risks and 
benefits of the proposed intervention or activity. 
 
Participation in RSI holds out the prospect of direct benefit to subjects. Critical illness requiring 
emergency tracheal intubation is a life-threatening condition with a high incidence of hypotension and 
cardiac arrest that necessitates immediate intervention.  Previous animal and clinical studies have 
established several mechanisms by which either ketamine or etomidate might provide a direct benefit to 
individual critically ill subjects undergoing tracheal intubation via improved hemodynamics and survival. 
 
The risks associated with the investigation are reasonable in relation to what is known about tracheal 
intubation of critically ill patients. All patients enrolled in the RSI trial would have received a sedative as 
part of emergency tracheal intubation in routine clinical care, regardless of participation in the RSI trial. 
The treatment groups represent the two most commonly used sedatives, and there is no evidence currently 
that either medication is superior with regard to peri-procedural hemodynamics or survival. Therefore, 
there is no reason to believe that participation in this study would expose patients to greater medical risks 
than those experienced by critically ill patients undergoing tracheal intubation as part of routine clinical 
care.  

 
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4) The RSI trial cannot be practicably carried out without exception from informed consent 
 
21 CFR 50.24(a)(4) The clinical investigation could not practicably be carried out without the 
waiver. 
 
This research could not be carried out without EFIC because emergency tracheal intubation of critically 
ill adults is a time-sensitive procedure for which every minute of delay increases the likelihood of 
hypoxemia, hypotension, and peri-procedural cardiac arrest. A meaningful informed consent process 
requires that the patient or LAR have time to understand the material presented, be able to ask questions 
and have time to consider their options. This is not possible in the brief therapeutic window between the 
decision to intubate a critically ill patient and the initiation of the procedure.  
 
5) The need for immediate treatment of critically ill patients requiring emergency tracheal intubation is 
expected to preclude obtaining informed consent from an LAR in most, if not all cases, during the brief 
therapeutic window 
 
21 CFR 50.24 (a)(5) The proposed investigational plan defines the length of the potential 
therapeutic window based on scientific evidence, and the investigator has committed to 
attempting to contact a legally authorized representative for each subject within that window of 
time and, if feasible, to asking the legally authorized representative contacted for consent within 
that window rather than proceeding without consent. The investigator will summarize efforts 
made to contact legally authorized representatives and make this information available to the 
IRB at the time of continuing review. 
 
For an induction medication used for emergency tracheal intubation, the therapeutic window begins at the 
time treating clinicians decide to perform emergency tracheal intubation with sedation and ends at the 
time an induction medication is administered for emergency tracheal intubation.  To our knowledge, no 
published literature has quantified this therapeutic window among critically ill adults.  Among a 
convenience sample of 25 consecutive critically ill adults undergoing emergency tracheal intubation in 
the ED or ICU in the planned study sites of the RSI trial, the median time from treating clinicians 
verbalizing the decision to intubate with sedation (or placing a written order for an induction medication) 
to the administration of an induction medication was 1 minute [interquartile range, 1 minute to 10 
minutes].  For no patient was this window longer than 30 minutes.  Tracheal intubation of critically ill 
adults is a time-sensitive procedure for which every minute of delay increases the likelihood of 
hypoxemia, hypotension, and peri-procedural cardiac arrest.  For most patients in the RSI trial, 
completion of the trial intervention (a one-time injection at the start of the emergency tracheal intubation 
procedure) is anticipated to occur less than 5 minutes after meeting trial eligibility criteria.  Thus, in the 
RSI trial, we anticipate that the therapeutic window for most patients will be less than 5 minutes.   
While a written informed consent is available and will be used when feasible, it is expected that written 
consent will be infeasible in most, if not all, cases because delaying the emergency tracheal intubation of 
critically ill adults would cause irreparable harm to patients.  Whenever feasible, however, the RSI trial 
will provide an opportunity for patients, LARs, or family members to opt-out of trial participation.   
 

 
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Because patient enrollment and delivery of the trial intervention are performed by treating clinicians (not 
research staff) and occur within a period of minutes after meeting eligibility, treating clinicians will use a 
brief written script, approved by the IRB, to describe the study and provide an opportunity for the patient, 
LAR, or family member to opt-out (Appendix D).  The decisional capacity of the patient and the safety 
and feasibility of reading the script during the brief therapeutic window will be determined by the treating 
clinicians.  Allowing a mechanism, whenever feasible, for patients to opt out of participation is consistent 
with the respect for autonomy emphasized in the EFIC guidelines.  
We will make every effort to contact legal representatives after enrollment to notify LARs that the patient 
was enrolled in a randomized trial and provide an opportunity to withdraw from further participation.  If 
legal representatives are not immediately available, research personnel will attempt to contact the 
subject’s legal representative as soon as feasible and a summary of these efforts will be documented in the 
patient’s study record. If the subject becomes competent during the study period, he/she will be 
approached by research personnel for notification of enrollment. 
Investigators will prospectively record the efforts by treating clinicians to allow patients, LARs, or family 
members to opt-out of participation and the efforts by study staff to notify patients and LAR of 
enrollment. These efforts will be summarized and reported to the DSMB at their semi-annual meetings 
and to the IRB at the initial and continuing reviews. 
6) Informed consent procedures and documents in the RSI trial will be reviewed and approved by the IRB 
 
21 CFR 50.24(a)(6) The IRB has reviewed and approved informed consent procedures and an 
informed consent document consistent with Sec. 50.25. These procedures and the informed 
consent document are to be used with subjects or their legally authorized representatives in 
situations where use of such procedures and documents is feasible. The IRB has reviewed and 
approved procedures and information to be used when providing an opportunity for a family 
member to object to a subject's participation in the clinical investigation consistent with 
paragraph (a)(7)(v) of this section. 
 
All consent procedures and documents that will be used in the RSI trial will be approved by the IRB prior 
to the initiation of enrollment.   
 
7) Additional protections of the rights and welfare of the subjects will be provided in the RSI trial, 
including: 
 
Community Consultation 
 
i. 21 CFR 50.24(a)(7) Additional: Consultation (including, where appropriate, consultation 
carried out by the IRB) with representatives of the communities in which the clinical 
investigation will be conducted and from which the subjects will be drawn; 
 
A detailed plan for community consultation has been developed for the RSI trial (see Community 
Consultation and Public Disclosure Plan).  The plan included in the initial draft of the RSI protocol was 
informed by two Community Engagement Studios, organized by the Vanderbilt Community Engagement 

 
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Research Core.  The first meeting, held on February 2, 2021, included healthcare providers who routinely 
participated in emergency tracheal intubation in the ED or ICU.  The second meeting, held on February 4, 
2021, included patients or caretakers of patients who had experienced critical illness with emergency 
tracheal intubation.  Investigators solicited feedback on the design of the RSI trial, potential risks and 
benefits of participation, the inability to obtain prospective informed consent, the opportunity to opt-out 
of participation, and the plans for further Community Consultation, Public Disclosure of the conduct and 
results of the trial.  The protocol, the plan for further Community Consultation, and the plan for Public 
Disclosure were refined based on this feedback to address the concerns of the community.  Enrollment in 
the RSI trial will not begin until 1) the IRB has approved the proposed community consultation plan, 2) 
study personnel have completed the proposed community consultation plan, and 3) the IRB has reviewed 
and certified the completion of community consultation and approved enrollment.  
 
Public Disclosure 
 
ii. 21 CFR 50.24(a)(7): Public disclosure to the communities in which the clinical investigation 
will be conducted and from which the subjects will be drawn, prior to initiation of the 
clinical investigation, of plans for the investigation and its risks and expected benefits; 
iii. Public disclosure of sufficient information following completion of the clinical investigation 
to apprise the community and researchers of the study, including the demographic 
characteristics of the research population, and its results; 
 
Public disclosure is a primary element in making certain that RSI is conducted in an entirely 
transparent manner. A detailed public disclosure plan has been developed for the RSI trial (see 
Community Consultation and Public Disclosure Plan).  The plan included in the initial draft of the RSI 
protocol was informed by two Community Engagement Studios, organized by the Vanderbilt Community 
Engagement Research Core.  The first meeting, held on February 2, 2021, included healthcare providers 
who routinely participated in emergency tracheal intubation in the ED or ICU.  The second meeting, held 
on February 4, 2021, included patients or caretakers of patients who had experienced critical illness with 
emergency tracheal intubation.  Investigators solicited feedback on the design of the RSI trial, potential 
risks and benefits of participation, the inability to obtain prospective consent, the opportunity to opt-out of 
participation, and the plans for further Community Consultation, Public Disclosure of the conduct and 
results of the trial.  The protocol, the plan for further Community Consultation, and the plan for Public 
Disclosure were refined based on this feedback to address the concerns of the community.  Enrollment in 
the RSI trial will not begin until 1) the IRB has approved the proposed public disclosure plan, 2) study 
personnel have completed the proposed public disclosure activities, and 3) the IRB has reviewed and 
certified the completion of public disclosure and approved enrollment.  
 
Data and Safety Monitoring Committee 
 
iv. 21 CFR 50.24(a)(7): Establishment of an independent data monitoring committee to 
exercise oversight of the clinical investigation;  
 

 
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The Data Safety Monitoring Board (DSMB) will function as an independent data monitoring committee 
who will exercise oversight of the study. The composition and responsibilities of the DSMB are described 
in protocol section 15. 
 
Contacting Other Family 
 
v. 21 CFR 50.24(a)(7) If obtaining informed consent is not feasible and a legally authorized 
representative is not reasonably available, the investigator has committed, if feasible, to 
attempting to contact within the therapeutic window the subject's family member who is not 
a legally authorized representative, and asking whether he or she objects to the subject's 
participation in the clinical investigation. The investigator will summarize efforts made to 
contact family members and make this information available to the IRB at the time of 
continuing review. 
 
It will not be feasible or ethically possible in the RSI trial, for the reasons described above, to delay 
treatment of a critically ill patient requiring emergency tracheal intubation for long enough to contact 
either an LAR or other family members who are not present. We will, however, provide patients and 
LARs or family members who are present with the opportunity to opt-out of enrollment using the 
recitation of a standardized script by treating clinicians during the brief therapeutic window (Appendix 
E). Further, we will provide a mechanism whereby community members who would not want to 
participate if undergoing tracheal intubation in the ED or ICU can communicate that decision to providers 
without causing any delay in treatment using opt-out bracelets. As part of the primary assessment of a 
critically ill patient, providers already check for a medical alert bracelet.  The study will provide medical 
alert bracelets with the words “RSI declined” to any community member requesting one. The process by 
which community members are notified of the study and requests an opt-out bracelet are explained in the 
Community Consultation and Public Disclosure Plan.  Medical alert bracelets are a common and effective 
means of communicating information to ED and ICU providers while unconscious or in acute distress. 
Requests for RSI opt-out bracelets and their use in identifying patients for exclusion will be tracked by 
study investigators and this information can be made available to the IRB at the time of continuing 
review.  
 
Post Enrollment Notification 
 
vi. 
21 CFR 50.24(b) The IRB is responsible for ensuring that procedures are in place to inform, 
at the earliest feasible opportunity, each subject, or if the subject remains incapacitated, a 
legally authorized representative of the subject, or if such a representative is not reasonably 
available, a family member, of the subject's inclusion in the clinical investigation, the details 
of the investigation and other information contained in the informed consent document. The 
IRB shall also ensure that there is a procedure to inform the subject, or if the subject 
remains incapacitated, a legally authorized representative of the subject, or if such a 
representative is not reasonably available, a family member, that he or she may discontinue 
the subject's participation at any time without penalty or loss of benefits to which the subject 
is otherwise entitled. If a legally authorized representative or family member is told about 
the clinical investigation and the subject's condition improves, the subject is also to be 

 
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informed as soon as feasible. If a subject is entered into a clinical investigation with waived 
consent and the subject dies before a legally authorized representative or family member 
can be contacted, information about the clinical investigation is to be provided to the 
subject's legally authorized representative or family member, if feasible. 
 
Subjects enrolled in RSI or their LAR or family will be informed of the subject’s inclusion in the clinical 
investigation at the earliest possible opportunity as detailed above. It is anticipated that the notification of 
patients’ LAR or family will most usually take place within 24 hours of enrollment. Attempts to notify 
the subject or an LAR are repeated until successful or at least three attempts have been made. If a 
patient’s LAR or family member is notified of enrollment and the patient subsequently regains decision-
making capacity, the patient will be notified of the study and will be asked if he or she wants to continue 
the study.  
 
All notification attempts will be logged and recorded in the study record. Reports of these logs will be 
summarized to the DSMB at semi-annual reports and available for inclusion in annual reports to the IRB. 
 
By the time patients, LARs, or family members are notified of participation, the study intervention (a one-
time infusion at the time of tracheal intubation) will have been completed and patients will have 
experienced all of the risks or benefits associated with the study intervention.  The only remaining study 
procedure will be review of the electronic health record by study personnel.  Requesting that patients, 
LARs, or family member provide informed consent for continued participation after completion of the 
study intervention would not provide any additional patient protections, but would risk diminishing the 
overall validity and value of the research by biasing estimates of safety and efficacy if consent for 
continued participation occurred differentially between the trial groups because of the effects of the trial 
interventions.  The RSI trial will, therefore, use public notification, community consultation, a pre-
enrollment opt-out conversation (by treating clinicians whenever feasible), medical alert bracelets, patient 
and LAR notification of enrollment, and a provision of an opportunity to opt out of ongoing participation. 
 
Record Keeping 
 
21 CFR 50.24(c) Like other IRB records, records of the determinations above must be kept for a 
minimum of three years after the completion of the clinical investigation. Again, like other IRB 
records, these are subject to inspection and copying by FDA. 
 
Records documenting the enrollment of patients using EFIC, procedures for opt-out prior to enrollment, 
and attempts to notify patients, LARs, and family members of enrollment will be kept for a minimum of 
three years after completion of the clinical investigation. 
 
IND Requirement 
 
21 CFR 50.24(d) Protocols involving an exception to the informed consent requirement under 
this section must be performed under a separate investigational new drug application (IND) or 
investigational device exemption (IDE) that clearly identifies such protocols as protocols that 
may include subjects who are unable to consent. The submission of those protocols in a separate 

 
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IND/IDE is required even if an IND for the same drug product or an IDE for the same device 
already exists. Applications for investigations under this section may not be submitted as 
amendments under Secs. 312.30 or 812.35 of this chapter. 
 
For critically ill adults undergoing emergency tracheal intubation for whom treating clinicians feel either 
ketamine or etomidate is consistent with optimal care, the incremental risks of participating in the RSI 
trial, compared to clinical care for the patient outside the trial, are minimal.  As such, the RSI trial might 
be considered to quality for waiver of consent and exemption from IND requirements under 21 CFR 312 
because: 
• 
Both ketamine and etomidate are lawfully marketed in the United States for use as sedative 
agents during tracheal intubation (the indication for which they will be used in the RSI trial) 
• 
The current study is not intended to be reported to FDA as a well-controlled study in support of a 
new indication for use nor intended to be used to support any other significant change in the 
labeling for either ketamine or etomidate 
• 
The current study is not intended to support a change in advertising for ketamine or etomidate 
• 
The current study does not involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of 
the risks) associated with the use of ketamine or etomidate. The current study will use ketamine 
and etomidate at the doses recommended by the FDA-approved package insert and excludes 
patient populations that would have increased risks of complications and any patients for whom 
any provider believes ketamine or etomidate is required or contraindicated 
• 
The study will be conducted with the requirements for institutional review set forth in FDA 
regulations 21 CFR 56.  
• 
The current study will be conducted in compliance with FDA regulations 21 CFR 312.7 regarding 
promotion and charging for investigational medication 
 
We will, however, conduct the RSI trial under EFIC in order to ensure patients receive the additional 
protections offered by community consultation and disclosure through EFIC.  As required by EFIC 
regulations 21 CFR 50.24(d), an IND for the RSI trial was obtained from the FDA (IND 141424).  The 
Study Principal Investigator serves as the sponsor of the IND.  
 
Communication of IRB Determinations 
 
21 CFR 50.24(e) If an IRB determines that it cannot approve a clinical investigation because the 
investigation does not meet the criteria in the exception provided under paragraph (a) of this 
section or because of other relevant ethical concerns, the IRB must document its findings and 
provide these findings promptly in writing to the clinical investigator and to the sponsor of the 
clinical investigation. The sponsor of the clinical investigation must promptly disclose this 
information to FDA and to the sponsor's clinical investigators who are participating or are asked 
to participate in this or a substantially equivalent clinical investigation of the sponsor, and to 
other IRBs that have been, or are, asked to review this or a substantially equivalent investigation 
by that sponsor. 
 

 
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If an application for RSI is disapproved by a local IRB, the Study PI/sponsor will promptly disclose this 
information to the FDA. 
 
 
 
 
 

 
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APPENDIX C. Script to Provide an Opportunity to Opt-Out of Participation 
The script below will be included in the enrollment materials available to treating clinicians at the time of 
emergency tracheal intubation.  
 
OPT-OUT SCRIPT  
If, in your clinical judgement, the patient lacks capacity and a family member is not at the bedside, OR 
you believe it would be unsafe or infeasible to delay the intubation while you read the script below, 
enroll the patient (open the envelope) and proceed with intubation without completing the section below.   
 
Otherwise, please read the following section aloud and provide an opportunity for the patient/family to 
opt-out of participation.  
1. You (your loved one) need(s) to be placed on a breathing machine, which requires a brief procedure to 
place a breathing tube.  
2. There are two medications that we commonly give patients to make them sleepy and relaxed for this 
procedure. As your medical team, we think either of these medications would be a good and safe choice 
for you.   
3. To help us understand which of the two medications is best, we are conducting a research study that 
compares the two medications.  
4. If you say “Yes” to participation, we will allow the study to choose which of the two medications you 
will receive and someone from the study will come by later to provide details and answer your questions.  
If you say “No”, we will choose one of the two medications ourselves.  Do you agree to participate? 
“Yes” - Patient/family agreed to participate (open envelope to enroll patient) 
“No” - Patient/family declined participation (place envelope in “used” bin; do not enroll) 
 
 
 

 
 
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APPENDIX D. Notification of Enrollment Form 

 
 
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Appendix E: Letter to be Mailed if Unable to Notify Patient prior to Discharge 
  
 

 
 
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Appendix F: Letter to Mailed if Patient Dies before Notification 
  
 

 
 
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Appendix G: Adverse Event Reporting and Unanticipated Events 
As noted in section 14, the lead investigator at each enrolling site is required to report all potentially 
reportable adverse events to the principal investigator within 24 hours of becoming aware of the event.  
Reportable events in the RSI trial are defined as adverse events that are unexpected and serious have a 
reasonable possibility that the event was due to a study medication or procedure (or of uncertain 
relatedness) 
The primary investigator will work collaboratively with the lead investigator at each enrolling site to 
determine if a serious adverse event has a reasonable possibility of having been caused by the study 
medication or study procedure, as outlined in 21 CFR 312.32(a)(1), and below. In this unblinded trial, 
both the investigator and primary investigator will be aware of group assignment and the receipt of either 
ketamine or etomidate.  An adverse is considered “unexpected” if it is not listed in the investigator 
brochure or the study protocol (21 CFR 312.32(a)). If a determination is made that a serious adverse event 
has a reasonable possibility of having been caused by a study procedure or the study medication, it will be 
classified as a suspected adverse reaction. If the suspected adverse reaction is unexpected, it will be 
classified as a serious unexpected suspected adverse reaction (SUSAR).  
H.1. Expedited Adverse Event Review and DSMB Notification Process 
The principal investigator will be responsible for notifying the NHLBI, the IRB, and the FDA and will 
follow NHLBI guidelines for reporting of adverse events, https://www.nhlbi.nih.gov/grants-and-
training/policies-and-guidelines/nhlbi-adverse-event-and-unanticipated-problem-reporting-policy 
The principal investigator will report, at a minimum: 
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 NHLBI 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 NHLBI 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 CCC will distribute the written summary of the DSMB’s periodic review of reported adverse events 
to the IRB and NHLBI in accordance with NIH guidelines (http://grants.nih.gov/grants/guide/notice-
files/not99-107.html).  
H.2. Unanticipated Problems (UP) 
Investigators must also report Unanticipated Problems, regardless of severity, associated with study 
procedures within 24 hours. An unanticipated problem is defined as follows: any incident, experience, or 
outcome that meets all of the following criteria:  

 
 
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• 
Unexpected, in terms of nature, severity, or frequency, given the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and patient 
notification document; and the characteristics of the subject population being studied;  
• 
Related or possibly related to participation in the research, in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research;  
• 
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.  
 
In accordance with NHLBI policy, an unanticipated problem that is not an SAE will be reported within 14 
days to the DSMB, IRB, and NHLBI. 
H.3. Determining Relationship of Adverse Events to Study Medication or Study 
Procedures 
Site investigators will be asked to grade the strength of the relationship of an adverse event to study 
medication or study procedures as follows:  
• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the patient’s clinical state 
or other therapies; and c) Evaluation of the patient’s clinical state indicates to the investigator that 
the experience is definitely related to study procedures.  
• 
Probably or Possibly Related: The event should be assessed following the same criteria for 
“Definitely Associated”. If in the investigator’s opinion at least one or more of the criteria are not 
present, then “Probably or Possibly” associated should be selected.  
• 
Probably Not Related: The 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.  
• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or by other 
modes of therapy administered to the patient.  
• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined.  
The principal investigator will work collaboratively with the reporting investigator to determine if a 
serious adverse event has a reasonable possibility of having been caused by the study medication or study 
procedure. The principal investigator will be responsible for the final adjudication of relatedness that will 
be used to determine if an adverse event is reportable. 
H.4. Clinical Outcomes that may be Exempt from Adverse Event 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 

 
 
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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 a reportable adverse event. For example, a 
cardiac arrest that the investigator considers Definitely Related to ketamine would be both recorded as a 
study-specific clinical outcome and recorded and reported as a Serious and Definitely Related adverse 
event. 
 
 
 
 

 
 
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Randomized Trial of Sedative Choice for Intubation (“RSI”) Trial Protocol 
The Pragmatic Critical Care Research Group Investigators 
 
 
 
Title:  
Randomized Trial of Sedative Choice for Intubation  
Acronym:  
RSI 
Funders:  
The National Heart, Lung, and Blood Institute (NHLBI) & Patient-Centered Outcomes 
Research Institute (PCORI) 
Network:  
Pragmatic Critical Care Research Group 
Protocol:  
Version 2.2 
Date: 
 
 March 7, 2025 
Study Chairs:  Jonathan Casey MD, MSc, Vanderbilt University Medical Center 
 
 
Matthew Semler MD, MSc, Vanderbilt University Medical Center  
 
 
Jin Han MD, MSc, Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
 
REVISIONS TO THE PROTOCOL ........................................................................................................... 71 
ABBREVIATIONS .................................................................................................................................... 73 
1. STUDY SUMMARY .............................................................................................................................. 74 
2. TRIAL DESCRIPTION .......................................................................................................................... 77 
2.1 Background ............................................................................................................................... 77 
2.1.1 Cardiovascular Collapse during Intubation .................................................................................... 77 
2.1.2 Sedative Medications Contribute to the Risk of Cardiovascular Collapse ..................................... 77 
2.1.3 Ketamine as a Sedative during Tracheal Intubation. ...................................................................... 78 
2.1.4 Etomidate as a Sedative during Tracheal Intubation. ..................................................................... 78 
2.1.5 Prior Evidence from Clinical Trials. ............................................................................................... 79 
2.1.6 Rationale for a Trial of Ketamine vs Etomidate in Non-Traumatic Critical Illness. ...................... 79 
2.1.7 Rationale for Two Stages of the RSI trial. ...................................................................................... 79 
2.2 Study Aims and Hypotheses ..................................................................................................... 80 
2.2.1 Study aims ...................................................................................................................................... 80 
2.2.2 Study hypothesis ............................................................................................................................. 80 
2.3 Study Design .............................................................................................................................. 81 
3. STUDY POPULATION AND ENROLLMENT ................................................................................... 81 
3.1 Inclusion Criteria ...................................................................................................................... 81 
3.2 Exclusion Criteria ..................................................................................................................... 81 
3.3 Justification of Exclusion Criteria ........................................................................................... 81 
4. Process of Obtaining Informed Consent ................................................................................................. 82 
4.1 Post-Enrollment Notification ................................................................................................... 83 
4.2 Consent for Long-Term Follow-Up ......................................................................................... 84 
5.0 Enrollment and Randomization ............................................................................................................ 84 
5.1 Monitoring and Reporting of Eligibility of Enrolled Patients .............................................. 84 
5.2 Handling of Patients Found to Be Prisoners after Enrollment ............................................. 84 
6.0 Blinding ................................................................................................................................................ 85 
7. STUDY INTERVENTIONS................................................................................................................... 85 
7.1 Treatment of Study Patients .................................................................................................... 85 
7.2 Ketamine Group ........................................................................................................................ 85 
7.3 Etomidate Group ...................................................................................................................... 86 

 
 
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7.4 Co-Interventions ....................................................................................................................... 86 
7.5 Packaging and Labeling ........................................................................................................... 86 
7.6 Storage and Accountability ...................................................................................................... 86 
7.7 On-Study Monitoring ............................................................................................................... 87 
8. OUTCOMES........................................................................................................................................... 87 
8.1 Primary Outcome ...................................................................................................................... 87 
8.2 Secondary Outcome .................................................................................................................. 87 
8.3 Exploratory Outcomes .............................................................................................................. 87 
8.4 Safety outcomes ......................................................................................................................... 88 
8.5 Long-term outcomes ................................................................................................................. 88 
9. DATA COLLECTION ........................................................................................................................... 88 
9.1 Baseline Variable Collection .................................................................................................... 88 
9.2 Peri-Procedural Variables ........................................................................................................ 89 
9.3 Assessments between Hospital Presentation and Hospital Discharge .................................. 89 
9.4 REDCap Clinical Data Interoperability Services .................................................................. 90 
10. STATISTICAL CONSIDERATIONS .................................................................................................. 90 
10.1 Stage 1 Sample Size Calculation ............................................................................................ 90 
10.2 Stage 2 Sample Size Calculation ............................................................................................ 90 
10.2 Stage 2 Sample Size Re-Estimation ....................................................................................... 91 
10.3 Progression from Stage 1 to Stage 2 of RSI .......................................................................... 91 
10.4 Primary Analysis ..................................................................................................................... 92 
10.5 Secondary Analyses ................................................................................................................ 92 
10.6 Subgroup Analyses .................................................................................................................. 92 
10.7 Interim Analysis ...................................................................................................................... 93 
10.8 Correction for Multiple Testing ............................................................................................. 93 
10.9 Handling of Missing Data ....................................................................................................... 93 
11. DATA QUALITY MONITORING AND STORAGE ......................................................................... 93 
11.1 Data Quality Monitoring ........................................................................................................ 93 
11.2 Data Storage ............................................................................................................................ 94 
12. RISK ASSESSMENT ........................................................................................................................... 94 
12.1 Potential Risks of Receiving Ketamine ................................................................................. 94 
12.2 Potential Risks of Receiving Etomidate ................................................................................ 95 
12.3 Potential Risk of Participation in the RSI Trial ................................................................... 96 

 
 
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12.4 Minimization of Risk .............................................................................................................. 96 
12.5 Potential Benefit ...................................................................................................................... 97 
12.6 Risk in Relation to Anticipated Benefit ................................................................................. 97 
13. HUMAN SUBJECTS PROTECTIONS ............................................................................................... 97 
13.1 Length of Therapeutic Window ............................................................................................. 98 
13.2 Inability to Conduct Trial without EFIC .............................................................................. 98 
13.3 Opportunity to Decline Participation .................................................................................... 99 
13.4 Notification of Enrollment ...................................................................................................... 99 
13.5 Documentation and Tracking of Notification Process ....................................................... 100 
13.6 Selection of Subjects.............................................................................................................. 100 
13.7 Justification of Including Vulnerable Subjects .................................................................. 100 
13.8 Investigational New Drug Application ................................................................................ 100 
13.9 Additional Safeguards for Vulnerable Patients ................................................................. 101 
13.10 Confidentiality ..................................................................................................................... 101 
14. ADVERSE EVENTS .......................................................................................................................... 101 
14.1 Adverse Event Definitions .................................................................................................... 101 
14.2 Safety Monitoring ................................................................................................................. 102 
14.3 Serious Adverse Events ........................................................................................................ 103 
15. Data and Safety Monitoring Board (DSMB) ...................................................................................... 103 
16. REFERENCES. .................................................................................................................................. 105 
17. APPENDICES .................................................................................................................................... 113 
Appendix A. Schedule of Events .................................................................................................. 113 
Appendix B: Compliance with Criteria and Processes Required for EFIC ............................ 114 
Appendix C. Script to Provide an Opportunity to Opt-Out of Participation .......................... 122 
Appendix D: Adverse Event Reporting and Unanticipated Events ......................................... 123 
Appendix E: Long-Term Outcomes in RSI ................................................................................ 127 
Appendix F: Analyses of Heterogeneity of Treatment Effect. .................................................. 138 
 
 
 

 
 
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REVISIONS TO THE PROTOCOL 
 
Protocol Version 1.0 
Date: March 9, 2022 
Initial protocol 
 
Protocol Version 1.1 
Date: May 23, 2022 
Purpose: This amendment is to add additional details regarding the approach to notifying, at the earliest 
feasible opportunity, each patient, or if the patient remains incapacitated, a legally authorized 
representative of the patient, or if such a representative is not reasonably available, a family member, of 
the patient’s inclusion in the study.  This amendment also describes the approach to obtaining prospective 
informed consent to be contacted for potential participation in ancillary trials.  
 
Protocol Version 2.0 
Date: October 18, 2023 
Description: This amendment triggers Stage 2 (multi-center) of the RSI trial, following the receipt of 
funding for Stage 2 of the RSI trial from PCORI, and includes revisions to the protocol to align with the 
grant approved by PCORI. Major changes made in version 2.0 of the grant include: 
• 
Activation of Stage 2 with pre-planned prioritization of Stage 2 outcomes (primary outcome: 
mortality at 1 month [28 days]) and removal of stage 1 analyses that will not be conducted with 
the activation of stage 2. 
• 
Increased sample size of 2,364 patients based on updated power calculation and input from 
stakeholders regarding the minimum clinically important difference. Sample size at which single 
pre-specified interim analysis would occur was updated to remain at 50% of total enrollment 
(1,182 patients). 
• 
The process for pre-enrollment opt-out was updated for operationalization at additional sites in 
Stage 2 (multi-center stage) of RSI. 
• 
Primary outcome changed to a generalized linear mixed effects model with a random effect for 
study site (e.g., Vanderbilt University ED, Vanderbilt University Medical ICU) and a fixed effect 
for group assignment (ketamine group vs etomidate group) and subgroup analysis updated to 
include a random effect for study site to match the primary analysis. 
• 
Addition of a plan to approach intubation survivors for consent to collect long-term outcomes. 
• 
Removal of example notification forms (following review and approval by IRB). 
• 
Replacement of the section “Consent to be Contacted for Ancillary Studies” by Appendix E 
describing the plan for collection of long-term outcomes.  
 
Protocol Version 2.1 
Date: April 30, 2024 
Description: This amendment is to make minor revisions to secondary analyses to match the research plan 
approved by the funder, clarify plans regarding enrollment of ineligible patients, add definitions for 
protocol deviations and protocol violations, and add detail regarding the provision of resources to patients 
participating with RSI-LTO who are found to have non-life-threatening psychiatric issues such as severe 
PTSD or depression. These changes include: 

 
 
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• 
Revising the covariates that will be included in the adjusted analysis of the primary outcome (a 
secondary analysis). 
• 
Adding details of a planned analysis of Heterogeneity of Treatment Effect (“Individualized 
Treatment Effect”) for the short- and long-term outcomes as a new appendix (Appendix F). 
• 
Adding definitions and reporting plans for protocol deviations and violations and details of the 
plan for communication to the funder to Appendix D. 
• 
Adding details regarding how patients who are found to be prisoners will be identified and 
withdrawn from the study. 
• 
Describing what information will be collected during follow-up phone calls about patients with a 
new diagnosis of PTSD, depression, or anxiety, and the resources that will be provided to them.  
Protocol Version 2.2 
Date: March 7, 2025 
Description: This amendment is (i) to make minor revisions to secondary analyses to match the final 
trial statistical analysis plan at the time of its submission for publication and (ii) to revise the trial 
protocol to permit Waiver of Documentation of informed consent for patients discharged from the 
hospital who have completed an informed consent discussion and consent to participate but for whom 
receiving, signing, and returning by mail the informed consent document would be logistically 
burdensome and increase the risk of disclosure of PHI. 
 
 

 
 
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ABBREVIATIONS 
 
AE 
Adverse event 
APACHE 
Acute Physiology and Chronic Health Evaluation 
DSMB 
Data safety monitoring board 
ED 
Emergency department 
EFIC 
Exception from Informed Consent (21 CFR 50.24.7) 
ICU 
Intensive care unit 
IV 
Intravenous 
LAR 
Legally authorized representative 
PI 
Principal investigator (the clinician leading the study across all sites) 
PTSD 
Post-traumatic stress disorder 
RCT 
Randomized control trial 
SAE 
Serious adverse events 
S/F 
SpO2/FiO2 ratio 
SOP 
Standard operating procedure 
 
 
 
 
 
 
 

 
 
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1. STUDY SUMMARY 
 
Title 
Randomized Trial of Sedative Choice for Intubation (RSI) 
Background 
Among critically ill adults undergoing emergency tracheal intubation, one in five 
experience hypotension, cardiac arrest, or death. The sedatives used to rapidly 
induce anesthesia for emergency tracheal intubation have been hypothesized to 
effect cardiovascular complications and patient outcomes, but the optimal 
sedative medication for intubation of critically ill adults remains unknown. 
Ketamine and etomidate are the two most commonly used sedatives during 
intubation of critically ill adults.  Data from a randomized clinical trial are 
urgently needed to determine the effect of ketamine versus etomidate on 
cardiovascular complications and clinical outcomes of emergency tracheal 
intubation.  
 
Study Design 
Multi-center non-blinded, parallel-group, randomized clinical trial 
Treatment Groups 
 
Ketamine group: Patients will receive intravenous ketamine at a recommended 
dose of 2 mg/kg for induction of anesthesia for emergency tracheal intubation. 
 
Etomidate group: Patients will receive intravenous etomidate at a recommended 
dose of 0.3 mg/kg for the induction of anesthesia for emergency tracheal 
intubation. 
 
In this investigator-initiated, multi-center, non-blinded, randomized trial 
comparing two commonly used medications within their approved indications, 
the assigned sedative medication will be dispensed from the clinical pharmacy 
and administered by clinical personnel as would occur in clinical care. 
 
Sample Size 
Stage 1 (feasibility): 464 patients 
Stage 2 (effectiveness): 1,900 patients 
Total Sample Size: 2,364 patients 
 
Inclusion Criteria 
4. Patient is critically ill and undergoing emergency tracheal intubation with 
sedation in an enrolling unit 
5. Planned procedure is orotracheal intubation using a laryngoscope 
6. Planned operator is a clinician expected to routinely perform tracheal  
intubation in the participating unit 
 
Exclusion Criteria 
11. Patient is known to be less than 18 years old 
12. Patient is known to be pregnant 
13. Patient is known to be a prisoner 
14. Patient is known to have an allergy to ketamine or etomidate 
15. Patient is presenting to the emergency department with a primary diagnosis 
of trauma  
16. Patient or LAR declines participation during pre-enrollment opt-out 
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17. Clinician feels ketamine is required or contraindicated for the optimal care 
of the patient 
18. Clinician feels etomidate is required or contraindicated for the optimal care 
of the patient 
19. Clinician feels an induction medication other than ketamine or etomidate is 
required for the optimal care of the patient 
20. Immediate need for tracheal intubation precludes safe performance of study 
procedures 
Consent 
Emergency tracheal intubation of critically ill patients is a time-sensitive 
procedure with a brief therapeutic window between the decision to perform 
intubation and the completion of the procedure. A written informed consent is 
available and will be used when feasible in RSI. However, it is expected that 
written consent will be infeasible in most, if not all, cases because delaying the 
emergency tracheal intubation of critically ill adults would cause irreparable 
harm to patients. Therefore, it is expected that most, if not all, patients will be 
enrolled under “Exception from informed consent required for emergency 
research” (EFIC).  
 
In conformance with EFIC requirements, measures to protect the rights and 
welfare of subjects will include: a) community consultation, b) public disclosure 
of plans to conduct the trial, c) public disclosure of trial results, d) independent 
data monitoring, and e) opportunity for pre-randomization opt-out (when 
feasible) and notification of the patient, legally authorized representative, or a 
family member at the soonest feasible opportunity of a patient’s enrollment in 
the trial with an opportunity to discontinue trial participation. 
 
For patients who are enrolled under EFIC and survive the intubation, the 
research team will approach the patient or legally authorized representative to 
obtain consent for the collection of long-term outcomes.  
Randomization 
 
Eligible patients will be randomized 1:1 to ketamine versus etomidate. 
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 operators 
until after the decision has been made to enroll the patient in the study. 
Following enrollment, the trial will not blind patients or treating clinicians to 
study group assignment. 
Primary Outcome of RSI 
trial 
All-cause, 28-day in-hospital mortality 
 
Secondary Outcome of 
RSI trial 
Cardiovascular Collapse, a composite of any of the following between induction 
and 2 minutes after intubation:  
o Systolic blood pressure < 65 mmHg 
o New or increased vasopressors  
o Cardiac arrest not resulting in death within 1 hour of induction 
o Cardiac arrest resulting in death within 1 hour of induction 

 
 
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Exploratory Outcomes of 
RSI trial 
• 
Procedural Characteristics & Complications 
o 
Cormack-Lehane Grade of glottic view 
o 
Successful intubation on the first attempt, defined as placement of 
an endotracheal tube in the trachea with a single insertion of a 
laryngoscope blade into the mouth and EITHER a single insertion 
of an endotracheal tube into the mouth OR a single insertion of a 
bougie into the mouth followed by a single insertion of an 
endotracheal tube over the bougie into the mouth. 
o 
Time from induction to successful tracheal intubation 
o 
Lowest oxygen saturation between induction and two minutes after 
intubation 
o 
Lowest oxygen saturation < 80% between induction to two minutes 
after intubation  
o 
Highest and lowest systolic blood pressure from induction to two 
minutes after intubation 
o 
Systolic blood pressure > 180 between induction and two minutes 
after intubation 
o 
Systolic blood pressure < 65 mmHg between induction and 2 
minutes after intubation 
o 
New or increased vasopressor between induction and 2 minutes 
after intubation 
o 
Cardiac arrest within 2 minutes of intubation not resulting in death 
o 
Cardiac arrest within 2 minutes of intubation resulting in death 
• 
Short-term Clinical Outcomes 
o 
Ventilator-free days to study day 28 
o 
Vasopressor-free days to study day 28 
o 
ICU-free days to study day 28 
Safety Outcomes of RSI 
trial 
• 
Systolic blood pressure at 24 hours after induction 
• 
Receipt of vasopressors at 24 hours after induction 
• 
Cardiac arrest receiving cardiopulmonary resuscitation between 
induction and hospital discharge 
Long-term Outcomes 
(RSI-LTO) 
For patients who provide consent for collection of long-term outcomes, the 
outcomes listed in Appendix E will be collected by phone at 3 and 12 months.  
The main long-term outcome will be symptoms of post-traumatic stress disorder 
(PTSD) at 12 months. 
Analysis 
The primary analysis will be an unadjusted, intention-to-treat comparison of 
patients randomized to ketamine versus patients randomized to etomidate with 
regard to the primary outcome.  
 
 
 

 
 
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2. TRIAL DESCRIPTION 
2.1 Background 
Each year more than 1.5 million critically ill adults receive invasive mechanical ventilation in the United 
States,1–3 at a cost of nearly $30 billion dollars annually.1,2 Recent research has dramatically improved 
patient safety during the maintenance, weaning, and liberation stages of invasive mechanical 
ventilation.4,5 In contrast, the optimal approach to the initiation of mechanical ventilation remains an 
important knowledge gap in the care of adults with respiratory failure. Among critically ill adults, life-
threatening complications during tracheal intubation and initiation of invasive mechanical ventilation 
remain common. One in five patients experiences hypotension and one-in-forty experiences cardiac arrest 
during the two-minute tracheal intubation procedure.6–10  
2.1.1 Cardiovascular Collapse during Intubation 
Cardiovascular collapse is a peri-procedural outcome defined as severe hypotension, new or increased 
vasopressors, cardiac arrest or death. The occurrence of cardiovascular collapse during tracheal intubation 
of critically ill adults increases patients’ risk of in-hospital mortality.11 Randomized trials examining 
intubation technique commonly target cardiovascular collapse as an outcome.12–14 Adherence to 
recommended best-practices for tracheal intubation (e.g., preoxygenation,15,16 optimization of patient 
positioning,9 and procedural checklists8) are insufficient to prevent 20-40% of critically ill adults from 
experiencing cardiovascular collapse during tracheal intubation.12,14,17–19  
2.1.2 Sedative Medications Contribute to the Risk of Cardiovascular Collapse 
Rapid sequence induction and tracheal intubation, the most common method of intubation for critically ill 
patients, is the nearly simultaneous administration of a sedative medication and neuromuscular blocking 
medication. The ideal sedative agent for rapid sequence intubation would rapidly provide a deep state of 
unconsciousness and analgesia without causing hemodynamic side effects. No available agent meets all of 
these criteria.20  The administration of any of the available sedative agents at a dose large enough to 
rapidly induce unconsciousness contributes to cardiovascular collapse through vasodilation, decreased 
cardiac filling pressures from sedation-induced venodilation, and decreased endogenous 
catecholamines.21–24 While all sedatives commonly used during emergency tracheal intubation of 
critically ill patients have been associated with unsatisfactory hypotension (21 CFR 50.24(a)(1)), 
ketamine and etomidate are the medications used most commonly in clinical practice due to their rapid 
onset and favorable hemodynamic profiles relative to the other available sedatives.25,26 Other sedatives 
that have been used in some settings during rapid sequence intubation include benzodiazepines, propofol, 
and barbiturates.  Benzodiazepines do not provide any analgesia and are associated with an unsatisfactory 
degree of hypotension, with a drop in mean arterial blood pressure of 10 to 25 percent, even among 
healthy patients.27–29  At present, barbiturates are rarely used for tracheal intubation in the US because of 
unsatisfactorily high rates of post-intubation hypotension and evidence of negative cardiac ionotropy.30  
While propofol is commonly used to induce anesthesia among healthy patients, and is commonly 
administered as a continuous infusion to maintain sedation for critically ill patients, it is used less 
commonly as a bolus during tracheal intubation of critically ill patients because it has been suggested to 
cause unsatisfactorily high rates of hypotension and cardiac depression, compared to ketamine or 
etomidate.31,32 

 
 
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2.1.3 Ketamine as a Sedative during Tracheal Intubation.  
Ketamine is a phencyclidine derivative that provides anesthesia via its effect at the NMDA receptors. 
Ketamine has been approved by the United States Food and Drug Administration (FDA) with approved 
indications including “use as the sole anesthetic agent for diagnostic and surgical procedures that do not 
require skeletal muscle relaxation” and “induction of anesthesia prior to the administration of other 
general anesthetic agents.” In addition to sedation, ketamine provides significant amnesia and analgesia 
via action at the opioid receptors, and is commonly used for procedural sedation and as a continuous 
infusion to control pain.33  
Ketamine activates the sympathetic nervous system, stimulating the release of catecholamines,34 which 
may increase heart rate and blood pressure during intubation and prevent peri-procedural cardiovascular 
collapse.33 Conversely ketamine has direct negative ionotropic effects, leading to myocardial 
depression.30,35,36 While the myocardial depression may be counteracted by increased catecholamine 
release, ketamine could cause cardiovascular collapse among patients with depleted catecholamine stores, 
and case reports of unexpected cardiac arrest during intubations with ketamine have been published.37 
Despite stimulating the release of catecholamines, using ketamine as the induction agent during 
emergency tracheal intubation does not appear to frequently cause or worsen hypertensive urgency or 
emergency; however, the literature on this topic is limited to case reports.38 
Historically, concerns have been raised that ketamine might increase intracranial pressure and cause 
deleterious decreases in cranial perfusion pressure. Recent studies have suggested, however, that 
ketamine may be associated with a beneficial increase in cranial perfusion pressure as a result of 
increased mean arterial pressure,39,40 and a recent, large before-after study showed no significant 
differences in clinical outcomes for trauma patients intubated with ketamine versus etomidate.41  
2.1.4 Etomidate as a Sedative during Tracheal Intubation.  
Etomidate is an imidazole derivative that acts at gamma-aminobutyric acid “A” (GABA) receptors. 
Etomidate has been approved by the FDA with an indication for “induction of general anesthesia.” In a 
recent review of more than 19,000 intubations by a large, multicenter emergency medicine registry, 
etomidate was the most commonly used sedative during emergency tracheal intubation.26  
Etomidate causes less hemodynamic instability than propofol42 and midazolam,27 but the data regarding 
the relative risk of hemodynamical instability with etomidate, compared to ketamine, is unclear.  It was 
initially suggested that ketamine might cause less hypotension than etomidate, given ketamine’s ability to 
stimulate the release of catecholamines,43,44 but a recent observational study comparing ketamine and 
etomidate among nearly 7,000 critically ill adults undergoing tracheal intubation in emergency 
departments suggested that ketamine was independently associated with an increased risk of peri-
intubation hypotension.26 
Etomidate was initially used both for induction of anesthesia and as a continuous drip for maintenance of 
anesthesia. Its use as a continuous drip for maintenance of anesthesia was halted after it was discovered 
that prolonged use of etomidate causes inhibition of adrenal cortisol production by blockade of 11-β-
hydroxylase, leading to adrenal insufficiency, and increased mortality.45–47 Etomidate use as a single bolus 
for induction of anesthesia has continued, but numerous studies have demonstrated that even a single dose 
of etomidate can cause transient adrenal insufficiency.48–53 The clinical significance of this relative 

 
 
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adrenal insufficiency, however, remains unclear. Contrasting observational studies have suggested that 
etomidate may have positive,41,54 negative 47,52,55–57 or neutral impacts41,48,49,51,58,59 on mortality.  
2.1.5 Prior Evidence from Clinical Trials.  
Two randomized trials have directly compared ketamine to etomidate for RSI among critically ill 
adults.60,61  
The Ketased trial, published in 2009, was a 469-patient trial conducted across 12 emergency medical 
services and emergency departments in France.60 Because many patients were enrolled in the pre-hospital 
setting without continuous blood pressure monitoring, peri-procedural outcomes such as cardiovascular 
collapse were not collected, and the results were indeterminate, in regards to the primary outcome, 
average Sequential Organ Failure Assessment (SOFA) scores in the 72 hours after intubation. The results, 
however, demonstrated significant heterogeneity. Patients with trauma (for whom increased intracranial 
pressure from ketamine may be important) experienced a non-significant 4% absolute increase in 
mortality when intubated with ketamine compared to etomidate. All other patients experienced a non-
significantly lower mortality when intubated with ketamine, particularly patients with sepsis who 
experienced a non-significant 7% absolute mortality benefit (and in whom adrenal insufficiency from 
etomidate may be particularly important). 
The EvK trial, published in January 2022, was a single-center, 801-patient trial conducted among 
hospitalized patients at a single hospital in Texas.61  Survival at 7 days, the primary outcome of the EvK 
trial, was higher in the ketamine group, compared to the etomidate group (85.1% vs 77.3%; p=0.005), but 
this difference was attenuated by day 28, at which point it was no longer significant (66.8% vs 64.1%, 
p=0.294).  The conclusion of this single-center trial was that “there was no significant difference in 
survival by Day 28”, however it was noted that this “could represent a small but durable long-term 
survival effect, one which our trial was under-powered to detect.”61 
2.1.6 Rationale for a Trial of Ketamine vs Etomidate in Non-Traumatic Critical Illness.  
Experts have pointed out that the currently available data on sedative choice during tracheal intubation of 
critically ill patients are inadequate and have called for additional randomized clinical trials.48,49,62 
Because (1) cardiovascular collapse is common during tracheal intubation of critically ill adults (2) 
sedatives are a driver of cardiovascular collapse, (3) use of ketamine or etomidate varies between centers, 
specialties, and operators, and (4) prior data suggests the potential for ketamine to significantly decrease 
mortality for patients without trauma, a large, multicenter trial is needed to determine the effects of 
ketamine and etomidate on mortality in non-traumatic critical illness.  
2.1.7 Rationale for Two Stages of the RSI trial. 
Stage 1 of the RSI trial will focus on feasibility and short-term, peri-procedural outcomes.  This stage is 
required to demonstrate the feasibility of performing a pragmatic trial comparing ketamine to etomidate 
during emergency tracheal intubation of critically ill adults under exception from informed-consent 
(EFIC) requirements for emergency research (under FDA code of regulations 21 CFR 50.24.7).99,100   
Stage 1 of the RSI trial (funded by the National Heart, Lung, and Blood Institute; grant number, 
K23HL153584) is designed to be of sufficient size to inform the effects of ketamine and etomidate on the 
short-term, peri-procedural outcome of cardiovascular collapse. 

 
 
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Stage 2 of the RSI trial will focus on the effect of ketamine vs etomidate on in-hospital mortality. Data on 
the effects of ketamine and etomidate on the short-term, peri-procedural outcome of cardiovascular 
collapse (the primary outcome of stage 1) could make an immediate impact on the use of these 
medications in clinical practice. However, the effects of ketamine and etomidate on in-hospital mortality 
may be mediated by mechanisms presenting after the peri-procedural period (e.g. adrenal insufficiency or 
increased intracranial pressure), and the effects of ketamine and etomidate on cardiovascular collapse 
may, therefore, be discordant with their effects on in-hospital mortality. A finding in stage 1 of the RSI 
trial that ketamine decreases, increases, or has no impact on cardiovascular collapse would in no way 
detract from the need for definitive data on the effect of ketamine and etomidate on in-hospital mortality.  
Completing a feasibility trial, closing enrollment, and subsequently initiating a separate, new, definitive 
trial using the same study design is inefficient.  Such an approach introduces delays in enrollment 
between the stages and fails to make use of data on clinical outcomes from patients enrolled during the 
feasibility stage.  This increases the total number of patients who must experience the potential risks of 
trial participation to obtain a definitive answer to the research question. The RSI trial is, therefore, 
planned as a single, adaptive trial with two stages.  
To increase efficiency and minimize the number of patients exposed to the potential risks of trial 
participation, the RSI trial is designed to allow progress from the stage assessing feasibility (Stage 1) to 
the stage assessing effectiveness (Stage 2) if the following criteria are met: (1) the data and safety 
monitoring board (DSMB) determines that the feasibility and safety of conducting the trial have been 
demonstrated; (2) the investigators determine that the observed enrollment rate, protocol compliance, 
separation between groups in receipt of the assigned therapy, and data completeness and quality permit 
progression to Stage 2; and (3) funding for a multicenter trial is available. Additional details regarding the 
progression from Stage 1 to Stage 2 are providing in section 10.3 of the protocol.   
2.2 Study Aims and Hypotheses 
2.2.1 Study aims 
Stage 1: To compare the effects of ketamine versus etomidate on cardiovascular collapse during tracheal 
intubation of critically ill adults.  To evaluate the feasibility of conducting a pragmatic trial of ketamine 
versus etomidate during tracheal intubation of critically ill adults in the ED or ICU using EFIC. 
Stage 2: To compare the effects of ketamine versus etomidate on in-hospital mortality among non-
traumatic critically ill adults undergoing tracheal intubation in the ED or ICU 
2.2.2 Study hypothesis 
Stage 1: Conducting a pragmatic trial comparing ketamine versus etomidate during tracheal intubation of 
non-traumatic critically ill adults in the ED or ICU using EFIC will be feasible. Ketamine will decrease 
the incidence of cardiovascular collapse.    
Stage 2: Ketamine will decrease the incidence of in-hospital mortality among non-traumatic critically ill 
adults undergoing intubation in the ED or ICU. 

 
 
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2.3 Study Design 
We will conduct an investigator-initiated non-blinded, pragmatic, parallel-group, randomized clinical trial 
evaluating the effect of ketamine versus etomidate on clinical outcomes of non-traumatic critically ill 
adults undergoing tracheal intubation in the ED and ICU. 
 
3. STUDY POPULATION AND ENROLLMENT 
3.1 Inclusion Criteria 
4. Patient is critically ill and undergoing emergency tracheal intubation with sedation in an enrolling 
unit 
5. Planned procedure is orotracheal intubation using a laryngoscope 
6. Planned operator is a clinician expected to routinely perform tracheal intubation in the 
participating unit 
3.2 Exclusion Criteria 
11. Patient is known to be less than 18 years old 
12. Patient is known to be pregnant 
13. Patient is known to be a prisoner 
14. Patient is known to have an allergy to ketamine or etomidate 
15. Patient is presenting to the emergency department with a primary diagnosis of trauma  
16. Patient or LAR declines participation during pre-enrollment opt-out conversation or by wearing 
opt-out bracelet for the RSI trial 
17. Clinician feels ketamine is required or contraindicated for the optimal care of the patient 
18. Clinician feels etomidate is required or contraindicated for the optimal care of the patient 
19. Clinician feels an induction medication other than ketamine or etomidate is required for the 
optimal care of the patient 
20. Immediate need for intubation precludes safe performance of study procedures 
 
3.3 Justification of Exclusion Criteria 
The RSI trial is intended to be broadly inclusive of critically ill patients who would receive ketamine or 
etomidate during intubation in usual care. The purpose of the exclusion criteria is to prevent the 
enrollment of patients who should not be enrolled under EFIC, patients who have a contraindication to 
study medications, or patients who have an indication for an alternative treatment. Pregnant women and 
prisoners are explicitly excluded from studies performed under EFIC. Patients with trauma are excluded 
from the RSI trial given the concern that ketamine may cause increased intracranial pressure among 
patients with head trauma.  No patients will be excluded on the basis of race, ethnicity, or sex.  
 

 
 
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4. Process of Obtaining Informed Consent 
 
Respect for human subjects and their safety is paramount in clinical research. Clinical research aiming to 
evaluate optimal care for critically ill adults during an emergency procedure presents unique ethical 
challenges. Protecting patient autonomy through the informed consent process is an ethical cornerstone of 
human subjects research.   
An informed consent document is available and will be used to obtain written informed consent from the 
patient or legally authorized representative for participation in the trial, when feasible. However, it is 
expected that obtaining written informed consent will be infeasible in most, if not all, cases due to:  
3. The expected medical condition of the patient. Based on prior trials in the same patient 
population and setting, approximately 70% of patients eligible for the trial will be experiencing 
encephalopathy (altered mental status) and the median Glasgow coma scale score will be 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 the trial will not have the capacity to provide informed consent.   
4. Sufficient time for the patient or legally authorized representative to consider participation 
& circumstances for consent that minimize the possibility of undue influence.  Even in 
instances in which a patient retains decisional capacity, or a legally authorized representative 
(LAR) is immediately available, the rapidity with which emergency tracheal intubation is 
clinically required (and the accompanying distress of the patient or LAR from the critical illness 
and need for emergency tracheal intubation) precludes execution of a meaningful informed 
consent process.  Although no published literature quantifies the time from the decision to 
perform emergency tracheal intubation (the inclusion criteria for the trial) until the initiation of 
intubation (the trial intervention), among a convenience sample of 25 consecutive critically ill 
adults undergoing emergency tracheal intubation in the VUMC ED or ICU, approximately 50% 
of intubations occurred within 5 minutes, 75% of intubations occurred within 10 minutes, and no 
intubations occurred longer than 30 minutes after treating clinicians verbalized the decision to 
intubate (or placed a written order for an induction medication).  Obtaining informed consent for 
research requires research personnel to assess decisional capacity, identify an 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 therefore cannot be executed in the 5 minutes 
before emergency tracheal intubation of a critically ill adult or their LAR in the ED or ICU.  
Moreover, obtaining informed consent for participation in research in the minutes before 
emergency tracheal intubation from a distressed patient or LAR places the informed consent 
process for research adjacent to the receipt of life-saving care and risks blurring the distinction 
between treatment and research.  Emergency tracheal intubation of critically ill adults is, 
definitionally, a time-sensitive procedure for which every minute of 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. 
 

 
 
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The RSI trial comparing ketamine versus etomidate during tracheal intubation of critically ill adults can, 
therefore, only be conducted with exception from informed consent (EFIC) for emergency research, and it 
is expected that most, if not all, patients will be enrolled under “Exception from informed consent 
required for emergency research” (EFIC).  
Complete details of the plan for conducting the RSI trial in compliance with FDA regulation for EFIC are 
provided in Appendix B.  In coordination with the IRB, investigators for the RSI trial will conduct 
community consultation and public disclosure prior to beginning enrollment (see Community 
Consultation and Public Disclosure Plan).  The trial will be overseen by the IRB and an independent data 
and safety monitoring board.   
 
While the nature of emergency tracheal intubation precludes a full, written, informed consent process in 
most, if not all, cases, the RSI trial will provide an opportunity for patients, LARs, or family members to 
object to participation based on more limited information whenever feasible using a pre-enrollment opt-
out script (details in section 13.3).  
4.1 Post-Enrollment Notification 
After enrollment of each patient, study personnel will attempt to notify the patients, LAR, or family 
members of enrollment in the trial in person at the soonest feasible opportunity. Notification of 
enrollment will be performed by research team members trained in informed consent processes, HIPAA 
laws, and the trial protocol. Patients or family members will be provided with a notification document 
approved by the Institutional Review Board (IRB). In the event that the patient, LAR, or family member 
cannot be contacted in person (for example, if they are outside of the state), study personnel will notify by 
telephone or by registered mail. There is no single timeline that is appropriate for all patients or families 
who are dealing with issues surrounding emergency tracheal intubation in the setting of critical illness. 
Study personnel will coordinate with treating clinicians to incorporate the judgement of treating clinicians 
as to the appropriate timing of notification for a given patient.  For cases in which a LAR or family 
member cannot be reached and the patient does not survive their critical illness, study personnel will send 
a letter approved by the IRB. Study personnel will keep a log that reflects the required steps for 
contacting the LAR or family member. The notification tracking log will be completed for each patient 
enrolled and included in the patient’s research records. 
 
Patients, families, or LARs may decline follow-up or access to medical record review, as stated in the 
notification document. If a patient, family or LAR declines follow up or access to medical record review, 
this information will be documented in the patient’s research record, along with the date and reason. As 
suggested in federal regulations for EFIC, the study investigators may examine data collected prior to 
patient withdrawal as this is necessary to maximize understanding of the safety of the study intervention, 
but the study team will not access the subject’s medical records after the date of discontinuation (even if 
the subject has not been discharged from the hospital). As suggested in federal regulations the study team 
may access data about the patient’s death from public vital statistics records and other public records not 
subject to restriction under 21 CFR 50.24 or other FDA regulations. 

 
 
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4.2 Consent for Long-Term Follow-Up 
For patients enrolled and notified under EFIC, the research team will continue to follow for an 
opportunity to consent the patient or LAR for collection of long-term outcomes at 3 and 12 months 
(additional details in Appendix E).  
In some cases, consent for long-term outcomes may occur at the same time as post-enrollment 
notification, shortly after intubation.  However, because federal regulations for EFIC require that post-
enrollment notification occur at the soonest feasible opportunity, even if the only person available to be 
notified is a family member who is not a LAR for the patient, consent for long-term outcome collection 
may occur days after post-enrollment notification. In some cases (e.g., where a LAR is not available and 
the patient does not regain decisional capacity before hospital discharge), written informed consent for 
long-term outcome collection may occur by phone following hospital discharge. 
 
5.0 Enrollment and Randomization  
Patients will be enrolled at the time that treating clinicians have decided to pursue tracheal intubation and 
confirmed that the patient meets eligibility criteria. The enrollment materials for the RSI trial will include 
instructions for a pre-procedural timeout to review the inclusion and exclusion criteria prior to enrollment. 
This process requires less than 10 seconds and can be easily completed during the 2-minute 
preoxygenation period. This approach has been successfully used in multiple prior trials.7–10  
Patients who are enrolled will be randomized 1:1 to ketamine or etomidate using random permuted blocks 
of two, four, and six.  Study group assignment will be stored and concealed prior to enrollment using 
opaque envelopes or the Randomization Module in the online database REDCap.  
5.1 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, site 
investigators will report it to the trial primary investigators and coordinating center within 24 hours of 
becoming aware of the occurrence. If the enrollment meets criteria for a protocol violation (section 12.6), 
it will be to the DSMB and IRB within 7 days of the site becoming aware of the occurrence.   
5.2 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. 
 
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 have been a prisoner, 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 except the anonymous study ID, study site, and the randomized group assignment. If a patient is not 

 
 
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a prisoner at the time of enrollment and becomes a prisoner between enrollment and the end of study 
follow up, all study procedures will stop immediately, the patient will be withdrawn from further 
participation the study, and no additional information will be entered into the study record. 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. 
 
6.0 Blinding  
The trial will not blind patients or treating clinicians to study group assignment. Obscuring treatment 
assignment in a controlled trial is particularly important when the outcomes are subjective, such as 
alleviation of pain, but less important for objective criteria, such as hypotension, cardiac arrest, or death.63 
Treating clinician’s awareness of study group assignment in the current trial may predispose to 
differential administration of co-interventions. For example, patients in the etomidate group may be more 
likely to be treated by clinicians with corticosteroid replacement therapy. In an explanatory trial focused 
on the mechanistic effects of a medication, such a difference in co-intervention could be viewed as 
confounding. In a pragmatic trial, the intent is to compare the manner in which the two interventions of 
interest would be administered as a part of routine clinical practice. Therefore, if patients in the etomidate 
group are administered corticosteroids at a higher rate than in the ketamine group, but the clinical 
outcomes in such circumstances are not different between groups, this provides the most robust answer to 
the question of the comparative effectiveness of ketamine versus etomidate for RSI as a part of routine 
clinical care.  
 
7. STUDY INTERVENTIONS 
7.1 Treatment of Study Patients 
Timing of study procedures is based on the time of the administration of sedative medication (e.g., 
ketamine or etomidate), which is the first step of rapid sequence induction and tracheal intubation and 
will be defined as “Time 0.”.  
Study medications will be administered by the same treating clinicians (e.g., registered nurse, physician, 
pharmacist) who would administer those medications as part of routine clinical care. 
7.2 Ketamine Group 
Patients in the ketamine group will be assigned to receive intravenous ketamine for induction of 
anesthesia during tracheal intubation. A dose of 2 mg/kg will be recommended, and the group assignment 
sheet will contain a nomogram providing the recommended dose for a range of patient weights (in pounds 
and kg). In this pragmatic trial, treating clinicians will be able elect to give a lesser or greater dose of 
ketamine than recommended if felt to be required for optimal patient care.      

 
 
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7.3 Etomidate Group 
Patients in the etomidate group will be assigned to receive intravenous etomidate for induction of 
anesthesia during tracheal intubation. A dose of 0.3 mg/kg will be recommended, and the group 
assignment sheet will contain a nomogram providing the recommended dose for a range of patient 
weights (in pounds and kg). In this pragmatic trial, treating clinicians will be able elect to give a lesser or 
greater dose of etomidate than recommended if felt to be required for optimal patient care.      
7.4 Co-Interventions 
The RSI trial will control only the first sedative medication administered during the intubation procedure. 
Subsequent sedative boluses or drips will be determined by treating clinicians. Other aspects of tracheal 
intubation (e.g., pre-intubation fluid management, pre-oxygenation, choice of neuromuscular blocking 
medication, choice of laryngoscopy device) will be performed by treating clinicians according to 
standardized clinical protocols already in place in the study units. Co-interventions that could modify the 
effect of ketamine or etomidate on cardiovascular collapse or clinical outcomes (e.g., vasopressors, 
corticosteroids) will be prospectively recorded. 
7.5 Packaging and Labeling 
Ketamine and etomidate will be packaged and labeled by the manufacturers of the medications. The 
labeling will not be altered. As the study is unblinded, concealment of the study medication after 
randomization is not necessary. 
Ketamine has been approved by the United States Food and Drug Administration (FDA) and is 
commercially available with approved indications including “use as the sole anesthetic agent for 
diagnostic and surgical procedures that do not require skeletal muscle relaxation” and “induction of 
anesthesia prior to the administration of other general anesthetic agents.” Etomidate has been approved by 
the FDA and is commercially available with an indication for “induction of general anesthesia.” 
Because both agents are FDA-approved and will be used in a manner consistent with FDA-labeling and 
standard of care for tracheal intubation in the ED and ICU, labeling ketamine and etomidate as 
investigational drugs is unnecessary. At all times and all study sites, study medications will already 
include standard labeling applied by the manufacturer.  
The IND application for the RSI trial will, therefore, request a waiver of 21 CFR 312.6, which requires 
labeling of investigational new drugs with the statement: “Caution: New Drug—Limited by Federal (or 
United States) law to investigational use.” Given ED and ICU staff familiarity with the current labeling 
applied by the manufacturer, lack of investigational labeling will not pose a significant or unreasonable 
risk for any patient. In fact, investigational labeling could introduce increased risk to patients by 
introducing a new and unfamiliar label to a commonly used medication during a high-risk, time-sensitive 
procedure.  
7.6 Storage and Accountability 
The medications administered in this investigation will be stored and handled as they are in routine 
clinical care in the study units, in accordance with institutional policies for each medication. This will 

 
 
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include secure storage in pharmacy and in study units with the use of a password-protected secure 
medication storage devices (e.g. Omnicell machine). When treatment allocation is revealed at the time of 
enrollment, the assigned medication will be ordered, procured, prepared, and administered by clinical 
pharmacists, registered nurses, or physicians as it would be as part of routine clinical care. 
7.7 On-Study Monitoring 
This study will take place in high-acuity clinical care environments (EDs and ICUs) at the time of a 
procedure routinely performed as part of usual care. Thus, at the time of the study intervention, the patient 
will have in the room: a physician trained in the care of critically ill adults, a critical care or emergency 
medicine nurse, and usually a respiratory therapist and pharmacist. The patient will be receiving 
continuous invasive or non-invasive monitoring.  
 
The intravenous injection of either ketamine or etomidate produces anesthetic effects that last for less 
than 10 minutes. Therefore, patients will be intensely monitored, with treating clinicians at the bedside for 
the duration of the primary effects of the study agents. Following intubation, no additional monitoring is 
planned beyond what occurs in the usual care of critically ill patients who have received these 
medications. 
8. OUTCOMES 
8.1 Primary Outcome  
• 
All-cause, 28-day, in-hospital mortality 
 
8.2 Secondary Outcome  
• Cardiovascular Collapse, a composite of any of the following between induction and 2 minutes 
after intubation:  
o Systolic blood pressure < 65 mmHg 
o New or increased vasopressors  
o Cardiac arrest not resulting in death within 1 hour of induction 
o Cardiac arrest resulting in death within 1 hour of induction 
 
8.3 Exploratory Outcomes 
• 
Procedural Characteristics & Complications 
o Cormack-Lehane Grade of glottic view 
o Successful intubation on the first attempt, defined as placement of an endotracheal tube in 
the trachea with a single insertion of a laryngoscope blade into the mouth and EITHER a 
single insertion of an endotracheal tube into the mouth OR a single insertion of a bougie 
into the mouth followed by a single insertion of an endotracheal tube over the bougie into 
the mouth. 
o Time from induction to successful tracheal intubation 
o Lowest oxygen saturation between induction and two minutes after intubation 
o Lowest oxygen saturation < 80% between induction to two minutes after intubation  

 
 
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o Highest and lowest systolic blood pressure from induction to two minutes after intubation 
o Systolic blood pressure > 180 between induction and two minutes after intubation 
o Systolic blood pressure < 65 mmHg between induction and 2 minutes after intubation 
o New or increased vasopressor between induction and 2 minutes after intubation 
o Cardiac arrest within 2 minutes of intubation not resulting in death within 1 hour of 
induction 
o Cardiac arrest within 2 minutes of intubation resulting in death within 1 hour of induction 
• 
Short-term Clinical Outcomes 
o Ventilator-free days to study day 28 
o Vasopressor-free days to study day 28 
o ICU-free days to study day 28 
8.4 Safety outcomes  
• 
Systolic blood pressure at 24 hours after induction 
• 
Receipt of vasopressors at 24 hours after induction 
• 
Cardiac arrest receiving cardiopulmonary resuscitation between induction and hospital discharge 
 
8.5 Long-term outcomes  
• 
Long-term outcomes for RSI (RSI-LTO) are described in Appendix E 
 
9. DATA COLLECTION 
Data will be stored in the secure, online database REDCap. A trained independent observer, not involved 
in the performance of the procedure, will collect peri-procedural outcomes, including oxygen saturation 
and systolic blood pressure at the time of induction, lowest oxygen saturation and lowest systolic blood 
pressure between induction and two minutes after tracheal intubation, peri-procedural cardiac arrest, and 
time from induction to intubation. This process for outcome collection has been used by the primary 
investigator during multiple prior trials with nearly perfect agreement with the reference standard of direct 
observation by research staff (Spearman's rho rank correlation coefficient = 0.998).9 Immediately after 
each intubation, the operator will report approach to preoxygenation, pre-intubation vasopressors, 
Cormack-Lehane grade of glottic view,64 airway complications during the procedure, and the level of 
operator experience.  Study personnel will manually collect data from the medical record on baseline 
characteristics, pre- and post-laryngoscopy management, and clinical outcomes.  
 
9.1 Baseline Variable Collection 
• Presence or absence of inclusion and exclusion criteria 
• Date and time of induction 
• Admission data: date and time of presentation, location at enrollment (ED, hospital ward, ICU) 
• Demographics (age, sex, race, ethnicity, height, weight) 
• Severity of illness score prior to induction 

 
 
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• Active medical problems at the time of induction 
• Active comorbidities complicating induction 
• Vasopressor use in the hour prior to induction 
• Noninvasive ventilator use in the 1 hour prior to induction 
• High flow nasal cannula use in the 1 hour prior to induction 
• Highest FiO2 delivered in the 1 hour prior to induction 
• Indication for intubation 
• Preoxygenation technique 
• Operator experience (number of prior intubations performed) 
• Receipt of corticosteroids in the 48 hours prior to induction 
• Vasopressor administration prior to or with induction 
• Oxygen saturation by pulse oximetry at time of induction  
• Systolic blood pressure at time of induction 
9.2 Peri-Procedural Variables 
• Lowest arterial oxygen saturation from induction to two minutes after intubation 
• Lowest systolic blood pressure from induction to two minutes after intubation 
• Highest systolic blood pressure from induction to two minutes after intubation 
• Vasopressor administration from induction to two minutes after intubation 
• Cardiac arrest from induction to one hour after intubation 
• Time from induction to tracheal intubation  
• Total number of attempts at intubation 
• Sedative agent and dose 
• Neuromuscular blocking agent and dose 
• Use of nasal cannula, high flow nasal cannula, oxygen by bag-valve-mask, ventilation by bag mask, 
non-invasive ventilation, or ventilation by laryngeal mask airway between sedative administration 
and intubation  
• Laryngoscope type 
• Use of a bougie 
• Presence of aspiration between induction and intubation 
• Cormack-Lehane grade of glottic view 
• Rescue device use 
• Need for additional operators 
• Mechanical complications (esophageal intubation) 
• Self-reported difficulty of the intubation 
9.3 Assessments between Hospital Presentation and Hospital Discharge 
• Cardiac arrest between one hour after intubation and hospital discharge  
• Oxygen saturation at 24 hours after intubation 
• FiO2 at 24 hours after intubation 
• PEEP at 24 hours after intubation 

 
 
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• Vital signs (e.g., heart rate, blood pressure, respiratory rate) and hemodynamic support (e.g., dose 
of vasopressors) during the hospitalization 
• Receipt of corticosteroids between induction and hospital discharge 
• Clinically recorded Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) scores 
on days 1-7 
• Clinically recorded Glasgow Coma Scale on days 1-7 
• Date and time of final receipt of invasive mechanical ventilation  
• Date and time of first and final receipt of vasopressors following sedative administration (if 
applicable)  
• Date and time of final ICU discharge (if applicable) 
• Date and time of hospital discharge (if applicable) 
• Date of death (if applicable) 
9.4 REDCap Clinical Data Interoperability Services 
This project will utilize the REDCap platform for data collection and management.  Project team 
members listed as Key Study Personnel with existing electronic health record (EHR) system access rights 
may also be granted use of REDCap Clinical Data Interoperability Services (CDIS) tools.  These tools are 
designed to enable transfer of relevant study-related data from the Vanderbilt Research Derivative (or 
local equivalents) and/or directly from the EHR into REDCap. 
 
10. STATISTICAL CONSIDERATIONS 
10.1 Stage 1 Sample Size Calculation 
Stage 1 of the RSI trial is primarily focused on feasibility. However, stage 1 will be of sufficient size to 
provide critical data on the short-term periprocedural outcome of cardiovascular collapse. Assuming that 
cardiovascular collapse will occur in 19% of patients in the etomidate group (a similar incidence as 
observed in a prior trial of airway management in which etomidate was the primary sedative),12 we 
calculate that enrolling 464 patients will provide 80% statistical power (at a two-sided alpha of 0.05) to 
demonstrate a relative risk reduction of 50% in the primary outcome of cardiovascular collapse in the 
ketamine group, compared to the etomidate group.  
10.2 Stage 2 Sample Size Calculation 
To estimate the incidence of in-hospital mortality in the etomidate group of stage 2 of the RSI trial, we 
used data from 656 adults undergoing tracheal intubation for non-traumatic critical illness who were 
recently enrolled from EDs and ICUs in two recent randomized trials in the ED and ICU. Among these 
patients, the incidence of 28-day in-hospital mortality was 31%. The minimum clinically important 
difference (MCID) in mortality used in the design of prior critical care RCTs has been an absolute risk 
reduction of a median of 8 percent (IQR, 6-10).65 We powered the RSI trial to detect a more conservative 
absolute risk reduction of 6 percent. This equates to an incidence of the primary outcome of 25% in the 
ketamine group and a relative risk of mortality with ketamine compared to etomidate of 0.81 – 

 
 
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comparable to the relative risk of 0.827 among adults with non-traumatic critical illness observed in the 
only prior RCT comparing ketamine vs etomidate.60 Achieving 80% statistical power at a two-sided alpha 
of 0.05 to detect a 6 percent absolute difference between groups in the primary outcome would require 
enrolling 911 patients per group (1,822 overall). Anticipating that, like prior EFIC trials, less than 5% of 
patients will discontinue participation after enrollment, we aim to enroll a total of 1,900 patients. 
10.2 Stage 2 Sample Size Re-Estimation 
At the time of progression from Stage 1 to Stage 2, the sample size estimate was updated. Using newly 
accrued data from clinical trials, the incidence of mortality by 1 month in the etomidate group was 
updated to 30%.66 Given the absolute difference in mortality between ketamine and etomidate in two 
small prior trials of 6-7%,67,68 patient and clinician stakeholders suggested that, for two common and 
inexpensive interventions, the trial should have adequate statistical power to detect an absolute difference 
between groups in mortality of approximately 5%. Thus, we used the bsamsize R function to calculate 
that achieving 80% statistical power at a two-sided alpha of 0.05 to detect a difference in mortality of 
5.2% (30.0% in the etomidate group vs 24.8% in the ketamine group) would require 2,308 patients. 
Anticipating that, like prior EFIC trials, less than 3% of participants will drop out before 1 month, we will 
enroll a total of 2,364 patients (1,182 per group). 
10.3 Progression from Stage 1 to Stage 2 of RSI 
At the time of initial trial planning, it was determined that if, between initiation of enrollment in Stage 1 
and enrollment of 464 patients in Stage 1, funding became available for Stage 2, the DSMB would 
perform a formal assessment of feasibility and issue a recommendation of whether the trial should 
progress from Stage 1 to Stage 2.  
 
To perform this assessment of feasibility, the DSMB reviewed data from at least 100 patients enrolled in 
Stage 1 regarding: 1) the rate of enrollment, 2) the number, proportion, and reasons for exclusion, 3) 
protocol adherence, 4) data quality, 5) compliance with the requirements of EFIC (under FDA code of 
regulations 21 CFR 50.24.7) including a review of the timeliness and success of patient or LAR 
notification,99,100 and 6) adverse events. Metrics upon which the DSMB could base their recommendation 
to progress to Stage 2 included: 
6. Enrollment of at least 16 patients per month. 
7. Appropriate documentation of patient eligibility and adherence to EFIC requirements for 
notification of enrollment for all patients. 
8. Greater than 95% of enrolled patients receiving the induction medication assigned by the trial 
9. Appropriate mechanisms for ongoing monitoring of EFIC compliance, tracking of excluded 
patients, and protocol adherence. 
10. Adequate completeness and timeliness of data entry. 
 
The initial trial protocol specified that if the DSMB recommended trial progress to Stage 2 and the 
investigators accept the DSMB’s recommendation, no analysis of Stage 1 outcomes (primary outcome of 
cardiovascular collapse) would be performed.  At the end of enrollment in Stage 2, all 2,364 patients 
enrolled in the trial (Stage 1 plus Stage 2) will be included in a single planned analysis of the Stage 2 
outcomes (primary outcome of 28-day in-hospital mortality).  

 
 
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On July 18, 2023, the investigators were notified that Stage 2 of the RSI trial had been funded by the 
Patient-Centered Outcomes Research Institute. The DSMB was provided with feasibility data from Stage 
1 and on August 1, 2023, recommended that the RSI trial advance to Stage 2. No outcome analyses were 
performed. 
10.4 Primary Analysis  
The primary analysis will be an intention-to-treat comparison of patients randomized to ketamine versus 
patients randomized to etomidate with regard to the primary outcome. The difference between the two 
study groups will be compared using a generalized linear mixed effects model with a random effect for 
study site (e.g., Vanderbilt University ED, Vanderbilt University Medical ICU) and a fixed effect for 
group assignment (ketamine group vs etomidate group). 
10.5 Secondary Analyses  
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 (e.g., Vanderbilt University ED, Vanderbilt 
University Medical ICU) and fixed effects for group assignment and the following pre-specified baseline 
variables: age; sex; race; ethnicity; area deprivation index (a proxy for socioeconomic status and an 
indicator of neighborhood disadvantage); rurality; number of comorbidities; and pre-enrollment severity 
of illness as assessed by the Acute Physiology and Chronic Health Evaluation II score. 
10.6 Subgroup Analyses 
To evaluate whether pre-specified baseline subgrouping variables modify the effect of study group 
assignment on the primary outcome, we will perform a generalized linear mixed effects model with a 
random effect for study site (e.g., Vanderbilt University ED, Vanderbilt University Medical ICU) with the 
primary outcome as the dependent variable and independent variables of study group, the proposed 
subgrouping variabke, and the interaction between the two.  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.  The 
subgrouping variables will be pre-specified in a statistical analysis plan that will be published before 
enrollment in the trial concludes. These variables will include:  
1. Sepsis or septic shock (Yes / No) 
2. Vasopressor receipt (Yes / No)  
3. Patient location (ED / ICU) 
4. Adrenal insufficiency or chronic receipt of corticosteroids (Yes / No) 
5. Acute neurologic condition (Yes / No) 
6. Active cardiac condition (Yes /No)  

 
 
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7. Baseline risk of the primary outcome (continuous) 
In addition to traditional one-variable-at-a-time subgroup analyses, we analyze heterogeneity of treatment 
effect using both a risk-modeling approach and an effect-modeling approach (see Appendix F), the details 
of which will be described in the statistical analysis plan published before the conclusion of enrollment. 
 
10.7 Interim Analysis 
The DSMB will review an interim analysis performed after the enrollment of 1,182 patients (50% of the 
anticipated trial enrollment). 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  generalized linear mixed effects model 
with a random effect for study site (e.g., Vanderbilt University ED, Vanderbilt University Medical ICU) 
and a fixed effect for group assignment (ketamine group vs etomidate group). 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). 
10.8 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 Administration69 and the European Medicines 
Association,70 each will be tested using a two-sided P value with a significance level of 0.05. For all other 
analyses, emphasis will be placed on the estimate of effect size with 95% confidence intervals, as 
recommended by the International Committee of Medical Journal Editors,71 and no corrections for 
multiple comparisons will be performed. 
10.9 Handling of Missing Data 
No patients will be lost to follow up before the measurement of the primary outcome, except those that 
choose to withdraw from the study. 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. 
 
11. DATA QUALITY MONITORING AND STORAGE 
11.1 Data Quality Monitoring 
Data quality will be reviewed using front-end range and logic checks at the time of data entry and back-
end monitoring of data using application programming interface tools connecting the online database to 
statistical software to generate data reports. The coordinating center will perform remote monitoring of 
documentation of eligibility criteria, completion of EFIC requirements, and the completeness of study 
outcome collection. 

 
 
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11.2 Data Storage  
Data will be entered into a secure online database. All data will be maintained in the secure online 
database until the time of study publication. At the time of publication, a de-identified version of the 
database will be generated. 
 
12. RISK ASSESSMENT 
12.1 Potential Risks of Receiving Ketamine 
Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound 
analgesia, normal pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle tone, 
cardiovascular and respiratory stimulation, and occasionally a transient and minimal respiratory 
depression. At an intravenous dose of 2 mg/kg of body weight, the onset of ketamine is rapid, usually 
producing surgical anesthesia within 30 seconds after injection. The anesthetic effect usually lasts five to 
ten minutes and the duration of action of the medication is less than fifteen minutes.  
Potential risks of receiving ketamine can be classified based on their severity as major or minor. Major 
potential risks of receiving ketamine include: 
6) Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration of 
ketamine alone. However, hypotension and bradycardia have been observed. Arrhythmia has also 
occurred. Elevation of blood pressure begins shortly after injection, reaches a maximum within a 
few minutes, and usually returns to preanesthetic values within 15 minutes after injection. In the 
majority of cases, the systolic and diastolic blood pressure peaks from 10% to 50% above 
preanesthetic levels shortly after induction of anesthesia. Regardless of which sedative is used, 
cardiovascular complications including hypotension and cardiac arrest are common during the 
tracheal intubation of critically ill adults. Determining whether or not use of ketamine for 
induction of anesthesia during intubation of critically ill adults effects the risk of cardiovascular 
events compared to etomidate is a key objective of the RSI trial. 
 
7) Respiration: Although respiration is frequently stimulated, severe depression of respiration or 
apnea may occur following rapid intravenous administration of high doses of ketamine. 
Laryngospasm has also been reported. Given that ketamine will be used in this trial only as part 
of the process of tracheal intubation and initiation of invasive mechanical ventilation, respiratory 
suppression from ketamine is not a significant concern in the RSI trial. 
 
8) Anaphylaxis: Allergic reactions to ketamine are extremely rare and only a few cases of 
anaphylaxis have been reported. Patients with known allergy to ketamine are excluded from the 
RSI trial.72,73  
 
9) Psychological: According to the FDA package insert for ketamine, adverse psychological 
manifestations with ketamine are common, reportedly occurring in up to 12% of patients. The 

 
 
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psychological manifestations vary in severity from pleasant dream-like states to hallucinations 
and emergence delirium. The duration is reported to be no more than several hours for most 
patients with rare occurrences up to 24 hours post postoperatively. Because patients in the RSI 
trial are critically ill and will receive ketamine at the time of tracheal intubation with a median 
duration of invasive mechanical ventilation and accompanying sedation and analgesia of 2-3 
days,10,12 psychological manifestations are unlikely to represent significant risk to patients in the 
RSI trial. 
 
10) Increased intracranial pressure: An increase in cerebrospinal fluid pressure has been reported 
following administration of ketamine hydrochloride and caution is recommended for patients 
with preanesthetic elevated cerebrospinal fluid pressure. However, the original evidence 
supporting this assertion is anecdotal and recent studies have contraindicated these findings, 
suggesting that ketamine may be associated with a beneficial increase in cranial perfusion 
pressure as a result of increased mean arterial pressure.39,40 Ketamine is routinely administered to 
patients with head trauma in routine clinical care in the study settings. However, to maximize 
patient safety, patients presenting with a primary diagnosis of trauma are excluded from the RSI 
trial.  
Minor potential risks of receiving ketamine include: diplopia, nystagmus, temporary increase in 
intraocular pressure, anorexia, nausea, and vomiting. Lower urinary tract and bladder symptoms have also 
been reported with chronic use. 
12.2 Potential Risks of Receiving Etomidate 
Etomidate is a rapidly acting general anesthetic without analgesic activity. At a dose of 0.3 mg/kg body 
weight, onset of action is usually within one minute with a duration of action of three to five minutes.  
Potential risks of receiving etomidate can be classified based on their severity as major or minor. Major 
potential risks of receiving etomidate include: 
5) Endocrine: Reduced plasma cortisol and aldosterone levels have been reported following the 
induction doses of etomidate that will be recommended in the RSI trial. These reductions in 
plasma cortisol and aldosterone persist for approximately 6-8 hours and appear to be 
unresponsive to ACTH stimulation.  They are likely related to blockage of 11 beta-hydroxylation 
within the adrenal cortex. Determining whether or not these transient reduction in cortisol and 
aldosterone levels influence clinical outcomes for patients is a key objective of the RSI trial. 
 
6) Circulatory: Hypertension, hypotension, tachycardia, bradycardia, and other arrhythmias have 
occasionally been observed during induction with etomidate. Geriatric patients, particularly those 
with hypertension, may be at increased risk for the development of cardiac depression following 
etomidate administration. Regardless of which sedative is used, cardiovascular complications 
including hypotension and cardiac arrest are common during the tracheal intubation of critically 
ill adults. Determining whether or not use of etomidate for induction of anesthesia during 
intubation of critically ill adults effects the risk of cardiovascular events compared to ketamine is 
a key objective of the RSI trial. 

 
 
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7) Respiration: Hyperventilation, hypoventilation, apnea of short duration (5 to 90 seconds with 
spontaneous recovery), laryngospasm, hiccup and snoring suggestive of partial upper airway 
obstruction have been observed in some patients. Given that etomidate will be used in this trial 
only as part of the process of tracheal intubation and initiation of invasive mechanical ventilation, 
respiratory suppression from etomidate is not a significant concern in the RSI trial. 
 
8) Anaphylaxis: Allergic reactions to etomidate are extremely rare and limited to one case of severe 
hypotension and tachycardia.  Patients with known allergy to etomidate are excluded from the 
RSI trial.  
Minor potential risks of receiving etomidate include: transient venous pain on injection (20% of the 
patients) and transient skeletal muscle movements (32% of patients) including myoclonus, nausea, or 
vomiting. 
12.3 Potential Risk of Participation in the RSI Trial 
The RSI trial will enroll critically ill adults whose treating clinicians have determined that (1) tracheal 
intubation is clinically required and (2) use of either ketamine or etomidate is consistent with optimal care 
for the patient.  Both ketamine and etomidate are FDA-approved medications being used within their 
FDA approved indications, and the only prior randomized trial reported no significant difference in 
outcome between the two medications.  More than 95% of patients undergoing tracheal intubation in the 
study sites receive either ketamine or etomidate as a part of routine clinical care.  All patients eligible for 
the RSI trial will experience the risks of emergency tracheal intubation and the risks of receipt of an 
induction medication such as ketamine or etomidate as a part of their routine clinical care, whether or not 
they are enrolled in the RSI trial.  The incremental risks of participation in the RSI trial are (1) the risk 
associated with collection of PHI and (2) the risk associated with allowing the choice between ketamine 
and etomidate to be made by trial group assignment rather than by the treating clinician.  Because the 
only patients eligible are those whose treating clinicians feel use of either ketamine or etomidate is 
consistent with optimal care, the incremental risk of participation in the RSI trial, compared to routine 
clinical care outside the trial, is minimal. 
12.4 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 subject protection 
requirement by incorporating numerous design elements to minimize risk to patients.  
Both therapies used in the RSI trial, ketamine and etomidate, are approved by the Food and Drug 
Administration and have been used in clinical practice for decades with an established safety profile in the 
same populations included in the RSI trial. Both medications will be administered at the recommended 
dose and route. 
To further mitigate risk, we will exclude patients with specific risk factors for adverse events from 
ketamine or etomidate including patients with known allergies to ketamine or etomidate, patients with a 
primary diagnosis of trauma, and any patient for whom treating clinicians believe that ketamine or 

 
 
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etomidate is required or contraindicated for the optimal care of the patient. Finally, 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.  
12.5 Potential Benefit 
Participation in the RSI trial holds the prospect of direct benefit to the subjects.  Previous animal and 
clinical studies have established several mechanisms by which either ketamine or etomidate might 
provide a direct benefit to individual critically ill subjects undergoing tracheal intubation via improved 
hemodynamics and survival. 
Determining whether ketamine or etomidate improves clinical outcomes among critically ill patients 
undergoing tracheal intubation in the ED or ICU will also benefit RSI trial patients who go on to require 
emergency tracheal intubation again in the future, as well as the millions of critically ill adults who 
undergo tracheal intubation each year.   
12.6 Risk in Relation to Anticipated Benefit 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in relation to 
anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be 
expected to result.”  The incremental risks of participation in the RSI trial, compared to routine clinical 
care outside the trial for eligible patients, are minimal as all patients enrolled in the RSI trial would have 
received a sedative as part of emergency tracheal intubation in routine clinical care, regardless of 
participation in the RSI trial.  Understanding the effect of these two commonly used medications on 
clinical outcomes will benefit RSI trial patients who go on to require emergency tracheal intubation again 
in the future, as well as the millions of critically ill adults who undergo tracheal intubation each year.  
Thus, the risks to subjects are reasonable in relation to the anticipated benefits and importance of the 
knowledge to be gained. 
 
13. HUMAN SUBJECTS PROTECTIONS 
Emergency tracheal intubation of critically ill adults is a time-sensitive procedure with a brief therapeutic 
window between the decision to perform intubation and the completion of the procedure. Critically ill 
patients requiring tracheal intubation are nearly uniformly unconscious, delirious, or in states of distress 
for which it would be unsafe to delay intubation for an informed consent discussion with the patient or a 
surrogate. Legally authorized representatives are rarely available during the narrow therapeutic window. 
Even in the rare cases where the patient retains decisional capacity or the patient’s legally authorized 
representative (LAR) is present at the bedside at the moment the decision is made to intubate a critically 
ill patient, the urgency of the intubation procedure would preclude the detailed discussion of risks and 
benefits required for informed consent in most, if not all, cases. 

 
 
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Therefore, it is expected that all patients will be enrolled under “Exception from informed consent 
required for emergency research” (EFIC).  Additional details regarding how the RSI trial will comply 
with each of the requirements of EFIC are provided in Appendix B. 
13.1 Length of Therapeutic Window 
For an induction medication used for emergency tracheal intubation, the therapeutic window begins at the 
time treating clinicians decide to perform emergency tracheal intubation with sedation and ends at the 
time an induction medication is administered for emergency tracheal intubation.  To our knowledge, no 
published literature has quantified this therapeutic window among critically ill adults.  Among a 
convenience sample of 25 consecutive critically ill adults undergoing emergency tracheal intubation in 
the ED or ICU in the planned study sites of the RSI trial, the median time from treating clinicians 
verbalizing the decision to intubate with sedation (or placing a written order for an induction medication) 
to the administration of an induction medication was 5 minutes [interquartile range, 1 minute to 10 
minutes].  For no patient was this window longer than 30 minutes.  Tracheal intubation of critically ill 
adults is a time-sensitive procedure for which every minute of delay increases the likelihood of 
hypoxemia, hypotension, and peri-procedural cardiac arrest.  For most patients in the RSI trial, 
completion of the trial intervention (a one-time injection at the start of the emergency tracheal intubation 
procedure) is anticipated to occur less than 5 minutes after meeting trial eligibility criteria.  Thus, in the 
RSI trial, we anticipate that the therapeutic window for most patients will be less than 5 minutes.   
13.2 Inability to Conduct Trial without EFIC 
Most patients eligible for the RSI trial will be experiencing unconsciousness or delirium due to critical 
illness.  More than half of critically ill adults undergoing tracheal intubation in the ED or ICU have a 
Glasgow Coma Scale score less than 12 (equivalent to moderate brain injury) and among those whose 
level of consciousness is not impaired, most experience acute delirium.  Even in instances in which a 
patient retains capacity, or an LAR is immediately available, the rapidity with which emergency tracheal 
intubation is clinically required, and the accompanying distress of the patient or LAR from the critical 
illness and need for emergency tracheal intubation, precludes a meaningful informed consent process in 
most, if not all, cases.  Delaying emergency tracheal intubation for a critically ill adults to attempt a 
meaningful informed consent process would be unsafe, impracticable, and unethical. 
One approach for obtaining prospective consent for interventions with short therapeutic window is to 
consent patients at high risk of requiring the intervention in the future.  Unfortunately, there is no 
reasonable method for prospectively identifying individuals who will develop a need for emergency 
tracheal intubation. Many different acute illnesses lead to emergency tracheal intubation in the ED or ICU 
including stroke, spontaneous intracranial hemorrhage, seizure, sepsis, drug overdose, acute coronary 
syndrome, aspiration pneumonitis, acute bacterial pneumonia, pneumothorax, and others. Any patient in 
the community or in the hospital may unexpectedly develop a need for emergency tracheal intubation 
within a period of minutes with no warning.  
For these reasons, the RSI trial could not be conducted without EFIC, and it is expected that all patients 
will be enrolled through EFIC.  

 
 
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13.3 Opportunity to Decline Participation 
 
Although it is expected that in most, if not all cases, the urgency of the procedure and the nature of the 
patient’s critical illness will preclude a detailed informed consent discussion between the trained research 
staff and the patient or LAR during the brief therapeutic window, a consent form will be available and the 
RSI trial will provide two mechanisms to opt-out of participation.   
First, medical alert bracelets will be made available prior to and throughout the trial for any community 
members who become aware of the trial and desire to express their preference against participation should 
they become critically ill and require tracheal intubation (details of public notification plan and process of 
requesting opt-out bracelets are provided in the Community Consultation and Public Disclosure Plan). 
Second, when feasible, the RSI trial will provide an opportunity for patients, LARs, or family members to 
express their objection immediately prior to research enrollment.  While the nature of emergency tracheal 
intubation precludes a full, written, informed consent process in most, if not all, cases, the RSI trial will 
provide an opportunity for patients, LARs, or family members to object to participation based on more 
limited information whenever feasible using a pre-enrollment opt-out script. This will occur in cases in 
which the patient retains decisional capacity or a family member or LAR is available, research staff are 
able to reach the patient or LAR before intubation, and treating clinicians have determined that based on 
the clinical status of the patient there is insufficient time to complete a formal informed consent process. 
The IRB-approved opt-out script will describe the study and provide an opportunity for patients, LARs, or 
family members to decline participation before enrollment (Appendix C). The decisional capacity of the 
patient and the safety and feasibility of reading the script during the brief therapeutic window will be 
determined by the treating clinicians.  Allowing a mechanism, whenever feasible, for patients to opt out 
of participation is consistent with the respect for autonomy emphasized in the EFIC guidelines.  
13.4 Notification of Enrollment 
At the earliest feasible opportunity, each patient, or if the patient remains incapacitated, a legally 
authorized representative of the patient, or if such a representative is not reasonably available, a family 
member, will be notified of the patient’s inclusion in the study. Details of the study will be provided, all 
questions will be answered, and the patient or patient’s LAR or family member will be informed of their 
right to discontinue study participation at any time without penalty or loss of benefits of which the patient 
is otherwise entitled. The patient or LAR or family member will be provided with a patient notification 
form which contains study details and contact information for study personnel and the IRB.  
Because the study intervention is a one-time injection occurring within minutes of enrollment, all patients 
will have completed the study intervention and experienced the risks and benefits of the study 
intervention by the time notification of participation occurs so written informed consent will not be 
obtained.  The only remaining study activity is review of the patient’s medical record by study personnel 
until the end of the patient’s hospitalization.  For those who wish to discontinue participation, no further 
data will be collected. Data collected prior to withdrawal will remain in the study database as per FDA 
requirements and guidance. 
A minimum of three attempts will be made to discuss the study with the patient or the patient’s LAR. 
Whenever feasible, this will occur in a face-to-face discussion in the hospital between trained study 

 
 
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personnel and the patient or LAR. If the patient is discharged before a face-to-face discussion occurs, 
these attempts will be made by phone, and a notification sheet will be mailed to the patient’s address. 
If a patient is enrolled in the RSI trial and dies before a face-to-face discussion with the patient or LAR, a 
reliable mailing address for the patient’s family or LAR will be obtained. After allowing a two to four-
week period of grieving, study personnel will send a letter with basic information about the clinical 
investigation, the patient’s inclusion, and contact information so that families can call or write to obtain 
more information or to get questions answered if desired. 
If the patient regains decision-making capacity prior to hospital discharge, study personnel will notify the 
patient of the study and ask if the patient wants to continue participation.  
13.5 Documentation and Tracking of Notification Process 
Notification logs will be incorporated into the study case report forms and will allow tracking and 
reporting of the timeliness of these processes. This log will include the types of attempts made, the 
number and timing of those attempts, and the outcome of each attempt. Notification logs will be available 
for IRB review as requested and will be summarized for the IRB at the time of continuing review.  
13.6 Selection of Subjects 
Federal regulations 45 CFR 46(a)(3) require the equitable selection of subjects. All patients undergoing 
tracheal intubation in a participating unit who meet inclusion criteria without meeting exclusion criteria 
will be enrolled. We will not discriminate based on gender, race, or ethnicity. Study exclusion criteria 
neither unjustly exclude classes of individuals from participation in the research nor unjustly include 
classes of individuals for participation in the research. Hence, the recruitment of patients conforms to the 
principle of distributive justice. 
13.7 Justification of Including Vulnerable Subjects 
The present research aims to investigate the safety and efficacy of ketamine and etomidate during the 
tracheal intubation of critically ill patients. Due to the nature of this patient population, most patients will 
have impaired decision-making capabilities. Moreover, those with intact decision-making capacities 
probably have milder disease than those with impaired capacity. Therefore, the validity of the study and 
its generalizability to severely ill patients would be compromised by enrolling only those patients with 
retained decision-making capacity. Hence, patients recruited for this trial are not being unfairly burdened 
with involvement in this research. 
13.8 Investigational New Drug Application 
As required by studies conducted under 21 CFR 50.24, the RSI protocol will be included as part of an 
Investigational New Drug Application to the United States Food and Drug Administration (FDA). The 
study will not proceed until the primary investigator has received written authorization from both the 
FDA and the Vanderbilt Institutional Review Board 

 
 
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13.9 Additional Safeguards for Vulnerable Patients 
The present research will involve patients who might be vulnerable to coercion or undue influence. As 
required in 45CFR46.111(b), we recommend that sites utilize additional safeguards to protect the rights 
and welfare of these patients. Such safeguards might include but are not limited to: a) assessment of the 
patient’s capacity to understand notification of enrollment and b) the availability of the LAR to monitor 
the patient’s participation and withdrawal from the study. The specific nature of the additional safeguards 
will be left to the discretion of the central IRB, in conjunction with the sites. 
13.10 Confidentiality 
Federal regulations 45 CFR 46 111 (a) (7) requires that, when appropriate, there are adequate provisions 
to protect the privacy of patients and to maintain the confidentiality of data. 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. All data collected for this study will be entered into a 
secure online database. All data will be maintained in the secure online database until the time of study 
publication. At the time of publication, a de-identified version of the database will be generated. Further, 
tools within the secure online database will be used so that only the coordinating center and investigators 
from the enrolling site will have access to data from patients enrolled at that site. 
 
14. ADVERSE EVENTS 
Assuring patient safety is an essential component of this protocol. Both ketamine and etomidate have 
been approved by the Food and Drug Administration and 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: 
4. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse events from 
ketamine or etomidate; 
5. Systematic collection of safety outcomes relevant to use of ketamine and etomidate in this setting; 
6. Structured reporting of adverse events. 
14.1 Adverse Event Definitions 
Adverse Event: Any untoward medical occurrence associated with the use of a medication or a study 
procedure, whether or not considered medication related. 
Serious Adverse Event: A serious adverse event is any adverse event that results in one of the outcomes 
listed in section 14.3 below.  

 
 
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Adverse Reaction: An adverse reaction means any adverse event caused by a study intervention. An 
adverse reaction is a subset of all suspected adverse events where there is a reason to conclude that the 
study intervention caused the event.  
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the 
study procedures caused the adverse event. Reasonable possibility means there is evidence to suggest a 
causal relationship between the study procedures and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction.  
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both 
unexpected (not consistent with risks outlined in the study protocol or investigator brochure), serious, and 
meets the definition of a suspected adverse reaction. 
14.2 Safety Monitoring 
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 for 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 as close as feasible to 24 hours after randomization during initial data 
collection.  The second will occur at the first of hospital discharge or 28 days after enrollment during 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. 
The following adverse events will be considered reportable and thus collected in the adverse event case 
report forms: 
 
 Serious adverse events that are considered by the investigator to be related to study 
procedures, possibly or probably related, or of uncertain relationship (Appendix D) 
 Unexpected adverse events that are considered by the investigator to be related to study 
procedures, possibly or probably related, or of uncertain relationship (Appendix D) 
Study-specific clinical outcomes (Primary, Secondary and Safety Outcomes), including serious 
outcomes such as organ failures and death, are systematically recorded in the case report forms 
and are exempt from adverse event reporting unless the investigator deems the adverse event to 
be serious and definitely related to the administration of study medication or the conduct of study 
procedures (or of uncertain relationship) as outlined in Appendix D.  
Because ketamine and etomidate are 1) FDA-approved, 2) used within their approved indications, 
and 3) have well-established safety profiles, the RSI trial will not plan to collect non-serious 

 
 
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adverse events as suggested in FDA guidelines for Investigator Reporting (21 CFR 312.64(b)) for 
post-marketing outcome trials conducted with an IND.  
Adverse events will be evaluated by the lead investigator at each enrolling site. If an adverse 
event is judged to be potentially reportable, as outlined above, then the lead investigator at each 
enrolling site will record the adverse event via electronic data entry for review. The principal 
investigator will be responsible for making final determinations regarding potential relatedness of 
adverse events, based on the criteria outlined in Section 14.3 and Appendix D. The principal 
investigators will also consider if the event is unexpected. Unexpected adverse events are events 
not listed in the study protocol or the investigator brochure for Ketamine or Etomidate. In making 
determinations, the principal investigator will determine if adverse events are unanticipated given 
the patient’s clinical course, previous medical conditions, and concomitant medications.  
14.3 Serious Adverse Events 
The lead investigator at each enrolling site must alert the primary investigator of any serious and study 
procedure related adverse event within 24 hours of investigator awareness of the event. Alerts issued via 
telephone are to be immediately followed with official notification on the adverse event case report form. 
See Appendix D for reporting timelines for serious, unexpected, study related events (SAEs) and serious, 
unexpected suspected adverse reactions (SUSARs). 
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in one of 
the following outcomes: 
 
• 
Death 
• 
A life-threatening experience (that is, immediate risk of dying) 
• 
Prolonged inpatient hospitalization or re-hospitalization 
• 
Persistent or significant disability/incapacity 
Reportable serious adverse events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon appropriate medical 
judgment, they may jeopardize the patient or require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
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:  
• 
Review of adverse events 
• 
Interim results of the study for evidence of efficacy or adverse events 
• 
Possible early termination of the trial because of new external information, early attainment of 
study objectives, safety concerns, or inadequate performance 
• 
Possible modifications in the clinical trial protocol  
• 
Performance of individual centers  

 
 
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The DSMB will consist of members with expertise in bioethics, emergency medicine, pulmonary critical 
care, 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 Principal 
Investigator and unblinded study biostatistician will be responsible for the preparation of all DSMB and 
adverse event 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 with the assistance of the Principal Investigator. The DSMB will have the ability to 
recommend that the trial end, be modified, or continued unchanged. 
 
 

 
 
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16. REFERENCES. 
 
1.  
Pfuntner A, Wier LM, Stocks C. Most Frequent Procedures Performed in U.S. Hospitals, 2011: 
Statistical Brief #165 [Internet]. In: Healthcare Cost and Utilization Project (HCUP) Statistical 
Briefs. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 [cited 2018 Jun 
4]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174682/ 
2.  
Wunsch H, Wagner J, Herlim M, Chong DH, Kramer AA, Halpern SD. ICU occupancy and 
mechanical ventilator use in the United States. Crit Care Med 2013;41(12):2712–9.  
3.  
Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JM. The 
epidemiology of mechanical ventilation use in the United States. Crit Care Med 2010;38(10):1947–
53.  
4.  
Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute 
Lung Injury and the Acute Respiratory Distress Syndrome. N Engl J Med 2000;342(18):1301–8.  
5.  
Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator 
weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing 
Controlled trial): a randomised controlled trial. The Lancet 2008;371(9607):126–34.  
6.  
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(5):792–9.  
7.  
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):273–80.  
8.  
Janz DR, Semler MW, Joffe AM, et al. A Multicenter Randomized Trial of a Checklist for 
Endotracheal Intubation of Critically Ill Adults. Chest 2018;153(4):816–24.  
9.  
Semler MW, Janz DR, Russell DW, et al. A Multicenter, Randomized Trial of Ramped Position 
vs Sniffing Position During Endotracheal Intubation of Critically Ill Adults. Chest 
2017;152(4):712–22.  
10.  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):811–21.  
11.  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.  
12.  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 [Internet] 2019 [cited 2019 Oct 3];0(0). Available from: 
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(19)30246-2/abstract 
13.  Russell DW, Casey JD, Gibbs KW, et al. 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(9):e036671.  

 
 
RSI Protocol Version 2.2 
 March 7, 2025 
 
Page 106 of 141 
14.  Jaber S, Jung B, Corne P, et al. An intervention to decrease complications related to endotracheal 
intubation in the intensive care unit: a prospective, multiple-center study. Intensive Care Med 
2009;36(2):248–55.  
15.  Baillard C, Fosse J-P, Sebbane M, et al. Noninvasive ventilation improves preoxygenation before 
intubation of hypoxic patients. Am J Respir Crit Care Med 2006;174(2):171–7.  
16.  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):1538–48.  
17.  Green RS, Turgeon AF, McIntyre LA, et al. Postintubation hypotension in intensive care unit 
patients: A multicenter cohort study. J Crit Care 2015;30(5):1055–60.  
18.  Ishimaru T, Goto T, Takahashi J, et al. Association of ketamine use with lower risks of post-
intubation hypotension in hemodynamically-unstable patients in the emergency department. Sci Rep 
2019;9(1):17230.  
19.  Smischney NJ, Kashyap R, Khanna AK, et al. Risk factors for and prediction of post-intubation 
hypotension in critically ill adults: A multicenter prospective cohort study. PLOS ONE 
2020;15(8):e0233852.  
20.  Brown C, Sakles JC. Rapid Sequence Intubation for Adults outside the Operating Room. [cited 
2019 Feb 17];Available from: https://www.uptodate.com/contents/rapid-sequence-intubation-for-
adults-outside-the-operating-
room?sectionName=Adjunct%20strategies&topicRef=8365&anchor=H3397071694&source=see_li
nk#H3397071694 
21.  Möller Petrun A, Kamenik M. Bispectral index-guided induction of general anaesthesia in patients 
undergoing major abdominal surgery using propofol or etomidate: a double-blind, randomized, 
clinical trial. Br J Anaesth 2013;110(3):388–96.  
22.  Shah SB, Chowdhury I, Bhargava AK, Sabbharwal B. Comparison of hemodynamic effects of 
intravenous etomidate versus propofol during induction and intubation using entropy guided 
hypnosis levels. J Anaesthesiol Clin Pharmacol 2015;31(2):180–5.  
23.  Kaushal RP, Vatal A, Pathak R. Effect of etomidate and propofol induction on hemodynamic and 
endocrine response in patients undergoing coronary artery bypass grafting/mitral valve and aortic 
valve replacement surgery on cardiopulmonary bypass. Ann Card Anaesth 2015;18(2):172–8.  
24.  Perbet S, De Jong A, Delmas J, et al. Incidence of and risk factors for severe cardiovascular collapse 
after endotracheal intubation in the ICU: a multicenter observational study. Crit Care Lond Engl 
2015;19:257.  
25.  Stollings JL, Diedrich DA, Oyen LJ, Brown DR. Rapid-Sequence Intubation: A Review of the 
Process and Considerations When Choosing Medications. Ann Pharmacother 2014;48(1):62–76.  
26.  April MD, Arana A, Schauer SG, et al. Ketamine Versus Etomidate and Peri-intubation 
Hypotension: A National Emergency Airway Registry Study. Acad Emerg Med [Internet] [cited 
2020 Sep 25];n/a(n/a). Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/acem.14063 

 
 
RSI Protocol Version 2.2 
 March 7, 2025 
 
Page 107 of 141 
27.  Choi YF, Wong TW, Lau CC. Midazolam is more likely to cause hypotension than etomidate in 
emergency department rapid sequence intubation. Emerg Med J EMJ 2004;21(6):700–2.  
28.  Nordt SP, Clark RF. Midazolam: a review of therapeutic uses and toxicity. J Emerg Med 
1997;15(3):357–65.  
29.  Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet 
1998;35(1):37–47.  
30.  Gelissen HPMM, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, Hertog A den. Inotropic Effects 
of Propofol, Thiopental, Midazolam, Etomidate, and Ketamine on Isolated Human Atrial Muscle. 
Anesthesiology 1996;84(2):397–403.  
31.  Stowe DF, Bosnjak ZJ, Kampine JP. Comparison of etomidate, ketamine, midazolam, propofol, and 
thiopental on function and metabolism of isolated hearts. Anesth Analg 1992;74(4):547–58.  
32.  Hannam JA, Mitchell SJ, Cumin D, et al. Haemodynamic profiles of etomidate vs propofol for 
induction of anaesthesia: a randomised controlled trial in patients undergoing cardiac surgery. Br J 
Anaesth 2019;122(2):198–205.  
33.  Brown CA. The Walls Manual of Emergency Airway Management [Internet]. 5th. Wolters Kluwer 
Health; 2017 [cited 2018 May 4]. Available from: 
http://proxy.library.vanderbilt.edu/login?url=http://ovidsp.ovid.com/ovidweb.cgi?T=JS&NEWS=n
&CSC=Y&PAGE=booktext&D=books&AN=01996178$&XPATH=/PG(0)&EPUB=Y 
34.  Spotoft H, Korshin JD, Sørensen MB, Skovsted P. The cardiovascular effects of ketamine used for 
induction of anaesthesia in patients with valvular heart disease. Can Anaesth Soc J 1979;26(6):463–
7.  
35.  Pagel PS, Kampine JP, Schmeling WT, Warltier DC. Ketamine Depresses Myocardial Contractility 
as Evaluated by the Preload Recruitable Stroke Work Relationship in Chronically Instrumented 
Dogs with Autonomic Nervous System Blockade. Anesthesiology 1992;76(4):564–72.  
36.  Waxman K, Shoemaker WC, Lippmann M. Cardiovascular effects of anesthetic induction with 
ketamine. Anesth Analg 1980;59(5):355–8.  
37.  Dewhirst E, Frazier WJ, Leder M, Fraser DD, Tobias JD. Cardiac arrest following ketamine 
administration for rapid sequence intubation. J Intensive Care Med 2013;28(6):375–9.  
38.  Burmon C, Adamakos F, Filardo M, Motov S. Acute pulmonary edema associated with ketamine-
induced hypertension during procedural sedation in the ED. Am J Emerg Med 2017;35(3):522.e1-
522.e4.  
39.  Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on ICP in traumatic brain 
injury. Neurocrit Care 2014;21(1):163–73.  
40.  Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on intracranial pressure in 
nontraumatic neurological illness. J Crit Care 2014;29(6):1096–106.  

 
 
RSI Protocol Version 2.2 
 March 7, 2025 
 
Page 108 of 141 
41.  Upchurch CP, Grijalva CG, Russ S, et al. Comparison of Etomidate and Ketamine for Induction 
During Rapid Sequence Intubation of Adult Trauma Patients. Ann Emerg Med 2017;69(1):24-
33.e2.  
42.  Harris CE, Murray AM, Anderson JM, Grounds RM, Morgan M. Effects of thiopentone, etomidate 
and propofol on the haemodynamic response to tracheal intubation. Anaesthesia 1988;43 Suppl:32–
6.  
43.  Myatra SN, Ahmed SM, Kundra P, et al. The All India Difficult Airway Association 2016 
guidelines for tracheal intubation in the Intensive Care Unit. Indian J Anaesth 2016;60(12):922–30.  
44.  Higgs A, McGrath BA, Goddard C, et al. Guidelines for the management of tracheal intubation in 
critically ill adults. Br J Anaesth [Internet] [cited 2018 Jan 15];Available from: 
https://www.sciencedirect.com/science/article/pii/S000709121754060X 
45.  de Jong FH, Mallios C, Jansen C, Scheck PA, Lamberts SW. Etomidate suppresses adrenocortical 
function by inhibition of 11 beta-hydroxylation. J Clin Endocrinol Metab 1984;59(6):1143–7.  
46.  Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition of adrenal steroidogenesis 
by the anesthetic etomidate. N Engl J Med 1984;310(22):1415–21.  
47.  Ledingham IMca, Watt I. INFLUENCE OF SEDATION ON MORTALITY IN CRITICALLY ILL 
MULTIPLE TRAUMA PATIENTS. The Lancet 1983;321(8336):1270.  
48.  Bruder EA, Ball IM, Ridi S, Pickett W, Hohl C. Single induction dose of etomidate versus other 
induction agents for endotracheal intubation in critically ill patients. Cochrane Database Syst Rev 
2015;1:CD010225.  
49.  Gu W-J, Wang F, Tang L, Liu J-C. Single-dose etomidate does not increase mortality in patients 
with sepsis: a systematic review and meta-analysis of randomized controlled trials and observational 
studies. Chest 2015;147(2):335–46.  
50.  Freund Y, Jabre P, Mourad J, et al. Relative adrenal insufficiency in critically ill patient after rapid 
sequence intubation: KETASED ancillary study. J Crit Care 2014;29(3):386–9.  
51.  Mohammad Z, Afessa B, Finkielman JD. The incidence of relative adrenal insufficiency in patients 
with septic shock after the administration of etomidate. Crit Care Lond Engl 2006;10(4):R105.  
52.  Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal responsiveness 
and mortality in patients with septic shock. Intensive Care Med 2009;35(11):1868–76.  
53.  Morel J, Salard M, Castelain C, et al. Haemodynamic consequences of etomidate administration in 
elective cardiac surgery: a randomized double-blinded study. Br J Anaesth 2011;107(4):503–9.  
54.  Jung B, Clavieras N, Nougaret S, et al. Effects of etomidate on complications related to intubation 
and on mortality in septic shock patients treated with hydrocortisone: a propensity score analysis. 
Crit Care Lond Engl 2012;16(6):R224.  
55.  Chan CM, Mitchell AL, Shorr AF. Etomidate is associated with mortality and adrenal insufficiency 
in sepsis: a meta-analysis*. Crit Care Med 2012;40(11):2945–53.  

 
 
RSI Protocol Version 2.2 
 March 7, 2025 
 
Page 109 of 141 
56.  Lipiner-Friedman D, Sprung CL, Laterre PF, et al. Adrenal function in sepsis: The retrospective 
Corticus cohort study: Crit Care Med 2007;35(4):1012–8.  
57.  Albert SG, Ariyan S, Rather A. The effect of etomidate on adrenal function in critical illness: a 
systematic review. Intensive Care Med 2011;37(6):901–10.  
58.  Ray DC, McKeown DW. Effect of induction agent on vasopressor and steroid use, and outcome in 
patients with septic shock. Crit Care 2007;11:R56.  
59.  Mcphee LC, Badawi O, Fraser GL, et al. Single-dose Etomidate Is Not Associated With Increased 
Mortality in Icu Patients With Sepsis: Analysis of a Large Electronic Icu Database*. Crit Care Med 
2013;41(3):774–83.  
60.  Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in 
acutely ill patients: a multicentre randomised controlled trial. The Lancet 2009;374(9686):293–300.  
61.  Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency endotracheal 
intubation: a randomized clinical trial. Intensive Care Med 2022;48(1):78–91.  
62.  Jones AE. The Etomidate Debate. Ann Emerg Med 2010;56(5):490–1.  
63.  Day SJ, Altman DG. Blinding in clinical trials and other studies. BMJ 2000;321(7259):504.  
64.  Cormack RS, Lehane J. Difficult tracheal intubation in obstetrics. Anaesthesia 1984;39(11):1105–
11.  
65.  Yarnell CJ, Abrams D, Baldwin MR, et al. Clinical trials in critical care: can a Bayesian approach 
enhance clinical and scientific decision making? Lancet Respir Med [Internet] 2020 [cited 2020 
Nov 25];Available from: http://www.sciencedirect.com/science/article/pii/S2213260020304719 
66.  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; 
67.  Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in 
acutely ill patients: a multicentre randomised controlled trial. Lancet Lond Engl 
2009;374(9686):293–300.  
68.  Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency endotracheal 
intubation: a randomized clinical trial. Intensive Care Med 2021; 
69.  Food and Drug Administration (FDA). Multiple Endpoints in Clinical Trials: Guidance for Industry. 
2017;Available from: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm53
6750.pdf 
70.  European Medicines Agency. Guideline on multiplicity issues in clinical trials. 2016;Available 
from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-multiplicity-
issues-clinical-trials_en.pdf 

 
 
RSI Protocol Version 2.2 
 March 7, 2025 
 
Page 110 of 141 
71.  Uniform requirements for manuscripts submitted to biomedical journals. International Committee of 
Medical Journal Editors. JAMA 1997;277(11):927–34.  
72.  Mathais Q, Paleiron N, Vatin L, Bordes J, Gaillard PE. Ketamine-induced anaphylactic shock 
during elective parotidectomy: A case report. Eur J Anaesthesiol EJA 2019;36(1):70–1.  
73.  Bylund W, Delahanty L, Cooper M. The Case of Ketamine Allergy. Clin Pract Cases Emerg Med 
2017;1(4):323–5.  
74.  Jones C, Griffiths RD, Humphris G, Skirrow PM. Memory, delusions, and the development of acute 
posttraumatic stress disorder-related symptoms after intensive care. Crit Care Med 2001;29(3):573–
80.  
75.  Svenningsen H. Associations between sedation, delirium and post-traumatic stress disorder and their 
impact on quality of life and memories following discharge from an intensive care unit. Dan Med J 
2013;60(4):B4630.  
76.  Wade DM, Brewin CR, Howell DC, White E, Mythen MG, Weinman JA. Intrusive memories of 
hallucinations and delusions in traumatized intensive care patients: An interview study. Br J Health 
Psychol 2015;20(3):613–31.  
77.  Wade D, Hardy R, Howell D, Mythen M. Identifying clinical and acute psychological risk factors 
for PTSD after critical care: a systematic review. Minerva Anestesiol 2013;79(8):944–63.  
78.  Bienvenu OJ, Williams JB, Yang A, Hopkins RO, Needham DM. Posttraumatic stress disorder in 
survivors of acute lung injury: evaluating the Impact of Event Scale-Revised. Chest 
2013;144(1):24–31.  
79.  Jackson JC, Jutte JE, Hunter CH, et al. Posttraumatic stress disorder (PTSD) after critical illness: A 
conceptual review of distinct clinical issues and their implications. Rehabil Psychol 
2016;61(2):132–40.  
80.  Jackson JC, Hart RP, Gordon SM, Hopkins RO, Girard TD, Ely EW. Post-traumatic stress disorder 
and post-traumatic stress symptoms following critical illness in medical intensive care unit patients: 
assessing the magnitude of the problem. Crit Care Lond Engl 2007;11(1):R27.  
81.  Garrouste-Orgeas M, Flahault C, Vinatier I, et al. Effect of an ICU Diary on Posttraumatic Stress 
Disorder Symptoms Among Patients Receiving Mechanical Ventilation: A Randomized Clinical 
Trial. Jama 2019;322(3):229–39.  
82.  Girard TD, Shintani AK, Jackson JC, et al. Risk factors for post-traumatic stress disorder symptoms 
following critical illness requiring mechanical ventilation: a prospective cohort study. Crit Care 
2007;11(1):R28.  
83.  Parker AM, Sricharoenchai T, Raparla S, Schneck KW, Bienvenu OJ, Needham DM. Posttraumatic 
stress disorder in critical illness survivors: a metaanalysis. Crit Care Med 2015;43(5):1121–9.  
84.  Smith MW, Schnurr PP, Rosenheck RA. Employment outcomes and PTSD symptom severity. Ment 
Health Serv Res 2005;7(2):89–101.  

 
 
RSI Protocol Version 2.2 
 March 7, 2025 
 
Page 111 of 141 
85.  Davydow DS, Desai SV, Needham DM, Bienvenu OJ. Psychiatric morbidity in survivors of the 
acute respiratory distress syndrome: a systematic review. Psychosom Med 2008;70(4):512–9.  
86.  Kapfhammer HP, Rothenhäusler HB, Krauseneck T, Stoll C, Schelling G. Posttraumatic stress 
disorder and health-related quality of life in long-term survivors of acute respiratory distress 
syndrome. Am J Psychiatry 2004;161(1):45–52.  
87.  Jackson JC, Pandharipande PP, Girard TD, et al. Depression, post-traumatic stress disorder, and 
functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort 
study. Lancet Respir Med 2014;2(5):369–79.  
88.  Friedman MJ, Schnurr PP, McDonagh-Coyle A. Post-traumatic stress disorder in the military 
veteran. Psychiatr Clin North Am 1994;17(2):265–77.  
89.  Fox V, Dalman C, Dal H, Hollander A-C, Kirkbride JB, Pitman A. Suicide risk in people with post-
traumatic stress disorder: A cohort study of 3.1 million people in Sweden. J Affect Disord 
2021;279:609–16.  
90.  Krystal JH, Abdallah CG, Averill LA, et al. Synaptic Loss and the Pathophysiology of PTSD: 
Implications for Ketamine as a Prototype Novel Therapeutic. Curr Psychiatry Rep 2017;19(10):74.  
91.  Nair J, Singh Ajit S. The role of the glutamatergic system in posttraumatic stress disorder. CNS 
Spectr 2008;13(7):585–91.  
92.  Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, Baca-Garcia E. New 
perspectives in glutamate and anxiety. Pharmacol Biochem Behav 2012;100(4):752–74.  
93.  Newcomer JW, Farber NB, Olney JW. NMDA receptor function, memory, and brain aging. 
Dialogues Clin Neurosci 2000;2(3):219–32.  
94.  Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of 
chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 
2014;71(6):681–8.  
95.  Feder A, Costi S, Rutter SB, et al. A Randomized Controlled Trial of Repeated Ketamine 
Administration for Chronic Posttraumatic Stress Disorder. Am J Psychiatry 2021;178(2):193–202.  
96.  Berman SE, Koscik RL, Clark LR, et al. Use of the Quick Dementia Rating System (QDRS) as an 
Initial Screening Measure in a Longitudinal Cohort at Risk for Alzheimer’s Disease. J Alzheimers 
Rep 2017;1(1):9–13.  
97.  Galvin JE. The Quick Dementia Rating System (Qdrs): A Rapid Dementia Staging Tool. 
Alzheimers Dement Amst 2015;1(2):249–59.  
98.  Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during 
anaesthesia. Br J Anaesth 1970;42(6):535–42.  
99.  Avidan MS, Jacobsohn E, Glick D, et al. Prevention of intraoperative awareness in a high-risk 
surgical population. N Engl J Med 2011;365(7):591–600.  

 
 
RSI Protocol Version 2.2 
 March 7, 2025 
 
Page 112 of 141 
100.  Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness and the bispectral index. N Engl J 
Med 2008;358(11):1097–108.  
101.  Samuelson KA, Lundberg D, Fridlund B. Stressful memories and psychological distress in adult 
mechanically ventilated intensive care patients - a 2-month follow-up study. Acta Anaesthesiol 
Scand 2007;51(6):671–8.  
102.  Pappal RD, Roberts BW, Mohr NM, et al. The ED-AWARENESS Study: A Prospective, 
Observational Cohort Study of Awareness With Paralysis in Mechanically Ventilated Patients 
Admitted From the Emergency Department. Ann Emerg Med 2021;77(5):532–44.  
103.  Rosellini AJ, Liu H, Petukhova MV, et al. Recovery from DSM-IV post-traumatic stress disorder in 
the WHO World Mental Health surveys. Psychol Med 2018;48(3):437–50.  
104.  Marx BP, Lee DJ, Norman SB, et al. Reliable and clinically significant change in the clinician-
administered PTSD Scale for DSM-5 and PTSD Checklist for DSM-5 among male veterans. 
Psychol Assess 2022;34(2):197–203.  
105.  Kind AJH, Buckingham WR. Making Neighborhood-Disadvantage Metrics Accessible — The 
Neighborhood Atlas. N Engl J Med 2018;378(26):2456–8.  
106.  USDA ERS - Rural-Urban Commuting Area Codes [Internet]. [cited 2021 Dec 14];Available from: 
https://www.ers.usda.gov/data-products/rural-urban-commuting-area-codes/ 
107.  Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative 
data. Med Care 1998;36(1):8–27.  
108.  Colantuoni E, Scharfstein DO, Wang C, et al. Statistical methods to compare functional outcomes in 
randomized controlled trials with high mortality. Bmj 2018;360:j5748.  
 
 

 
 
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17. APPENDICES  
Appendix A. Schedule of Events 
Study Activity 
Pre-
Induction 
Administration 
of Sedatives 
(Induction) 
Tracheal 
Intubation 
Day 1 
Days  
2-27 
Day 28 
Eligibility assessment 
X 
 
 
 
 
 
Opt-out conversation 
(when feasible) 
X 
 
 
 
 
 
Pre-enrollment time-out 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Recording of baseline 
blood pressure and 
oxygen saturation 
X 
 
 
 
 
 
Study medication 
delivery (Ketamine or 
Etomidate) 
 
X 
 
 
 
 
Recording of  
peri-procedural 
outcomes  
 
X 
X 
X 
 
 
Assessment for study 
medication adherence 
 
X 
X 
X 
 
 
Safety monitoring for 
adverse events 
 
X 
X 
X 
 
X 
Notification of 
Enrollment 
 
 
 
X 
X 
 
Mortality assessment 
 
 
X 
X 
X 
X 
28-day in-hospital 
outcomes  
(chart review) 
 
 
 
 
 
X 

 
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Appendix B: Compliance with Criteria and Processes Required for EFIC 
 
 
1) Critical illness requiring emergency tracheal intubation is a life-threatening situation and available 
treatments are unsatisfactory or unproven. 
 
21 CFR 50.24(a)(1) The human subjects are in a life-threatening situation, available treatments 
are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include 
evidence obtained through randomized placebo-controlled investigations, is necessary to 
determine the safety and effectiveness of particular interventions. 
 
Each year more than 1.5 million critically ill patients receive mechanical ventilation in the United 
States.1–3 Despite adherence to recommended best-practices for tracheal intubation (e.g., 
preoxygenation,15,16 optimization of patient positioning,9 and procedural checklists8), one in five critically 
ill patients experiences hypotension and one-in-forty experiences cardiac arrest during the brief, two-
minute procedure to place an endotracheal tube.6–10 Around 30% of critically ill adults undergoing 
emergency tracheal intubation die prior to hospital discharge. 
 
Rapid sequence induction and tracheal intubation, the most common method of intubation for critically ill 
patients, is the nearly simultaneous administration of a sedative medication and neuromuscular blocking 
medication. The ideal sedative agent for rapid sequence intubation would rapidly provide a deep state of 
unconsciousness and analgesia without causing hemodynamic side effects, but no available agent meets 
all criteria.20  The administration of any available sedative at a dose large enough to rapidly induce 
unconsciousness contributes to cardiovascular collapse through vasodilation, decreased cardiac filling 
pressures from sedation-induced venodilation, and decreased endogenous catecholamines.21–24 While all 
sedatives commonly used during emergency tracheal intubation of critically ill patients have been 
associated with unsatisfactory hypotension (21 CFR 50.24(a)(1)), ketamine and etomidate are the 
medications used most commonly in clinical practice due to their rapid onset and relatively favorable 
hemodynamic profiles (as described in section 2.1.2).25,26 A large multi-center trial is needed to determine 
the effects on peri-procedural hemodynamics and mortality of the two most commonly used sedatives for 
the tracheal intubation of critically ill adults.  
 
2) Obtaining prospective informed consent is not feasible during emergency tracheal intubation. 
21 CFR 50.24(a)(2) Obtaining informed consent is not feasible because: (i) the subjects will not 
be able to give their informed consent as a result of their medical condition; (ii) the intervention 
under investigation must be administered before consent from the subjects' legally authorized 
representatives is feasible; and (iii) There is no reasonable way to identify prospectively the 
individuals likely to become eligible for participation in the clinical investigation. 
 
Most patients eligible for the RSI trial will be experiencing unconsciousness or delirium due to critical 
illness.  More than half of critically ill adults undergoing tracheal intubation in the ED or ICU have a 
Glasgow Coma Scale score less than 12 (equivalent to moderate brain injury) and among those whose 
level of consciousness is not impaired, most experience acute delirium.  Even in instances in which a 

 
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patient retains capacity, or an LAR is immediately available, the rapidity with which emergency tracheal 
intubation is clinically required, and the accompanying distress of the patient or LAR from the critical 
illness and need for emergency tracheal intubation, precludes a meaningful informed consent process.  
Delaying emergency tracheal intubation for a critically ill adults to attempt a meaningful informed 
consent process would be unsafe, impracticable, and unethical. 
There is no reasonable method for prospectively identifying individuals for informed consent prior to 
developing a need for emergency tracheal intubation. Many different acute illnesses lead to emergency 
tracheal intubation in the ED or ICU including stroke, spontaneous intracranial hemorrhage, seizure, 
sepsis, drug overdose, acute coronary syndrome, aspiration pneumonitis, acute bacterial pneumonia, 
pneumothorax, and others. Any patient in the community or in the hospital may unexpectedly develop a 
need for emergency tracheal intubation within a period of minutes with no warning.  
For these reasons, the RSI trial could not be conducted without EFIC, and it is expected that most, if not 
all, patients will be enrolled through EFIC.  
3) Participation in RSI holds prospect of direct benefit to subjects 
 
21 CFR 50.24(a)(3) Participation in the research holds out the prospect of direct benefit to the 
subjects because: (i) subjects are facing a life-threatening situation that necessitates intervention; 
(ii) appropriate animal and other preclinical studies have been conducted, and the information 
derived from those studies and related evidence support the potential for the intervention to 
provide a direct benefit to the individual subjects; and (iii) risks associated with the investigation 
are reasonable in relation to what is known about the medical condition of the potential class of 
subjects, the risks and benefits of standard therapy, if any, and what is known about the risks and 
benefits of the proposed intervention or activity. 
 
Participation in RSI holds out the prospect of direct benefit to subjects. Critical illness requiring 
emergency tracheal intubation is a life-threatening condition with a high incidence of hypotension and 
cardiac arrest that necessitates immediate intervention.  Previous animal and clinical studies have 
established several mechanisms by which either ketamine or etomidate might provide a direct benefit to 
individual critically ill subjects undergoing tracheal intubation via improved hemodynamics and survival. 
 
The risks associated with the investigation are reasonable in relation to what is known about tracheal 
intubation of critically ill patients. All patients enrolled in the RSI trial would have received a sedative as 
part of emergency tracheal intubation in routine clinical care, regardless of participation in the RSI trial. 
The treatment groups represent the two most commonly used sedatives, and there is no evidence currently 
that either medication is superior with regard to peri-procedural hemodynamics or survival. Therefore, 
there is no reason to believe that participation in this study would expose patients to greater medical risks 
than those experienced by critically ill patients undergoing tracheal intubation as part of routine clinical 
care.  
4) The RSI trial cannot be practicably carried out without exception from informed consent 
 
21 CFR 50.24(a)(4) The clinical investigation could not practicably be carried out without the 
waiver. 

 
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This research could not be carried out without EFIC because emergency tracheal intubation of critically 
ill adults is a time-sensitive procedure for which every minute of delay increases the likelihood of 
hypoxemia, hypotension, and peri-procedural cardiac arrest. A meaningful informed consent process 
requires that the patient or LAR have time to understand the material presented, be able to ask questions 
and have time to consider their options. This is not possible in the brief therapeutic window between the 
decision to intubate a critically ill patient and the initiation of the procedure.  
 
5) The need for immediate treatment of critically ill patients requiring emergency tracheal intubation is 
expected to preclude obtaining informed consent from an LAR in most, if not all cases, during the brief 
therapeutic window 
 
21 CFR 50.24 (a)(5) The proposed investigational plan defines the length of the potential 
therapeutic window based on scientific evidence, and the investigator has committed to 
attempting to contact a legally authorized representative for each subject within that window of 
time and, if feasible, to asking the legally authorized representative contacted for consent within 
that window rather than proceeding without consent. The investigator will summarize efforts 
made to contact legally authorized representatives and make this information available to the 
IRB at the time of continuing review. 
 
For an induction medication used for emergency tracheal intubation, the therapeutic window begins at the 
time treating clinicians decide to perform emergency tracheal intubation with sedation and ends at the 
time an induction medication is administered for emergency tracheal intubation.  To our knowledge, no 
published literature has quantified this therapeutic window among critically ill adults.  Among a 
convenience sample of 25 consecutive critically ill adults undergoing emergency tracheal intubation in 
the ED or ICU in the planned study sites of the RSI trial, the median time from treating clinicians 
verbalizing the decision to intubate with sedation (or placing a written order for an induction medication) 
to the administration of an induction medication was 1 minute [interquartile range, 1 minute to 10 
minutes].  For no patient was this window longer than 30 minutes.  Tracheal intubation of critically ill 
adults is a time-sensitive procedure for which every minute of delay increases the likelihood of 
hypoxemia, hypotension, and peri-procedural cardiac arrest.  For most patients in the RSI trial, 
completion of the trial intervention (a one-time injection at the start of the emergency tracheal intubation 
procedure) is anticipated to occur less than 5 minutes after meeting trial eligibility criteria.  Thus, in the 
RSI trial, we anticipate that the therapeutic window for most patients will be less than 5 minutes.   
While a written informed consent is available and will be used when feasible, it is expected that written 
consent will be infeasible in most, if not all, cases because delaying the emergency tracheal intubation of 
critically ill adults would cause irreparable harm to patients.  Whenever feasible, however, the RSI trial 
will provide an opportunity for patients, LARs, or family members to opt-out of trial participation.   
 
This will occur in cases in which the patient retains decisional capacity or a family member or LAR is 
available, research staff are able to reach the patient or LAR before intubation, and treating clinicians 
have determined that based on the clinical status of the patient there is insufficient time to complete a 
formal informed consent process (Appendix C).  The decisional capacity of the patient and the safety and 
feasibility of reading the script during the brief therapeutic window will be determined by the treating 

 
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clinicians.  Allowing a mechanism, whenever feasible, for patients to opt out of participation is consistent 
with the respect for autonomy emphasized in the EFIC guidelines.  
We will make every effort to contact legal representatives after enrollment to notify LARs that the patient 
was enrolled in a randomized trial and provide an opportunity to withdraw from further participation.  If 
legal representatives are not immediately available, research personnel will attempt to contact the 
subject’s legal representative as soon as feasible and a summary of these efforts will be documented in the 
patient’s study record. If the subject becomes competent during the study period, he/she will be 
approached by research personnel for notification of enrollment. 
Investigators will prospectively record cases when patients, LARs, or family members opt-out of 
participation and the efforts by study staff to notify patients and LAR of enrollment. These efforts will be 
summarized and reported to the DSMB at their semi-annual meetings and to the IRB at the initial and 
continuing reviews. 
6) Informed consent procedures and documents in the RSI trial will be reviewed and approved by the IRB 
 
21 CFR 50.24(a)(6) The IRB has reviewed and approved informed consent procedures and an 
informed consent document consistent with Sec. 50.25. These procedures and the informed 
consent document are to be used with subjects or their legally authorized representatives in 
situations where use of such procedures and documents is feasible. The IRB has reviewed and 
approved procedures and information to be used when providing an opportunity for a family 
member to object to a subject's participation in the clinical investigation consistent with 
paragraph (a)(7)(v) of this section. 
 
All consent procedures and documents that will be used in the RSI trial will be approved by the IRB prior 
to the initiation of enrollment.   
 
7) Additional protections of the rights and welfare of the subjects will be provided in the RSI trial, 
including: 
 
Community Consultation 
 
vii. 21 CFR 50.24(a)(7) Additional: Consultation (including, where appropriate, consultation 
carried out by the IRB) with representatives of the communities in which the clinical 
investigation will be conducted and from which the subjects will be drawn; 
 
A detailed plan for community consultation has been developed for the RSI trial (see Community 
Consultation and Public Disclosure Plan).  The plan included in the initial draft of the RSI protocol was 
informed by two Community Engagement Studios, organized by the Vanderbilt Community Engagement 
Research Core.  The first meeting, held on February 2, 2021, included healthcare providers who routinely 
participated in emergency tracheal intubation in the ED or ICU.  The second meeting, held on February 4, 
2021, included patients or caretakers of patients who had experienced critical illness with emergency 
tracheal intubation.  Investigators solicited feedback on the design of the RSI trial, potential risks and 
benefits of participation, the inability to obtain prospective informed consent, the opportunity to opt-out 

 
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of participation, and the plans for further Community Consultation, Public Disclosure of the conduct and 
results of the trial.  The protocol, the plan for further Community Consultation, and the plan for Public 
Disclosure were refined based on this feedback to address the concerns of the community.  Enrollment in 
the RSI trial will not begin until 1) the IRB has approved the proposed community consultation plan, 2) 
study personnel have completed the proposed community consultation plan, and 3) the IRB has reviewed 
and certified the completion of community consultation and approved enrollment.  
 
Public Disclosure 
 
viii. 21 CFR 50.24(a)(7): Public disclosure to the communities in which the clinical investigation 
will be conducted and from which the subjects will be drawn, prior to initiation of the 
clinical investigation, of plans for the investigation and its risks and expected benefits; 
ix. Public disclosure of sufficient information following completion of the clinical investigation 
to apprise the community and researchers of the study, including the demographic 
characteristics of the research population, and its results; 
 
Public disclosure is a primary element in making certain that RSI is conducted in an entirely 
transparent manner. A detailed public disclosure plan has been developed for the RSI trial (see 
Community Consultation and Public Disclosure Plan).  The plan included in the initial draft of the RSI 
protocol was informed by two Community Engagement Studios, organized by the Vanderbilt Community 
Engagement Research Core.  The first meeting, held on February 2, 2021, included healthcare providers 
who routinely participated in emergency tracheal intubation in the ED or ICU.  The second meeting, held 
on February 4, 2021, included patients or caretakers of patients who had experienced critical illness with 
emergency tracheal intubation.  Investigators solicited feedback on the design of the RSI trial, potential 
risks and benefits of participation, the inability to obtain prospective consent, the opportunity to opt-out of 
participation, and the plans for further Community Consultation, Public Disclosure of the conduct and 
results of the trial.  The protocol, the plan for further Community Consultation, and the plan for Public 
Disclosure were refined based on this feedback to address the concerns of the community.  Enrollment in 
the RSI trial will not begin until 1) the IRB has approved the proposed public disclosure plan, 2) study 
personnel have completed the proposed public disclosure activities, and 3) the IRB has reviewed and 
certified the completion of public disclosure and approved enrollment.  
 
Data and Safety Monitoring Committee 
 
x. 21 CFR 50.24(a)(7): Establishment of an independent data monitoring committee to 
exercise oversight of the clinical investigation;  
 
The Data Safety Monitoring Board (DSMB) will function as an independent data monitoring committee 
who will exercise oversight of the study. The composition and responsibilities of the DSMB are described 
in protocol section 15. 
 
Contacting Other Family 
 

 
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xi. 21 CFR 50.24(a)(7) If obtaining informed consent is not feasible and a legally authorized 
representative is not reasonably available, the investigator has committed, if feasible, to 
attempting to contact within the therapeutic window the subject's family member who is not 
a legally authorized representative, and asking whether he or she objects to the subject's 
participation in the clinical investigation. The investigator will summarize efforts made to 
contact family members and make this information available to the IRB at the time of 
continuing review. 
 
It will not be feasible or ethically possible in the RSI trial, for the reasons described above, to delay 
treatment of a critically ill patient requiring emergency tracheal intubation for long enough to contact 
either an LAR or other family members who are not present. We will, however, provide patients and 
LARs or family members who are present with the opportunity to opt-out of enrollment using the 
recitation of a standardized script by research staff during the brief therapeutic window (Appendix C). 
Further, we will provide a mechanism whereby community members who would not want to participate if 
undergoing tracheal intubation in the ED or ICU can communicate that decision to providers without 
causing any delay in treatment using opt-out bracelets. As part of the primary assessment of a critically ill 
patient, providers already check for a medical alert bracelet.  The study will provide medical alert 
bracelets with the words “RSI declined” to any community member requesting one. The process by which 
community members are notified of the study and requests an opt-out bracelet are explained in the 
Community Consultation and Public Disclosure Plan.  Medical alert bracelets are a common and effective 
means of communicating information to ED and ICU providers while unconscious or in acute distress. 
Requests for RSI opt-out bracelets and their use in identifying patients for exclusion will be tracked by 
study investigators and this information can be made available to the IRB at the time of continuing 
review.  
 
Post Enrollment Notification 
 
xii. 
21 CFR 50.24(b) The IRB is responsible for ensuring that procedures are in place to inform, 
at the earliest feasible opportunity, each subject, or if the subject remains incapacitated, a 
legally authorized representative of the subject, or if such a representative is not reasonably 
available, a family member, of the subject's inclusion in the clinical investigation, the details 
of the investigation and other information contained in the informed consent document. The 
IRB shall also ensure that there is a procedure to inform the subject, or if the subject 
remains incapacitated, a legally authorized representative of the subject, or if such a 
representative is not reasonably available, a family member, that he or she may discontinue 
the subject's participation at any time without penalty or loss of benefits to which the subject 
is otherwise entitled. If a legally authorized representative or family member is told about 
the clinical investigation and the subject's condition improves, the subject is also to be 
informed as soon as feasible. If a subject is entered into a clinical investigation with waived 
consent and the subject dies before a legally authorized representative or family member 
can be contacted, information about the clinical investigation is to be provided to the 
subject's legally authorized representative or family member, if feasible. 
 

 
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Subjects enrolled in RSI or their LAR or family will be informed of the subject’s inclusion in the clinical 
investigation at the earliest possible opportunity as detailed above. It is anticipated that the notification of 
patients’ LAR or family will most usually take place within 24 hours of enrollment. Attempts to notify 
the subject or an LAR are repeated until successful or at least three attempts have been made. If a 
patient’s LAR or family member is notified of enrollment and the patient subsequently regains decision-
making capacity, the patient will be notified of the study and will be asked if he or she wants to continue 
the study.  
 
All notification attempts will be logged and recorded in the study record. Reports of these logs will be 
summarized to the DSMB at semi-annual reports and available for inclusion in annual reports to the IRB. 
 
By the time patients, LARs, or family members are notified of participation, the study intervention (a one-
time infusion at the time of tracheal intubation) will have been completed and patients will have 
experienced all of the risks or benefits associated with the study intervention.  The only remaining study 
procedure will be review of the electronic health record by study personnel.  Requesting that patients, 
LARs, or family member provide informed consent for continued participation after completion of the 
study intervention would not provide any additional patient protections, but would risk diminishing the 
overall validity and value of the research by biasing estimates of safety and efficacy if consent for 
continued participation occurred differentially between the trial groups because of the effects of the trial 
interventions.  The RSI trial will, therefore, use public notification, community consultation, a pre-
enrollment opt-out conversation (by research staff), medical alert bracelets, patient and LAR notification 
of enrollment, and a provision of an opportunity to opt out of ongoing participation. 
 
Record Keeping 
 
21 CFR 50.24(c) Like other IRB records, records of the determinations above must be kept for a 
minimum of three years after the completion of the clinical investigation. Again, like other IRB 
records, these are subject to inspection and copying by FDA. 
 
Records documenting the enrollment of patients using EFIC, procedures for opt-out prior to enrollment, 
and attempts to notify patients, LARs, and family members of enrollment will be kept for a minimum of 
three years after completion of the clinical investigation. 
 
IND Requirement 
 
21 CFR 50.24(d) Protocols involving an exception to the informed consent requirement under 
this section must be performed under a separate investigational new drug application (IND) or 
investigational device exemption (IDE) that clearly identifies such protocols as protocols that 
may include subjects who are unable to consent. The submission of those protocols in a separate 
IND/IDE is required even if an IND for the same drug product or an IDE for the same device 
already exists. Applications for investigations under this section may not be submitted as 
amendments under Secs. 312.30 or 812.35 of this chapter. 
 

 
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For critically ill adults undergoing emergency tracheal intubation for whom treating clinicians feel either 
ketamine or etomidate is consistent with optimal care, the incremental risks of participating in the RSI 
trial, compared to clinical care for the patient outside the trial, are minimal.  As such, the RSI trial might 
be considered to quality for waiver of consent and exemption from IND requirements under 21 CFR 312 
because: 
• 
Both ketamine and etomidate are lawfully marketed in the United States for use as sedative 
agents during tracheal intubation (the indication for which they will be used in the RSI trial) 
• 
The current study is not intended to be reported to FDA as a well-controlled study in support of a 
new indication for use nor intended to be used to support any other significant change in the 
labeling for either ketamine or etomidate 
• 
The current study is not intended to support a change in advertising for ketamine or etomidate 
• 
The current study does not involve a route of administration or dosage level or use in a patient 
population or other factor that significantly increases the risks (or decreases the acceptability of 
the risks) associated with the use of ketamine or etomidate. The current study will use ketamine 
and etomidate at the doses recommended by the FDA-approved package insert and excludes 
patient populations that would have increased risks of complications and any patients for whom 
any provider believes ketamine or etomidate is required or contraindicated 
• 
The study will be conducted with the requirements for institutional review set forth in FDA 
regulations 21 CFR 56.  
• 
The current study will be conducted in compliance with FDA regulations 21 CFR 312.7 regarding 
promotion and charging for investigational medication 
 
We will, however, conduct the RSI trial under EFIC in order to ensure patients receive the additional 
protections offered by community consultation and disclosure through EFIC.  As required by EFIC 
regulations 21 CFR 50.24(d), an IND for the RSI trial was obtained from the FDA (IND 141424).  The 
Study Principal Investigator serves as the sponsor of the IND.  
 
Communication of IRB Determinations 
 
21 CFR 50.24(e) If an IRB determines that it cannot approve a clinical investigation because the 
investigation does not meet the criteria in the exception provided under paragraph (a) of this 
section or because of other relevant ethical concerns, the IRB must document its findings and 
provide these findings promptly in writing to the clinical investigator and to the sponsor of the 
clinical investigation. The sponsor of the clinical investigation must promptly disclose this 
information to FDA and to the sponsor's clinical investigators who are participating or are asked 
to participate in this or a substantially equivalent clinical investigation of the sponsor, and to 
other IRBs that have been, or are, asked to review this or a substantially equivalent investigation 
by that sponsor. 
 
If an application for RSI is disapproved by a local IRB, the Study PI/sponsor will promptly disclose this 
information to the FDA. 

 
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Appendix C. Script to Provide an Opportunity to Opt-Out of Participation 
The script below will be used by research staff in cases in which the patient retains decisional capacity or 
a family member or LAR is available, the research team reaches the patient or LAR before intubation and 
based on the clinical status of the patient there is insufficient time to complete the intubation process 
prior to intubation.  
 
OPT-OUT SCRIPT  
1. You (your loved one) need(s) to be placed on a breathing machine, which requires a brief procedure to 
place a breathing tube.  
2. There are two medications that we commonly give patients to make them sleepy and relaxed for this 
procedure. As your medical team, we think either of these medications would be a good and safe choice 
for you.   
3. To help us understand which of the two medications is best, we are conducting a research study that 
compares the two medications.  
4. If you say “Yes” to participation, we will allow the study to choose which of the two medications you 
will receive and someone from the study will come by later to provide details and answer your questions.  
If you say “No”, we will choose one of the two medications ourselves.  Do you agree to participate? 
“Yes” - Patient/family agreed to participate (open envelope to enroll patient) 
“No” - Patient/family declined participation (place envelope in “used” bin; do not enroll) 
 
 
 

 
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Appendix D: Adverse Event Reporting and Unanticipated Events 
As noted in section 14, the lead investigator at each enrolling site is required to report all potentially 
reportable adverse events to the principal investigator within 24 hours of becoming aware of the event.  
Reportable events in the RSI trial are defined as adverse events that are unexpected and serious have a 
reasonable possibility that the event was due to a study medication or procedure (or of uncertain 
relatedness) 
The primary investigator will work collaboratively with the lead investigator at each enrolling site to 
determine if a serious adverse event has a reasonable possibility of having been caused by the study 
medication or study procedure, as outlined in 21 CFR 312.32(a)(1), and below. In this unblinded trial, 
both the investigator and primary investigator will be aware of group assignment and the receipt of either 
ketamine or etomidate.  An adverse is considered “unexpected” if it is not listed in the investigator 
brochure or the study protocol (21 CFR 312.32(a)). If a determination is made that a serious adverse event 
has a reasonable possibility of having been caused by a study procedure or the study medication, it will be 
classified as a suspected adverse reaction. If the suspected adverse reaction is unexpected, it will be 
classified as a serious unexpected suspected adverse reaction (SUSAR).  
D.1. Expedited Adverse Event Review and DSMB Notification Process 
The principal investigator will be responsible for notifying the funder, the IRB, and the FDA and will 
follow NHLBI guidelines for reporting of adverse events, https://www.nhlbi.nih.gov/grants-and-
training/policies-and-guidelines/nhlbi-adverse-event-and-unanticipated-problem-reporting-policy 
The principal investigator will report, at a minimum: 
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 funder 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 funder 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 CCC will distribute the written summary of the DSMB’s periodic review of reported adverse events 
to the IRB and funder in accordance with NIH guidelines (http://grants.nih.gov/grants/guide/notice-
files/not99-107.html).  
 
 
 

 
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D.2. Unanticipated Problems (UP) 
Investigators must also report Unanticipated Problems, regardless of severity, associated with study 
procedures within 24 hours. An unanticipated problem is defined as follows: any incident, experience, or 
outcome that meets all of the following criteria:  
• 
Unexpected, in terms of nature, severity, or frequency, given the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and patient 
notification document; and the characteristics of the subject population being studied;  
• 
Related or possibly related to participation in the research, in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research;  
• 
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.  
 
In accordance with NHLBI policy, an unanticipated problem that is not an SAE will be reported within 14 
days to the DSMB, IRB, and NHLBI. 
 
D.3. Determining Relationship of Adverse Events to Study Medication or Study Procedures 
Site investigators will be asked to grade the strength of the relationship of an adverse event to study 
medication or study procedures as follows:  
• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the patient’s clinical state 
or other therapies; and c) Evaluation of the patient’s clinical state indicates to the investigator that 
the experience is definitely related to study procedures.  
• 
Probably or Possibly Related: The event should be assessed following the same criteria for 
“Definitely Associated”. If in the investigator’s opinion at least one or more of the criteria are not 
present, then “Probably or Possibly” associated should be selected.  
• 
Probably Not Related: The 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.  
• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or by other 
modes of therapy administered to the patient.  
• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined.  
The principal investigator will work collaboratively with the reporting investigator to determine if a 
serious adverse event has a reasonable possibility of having been caused by the study medication or study 
procedure. The principal investigator will be responsible for the final adjudication of relatedness that will 
be used to determine if an adverse event is reportable. 
D.4. Clinical Outcomes that may be Exempt from Adverse Event 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 

 
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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 a reportable adverse event. For example, a 
cardiac arrest that the investigator considers Definitely Related to ketamine would be both recorded as a 
study-specific clinical outcome and recorded and reported as a Serious and Definitely Related adverse 
event. 
 
D.5 Protocol Deviations and Violations 
Investigators will also monitor for Protocol Deviations and Protocol Violations. Protocol Deviations and 
Protocol Violations are defined as follows: 
• 
Protocol Deviation: An incident involving noncompliance with the trial protocol that typically 
does not have a significant effect on the subject’s rights, safety, welfare, and/or the integrity of 
the resultant data. Deviations may result from the action of the participant, investigator, or staff. 
• 
Protocol Violation: Accidental or unintentional changes to the IRB approved protocol procedures 
that affect the subject’s rights, safety, welfare, and/or the integrity of the resultant data. 
Protocol violations will be reported to the DSMB and IRB within 7 days of becoming aware of the event. 
Protocol deviations will be tracked and reported to the DSMB at the time of semi-annual meetings and to 
the IRB through continuing reviews. 
D.6 Communication with the Funder(s) 
With the support of personnel at the Coordinating Center, the investigators leading the trial will ensure 
that the funder(s) of the research study is/are informed in a timely manner of reporting relating to and 
recommendations, decisions, findings, actions, and steps taken emanating from activities relevant to the 
DSMP, including those from the DSMP, sIRB, FDA, and any other relevant regulatory bodies.  This will 
include providing documentation of: 
• 
New and continuing IRB approvals 
• 
Approval of a DSMB charter by IRB or DSMB 

 
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• 
Copies of documents or materials relating to the DSMP, such as minutes of open sessions of the 
DSMB (upon request by the funder) 
• 
Summary of any significant data and safety monitoring issues, including 
o Summary of reports submitted to DSMB, IRB, FDA, or other regulatory body about 
unanticipated problems involving risks to patients (e.g., adverse events, deviation from 
approved protocol that places patients at increased risk of harm, data breach, procedural 
or medication error) 
o Summary of any significant decisions, findings, recommendations, actions, and directions 
of a DSMB, IRB, FDA or other regulatory body relating to the research 
With the support of personnel at the Coordinating Center, the investigators leading the trial will fulfill all 
reporting obligations relating to any serious unanticipated problems (e.g., serious adverse events, serious 
safety issues, or other serious problems) relating to the research study that are required by the funder, 
DSMB, IRB, FDA, or other regulatory body.  The investigators and awardee institution will notify the 
funder within 10 days after: 
• 
Reporting any serious unanticipated problem (e.g., serious adverse event, serious safety issue, or 
other serious problem) relating to the research study to the DSMB, IRB, FDA, or other regulatory 
body 
• 
Any decision, finding, recommendation, action, or direction of a DSMB, IRB, FDA, or other 
regulatory body relating to any serious unanticipated problem (e.g., serious adverse event, serious 
safety issue, or other serious problem) relating to the research study. 
 
 
 
 
 

 
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Appendix E: Long-Term Outcomes in RSI 
1. Title: Effect of Ketamine and Etomidate during RSI on Long-Term Outcomes (RSI-LTO) 
2. Background: One-third of adults who are intubated in the ED or ICU experience symptoms of post-
traumatic stress disorder (PTSD). PTSD is a psychiatric disorder triggered by a “shocking, scary, or 
dangerous event.”1–4 Critical illness, tracheal intubation, and mechanical ventilation can be traumatic 
and distressing events. Patients may recall the intubation procedure, the feeling of the breathing tube 
in their throat, or being unable to move (“paralyzed”). While on the breathing machine, patients may 
experience delirium, frightening hallucinations, and delusions. Patients with PTSD after critical 
illness can be hypervigilant, anxious, and troubled by intrusive thoughts, nightmares, and flashbacks 
that last months to years after critical illness5–10 and that PTSD negatively impacts patients’ 
marriages, work, and quality of life and increases patients’ risk of depression, anxiety, substance use 
disorder, and suicide.2,6,10–16 Ketamine may prevent PTSD symptoms by blocking the pathways in the 
brain’s glutaminergic system that are responsible for the formation of traumatic memories.17–20 In 
outpatients with chronic PTSD, a single dose of ketamine has been shown to reduce PTSD symptoms 
for up to 2 weeks.21,22 Even a modest reduction in PTSD would translate into tens of thousands of 
fewer cases of PTSD each year, more cases of PTSD each year than any other medical intervention 
evaluated to date. 
3. Objective of RSI-LTO: To compare the effectiveness of ketamine vs etomidate as sedatives during 
tracheal intubation of critically ill adults with regard to survival and PTSD symptoms at 12-months. 
4. Hypothesis of RSI-LTO: The primary hypothesis of this proposal is that patients who receive 
ketamine will have fewer PTSD symptoms at 12-months than patients who receive etomidate. 
5. Inclusion/Exclusion Criteria for RSI-LTO: 
5.1 Inclusion Criteria for RSI-LTO: 
• 
Enrolled in RSI trial 
5.2 Exclusion Criteria for RSI-LTO 
• 
Aphasic or non-verbal prior to tracheal intubation 
• 
Cannot follow commands prior to tracheal intubation 
• 
Non-English speaking 
• 
Deaf 
 
6. Informed Consent for RSI-LTO: For patients who survive intubation, the research team will approach 
the patient or LAR for consent for collection of long-term outcomes. The research staff will review 
the study in lay terms and, if the patient/LAR is interested in participating in the collection of long-
term outcomes, the research staff will review the informed consent document for RSI-LTO. The 
patient/LAR will be provided an opportunity to ask any questions.  
 
Patients in the hospital.  Research staff will approach the patient/LAR after extubation from 
mechanical ventilation or shortly before hospital discharge, whichever occurs first. For patients 
located in the hospital at the time that the patient/LAR agrees to participate in RSI-LTO, the 
patient/LAR will sign the informed consent document. A copy of the informed consent document will 
be provided to the patient/LAR. 

 
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Patients not in the hospital.  For eligible patients discharged from the hospital without an opportunity 
to complete an informed consent discussion for RSI-LTO (e.g., a patient discharged to post-acute care 
or skilled nursing facility without regaining decisional capacity and no available LAR), the patient or 
legally authorized representative will be contacted by phone, e-mail, or text by research staff from the 
site where the patient was enrolled, using a script approved by the sIRB. The script will review the 
details of the RSI trial and offer the opportunity to participate in the collection of long-term outcomes 
as part of RSI-LTO. For patients or legally authorized representatives who are potentially interested, 
research staff will assess decisional capacity and initiate the informed consent process. The flow 
diagram and figure below describe the process by which study personnel will identify who will be 
contacted for consent in RSI-LTO (patient or LAR) and the process by which that person will be 
assessed for decisional capacity.  
 

 
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Trained study personnel from the site where the patient was enrolled will complete each aspect of the 
informed consent process with the patient or LAR by phone, including going over the risks and 
benefits of participation and answering any questions. Study personnel will obtain consent from the 
patient or the legally authorized representative for the patient to participate in the collection of long-
term outcomes. Research staff will document the informed consent process in the research record 
including confirmation that a reminder of the details of the RSI trial was provided, and the date, time, 
and identity of the person who provided the information for informed consent. A waiver of 
documentation of informed consent will be used and a written signature will not be obtained from the 
patient or legally authorized representative because: 
• 
The long-term follow-up surveys involve no procedures for which written consent is 
normally required outside of the research context and pose no more than minimal risk of 
harm to the patient.   
• 
Many survivors of critical illness and their surrogates are of advanced age, spend months in a 
long-term acute care hospital or skilled nursing facility following discharge, or have 
executive dysfunction and physical disability. All of these make the process of returning a 
written consent document to the local site by mail or eConsent challenging and even 
distressing to patients. In prior studies of survivors of critical illness, many patients and 
surrogates have reported frustration that the process of mailing the physical consent form 
required more time and effort than the remainder of the study, combined.  

 
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• 
The informed consent document contains PHI and returning a signed informed consent 
document by mail would increase the risk of disclosures of PHI without adding significant 
additional protections over an informed consent process with a waiver of documentation.  
Patient compensation for RSI-LTO: Patients will be provided financial compensation for time spent 
participating in the collection of long-term outcomes.  They will receive $80 when the 3-month 
follow-up visit has been completed and $100 when the 12-month follow-up has been complete.  
7. Study Procedures for RSI-LTO: 
7.1 Baseline Patient Interview: (In-hospital or immediately following remote consent) 
7.1.1 Demographics and Patient Characteristics. Research staff will collect patient 
demographics, past psychiatric history, psychiatric medications, years of education, 
employment status, where they grew up, marital status, place of residence, zip code, 
and highest occupation from the patient or LAR. It is estimated that it will take 8 
minutes to collect this data. 
7.1.2 Resiliency.  Because coping skills may be an important determinant of PTSD 
development, we will also collect the Brief Resilient Coping Scale (BRCS, 4 items, 2 
minutes). The BRCS is a 4-item survey that asks patients questions about their ability 
to cope with stress.  
7.1.3 Prior traumatic experiences and psychological flexibility. We will collect the Life 
Events Checklist for DSM-5 (LEC-5), a self-reported measure for potentially traumatic 
events in a respondent's lifetime and the Acceptance and Action Questionnaire (AAQ-
2) to characterize psychological flexibility. 
7.1.4 Social Determinants of Health. The research staff will collect social determinants of 
health including financial strain, social support, and social network. It is estimated that 
these questions will take 10 minutes to collect. 
 
7.2 Electronic Health Record Review: 
7.2.1 
Baseline: Zip code, psychiatric history including PTSD, depression, bipolar disease, 
anxiety, and dementia; Elixhauser Comorbidity Index; psychiatric medications such as 
anti-depressants, mood stabilizers, and sedative hypnotics; height; weight; APACHE II 
score. 
7.2.2 
On-study: Electronic health record review will be conducted throughout the follow-up 
period to evaluate for the occurrence of delirium or coma between randomization and 14 
days after randomization and to monitor for death or hospital readmissions to help 
coordinate follow-up phone calls.  Medical record review may continue after the follow-
up is completed for data cleaning and additional analyses. 
7.2.3 
Electronic health record review will also be conducted to obtain the patient’s Social 
Security Number for disbursal of the compensation from the Coordinating Center, as 
well as evaluation of vital status using national death indices if the patient is lost to 
follow-up.   
7.2.4 
Contact information (e.g., phone number, address) by which to reach patients for the 
RSI-LTO surveys will be collected from the patient, LAR, family members, electronic 

 
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health record, and other publicly available data sources (e.g., internet search, 
intelius.com). 
 
7.3 Outcomes for RSI-LTO (Obtained by Follow-Up Phone Interviews at 3 and 12 months): 
7.3.1 
Main Outcome of RSI-LTO:  
o PTSD symptoms at 12 months: We will measure PTSD symptoms at 3 and 12 months 
using the Checklist for Diagnostic and Statistical Manual of Mental Disorders (DSM–5) 
(PCL-5). The PCL-5 is a widely used 5-10 minute patient survey validated to characterize 
severity of symptoms of PTSD. Patients rate 20 items corresponding to the DSM-5 
criteria for PTSD on a 5-point Likert scale ranging from 0 (not bothersome) to 4 
(extremely bothersome). Total scores range from 0 to 80, with higher scores indicating 
more severe symptoms of PTSD. We chose the PCL-5 over the Clinician Assessment of 
Post-Traumatic Stress Symptoms for the DSM-5 (CAPS-5) which is the “reference 
standard” tool for PTSD diagnosis. The CAPS-5 takes 45- to 60-minutes to complete and 
places significant burden on the patients who can be easily fatigued due to concurrent 
psychiatric comorbidities, physical disability, and cognitive impairment.  
7.3.2 
Additional Outcomes of RSI-LTO: 
o Awareness of paralysis, recollection of experiences, and psychological distress: These 
will be determined by the modified Brice questionnaire25–27 and ICU Memory Tool1,2,28  
(15-20 minutes). These semi-structured interviews ask subjects about their recollection of 
the ICU experience, including emotions, delusional memories, the worst thing 
experienced during mechanical ventilation, and awareness of being paralyzed. Possible 
awareness with paralysis event will be defined as: (1) reporting memories of the period 
between losing consciousness and waking up and (2) a sensation/feeling of wakeful 
paralysis.29 
o Anxiety and depression: Generalized Anxiety Disorder-7 and Patient Health 
Questionnaire-9 – Multiple-choice inventories used for measuring the severity of anxiety 
and depression. 
o Quality of life: EQ-5D-5L156,157 – Quantifies quality of life by characterizing mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression, and global health status. 
o Cognition: MOCA-Blind159 – Assess naming, immediate recall, attention, language, 
abstraction, delayed recall, and orientation. The Vigilance A task asks the patient to tap 
on the table when they hear the letter “A” while being given a series of letters. Because 
the MOCA-Blind is administered by phone, study participants will say “yes” when they 
hear the letter “A.” Participants are told that if they hear a different letter, they will not 
say “yes”. 
o Executive function: Oral Trailmaking Test – Patient counts from 1 to 25 and then 
alternates between numbers and letters (i.e., 1-A-2-B-3-C, etc.,) 
o Employment: Employment Questionnaire – A 15-item survey characterizing current level 
of employment (full, partial, or not employed). 
o Physical disability (collected at 12 months only): Duke Activity Status Index (DASI) – 
An 11-item survey that assesses the patient’s current ability to perform various physical 
activities.  

 
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o Vital Status: Date and location of death will be assessed from enrollment until 12 months 
after enrollment by trial personnel using review of electronic health records, phone calls 
with families, and national death indices. 
 
8. Risks: The collection of long-term outcomes represents minimal risk to patients.  However, there are 
some risks to the data collection.  There is a small risk that a patient enrolled in may become fatigued 
or distressed during the study assessments. In these cases, we will immediately stop the assessment 
and give the patient an opportunity to rest. Afterwards, we will ask the patient if we can continue with 
the assessments or if we should reschedule the phone-call.  Occasionally, patients or families may get 
frustrated and distressed if the patient is unable to perform the cognitive tasks. We will reassure them 
that these tasks can be difficult to perform, and that such difficulties are common. If the patient or his 
or her family continue to be distressed after this reassurance, we will skip that particular task or stop 
the assessment altogether.  
 
Patients will be asked to recall their memories of the traumatic experiences during their lifetime and 
the ICU experience. Some of these memories may be distressful and cause patients to become tearful, 
angry, frightened, or agitated.  In these cases, we will immediately stop the assessment and give the 
patient an opportunity to collect themselves.  If necessary, we will stop the interview and contact 
them at a later time. 
 
Because patient identifiers are accessed throughout all phases of the study, there is a small risk of loss 
of patient confidentiality. Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, 
there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of 
data. To maintain confidentiality, all paper-based evaluation forms and reports will be identified only 
by a coded number.  All paper case report forms will be maintained inside a locked office.  All related 
participant study records will be kept in a locked, password protected computer. Only the study team 
will have access to the codes. All records will be kept in a locked, password protected computer. All 
statistical analyses will use de-identified data only.  Patient name, address, phone number and medical 
record number will be collected from the electronic medical record to facilitate follow-up and patient 
re-imbursement.  These data will be stored in a secure, password-protected database only accessible 
to the study team.  These patient identifiers will be deleted once all study assessments has been 
completed and subject has been financially reimbursed. 
 
9. Safety of Participants with Suicidal Ideation: During follow-up phone call, patients will be asked 
questions about their psychological being.  In the very rare event that patients express thoughts about 
suicide (e.g., suicidal ideation), the research team will instruct the patient to do the following: 
• 
For patients who are expressing active suicidal ideation and are at highest risk for causing 
imminent harm requiring immediate assistance, patients will be instructed to call 911 or drive 
to the nearest ED. The local police may be called, especially if the patient refuses to seek 
help.   
• 
For those who have a mental health provider, they will be instructed to contact them by phone 
immediately.  
• 
If the patient does not have a mental health provider and does not require immediate 
assistance, they will be instructed to call one of the following 24/7 resources: 

 
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o National Suicide Prevention Lifeline: 
 
Phone: 800-273-8255 or 988 
 
Website: https://suicidepreventionlifeline.org 
o SAMHSA National Helpline 
 
Phone: 800-662-HELP (800-662-4357) 
 
Website: https://www.samhsa.gov/find-help/national-helpline 
o Local mobile crisis 
For all high-risk patients, one of the members from the Critical Illness, Brain Dysfunction, and 
Survivorship Center (CIBS) neuropsychology core, Dr. Han (PI) or a delegate will contact the patient 
within one day to do a “well check” and ensure that the patient received the appropriate resources. If 
the patient cannot be reached for this “well check,” the local police may be called. 
 
To ensure appropriate resources are provided for patients found to have severe PTSD or depression, 
we will do the following: 
• 
We will collect information on whether patients received a new diagnosis or treatment of 
PTSD, depression, or anxiety or saw a therapist, social worker, psychologist, or psychiatrist 
since they were placed on the breathing machine.   
• 
For patients with severe PTSD or depression, a CIBS social worker, neuropsychologist, or 
investigator (Drs. Jackson or Han) will call the patient. He/she will instruct the patient to 
make an appointment with their psychiatrist. If they do not have a psychiatrist, then they will 
be instructed to see their primary care provider. They will be directed to 
www.icudelirium.org that has resources for ICU survivors who are suffering from PTSD and 
depression. If requested, the CIBS social worker will help connect them to a local resource to 
assist them with their PTSD or depression symptoms.  If needed, a CIBS neuropsychologist 
may offer a one-time consultation. 
 
10. Communication of Participant Results: The cognitive and psychological tests conducted in RSI-LTO 
are screening tests and not diagnostic tests.  Further, the results of screening tests suggesting possible 
cognitive impairments or psychiatric disease may in themselves be distressing to patients and 
families, particularly given the absence of available treatments for many of the conditions being 
evaluated (e.g., cognitive impairments and dementia). We, therefore, do not plan to routinely provide 
the results of screening tests to patients. However, if patients request the results of testing, they will 
be provided, and investigators will emphasize that the study measures are screening tests and patients 
should follow up with their medical providers for a more detailed evaluation.   
 
11. Study Withdrawal/Discontinuation: If the patients does not meet eligibility criteria for RSI-LTO or 
the patient or caregiver declines participation in RSI-LTO, they will not be included in RSI-LTO. If a 
patient who has agreed to participate in RSI-LTO elects to discontinue taking part in the RSI-LTO, 
they can inform the research staff of their wish to withdraw.  At that time, no further data will be 
collected on the patient. All health data previously collected before they withdraw their consent will 
still be used for reporting and research quality.  As suggested in federal regulations, the study team 
may access data about the patient’s death from public vital statistics records and other public records 
not subject to restriction under 21 CFR 50.24 or other FDA regulations. 
 

 
RSI Protocol Version 2.2 
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Participants who become incarcerated during the follow-up period: As required by the U.S. 
Department of Health and Human Services, study staff will cease all research interactions and 
interventions, including collection of identifiable private information, if informed that a study 
participant has become incarcerated during the 12-month follow-up period. The patient will also 
be withdrawn from the RSI-LTO study.   
12. Statistical Considerations:  
12.1 PTSD symptoms (Main Outcome of RSI-LTO): We will compare PTSD symptoms at 12 
months between groups using participants’ scores on the PCL-5 as an ordinal variable from 0 
(no symptoms) to 80 (most severe symptoms). Because a value for the PCL-5 score will not 
exist for patients who die prior to assessment, our main analysis will use a composite endpoint 
approach where we will assign patients whose PCL-5 could not be assessed because they died 
a value of 81 (higher than the worst value on the PTSD symptom scale). We will consider 
death a worse outcome than being alive with severe PTSD because: [1] 60-80% of patients 
with PTSD eventually experience full recovery30 and [2] our stakeholders with PTSD 
unanimously felt that, despite their symptoms, it was still better to have survived. Our main 
analysis will compare the PCL-5 at 12 months between patients randomized to ketamine vs 
patients randomized to etomidate using a partial proportional odds model to permit separate 
estimates of the effect of ketamine vs etomidate on (1) death and (2) symptoms of PTSD. The 
partial proportional odds model is a flexible regression model that estimates the treatment 
effect separately for each of the ordinal outcome categories (i.e., relaxes the proportional odds 
assumption).  For the partial proportional odds model, the PCL-5 scores will be categorized to 
create the ordinal outcome variables as in the following groupings of values: 0, 1-5, 6-10, 11-
15, 16-20, 21-25, 26-30, 31-35, 36-40, 41-45, 46-50, and ≥50 (and death).  The reason for 
groupings of 5 values is that serial changes in individuals of ≥5 on the PCL-5 total score are 
considered reliable.31 The reason for grouping all values of 50 or greater is that less that too 
few patients (<5%) have values in this range to allow smaller groupings.  We will perform 
additional sensitivity analyses.  First, we will compare the outcome between trial groups using 
an unadjusted Wilcoxon Rank Sum Test. Second, we will perform a proportional odds mixed 
effects model with a random effect for site and fixed effects for trial group and pre-specified 
covariates: age; sex; race; ethnicity; neighborhood disadvantage;32 rurality;33 Elixhauser 
comorbidity index;34 pre-enrollment PTSD; pre-enrollment depression, anxiety or bipolar 
disorder; and APACHE II score. We will also compare PTSD symptoms between groups in 
survivors-only analysis both unadjusted and adjusting for the above variables plus baseline 
measures of traumatic experiences (LEC-5), resilience (Brief Resilient Coping Scale), and the 
social determinants of health in Figure 9. Finally, we will perform Survivor Average Causal 
Effect analysis35 and compare PTSD diagnosis using generalized linear models. 
12.2 Additional RSI-LTO Outcomes: We will perform intention-to-treat comparisons of additional 
RSI-LTO 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. 
 
13. Communication with Patients in RSI-LTO: Patients who consent to participate in RSI-LTO will 
receive an IRB-approved post-card with general information about the RSI-LTO study at the time of 

 
RSI Protocol Version 2.2 
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Page 135 of 141 
consent to participate in RSI-LTO and by mail one month prior to the 12-month follow up 
assessment. 
 
14. Return of Aggregate Results in RSI-LTO: We will keep participants informed of any preliminary 
results through an newsletter, distributed electronically or in paper format, depending on the 
participant’s stated communication preferences. We will continue to distribute the newsletter to all 
participants (except those who opt not to receive it) until final results are available, at which point, we 
will provide a lay-person summary of results to that will be made available to participants via the 
final newsletter, by email or text, by mail, and through the study’s website and twitter account.  
 
 
 
 
 
15. References for Appendix E 
1.  
Jones C, Griffiths RD, Humphris G, Skirrow PM. Memory, delusions, and the development of acute 
posttraumatic stress disorder-related symptoms after intensive care. Critical care medicine 
2001;29(3):573–80.  
2.  
Svenningsen H. Associations between sedation, delirium and post-traumatic stress disorder and their 
impact on quality of life and memories following discharge from an intensive care unit. Dan Med J 
2013;60(4):B4630.  
3.  
Wade DM, Brewin CR, Howell DC, White E, Mythen MG, Weinman JA. Intrusive memories of 
hallucinations and delusions in traumatized intensive care patients: An interview study. Br J Health 
Psychol 2015;20(3):613–31.  
4.  
Wade D, Hardy R, Howell D, Mythen M. Identifying clinical and acute psychological risk factors 
for PTSD after critical care: a systematic review. Minerva Anestesiol 2013;79(8):944–63.  
5.  
Bienvenu OJ, Williams JB, Yang A, Hopkins RO, Needham DM. Posttraumatic stress disorder in 
survivors of acute lung injury: evaluating the Impact of Event Scale-Revised. Chest 
2013;144(1):24–31.  
6.  
Jackson JC, Jutte JE, Hunter CH, et al. Posttraumatic stress disorder (PTSD) after critical illness: A 
conceptual review of distinct clinical issues and their implications. Rehabil Psychol 
2016;61(2):132–40.  
7.  
Jackson JC, Hart RP, Gordon SM, Hopkins RO, Girard TD, Ely EW. Post-traumatic stress disorder 
and post-traumatic stress symptoms following critical illness in medical intensive care unit patients: 
assessing the magnitude of the problem. Crit Care 2007;11(1):R27.  
8.  
Garrouste-Orgeas M, Flahault C, Vinatier I, et al. Effect of an ICU Diary on Posttraumatic Stress 
Disorder Symptoms Among Patients Receiving Mechanical Ventilation: A Randomized Clinical 
Trial. Jama 2019;322(3):229–39.  

 
RSI Protocol Version 2.2 
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9.  
Girard TD, Shintani AK, Jackson JC, et al. Risk factors for post-traumatic stress disorder symptoms 
following critical illness requiring mechanical ventilation: a prospective cohort study. Critical care 
(London, England) 2007;11(1):R28.  
10.  Parker AM, Sricharoenchai T, Raparla S, Schneck KW, Bienvenu OJ, Needham DM. Posttraumatic 
stress disorder in critical illness survivors: a metaanalysis. Critical care medicine 2015;43(5):1121–
9.  
11.  Smith MW, Schnurr PP, Rosenheck RA. Employment outcomes and PTSD symptom severity. Ment 
Health Serv Res 2005;7(2):89–101.  
12.  Davydow DS, Desai SV, Needham DM, Bienvenu OJ. Psychiatric morbidity in survivors of the 
acute respiratory distress syndrome: a systematic review. Psychosom Med 2008;70(4):512–9.  
13.  Kapfhammer HP, Rothenhäusler HB, Krauseneck T, Stoll C, Schelling G. Posttraumatic stress 
disorder and health-related quality of life in long-term survivors of acute respiratory distress 
syndrome. Am J Psychiatry 2004;161(1):45–52.  
14.  Jackson JC, Pandharipande PP, Girard TD, et al. Depression, post-traumatic stress disorder, and 
functional disability in survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort 
study. Lancet Respir Med 2014;2(5):369–79.  
15.  Friedman MJ, Schnurr PP, McDonagh-Coyle A. Post-traumatic stress disorder in the military 
veteran. Psychiatr Clin North Am 1994;17(2):265–77.  
16.  Fox V, Dalman C, Dal H, Hollander A-C, Kirkbride JB, Pitman A. Suicide risk in people with post-
traumatic stress disorder: A cohort study of 3.1 million people in Sweden. J Affect Disord 
2021;279:609–16.  
17.  Krystal JH, Abdallah CG, Averill LA, et al. Synaptic Loss and the Pathophysiology of PTSD: 
Implications for Ketamine as a Prototype Novel Therapeutic. Curr Psychiatry Rep 2017;19(10):74.  
18.  Nair J, Singh Ajit S. The role of the glutamatergic system in posttraumatic stress disorder. CNS 
Spectr 2008;13(7):585–91.  
19.  Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, Baca-Garcia E. New 
perspectives in glutamate and anxiety. Pharmacol Biochem Behav 2012;100(4):752–74.  
20.  Newcomer JW, Farber NB, Olney JW. NMDA receptor function, memory, and brain aging. 
Dialogues Clin Neurosci 2000;2(3):219–32.  
21.  Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of 
chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry 
2014;71(6):681–8.  
22.  Feder A, Costi S, Rutter SB, et al. A Randomized Controlled Trial of Repeated Ketamine 
Administration for Chronic Posttraumatic Stress Disorder. Am J Psychiatry 2021;178(2):193–202.  
23.  Berman SE, Koscik RL, Clark LR, et al. Use of the Quick Dementia Rating System (QDRS) as an 
Initial Screening Measure in a Longitudinal Cohort at Risk for Alzheimer’s Disease. J Alzheimers 
Dis Rep 2017;1(1):9–13.  

 
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24.  Galvin JE. The Quick Dementia Rating System (Qdrs): A Rapid Dementia Staging Tool. 
Alzheimers Dement (Amst) 2015;1(2):249–59.  
25.  Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during 
anaesthesia. British journal of anaesthesia 1970;42(6):535–42.  
26.  Avidan MS, Jacobsohn E, Glick D, et al. Prevention of intraoperative awareness in a high-risk 
surgical population. The New England journal of medicine 2011;365(7):591–600.  
27.  Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness and the bispectral index. The New 
England journal of medicine 2008;358(11):1097–108.  
28.  Samuelson KA, Lundberg D, Fridlund B. Stressful memories and psychological distress in adult 
mechanically ventilated intensive care patients - a 2-month follow-up study. Acta anaesthesiologica 
Scandinavica 2007;51(6):671–8.  
29.  Pappal RD, Roberts BW, Mohr NM, et al. The ED-AWARENESS Study: A Prospective, 
Observational Cohort Study of Awareness With Paralysis in Mechanically Ventilated Patients 
Admitted From the Emergency Department. Annals of emergency medicine 2021;77(5):532–44.  
30.  Rosellini AJ, Liu H, Petukhova MV, et al. Recovery from DSM-IV post-traumatic stress disorder in 
the WHO World Mental Health surveys. Psychol Med 2018;48(3):437–50.  
31.  Marx BP, Lee DJ, Norman SB, et al. Reliable and clinically significant change in the clinician-
administered PTSD Scale for DSM-5 and PTSD Checklist for DSM-5 among male veterans. 
Psychol Assess 2022;34(2):197–203.  
32.  Kind AJH, Buckingham WR. Making Neighborhood-Disadvantage Metrics Accessible — The 
Neighborhood Atlas. N Engl J Med 2018;378(26):2456–8.  
33.  USDA ERS - Rural-Urban Commuting Area Codes [Internet]. [cited 2021 Dec 14];Available from: 
https://www.ers.usda.gov/data-products/rural-urban-commuting-area-codes/ 
34.  Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative 
data. Med Care 1998;36(1):8–27.  
35.  Colantuoni E, Scharfstein DO, Wang C, et al. Statistical methods to compare functional outcomes in 
randomized controlled trials with high mortality. BMJ (Clinical research ed) 2018;360:j5748.  
 
 

 
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Appendix F: Analyses of Heterogeneity of Treatment Effect. 
 
Our analyses of heterogeneity of treatment effect (“individualized treatment effect”) will adhere to 
published standards1 and the Predictive Approaches to Treatment Effect Heterogeneity (PATH) 
guidelines.2 The goal of our analyses will be to provide estimates of the effect of ketamine vs etomidate 
on [1] “mortality by 1 month (28 days)” and [2] “PTSD symptoms at 12 months” for an individual 
patient, considering all of the patient’s characteristics simultaneously.2,3 Our analyses will use a 
computational pipeline that incorporates careful cross-validation to prevent overfitting and optimizes 
information content. First, in a derivation cohort of the first 1,700 patients enrolled in the RSI trial, we 
will compare the performance of candidate effect models using 5-fold cross-validation. Specifically, we 
will consider X-learners with elastic net and random forest base-learners, S-learners with random forest 
and conditional random forest (cforest) base-learners, T-learner with Bayesian Adaptive Regression Trees 
(BART) as the base-learner, R-learner with Extreme Gradient Boosting (Xgboost) as the base-learner, and 
causal forest. The algorithm and base-learner combination resulting in the highest qini coefficient in the 
out-of-sample predictions from the 5-fold cross-validation will then be fit using all the derivation data to 
create a final effect model.  Second, in a validation cohort of the final 664 patients enrolled, we will 
validate the performance of the individualized treatment effect model.  To do this, we will use the model 
to predict the effect of ketamine vs etomidate on 28-day in-hospital mortality for each of the 664 patients 
in the validation cohort (the patient’s predicted individualized treatment effect at the time of enrollment). 
We will compare the treatment effect predicted by the model to the treatment effect observed in the 
validation cohort, using the adjusted Qini coefficient,4 the C statistic for benefit,5 and measures of clinical 
utility, in alignment with the PATH guidelines (examining characteristics by quartile of predicted 
benefit). We will evaluate the credibility of any effect modification using rigorous, multidimensional 
criteria,6 including examination of alignment with the hypothesis, prior evidence, and the number of tests 
being performed.  Third, once models for estimating the effect of ketamine vs etomidate on “mortality by 
1 month” and “PTSD symptoms at 12 months” for individual patients based on their unique 
characteristics have been derived and validated, we will disseminate the full models and make available a 
simplified online calculator for the predicted treatment effect for a future patient. We also will 
disseminate a simplified tree diagram that clinicians can print and use at the bedside to rapidly select the 
best sedative medication for a future patient based on his or her characteristics. We will report all 
prespecified and post hoc analyses. The effect-modeling analyses may be presented separately from the 
other trial results if the time required to conduct them or the space required to present them requires doing 
so. 
 
 
References for Appendix F 
 
1. Category 5: Standards for Heterogeneity of Treatment Effects [Internet]. Categ. 5 Stand. Heterog. 
Treat. Eff. PCORI. 2016 [cited 2022 Jan 3];Available from: https://www.pcori.org/research-
results/about-our-research/research-methodology/methodology-standards-academic-curriculum-3 
 
2. Kent DM, Paulus JK, van Klaveren D, et al. The Predictive Approaches to Treatment effect 
Heterogeneity (PATH) Statement. Ann Intern Med 2020;172(1):35–45.  
 

 
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3. Varadhan R, Segal JB, Boyd CM, Wu AW, Weiss CO. A framework for the analysis of 
heterogeneity of treatment effect in patient-centered outcomes research. J Clin Epidemiol 
2013;66(8):818–25.  
 
 
4. Belbahri M, Murua A, Gandouet O, Nia VP. Uplift Regression: The R Package tools4uplift. :22. 
 
5. van Klaveren D, Steyerberg EW, Serruys PW, Kent DM. The proposed “concordance-statistic for 
benefit” provided a useful metric when modeling heterogeneous treatment effects. J Clin 
Epidemiol 2018;94:59–68.  
 
6. Schandelmaier S, Briel M, Varadhan R, et al. Development of the Instrument to assess the 
Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-
analyses. CMAJ Can Med Assoc J J Assoc Medicale Can 2020;192(32):E901–6.  
 
 
 
 
 
 
 
 
 
 
 

 
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Summary of changes to the RSI trial protocol  
 
Protocol Version 1.0 
Date: March 9, 2022 
Initial protocol 
 
Protocol Version 1.1 
Date: May 23, 2022 
Purpose: This amendment is to add additional details regarding the approach to notifying, at the earliest 
feasible opportunity, each patient, or if the patient remains incapacitated, a legally authorized 
representative of the patient, or if such a representative is not reasonably available, a family member, of 
the patient’s inclusion in the study.  This amendment also describes the approach to obtaining prospective 
informed consent to be contacted for potential participation in ancillary trials.  
 
Protocol Version 2.0 
Date: October 18, 2023 
Description: This amendment triggers Stage 2 (multi-center) of the RSI trial, following the receipt of 
funding for Stage 2 of the RSI trial from PCORI, and includes revisions to the protocol to align with the 
grant approved by PCORI. Major changes made in version 2.0 of the grant include: 
• 
Activation of Stage 2 with pre-planned prioritization of Stage 2 outcomes (primary outcome: 
mortality at 1 month [28 days]) and removal of stage 1 analyses that will not be conducted with 
the activation of stage 2. 
• 
Increased sample size of 2,364 patients based on updated power calculation and input from 
stakeholders regarding the minimum clinically important difference. Sample size at which single 
pre-specified interim analysis would occur was updated to remain at 50% of total enrollment 
(1,182 patients). 
• 
The process for pre-enrollment opt-out was updated for operationalization at additional sites in 
Stage 2 (multi-center stage) of RSI. 
• 
Primary outcome changed to a generalized linear mixed effects model with a random effect for 
study site (e.g., Vanderbilt University ED, Vanderbilt University Medical ICU) and a fixed effect 
for group assignment (ketamine group vs etomidate group) and subgroup analysis updated to 
include a random effect for study site to match the primary analysis. 
• 
Addition of a plan to approach intubation survivors for consent to collect long-term outcomes. 
• 
Removal of example notification forms (following review and approval by IRB). 
• 
Replacement of the section “Consent to be Contacted for Ancillary Studies” by Appendix E 
describing the plan for collection of long-term outcomes.  
 
Protocol Version 2.1 
Date: April 30, 2024 
Description: This amendment is to make minor revisions to secondary analyses to match the research plan 
approved by the funder, clarify plans regarding enrollment of ineligible patients, add definitions for 
protocol deviations and protocol violations, and add detail regarding the provision of resources to patients 
participating with RSI-LTO who are found to have non-life-threatening psychiatric issues such as severe 
PTSD or depression. These changes include: 

 
RSI Protocol Version 2.2 
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Page 141 of 141 
• 
Revising the covariates that will be included in the adjusted analysis of the primary outcome (a 
secondary analysis). 
• 
Adding details of a planned analysis of Heterogeneity of Treatment Effect (“Individualized 
Treatment Effect”) for the short- and long-term outcomes as a new appendix (Appendix F). 
• 
Adding definitions and reporting plans for protocol deviations and violations and details of the 
plan for communication to the funder to Appendix D. 
• 
Adding details regarding how patients who are found to be prisoners will be identified and 
withdrawn from the study. 
• 
Describing what information will be collected during follow-up phone calls about patients with a 
new diagnosis of PTSD, depression, or anxiety, and the resources that will be provided to them.  
Protocol Version 2.2 
Date: March 7, 2025 
Description: This amendment is (i) to make minor revisions to secondary analyses to match the final 
trial statistical analysis plan at the time of its submission for publication and (ii) to revise the trial 
protocol to permit Waiver of Documentation of informed consent for patients discharged from the 
hospital who have completed an informed consent discussion and consent to participate but for whom 
receiving, signing, and returning by mail the informed consent document would be logistically 
burdensome and increase the risk of disclosure of PHI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol and Statistical Analysis Plan for the Randomized Trial of Sedative 
Choice for Intubation (RSI) 
  
Stephanie C. DeMasi MD1; Brant Imhoff MS2; Ariel A. Lewis MPH, BSN, RN3; Kevin P. Seitz 
MD, MSc4; Brian E. Driver MD5; Kevin W. Gibbs MD6; Adit A Ginde MD, MPH7; Stacy A. Trent 
MD, MPH7,8; Derek W. Russell MD9,10; Amelia L. Muhs MD4; Matthew E Prekker MD, MPH5,11,; 
John P. Gaillard MD12,13; Daniel Resnick-Ault, MD7; L. Jane Stewart MD, JD, MPH14,15; Micah R. 
Whitson MD9,16; Graham W. W. Van Schaik MD, MBA1; Aaron E. Robinson MD, MPH5; Jessica 
A. Palakshappa MD, MS6; Neil R. Aggarwal MD MHSc17; Jason C. Brainard MD14; David J. 
Douin MD, MSc14; Carolynn Lyle PA-C, MPH8; Sheetal Gandotra MD9; Aaron J. Lacy MD1; 
Kristen C. Sherlin PharmD18; Greta K. Carlson MD5,11; J. Maycee Cain BS6; Brianne Redman 
MD13; Carrie Higgins BSN17; Cori Withers BS7; Logan L. Beach MD16; Barbara Gould19, Jasmine 
McIntosh20, Bradley D. Lloyd RRT-ACCS3; Tiffany L. Israel MSSW3, Li Wang MS2, Todd W. 
Rice MD MSc3,4, Wesley H. Self MD MPH1,3, Jin H. Han MD, MSc1,21; Jonathan D. Casey MD, 
MSc3,4; Matthew W. Semler, MD, MSc3,4 for the RSI investigators and the Pragmatic Critical 
Care Research Group  
 
1 Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN  
2 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN  
3 Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical 
Center Nashville, TN  
4 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical 
Center, Nashville, TN  
5 Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN  
6 Department of Medicine, Section of Pulmonary, Critical Care, Allergy and Immunologic 
Disease, Wake Forest School of Medicine, Winston-Salem, North Carolina  
7 Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, 
Colorado  
8 Department of Emergency Medicine, Denver Health Medical Center, Denver, Colorado  
9 Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University 
of Alabama at Birmingham, Birmingham, AL  
10 Pulmonary Section, Birmingham Veteran's Affairs Medical Center; Birmingham, AL  
11Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, 
Hennepin County Medical Center, Minneapolis, MN  
12 Department of Anesthesiology-Critical Care, Wake Forest School of Medicine, Winston-
Salem, NC  
13 Department of Emergency Medicine, Wake Forest School of Medicine, Winston-Salem, NC  
14 Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado  
15 Department of Anesthesiology, Denver Health Medical Center, Denver, Colorado  
16 Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham AL  
17 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, 
University of Colorado Anschutz Medical Center, Aurora, CO  
18 Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN  
19 Denver, Colorado  
20 Birmingham, AL    
21 Geriatric Research, Education, and Clinical Center, Tennessee Valley Healthcare System, 
Nashville, TN  
  
Dr. DeMasi, Mr. Imhoff, and Ms. Lewis contributed equally to this manuscript as first 
authors.  
All rights reserved. No reuse allowed without permission. 
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
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; 
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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.

  
Drs. Semler and Casey contributed equally to this manuscript as senior authors.  
  
Collaborators for the RSI Investigators are listed in Section 1 of e-Appendix 1.  
  
Corresponding Author:   
Matthew W. Semler  
Email: matthew.w.semler@vumc.org  
Address: Vanderbilt Institute for Clinical and Translational Research, 2525 West End 
Ave., Suite 600, Room 672, Nashville, TN, 37203  
  
Funding/Support:  
Research reported in this article was funded through a Patient-Centered Outcomes 
Research Institute® (PCORI®) Award (BPS-2022C3-30021).  The views and 
statements presented in this article are solely the responsibility of the authors and do 
not necessarily represent the views of the PCORI®.  Funding for the trial was also 
provided by the National Heart, Blood, and Lung Institute (NHLBI) (K23HL153584). The 
views and statements presented in this article are solely the responsibility of the authors 
and do not necessarily represent the views of the NHLBI.  
  
Financial/Nonfinancial Disclosures  
The authors have no financial conflicts of interest relevant to the current work.  
  
  
 
 
 
 
 
 
 
 
 
 
 
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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
The copyright holder for this preprint
this version posted January 18, 2025. 
; 
https://doi.org/10.1101/2025.01.18.25320768
doi: 
medRxiv preprint 

Take-Home Points 
Study Question: Does use of ketamine for induction of anesthesia during emergency 
tracheal intubation decrease the incidence of death, compared with use of etomidate?  
Results: This manuscript describes the protocol and statistical analysis plan for the 
Randomized trial of Sedative choice for Intubation (RSI) comparing ketamine vs 
etomidate for induction of anesthesia for emergency tracheal intubation. 
Interpretation: Prespecifying the full statistical analysis plan before completion of 
enrollment increases rigor, reproducibility, and transparency of the trial results. 
 
 
 
All rights reserved. No reuse allowed without permission. 
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
The copyright holder for this preprint
this version posted January 18, 2025. 
; 
https://doi.org/10.1101/2025.01.18.25320768
doi: 
medRxiv preprint 

ABSTRACT 
Background: Emergency tracheal intubation is a common and high-risk procedure.  
Ketamine and etomidate are sedative medicines commonly used to induce anesthesia 
for emergency tracheal intubation, but whether the induction medication used affects 
patient outcomes is uncertain. 
Research Question: Does the use of ketamine for induction of anesthesia decrease 
the incidence of death among adults undergoing emergency tracheal intubation, 
compared to the use of etomidate? 
Study Design and Methods: The Randomized trial of Sedative choice for Intubation 
(RSI) is a pragmatic, multicenter, unblinded, parallel-group, randomized trial being 
conducted in 14 sites (6 emergency departments and 8 intensive care units) in the 
United States.  The trial compares ketamine vs etomidate for induction of anesthesia 
among 2,364 critically ill adults undergoing emergency tracheal intubation.  The primary 
outcome is all-cause, 28-day in-hospital mortality.  The secondary outcome is the 
incidence of cardiovascular collapse during intubation, a composite of hypotension, 
receipt of vasopressors, and cardiac arrest.  Enrollment began on April 6, 2022, and is 
expected to conclude in 2025. 
Interpretation: The RSI trial will provide important data on the effects of ketamine vs 
etomidate on death and other outcomes for critically ill adults undergoing 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.: NCT05277896; URL: www.clinicaltrials.gov
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INTRODUCTION 
Millions of critically ill adults undergo emergency tracheal intubation every year 
worldwide,1 approximately 30% of whom die before hospital discharge.2,3  Nearly all 
patients undergoing emergency tracheal intubation in an emergency department (ED) or 
intensive care unit (ICU) receive a medication to induce anesthesia for the procedure.4,5  
Whether the medication used to induce anesthesia affects patient outcomes is 
uncertain. 
Etomidate, an imidazole-derived, sedative-hypnotic agent that produces 
anesthesia by acting on gamma-aminobutyric acid (GABA) receptors, is the medication 
most often used to induce anesthesia during emergency tracheal intubation in some 
EDs and ICUs.5–9  Etomidate has been described as an “ideal” medication for induction 
of anesthesia in critically ill adults because of its rapid onset, short duration of action, 
and limited effect on blood pressure.10 However, etomidate inhibits 11-β-hydroxylase in 
the adrenal glands, which decreases cortisol production and causes adrenal 
insufficiency for 24 to 72 hours.11–14 Among critically ill adults, many of whom 
experience critical illness-related corticosteroid insufficiency from sepsis or other 
causes,15–18 etomidate-induced adrenal insufficiency has been hypothesized to be 
associated with organ dysfunction and death.6  
Ketamine, a dissociative agent that produces anesthesia by acting on N-methyl-
D-aspartate (NMDA) receptors, is the medication most often used to induce anesthesia 
during emergency tracheal intubation in some EDs and ICUs.8,19 In contrast to 
etomidate, ketamine increases cortisol production.20,21  However, while ketamine 
generally increases blood pressure by stimulating the release of catecholamines,22 it is 
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a direct negative inotrope23–26 and has been reported to precipitate rare episodes of 
severe hypotension8,27–29 or even cardiac arrest, particularly among critically ill patients 
who have depleted their stores of endogenous catecholamines.28,30 
Previous small-to-moderate sized randomized trials comparing ketamine and 
etomidate for emergency tracheal intubation have reported conflicting results, with some 
finding that use of ketamine decreased short-term mortality28,31 and others finding no 
significant differences in outcomes.32–34  Currently, whether use of ketamine decreases 
mortality for critically ill adults undergoing emergency tracheal intubation compared to 
use of etomidate remains uncertain. 
To address this uncertainty, we designed the Randomized trial of Sedative 
Choice for Intubation (RSI), which will compare ketamine vs etomidate for induction of 
anesthesia among 2,364 adults undergoing emergency tracheal intubation. We 
hypothesize that use of ketamine will decrease the incidence of death, compared to 
etomidate.  
 
STUDY DESIGN AND METHODS 
This article was written in accordance with Standard Protocol Items: 
Recommendations for Interventional Trials (SPIRIT) guidelines (Table 1 and Section 2 
of e-Appendix 1).35 
 
 
 
 
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Engagement of Patients, Families, and Community Members 
Detailed information on engagement with survivors of emergency tracheal 
intubation, family members, and community members in each phase of the design and 
conduct of the RSI trial are summarized in Section 3 of e-Appendix 1. 
 
Study Design 
 
RSI is a pragmatic, multicenter, unblinded, parallel-group, randomized trial 
comparing the use of ketamine versus etomidate for induction of anesthesia in 2,364 
critically ill adults undergoing emergency tracheal intubation in 14 sites (6 EDs and 8 
ICUs) in the United States. The primary outcome is all-cause, 28-day in-hospital 
mortality. The trial is being conducted by the Pragmatic Critical Care Research Group 
(www.pragmaticcriticalcare.org). The trial was registered prior to initiation of enrollment 
(ClinicalTrials.gov identifier: NCT05277896).  
 
Ethics and Regulatory Approval 
The RSI trial protocol was approved by the institutional review board (IRB) at 
Vanderbilt University Medical Center (IRB number: 210500) and the US Food and Drug 
Administration (FDA) (IND 141424).  
The study is being conducted with Exception from Informed Consent 
Requirements for Emergency Research (EFIC) (21 CFR 50.24).36 Plans for community 
consultation and public disclosure were approved by the single IRB at Vanderbilt 
University Medical Center. The IRB of each participating site provided local context for 
the community consultation and public disclosure plan and activities.  
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Whenever feasible, patients or their legally authorized representatives (LAR) are 
approached by research personnel to provide prospective, written informed consent to 
participate in the trial. When prospective, written informed consent is infeasible, patients 
are enrolled under EFIC and the patient, the patient’s LAR, or a family member is 
notified of enrollment in the trial at the earliest feasible opportunity (additional details in 
Section 4 of e-Appendix 1). 
 
Study Population 
Critically ill adults undergoing emergency tracheal intubation with sedation in a 
participating unit are potentially 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 ketamine or etomidate 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 
clinician performing the tracheal intubation procedure (referred to as 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 and randomized 
once the operator opens the trial envelope to reveal study group assignment. After 
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randomization, patients, clinicians, and study personnel are not blinded to trial group 
assignment. 
 
STUDY INTERVENTIONS 
 
Ketamine group 
For patients in the ketamine group, clinicians are instructed to administer 
ketamine intravenously to induce anesthesia for emergency tracheal intubation.  The 
dose of ketamine is determined by the clinicians based on the clinical condition of the 
patient.  A nomogram on the study group assignment sheet provides clinicians with 
doses of ketamine (in milligrams) that correspond to a full dose (2.0 mg/kg), an 
intermediate dose (1.5 mg/kg), and a reduced dose (1.0 mg/kg) for a range of patient 
weights (see Section 5 of e-Appendix 1).37 
 
Etomidate Group 
For patients in the etomidate group, clinicians are instructed to administer 
etomidate intravenously to induce anesthesia for emergency tracheal intubation.  The 
dose of etomidate is determined by the clinicians based on the clinical condition of the 
patient.  A nomogram on the study group assignment sheet provides clinicians with 
doses of etomidate (in milligrams) that correspond to a full dose (0.3 mg/kg), an 
intermediate dose (0.25 mg/kg), and a reduced dose (0.2 mg/kg) for a range of patient 
weights (see Section 6 of e-Appendix 1). 
 
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Co-Interventions 
The RSI trial determines only the sedative medication administered for induction 
of anesthesia during the emergency tracheal intubation procedure.  Subsequent 
boluses or infusions of sedative medications are determined by clinicians. Other 
aspects of emergency tracheal intubation (e.g., pre-intubation fluid and vasopressor 
management, choice of neuromuscular blocking medication) are determined by treating 
clinicians according to clinical protocols in the study units. Co-interventions that could 
potentially modify the effect of ketamine or etomidate on patient outcomes (e.g., 
administration of corticosteroids after intubation) are prospectively recorded.  
 
Data Collection 
An observer not directly involved with the intubation procedure collects data in 
real time for key periprocedural outcomes, including oxygen saturation and systolic 
blood pressure at the time of induction and lowest oxygen saturation, lowest systolic 
blood pressure, and administration of vasopressors between induction and two minutes 
after intubation.  Observers are either research personnel or trained clinical personnel 
(e.g., physicians or nurses).  The accuracy of this method of data collection has been 
validated previously38 and used in numerous previous trials of emergency tracheal 
intubation.3,5,7   
Immediately after the intubation procedure, the operator completes a paper data 
collection form to record characteristics of the procedure (e.g., Cormack-Lehane grade 
of glottic view39), complications during intubation (e.g., cardiac arrest), and the 
operator’s prior intubating experience.  Study personnel at each site review the 
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electronic health record to collect data on baseline characteristics, management before 
and after laryngoscopy, and in-hospital clinical outcomes such as systolic blood 
pressure at 24 hours after induction, receipt of vasopressors at 24 hours after induction, 
ventilator duration, and mortality. Study personnel collect information on mortality 
occurring after hospital discharge from the electronic health record, public vital statistics 
records and other public records, and phone calls with patients participating in the long-
term outcome assessments at 3 and 12 months (the results of the long-term outcome 
assessments will be reported separately).  
 
Primary Outcome 
 
The primary outcome is all-cause, 28-day, in-hospital mortality, defined as death 
from any cause occurring between enrollment and 28 days after enrollment with 
outcome ascertainment ending at hospital discharge.  
 
Secondary Outcome 
The sole secondary outcome is cardiovascular collapse, defined as the 
occurrence of any of the following between induction and 2 minutes after intubation: (1) 
systolic blood pressure < 65 mmHg; (2) new or increased vasopressors; (3) cardiac 
arrest not resulting in death within 1 hour of induction; (4) cardiac arrest resulting in 
death within 1 hour of induction. 
 
 
 
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Procedural, Clinical, and Safety Outcomes 
Table 3 reports the exploratory procedural outcomes, exploratory clinical 
outcomes, and safety outcomes. Definitions of free-day outcomes are included in 
Supplemental Section 7 of e-Appendix 1.5,7  
 
Long-term Outcomes 
The definitions, collection, and analysis of survival and functional outcomes (e.g., 
symptoms of post-traumatic stress disorder) at 3 months and 12 months will be 
prespecified in a separate statistical analysis plan.  Because these outcomes will not be 
available for more than a year after completion of enrollment in the trial, these long-term 
outcomes have been registered separately (NCT06179485) and will be reported 
separately from the 28-day outcomes described in this statistical analysis plan. 
 
Data and Safety Monitoring Board 
The composition and responsibilities of the Data and Safety Monitoring Board 
(DSMB) are described in Section 8 of e-Appendix 1.  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. 
 
Trial Stages 
The RSI trial was funded in two stages.  First, the single-center, feasibility stage 
of the trial was funded by an award from the National Heart Lung and Blood Institute 
(K23HL153584).  Second, the multicenter stage of trial was funded by a contract from 
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the Patient-Centered Outcomes Research Institute® (BPS-2022C3-30021).  The initial 
trial protocol specified both stages of the trial and the criteria that had to be met to 
transition from the single-center stage to the multicenter stage.  On August 1, 2023, the 
DSMB (i) reviewed information on funding for the multicenter stage, (ii) reviewed data 
on enrollment rate, adherence to trial procedures, and completeness and quality of trial 
data from the single-center stage, and (iii) approved transition to the multicenter stage 
of the trial.  Neither the DSMB nor the investigators reviewed any analysis of trial 
outcomes as part of the transition between stages. 
 
Interim Analysis 
On January 7, 2025, the DSMB reviewed a single interim analysis, prepared by 
the unblinded study biostatistician at the anticipated halfway point of the trial after 
enrolment of 1,182 patients. The pre-specified stopping boundary for efficacy was a P 
value < 0.001 for the difference between trial groups in the primary outcome using a 
generalized linear mixed effects model with a random effect for study site and a fixed 
effect for group assignment (ketamine group vs etomidate group).  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).  After reviewing the interim 
analysis, the DSMB recommended continuing the RSI trial without modification. 
 
 
 
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Sample Size Estimation 
 
The final sample size for the RSI trial was calculated at the time of receipt of 
funding for the multicenter stage of the trial from PCORI® (details of the initial sample 
size calculation are provided in Section 9 of e-Appendix 1). Based on prior trials in the 
same settings,5,7 we estimated that the incidence of all-cause, 28-day in-hospital 
mortality (primary outcome) in the etomidate group would be 30%.  The patient and 
clinician partners recommended that the trial should have adequate statistical power to 
detect an absolute difference between groups in mortality of approximately 5 
percentage points.  This difference is more conservative than the median of 8 
percentage points (interquartile range, 6-10) used as the minimum clinically important 
difference in the design of prior randomized trials in critical care40 and is smaller than 
the observed difference in mortality between ketamine and etomidate of 6-7 percentage 
points observed in two previous trials.28,32 We used the bsamsize R function to calculate 
that achieving 80% statistical power at a two-sided alpha of 0.05 to detect a difference 
in mortality of 5.2 percentage points (30.0% in the etomidate group vs 24.8% in the 
ketamine group) would require enrollment of 2,308 patients. Anticipating that, like 
previous EFIC trials,41 less than 3% of participants would discontinue follow up before 
ascertainment of the primary outcome, we planned to enroll a total of 2,364 patients 
(1,182 per group).  
 
Statistical Analysis Principles 
 
Analyses will be conducted following reproducible research principles using R (R 
Foundation for Statistical Computing, Vienna, Austria).  Categorical variables will be 
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presented as number and percentage.  Continuous variables will be presented as mean 
± SD or median (interquartile range).  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 analyses of 
secondary and exploratory, emphasis will be placed on the magnitude of differences 
between groups with 95% confidence intervals, rather than statistical significance. 
Templates for the tables that will be presented in the results manuscript and supplement 
for baseline, periprocedural, and in-hospital outcome variables are provided in 
Supplementary Tables 1-3 in e-Appendix 1. 
 
Main Analysis of the Primary Outcome 
The primary analysis will be an intention-to-treat comparison of patients 
randomized to the ketamine group versus patients randomized to the etomidate group 
with regard to the primary outcome of all-cause, 28-day in-hospital mortality among all 
patients in the trial population except those who withdrew from follow up prior to 
ascertainment of the primary outcome. The primary outcome will be compared between 
the two trials groups using a generalized linear mixed effects model with a random 
effect for study site and a fixed effect for group assignment (ketamine group vs 
etomidate group). The absolute difference in percentages, associated 95% confidence 
intervals, and a P value for the comparison will be presented.  A rationale for the 
primary outcome and its analysis can be found in Section 10 of e-Appendix 1. 
 
 
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Additional Analyses of the Primary Outcome 
Sensitivity Analyses 
We will assess the robustness of the findings of the primary analysis in a series 
of sensitivity analyses using different approaches to defining and analyzing the primary 
outcome.  First, we will repeat the primary analysis among all patients in the trial 
population, with patients who withdrew from follow up prior to outcome ascertainment 
treated as (i) all having experienced the primary outcome or (ii) all having not 
experienced the primary outcome.  Second, we will repeat the primary analysis using 
all-cause, all-location mortality at 28 days (i.e., including available information on deaths 
that occur after hospital discharge).  Third, we will repeat the primary analysis using a 
Chi-square test rather than a generalized linear mixed effects model.  Fourth, we will 
compare survival to day 28 between trial groups using the Kaplan-Meier method.  Fifth, 
we will perform an adjusted analysis comparing the primary outcome between groups 
using a generalized linear mixed effects model with a random effect for trial site and 
fixed effects for trial group assignment and the following pre-specified baseline 
variables: age; sex; race; ethnicity; area deprivation index (a proxy for socioeconomic 
status and an indicator of neighborhood disadvantage);42 rurality;43 number of 
comorbidities; and pre-enrollment severity of illness as assessed by the Acute 
Physiology and Chronic Health Evaluation II score.44  Continuous variables will be 
modelled assuming a non-linear relationship to the outcome using restricted cubic 
splines with between 3 and 5 knots. 
 
 
 
 
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Analyses of heterogeneity of treatment effect 
Heterogeneity of treatment effect is nonrandom variation in the magnitude or 
direction of the effect of a treatment on an outcome across levels of a baseline 
covariate.  We will apply the three complementary approaches to analysis of 
heterogeneity of treatment effect described in the Predictive Approaches to Treatment 
effect Heterogeneity Statement: (1) traditional one-variable-at-a-time subgroup 
analyses; (2) a risk-modeling approach; and (3) an effect-modeling approach.45  
Complete details of all three approaches are described in Section 11 of e-Appendix 1. 
Our subgroup analyses will examine whether prespecified baseline variables 
modify the effect of trial group assignment 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, a random effect for trial site, and independent 
variables of trial group, the proposed effect modifier, and the interaction between the 
effect modifier and trial group for each of the following prespecified baseline variables: 
1. Sepsis or septic shock (Yes / No) 
2. Vasopressor receipt (Yes / No) 
3. Patient location (ED / ICU) 
4. Adrenal insufficiency or chronic receipt of corticosteroids (Yes / No) 
5. Acute neurologic condition (Yes / No) 
6. Active cardiac condition (Yes /No) 
7. Baseline risk of the primary outcome (continuous) 
 
 
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Analysis of the Secondary Outcome  
We will perform an unadjusted, intention-to-treat comparison of patients 
randomized to the ketamine group versus patients randomized to the etomidate group 
with regard to the secondary outcome of cardiovascular collapse.  A Chi-square test will 
be used to generate between-group differences and the associated 95% confidence 
intervals.   
 
Analyses of Additional Outcomes: 
We will conduct unadjusted, intention-to-treat analyses comparing patients 
randomized to the ketamine group versus patients randomized to the etomidate group 
with regard to each pre-specified exploratory procedural outcome, exploratory clinical 
outcome, and safety outcome.  Between-group differences and the associated 95% 
confidence intervals will be generated using a Chi-square test for categorical outcomes 
and a Wilcoxon rank-sum test for continuous outcomes.  
 
Handling of Missing Data 
We anticipate that no data on the primary outcome will be missing except for 
patients who withdrew from participation prior to the collection of the primary outcome. 
When data are missing for an outcome, we will perform complete-case analysis, 
excluding cases where the data for the analyzed outcome are missing. In adjusted 
analyses, missing data for covariates will be imputed using multiple imputations. 
 
 
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Discussion 
This article reports the rationale, design, and analysis plan for the RSI trial, a 
2,364-patient randomized trial of ketamine vs etomidate for induction of anesthesia 
among critically ill adults undergoing emergency tracheal intubation.  Several elements 
of the trial’s design warrant discussion. 
The RSI trial was designed to compare ketamine vs etomidate and does not 
examine other medications capable of inducing anesthesia for emergency tracheal 
intubation, such as propofol or benzodiazepines.  These comparators were selected for 
several reasons.  First, ketamine and etomidate are the medications most often used for 
emergency tracheal intubation in many EDs8 and ICUs6, particularly in the US.3,46–51  
Second, ketamine and etomidate are the only medications consistently used for 
emergency tracheal intubation in clinical care at the 14 sites participating in the trial.5,7,19  
Third, although propofol and benzodiazepines are more commonly used by some 
clinical specialties (e.g., anesthesiologists)52,53 and in some clinical settings (e.g., some 
ICUs outside of the US),4 observational studies have consistently reported these 
medications to be associated with higher rates of hypotension during intubation, 
particularly for patients with pre-existing hemodynamic instability.4,54  We anticipate that 
approximately 1-in-4 patients in the RSI trial will be receiving vasopressors before 
enrollment.  Thus, we designed the trial to compare two medications with a 
hemodynamic profile that permits their use for nearly all critically ill adults, including 
those with hypotension or shock prior to intubation. 
In the RSI trial, clinicians determine what dose of the assigned sedative 
medication each patient receives based on the clinical condition of the patient using a 
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dosing nomogram provided by the trial.  The nomogram specifies 2 mg/kg of ketamine 
and 0.3 mg/kg of etomidate as a “full dose”.  These are the doses specified in the US 
FDA labeling information for the induction of anesthesia.37,55  These are also the doses 
used in two of the largest previous randomized trials comparing ketamine vs etomidate 
among critically ill adults.28,32  For patients who clinicians determine require a lower 
dose, the nomogram also provides information on an intermediate dose (1.5 mg/kg of 
ketamine or 0.25 mg/kg of etomidate) and a reduced dose (1.0 mg/kg of ketamine or 0.2 
mg/kg of etomidate) across a range of patient weights. 
 
The design of the RSI trial differs from that of previous trials comparing ketamine 
vs etomidate in several respects.  First, the planned sample size of 2,364 patients is 
almost three times as large as any prior trial and will permit more precise estimates of 
treatment effect.28,32,33,56 Second, unlike prior trials that excluded patients intubated in 
the ED,28 excluded patients intubated in the ICU,33 or enrolled only patients with 
sepsis,56 the RSI trial includes a broad range of patients undergoing emergency 
tracheal intubation in an ED or ICU, which increases generalizability.56  The only 
diagnosis excluded from the RSI trial is patients presenting to the emergency 
department with a primary diagnosis of trauma.  Because some prior data suggested 
that ketamine might increase intracranial pressure57 and results of one prior trial 
suggested a potential difference in treatment effect between patients with and without 
trauma,32 we determined that the effect of ketamine vs etomidate on outcomes for 
patients presenting with trauma was best evaluated in a separate trial.  Third, unlike 
prior trials that did not collect procedural outcomes32 or long-term patient-centered 
outcomes,28,32,33,56 the RSI trial collects physiological outcomes during the procedure 
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(e.g., cardiovascular collapse during intubation), short-term patient-centered outcomes 
(e.g., death by day 28), and  long-term patient-centered outcomes (e.g., survival and 
symptoms of post-traumatic stress disorder at 12 months). 
 
Interpretation 
The RSI trial will provide important evidence regarding the effect of ketamine vs 
etomidate on death and other clinical outcomes among critically ill adults undergoing 
emergency tracheal intubation in an ED or ICU. To aid in the transparency and 
interpretation of trial results, this manuscript detailing the protocol and statistical 
analysis plan for the RSI trial has been finalized prior to the conclusion of patient 
enrollment.  
 
 
 
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Abbreviations  
DSMB: Data and Safety Monitoring Board 
ED: Emergency Department 
EFIC: Exception from Informed Consent Requirements for Emergency Research 
FDA: Food and Drug Administration  
ICU: Intensive Care Unit 
IRB: Institutional Review Board 
LAR: Legally Authorized Representative 
SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials 
 
 
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Table 1: Schedule of Enrollment, Interventions, and Assessments in the RSI trial. 
Information on the collection of outcomes at 3 and 12 months will be reported in a 
separate statistical analysis plan.  Table entries without data mean that data elements 
were not collected at that time.  RSI = Randomized trial of Sedative Choice during 
Intubation.  
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 
28 days  
Enrollment: 
Eligibility screen 
X
Enrollment 
X
Allocation 
X
Interventions: 
Ketamine 
X
Etomidate 
X
Screening for 
contraindications 
X 
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 
X 
 
 
 
 
 
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Table 2: Inclusion and Exclusion Criteria.  
Inclusion Criteria
Patient is critically ill and undergoing emergency tracheal intubation with sedation in 
an enrolling unit 
Planned procedure is orotracheal intubation using a laryngoscope 
Planned operator is a clinician expected to routinely perform tracheal intubation in the 
participating unit 
Exclusion Criteria 
Patient is known to be less than 18 years old 
Patient is known to be pregnant 
Patient is known to be a prisoner 
Patient is known to have an allergy to ketamine or etomidate 
Patient is presenting to the emergency department with a primary diagnosis of trauma 
Patient or LAR declines participation during pre-enrollment opt-out conversation or by 
wearing opt-out bracelet for the RSI trial 
Clinician feels ketamine is required or contraindicated for the optimal care of the 
patient 
Clinician feels etomidate is required or contraindicated for the optimal care of the 
patient 
Clinician feels an induction medication other than ketamine or etomidate is required 
for the optimal care of the patient 
Immediate need for intubation precludes safe performance of study procedures 
 
 
 
 
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Table 3: Study outcomes 
 
Primary Outcome
All-cause, 28-day, in-hospital mortality 
Secondary 
Outcome 
Cardiovascular collapse, a composite of any of the following between 
induction and 2 minutes after intubation: (1) systolic blood pressure < 
65 mmHg; (2) new or increased vasopressors; (3) cardiac arrest not 
resulting in death within 1 hour of induction; (4) cardiac arrest resulting 
in death within 1 hour of induction. 
Exploratory 
Procedural 
Outcomes 
Cormack-Lehane Grade of glottic view 
Successful intubation on the first attempt, defined as placement of an 
endotracheal tube in the trachea with a single insertion of a 
laryngoscope blade into the mouth and EITHER a single insertion of an 
endotracheal tube into the mouth OR a single insertion of a bougie into 
the mouth followed by a single insertion of an endotracheal tube over 
the bougie into the mouth. 
Time from induction to successful tracheal intubation 
Lowest oxygen saturation between induction and two minutes after 
intubation 
Lowest oxygen saturation < 80% between induction to two minutes 
after intubation 
Highest and lowest systolic blood pressure from induction to two 
minutes after intubation 
Systolic blood pressure > 180 between induction and two minutes after 
intubation 
Systolic blood pressure < 65 mmHg between induction and 2 minutes 
after intubation 
New or increased vasopressor between induction and 2 minutes after 
intubation 
Cardiac arrest within 2 minutes of intubation not resulting in death 
within 1 hour of induction 
Cardiac arrest within 2 minutes of intubation resulting in death within 1 
hour of induction 
Exploratory 
Clinical Outcomes 
Ventilator-free days to study day 28 
Vasopressor-free days to study day 28 
ICU-free days to study day 28 
Safety Outcomes 
Systolic blood pressure at 24 hours after induction 
Receipt of vasopressors at 24 hours after induction 
Cardiac arrest receiving cardiopulmonary resuscitation between 
induction and hospital discharge 
 
 
 
 
 
 
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References 
1.  
Kempker JA, Abril MK, Chen Y, Kramer MR, Waller LA, Martin GS. The Epidemiology of 
Respiratory Failure in the United States 2002-2017: A Serial Cross-Sectional Study. Crit Care Explor 
2020;2(6):e0128.  
2.  
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.  
3.  
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.  
4.  
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.  
5.  
Gibbs KW, Semler MW, Driver BE, et al. Noninvasive Ventilation for Preoxygenation during 
Emergency Intubation. N Engl J Med 2024;390(23):2165–2177.  
6.  
Wunsch H, Bosch NA, Law AC, et al. Evaluation of Etomidate Use and Association with Mortality 
Compared with Ketamine Among Critically Ill Patients. Am J Respir Crit Care Med 2024; 
7.  
Prekker ME, Driver BE, Trent SA, et al. Video versus Direct Laryngoscopy for Tracheal Intubation 
of Critically Ill Adults. N Engl J Med 2023;389(5):418–429.  
8.  
April MD, Arana A, Schauer SG, et al. Ketamine Versus Etomidate and Peri-intubation 
Hypotension: A National Emergency Airway Registry Study. Acad Emerg Med Off J Soc Acad Emerg Med 
2020;27(11):1106–1115.  
9.  
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.  
10.  
Etomidate or Midazolam for Rapid Sequence Induction in Patients with Suspected Sepsis? 
Accessed December 29, 2021. [Internet]. Available from: 
https://www.jwatch.org/em201012170000001/2010/12/17/etomidate-or-midazolam-rapid-sequence-
induction 
11.  
Chan CM, Mitchell AL, Shorr AF. Etomidate is associated with mortality and adrenal insufficiency 
in sepsis: a meta-analysis*. Crit Care Med 2012;40(11):2945–53.  
12.  
Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal responsiveness 
and mortality in patients with septic shock. Intensive Care Med 2009;35(11):1868–1876.  
13.  
Lipiner-Friedman D, Sprung CL, Laterre PF, et al. Adrenal function in sepsis: The retrospective 
Corticus cohort study: Crit Care Med 2007;35(4):1012–1018.  
14.  
Tsai M-H, Peng Y-S, Chen Y-C, et al. Adrenal insufficiency in patients with cirrhosis, severe sepsis 
and septic shock. Hepatol Baltim Md 2006;43(4):673–681.  
15.  
Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism during critical illness. 
N Engl J Med 2013;368(16):1477–1488.  
All rights reserved. No reuse allowed without permission. 
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
The copyright holder for this preprint
this version posted January 18, 2025. 
; 
https://doi.org/10.1101/2025.01.18.25320768
doi: 
medRxiv preprint 

16.  
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med 
2003;348(8):727–734.  
17.  
Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic 
Shock. N Engl J Med 2018;378(9):797–808.  
18.  
Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with 
Septic Shock. N Engl J Med 2018;378(9):809–818.  
19.  
Upchurch CP, Grijalva CG, Russ S, et al. Comparison of Etomidate and Ketamine for Induction 
During Rapid Sequence Intubation of Adult Trauma Patients. Ann Emerg Med 2017;69(1):24-33.e2.  
20.  
Khalili-Mahani N, Martini CH, Olofsen E, Dahan A, Niesters M. Effect of subanaesthetic ketamine 
on plasma and saliva cortisol secretion. Br J Anaesth 2015;115(1):68–75.  
21.  
Hergovich N, Singer E, Agneter E, et al. Comparison of the effects of ketamine and memantine 
on prolactin and cortisol release in men. a randomized, double-blind, placebo-controlled trial. 
Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 2001;24(5):590–593.  
22.  
Spotoft H, Korshin JD, Sørensen MB, Skovsted P. The cardiovascular effects of ketamine used for 
induction of anaesthesia in patients with valvular heart disease. Can Anaesth Soc J 1979;26(6):463–467.  
23.  
Pagel PS, Kampine JP, Schmeling WT, Warltier DC. Ketamine Depresses Myocardial Contractility 
as Evaluated by the Preload Recruitable Stroke Work Relationship in Chronically Instrumented Dogs with 
Autonomic Nervous System Blockade. Anesthesiology 1992;76(4):564–572.  
24.  
Waxman K, Shoemaker WC, Lippmann M. Cardiovascular effects of anesthetic induction with 
ketamine. Anesth Analg 1980;59(5):355–358.  
25.  
Gelissen HPMM, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, Hertog A den. Inotropic Effects 
of Propofol, Thiopental, Midazolam, Etomidate, and Ketamine on Isolated Human Atrial Muscle. 
Anesthesiology 1996;84(2):397–403.  
26.  
Sprung J, Schuetz SM, Stewart RW, Moravec CS. Effects of ketamine on the contractility of failing 
and nonfailing human heart muscles in vitro. Anesthesiology 1998;88(5):1202–1210.  
27.  
Brown CA, Bair AE, Pallin DJ, Walls RM, NEAR III Investigators. Techniques, success, and adverse 
events of emergency department adult intubations. Ann Emerg Med 2015;65(4):363-370.e1.  
28.  
Matchett G, Gasanova I, Riccio CA, et al. Etomidate versus ketamine for emergency 
endotracheal intubation: a randomized clinical trial. Intensive Care Med 2021; 
29.  
Mohr NM, Pape SG, Runde D, Kaji AH, Walls RM, Brown CA. Etomidate Use Is Associated With 
Less Hypotension Than Ketamine for Emergency Department Sepsis Intubations: A NEAR Cohort Study. 
Acad Emerg Med Off J Soc Acad Emerg Med 2020;27(11):1140–1149.  
30.  
Dewhirst E, Frazier WJ, Leder M, Fraser DD, Tobias JD. Cardiac arrest following ketamine 
administration for rapid sequence intubation. J Intensive Care Med 2013;28(6):375–379.  
31.  
Koroki T, Kotani Y, Yaguchi T, et al. Ketamine versus etomidate as an induction agent for tracheal 
intubation in critically ill adults: a Bayesian meta-analysis. Crit Care Lond Engl 2024;28(1):48.  
All rights reserved. No reuse allowed without permission. 
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
The copyright holder for this preprint
this version posted January 18, 2025. 
; 
https://doi.org/10.1101/2025.01.18.25320768
doi: 
medRxiv preprint 

32.  
Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation 
in acutely ill patients: a multicentre randomised controlled trial. Lancet Lond Engl 2009;374(9686):293–
300.  
33.  
Knack SKS, Prekker ME, Moore JC, et al. The Effect of Ketamine Versus Etomidate for Rapid 
Sequence Intubation on Maximum Sequential Organ Failure Assessment Score: A Randomized Clinical 
Trial. J Emerg Med 2023;65(5):e371–e382.  
34.  
Greer A, Hewitt M, Khazaneh PT, et al. Ketamine Versus Etomidate for Rapid Sequence 
Intubation: A Systematic Review and Meta-Analysis of Randomized Trials. Crit Care Med 2024; 
35.  
Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 Statement: Defining Standard Protocol 
Items for Clinical Trials. Ann Intern Med 2013;158(3):200.  
36.  
50.24 Exception from informed consent requirements for emergency research. Accessed 
11/19/2024.  
37.  
FDA Ketamine. Date Accessed: 11/12/2024 [Internet]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf 
38.  
Semler MW, Janz DR, Russell DW, et al. A Multicenter, Randomized Trial of Ramped Position 
vs Sniffing Position During Endotracheal Intubation of Critically Ill Adults. Chest 2017;152(4):712–722.  
39.  
Cormack RS, Lehane JR, Adams AP, Carli F. Laryngoscopy grades and percentage glottic opening. 
Anaesthesia 2000;55(2):184–184.  
40.  
Yarnell CJ, Abrams D, Baldwin MR, et al. Clinical trials in critical care: can a Bayesian approach 
enhance clinical and scientific decision making? Lancet Respir Med [Internet] 2020 [cited 2020 Nov 
25];Available from: http://www.sciencedirect.com/science/article/pii/S2213260020304719 
41.  
Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for 
prehospital status epilepticus. N Engl J Med 2012;366(7):591–600.  
42.  
Kind AJH, Buckingham WR. Making Neighborhood-Disadvantage Metrics Accessible — The 
Neighborhood Atlas. N Engl J Med 2018;378(26):2456–2458.  
43.  
USDA ERS - Rural-Urban Commuting Area Codes [Internet]. [cited 2021 Dec 14];Available from: 
https://www.ers.usda.gov/data-products/rural-urban-commuting-area-codes/ 
44.  
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification 
system. Crit Care Med 1985;13(10):818–829.  
45.  
Kent DM, Klaveren D van, Paulus JK, et al. The Predictive Approaches to Treatment effect 
Heterogeneity (PATH) Statement: Explanation and Elaboration. Ann Intern Med 2020;172(1):W1–W25.  
46.  
Ferguson I, Buttfield A, Burns B, et al. Fentanyl versus placebo with ketamine and rocuronium 
for patients undergoing rapid sequence intubation in the emergency department: The FAKT study-A 
randomized clinical trial. Acad Emerg Med Off J Soc Acad Emerg Med 2022;29(6):719–728.  
All rights reserved. No reuse allowed without permission. 
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 
The copyright holder for this preprint
this version posted January 18, 2025. 
; 
https://doi.org/10.1101/2025.01.18.25320768
doi: 
medRxiv preprint 

47.  
Ferguson I, Alkhouri H, Fogg T, Aneman A. Ketamine use for rapid sequence intubation in 
Australian and New Zealand emergency departments from 2010 to 2015: A registry study. Emerg Med 
Australas EMA 2019;31(2):205–210.  
48.  
Sagarin MJ, Barton ED, Chng Y-M, Walls RM, National Emergency Airway Registry Investigators. 
Airway management by US and Canadian emergency medicine residents: a multicenter analysis of more 
than 6,000 endotracheal intubation attempts. Ann Emerg Med 2005;46(4):328–336.  
49.  
Sakles JC, Laurin EG, Rantapaa AA, Panacek EA. Airway management in the emergency 
department: a one-year study of 610 tracheal intubations. Ann Emerg Med 1998;31(3):325–332.  
50.  
April MD, Long B, Brown CA. Etomidate Should be the Default Agent for Rapid Sequence 
Intubation in the Emergency Department. Ann Emerg Med 2021;78(6):720–721.  
51.  
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.  
52.  
Wahlen BM, El-Menyar A, Asim M, Al-Thani H. Rapid sequence induction (RSI) in trauma 
patients: Insights from healthcare providers. World J Emerg Med 2019;10(1):19–26.  
53.  
Sneyd JR, Gambus PL, Rigby-Jones AE. Current status of perioperative hypnotics, role of 
benzodiazepines, and the case for remimazolam: a narrative review. Br J Anaesth 2021;127(1):41–55.  
54.  
Wan C, Hanson AC, Schulte PJ, Dong Y, Bauer PR. Propofol, Ketamine, and Etomidate as 
Induction Agents for Intubation and Outcomes in Critically Ill Patients: A Retrospective Cohort Study. Crit 
Care Explor 2021;3(5):e0435.  
55.  
FDA Etomidate. Date Accessed: 11/12/2024 [Internet]. 2024;Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018227s032lbl.pdf 
56.  
Srivilaithon W, Bumrungphanithaworn A, Daorattanachai K, et al. Clinical outcomes after a single 
induction dose of etomidate versus ketamine for emergency department sepsis intubation: a 
randomized controlled trial. Sci Rep 2023;13(1):6362.  
57.  
Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on ICP in traumatic brain 
injury. Neurocrit Care 2014;21(1):163–173.  
 
All rights reserved. No reuse allowed without permission. 
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medRxiv preprint 

Protocol and Statistical Analysis Plan
for a Multicenter Randomized Trial
of Ketamine vs Etomidate for Emergency
Tracheal Intubation
Stephanie C. DeMasi, MD; Brant Imhoff, MS; Ariel A. Lewis, BSN, RN, MPH; Kevin P. Seitz, MD; Brian E. Driver, MD;
Kevin W. Gibbs, MD; Adit A. Ginde, MD, MPH; Stacy A. Trent, MD, MPH; Derek W. Russell, MD; Amelia L. Muhs, MD;
Matthew E. Prekker, MD, MPH; John P. Gaillard, MD; Daniel Resnick-Ault, MD; L. Jane Stewart, MD, JD, MPH;
Micah R. Whitson, MD; Graham W. W. Van Schaik, MD, MBA; Aaron E. Robinson, MD, MPH; Jessica A. Palakshappa, MD;
Neil R. Aggarwal, MD, MHSc; Jason C. Brainard, MD; David J. Douin, MD; Carolynn Lyle, PA-C, MPH;
Sheetal Gandotra, MD; Aaron J. Lacy, MD; Kristen C. Sherlin, PharmD; Greta K. Carlson, MD; J. Maycee Cain, BS;
Brianne Redman, MD; Carrie Higgins, BSN; Cori Withers, BS; Logan L. Beach, MD; Barbara Gould; Jasmine McIntosh;
Bradley D. Lloyd, RRT-ACCS; Tiffany L. Israel, MSSW; Li Wang, MS; Todd W. Rice, MD; Wesley H. Self, MD MPH;
Jin H. Han, MD; Jonathan D. Casey, MD; and Matthew W. Semler, MD; for the Randomized Trial of Sedative Choice for
Intubation Investigators, and the Pragmatic Critical Care Research Group*
BACKGROUND: Emergency tracheal intubation is a common and high-risk procedure. Keta-
mine and etomidate are medicines commonly used to induce anesthesia for emergency
tracheal intubation, but whether the induction medication used affects patient outcomes is
uncertain.
RESEARCH QUESTION: Does the use of ketamine for induction of anesthesia decrease the
incidence of death among adults undergoing emergency tracheal intubation compared with
the use of etomidate?
STUDY DESIGN AND METHODS: The Randomized Trial of Sedative Choice for Intubation (RSI)
is a pragmatic, multicenter, unmasked, parallel-group randomized trial being conducted at 14
sites (6 emergency departments and 8 ICUs) in the United States. The trial compares ke-
tamine vs etomidate for induction of anesthesia among 2,364 critically ill adults undergoing
emergency tracheal intubation. The primary outcome is all-cause 28-day in-hospital mor-
tality. The secondary outcome is the incidence of cardiovascular collapse during intubation, a
composite of hypotension, receipt of vasopressors, and cardiac arrest.
RESULTS: Enrollment began on April 6, 2022, and is expected to conclude in 2025.
INTERPRETATION: The RSI will provide important data on the effects of ketamine
vs etomidate on death and other outcomes for critically ill adults undergoing emergency
tracheal intubation. Specifying the protocol and statistical analysis plan before the conclusion
of enrollment increases the rigor, reproducibility, and transparency of the trial.
CLINICAL
TRIAL
REGISTRATION:
ClinicalTrials.gov;
No.:
NCT05277896;
URL:
www.
clinicaltrials.gov
CHEST Critical Care 2025; 3(3):100177
KEY WORDS: emergency tracheal intubation; etomidate; induction; ketamine
[
ARDS and Acute Respiratory Failure Original Research ]
chestcc.org
1

Millions of critically ill adults undergo emergency
tracheal intubation every year worldwide,1
approximately 30% of whom die before hospital
discharge.2,3 Nearly all patients undergoing emergency
tracheal intubation in an emergency department (ED) or
ICU receive a medication to induce anesthesia for the
procedure.2,4 Whether the medication used to induce
anesthesia affects patient outcomes is uncertain.
Etomidate, an imidazole-derived sedative-hypnotic agent
that produces anesthesia by acting on g-aminobutyric
acid receptors, is the medication most often used to
induce anesthesia during emergency tracheal intubation
in some EDs and ICUs.4-6 Etomidate has been described
as an “ideal” medication for induction of anesthesia in
critically ill adults because of its rapid onset, short
duration of action, and limited effect on BP.7 However,
etomidate inhibits 11-b-hydroxylase in the adrenal
glands, which decreases cortisol production and causes
adrenal insufﬁciency for 24 to 72 hours.8,9 Among
critically ill adults, many of whom experience critical
illness-related corticosteroid insufﬁciency resulting from
sepsis or other causes,10-12 etomidate-induced adrenal
insufﬁciency has been hypothesized to be associated with
organ dysfunction and death.5 Concern that adrenal
insufﬁciency caused by etomidate may decrease survival
has led federal regulatory agencies in some countries not
to approve etomidate for clinical use.13
Ketamine, a dissociative agent that produces anesthesia
by acting on N-methyl-D-aspartate receptors, is the
medication most often used to induce anesthesia during
emergency tracheal intubation in some EDs and
ICUs.14,15 In contrast to etomidate, ketamine increases
cortisol production.16,17 However, whereas ketamine
generally increases BP by stimulating the release of
catecholamines,18 it is a direct negative inotrope19-22 and
has been reported to precipitate rare episodes of severe
hypotension14,23-25 or even cardiac arrest, particularly
among critically ill patients with depleted stores of
endogenous catecholamines.24,26
Previous small to moderate randomized trials
comparing ketamine and etomidate for emergency
tracheal intubation have reported conﬂicting results,
with some ﬁnding that use of ketamine decreased short-
term mortality24,27 and others ﬁnding no signiﬁcant
differences in outcomes.28-30 Currently, whether use of
Take-Home Points
Study Question: Does use of ketamine for induction
of anesthesia during emergency tracheal intubation
decrease the incidence of death compared with use of
etomidate?
Results: This article describes the protocol and sta-
tistical analysis plan for the Randomized Trial of
Sedative Choice for Intubation comparing ketamine
vs etomidate for induction of anesthesia for emer-
gency tracheal intubation.
Interpretation:
Prespecifying
the
full
statistical
analysis plan before completion of enrollment in-
creases rigor, reproducibility, and transparency of the
trial results.
ABBREVIATIONS: DSMB = data and safety monitoring board; ED =
emergency
department;
PCORI
=
Patient-Centered
Outcomes
Research Institute; RSI = Randomized Trial of Sedative Choice for
Intubation
AFFILIATIONS: From the Department of Emergency Medicine (S. C.
D., G. W. W. V. S., A. J. L., W. H. S., and J. H. H.), the Department of
Biostatistics (B. I. and L. W.), the Vanderbilt Institute for Clinical and
Translational Research (A. A. L., B. D. L., T. L. I., T. W. R., W. H. S., J.
D. C., and M. W. S.), the Division of Allergy, Pulmonary, and Critical
Care Medicine (K.P. S., A. L. M., T. W. R., J. D. C., and M. W. S.), the
Department of Pharmacy (K. C. S.), Vanderbilt University Medical
Center, the Geriatric Research, Education, and Clinical Center (J. H.
H.), Tennessee Valley Healthcare System, Nashville, TN; the Depart-
ment of Emergency Medicine (B. E. D., M. E.P., A. E. R., and G. K. C.),
the Division of Pulmonary, Allergy, and Critical Care Medicine (M.
E.P. and G. K. C.), Department of Medicine, Hennepin County
Medical Center, Minneapolis, MN; the Section of Pulmonary, Critical
Care, Allergy and Immunologic Disease (K. W. G., J. A.P., and J. M.
C.), Department of Medicine, the Department of Anesthesiology-
Critical Care (J.P. G.), the Department of Emergency Medicine (J.P. G.
and B. R.), Wake Forest School of Medicine, Winston-Salem, NC; the
Department of Emergency Medicine (A. A. G., S. A. T., D. R.-A., and
C. W.), the Department of Anesthesiology (L. J. S., J. C. B., and D. J.
D.), University of Colorado School of Medicine; the Division of
Pulmonary Sciences and Critical Care Medicine (N. R. A. and C. H.),
Department of Medicine, University of Colorado Anschutz Medical
Center, Aurora; the Department of Emergency Medicine (S. A. T. and
C. L.), the Department of Anesthesiology (L. J. S.), Denver Health
Medical Center (B. G.), Denver, CO; the Division of Pulmonary, Al-
lergy and Critical Care Medicine (D. W. R., M. R. W., and S. G.),
Department of Medicine, the Department of Emergency Medicine (M.
R. W. and L. L. B.), University of Alabama at Birmingham, the Pul-
monary Section (D. W. R.), Birmingham Veteran’s Affairs Medical
Center (J. M.), Birmingham, AL.
S. C. D., B. I., and A. A. L. contributed equally to this manuscript as
ﬁrst authors.
M. W. S. and J. D. C. contributed equally to this manuscript as senior
authors.
*Collaborators from the Randomized Trial of Sedative Choice for
Intubation Investigators are listed in section 1 of e-Appendix 1.
CORRESPONDENCE TO: Matthew W. Semler, MD; email: matthew.w.
semler@vumc.org
Copyright  2025 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 license (http://creativecommons.org/
licenses/by/4.0/).
DOI: https://doi.org/10.1016/j.chstcc.2025.100177
2
Original Research
[ 3 # 3 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 5 ]

ketamine decreases mortality for critically ill adults
undergoing emergency tracheal intubation compared
with the use of etomidate remains uncertain.
To address this uncertainty, we designed the
Randomized Trial of Sedative Choice for
Intubation (RSI), which will compare ketamine
vs etomidate for induction of anesthesia among
2,364 adults undergoing emergency tracheal intubation.
We hypothesize that use of ketamine will decrease the
incidence of death compared with etomidate.
Study Design and Methods
This article was written in accordance with Standard
Protocol Items: Recommendations for Interventional
Trials guidelines (Table 1, section 2 of e-Appendix 1).31
Engagement of Patients, Families, and Community
Members
Detailed information on engagement with survivors of
emergency tracheal intubation, family members, and
community members in each phase of the design and
conduct of the RSI are summarized in section 3 of
e-Appendix 1.
Study Design
The RSI is a pragmatic, multicenter, unmasked, parallel-
group randomized trial comparing the use of ketamine
vs etomidate for induction of anesthesia in 2,364 criti-
cally ill adults undergoing emergency tracheal intubation
in 14 sites (6 EDs and 8 ICUs) in the United States. The
primary outcome is all-cause 28-day in-hospital mortal-
ity. The trial is being conducted by the Pragmatic Crit-
ical Care Research Group (www.pragmaticcriticalcare.
org). The trial was registered before initiation of enroll-
ment (ClinicalTrials.gov Identiﬁer: NCT05277896).
Ethics and Regulatory Approval
The RSI protocol was approved by the institutional re-
view board at Vanderbilt University Medical Center
(Identiﬁer: 210500) and the US Food and Drug Admin-
istration (Investigational New Drug Identiﬁer: 141424).
The study is being conducted with Exception From
Informed
Consent
Requirements
for
Emergency
Research (21 CFR 50.24).32 Whenever feasible, patients
or
their
legally
authorized
representatives
are
approached by research personnel to provide prospec-
tive, written informed consent to participate in the trial.
When prospective, written informed consent is infea-
sible, patients are enrolled under Exception From
TABLE 1 ] Schedule of Enrollment, Interventions, and Assessments in the RSI
Time Point
Eligibility
Screening:
Decision to
Perform
Tracheal
Intubation
Randomization
and Allocation:
Before Tracheal
Intubation
During the Procedure
Final Outcome
Assessment at
28 d
Induction
Tracheal
Intubation
0-2 min
After
Tracheal
Intubation
0-24 h
After
Tracheal
Intubation
Enrollment
Eligibility screen
X
Enrollment
X
Allocation
X
Interventions
Ketamine
X
Etomidate
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
X
Information on the collection of outcomes at 3 and 12 months will be reported in a separate statistical analysis plan. Table entries without data mean that
data elements were not collected at that time. RSI ¼ Randomized Trial of Sedative Choice During intubation.
chestcc.org
3

Informed
Consent
Requirements
for
Emergency
Research and the patient, the patient’s legally authorized
representative, or a family member is notiﬁed of enroll-
ment in the trial at the earliest feasible opportunity
(additional details in section 4 of e-Appendix 1). Plans
for community consultation and public disclosure were
approved by the single institutional review board at
Vanderbilt University Medical Center. The institutional
review board of each participating site provided local
context for the community consultation and public
disclosure plan and activities.
Study Population
Critically ill adults undergoing emergency tracheal intu-
bation with sedation in a participating unit are poten-
tially eligible. The trial excludes patients who are
pregnant, incarcerated, or younger than 18 years. Com-
plete lists of inclusion and exclusion criteria are pro-
vided in Table 2.
Randomization and Treatment Allocation
Patients are randomized in a 1:1 ratio to ketamine or
etomidate in permuted blocks of variable size, stratiﬁed
by study site. Study group assignments are generated us-
ing a computerized randomization sequence, placed in
sequentially numbered opaque envelopes, and distrib-
uted to enrolling sites. Before opening the envelope,
the clinician performing the tracheal intubation proced-
ure (referred to as the operator) determines that the pa-
tient meets eligibility criteria. Study group assignment
remains concealed to study personnel and clinicians un-
til after the decision has been made to enroll the patient
and the envelope is opened. Patients are enrolled and
randomized as soon as the operator opens the trial enve-
lope to reveal study group assignment. After randomiza-
tion, patients, clinicians, and study personnel are not
masked to trial group assignment.
Study Interventions
Ketamine Group: For patients in the ketamine group, cli-
nicians are instructed to administer IV ketamine to
induce anesthesia for emergency tracheal intubation.
The dose of ketamine is determined by the clinicians
based on the clinical condition of the patient. A nomo-
gram on the study group assignment sheet provides cli-
nicians with doses of ketamine (in milligrams) that
correspond to a full dose (2.0 mg/kg), an intermediate
dose (1.5 mg/kg), and a reduced dose (1.0 mg/kg) for
a range of patient weights (section 5 of e-Appendix 1).33
Etomidate Group: For patients in the etomidate group,
clinicians are instructed to administer IV etomidate to
induce anesthesia for emergency tracheal intubation.
The dose of etomidate is determined by the clinicians
based on the clinical condition of the patient. A nomo-
gram on the study group assignment sheet provides cli-
nicians with doses of etomidate (in milligrams) that
correspond to a full dose (0.3 mg/kg), an intermediate
dose (0.25 mg/kg), and a reduced dose (0.2 mg/kg) for
a range of patient weights (section 6 of e-Appendix 1).
TABLE 2 ] Inclusion and Exclusion Criteria
Inclusion criteria
Patient is critically ill and undergoing emergency tracheal intubation with sedation in an enrolling unit
Planned procedure is orotracheal intubation using a laryngoscope
Planned operator is a clinician expected to perform tracheal intubation in the participating unit routinely
Exclusion criteria
Patient is known to be younger than 18 y
Patient is known to be pregnant
Patient is known to be incarcerated
Patient is known to have an allergy to ketamine or etomidate
Patient is seeking treatment at the emergency department with a primary diagnosis of trauma
Patient or legally authorized representative declines participation during pre-enrollment opt-out conversation or by
wearing opt-out bracelet for the RSI
Clinician believes that ketamine is required or contraindicated for the optimal care of the patient
Clinician believes that etomidate is required or contraindicated for the optimal care of the patient
Clinician believes that an induction medication other than ketamine or etomidate is required for the optimal care of the
patient
Immediate need for intubation precludes safe performance of study procedures
RSI ¼ Randomized Trial of Sedative Choice for Intubation.
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Cointerventions: The RSI determines the initial primary
medication administered for induction of anesthesia
during the emergency tracheal intubation procedure.
Subsequent boluses or infusions of sedative medications
are determined by clinicians. Other aspects of emer-
gency tracheal intubation (eg, ﬂuid and vasopressor
management before intubation, choice of neuromus-
cular blocking medication) are determined by treating
clinicians according to clinical protocols in the study
units. Cointerventions that potentially could modify
the effect of ketamine or etomidate on patient outcomes
(eg, administration of corticosteroids after intubation)
are recorded prospectively.
Data Collection
An observer not directly involved with the intubation
procedure collects data in real time for key periproce-
dural outcomes, including oxygen saturation and sys-
tolic BP at the time of induction and lowest oxygen
saturation, lowest systolic BP, and administration of va-
sopressors between induction and 2 minutes after intu-
bation. Observers are either research personnel or
trained clinical personnel (eg, physicians or nurses).
The accuracy of this method of data collection has
been validated previously34 and has been used in
numerous
previous
trials
of
emergency
tracheal
intubation.3,4,6
Immediately after the intubation procedure, the operator
completes a paper data collection form to record charac-
teristics of the procedure (eg, Cormack-Lehane grade of
glottic view35), complications during intubation (eg, car-
diac arrest), and the operator’s prior intubating experi-
ence. Study personnel at each site review the electronic
health record to collect data on baseline characteristics,
management before and after laryngoscopy, and in-
hospital clinical outcomes such as systolic BP at 24
hours after induction, receipt of vasopressors at 24 hours
after induction, ventilator duration, and mortality. Study
personnel collect information on mortality occurring af-
ter hospital discharge from the electronic health record,
public vital statistics records and other public records,
and phone calls with patients participating in the long-
term outcome assessments at 3 and 12 months (the re-
sults of the long-term outcome assessments will be re-
ported separately).
Primary Outcome
The primary outcome is all-cause 28-day in-hospital
mortality, deﬁned as death resulting from any cause
occurring
between
enrollment
and
28
days
after
enrollment with outcome ascertainment ending at hos-
pital discharge.
Secondary Outcome
The sole secondary outcome is cardiovascular collapse,
deﬁned as the occurrence of any of the following be-
tween induction and 2 minutes after intubation: (1) sys-
tolic BP of < 65 mm Hg, (2) new or increased
vasopressor use, (3) cardiac arrest not resulting in death,
and (4) cardiac arrest resulting in death.
Procedural, Clinical, and Safety Outcomes
Table 3 reports the exploratory procedural outcomes,
exploratory clinical outcomes, and safety outcomes. Def-
initions of free-day outcomes are included in section 7 of
e-Appendix 1.4,6
Long-Term Outcomes
The deﬁnitions, collection, and analysis of survival and
functional outcomes (eg, symptoms of posttraumatic
stress disorder) at 3 months and 12 months will be pre-
speciﬁed in a separate statistical analysis plan. Because
these outcomes will not be available for more than 1
year after completion of enrollment in the trial, these
long-term outcomes have been registered separately
(ClinicalTrials.org Identiﬁer: NCT06179485)36 and will
be reported separately from the 28-day outcomes
described in this statistical analysis plan.
Data and Safety Monitoring Board
The composition and responsibilities of the data and
safety monitoring board (DSMB) are described in sec-
tion 8 of e-Appendix 1. The DSMB developed a charter,
approved the trial protocol, approved the patient notiﬁ-
cation forms, and approved the trial monitoring plan
before trial initiation of enrollment. The DSMB has
the authority to recommend that the trial stop at any
point, to request additional data, to request additional
interim analyses, or to request modiﬁcations to the study
protocol.
Trial Stages
The RSI was funded in 2 stages. First, the single-center
feasibility stage of the trial was funded by an award
from the National Heart Lung and Blood Institute
(Grant: K23HL153584). Second, the multicenter stage
of trial was funded by a contract from the Patient-
Centered Outcomes Research Institute (PCORI; Identi-
ﬁer: BPS-2022C3-30021). The initial trial protocol spec-
iﬁed both stages of the trial and the criteria that had to
be met to transition from the single-center stage to the
multicenter stage. On August 1, 2023, the DSMB (1)
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5

reviewed information on funding for the multicenter
stage; (2) reviewed data on enrollment rate, adherence
to trial procedures, and completeness and quality of trial
data from the single-center stage; and (3) approved tran-
sition to the multicenter stage of the trial. Neither the
DSMB nor the investigators reviewed any analysis of
trial outcomes as part of the transition between stages.
Interim Analysis
On January 7, 2025, the DSMB reviewed a single interim
analysis, prepared by the unmasked study biostatistician
at the anticipated halfway point of the trial after enrol-
ment of 1,182 patients. The prespeciﬁed stopping
boundary for efﬁcacy was a P value of < .001 for the dif-
ference between trial groups in the primary outcome us-
ing a generalized linear mixed-effects model with a
random effect for study site and a ﬁxed effect for group
assignment (ketamine group vs etomidate group). This
conservative Haybittle-Peto boundary will allow the ﬁnal
analysis to be performed using an unchanged level of
signiﬁcance (2-sided P value of < .05). After reviewing
the
interim
analysis,
the
DSMB
recommended
continuing the RSI without modiﬁcation.
Sample Size Estimation
The ﬁnal sample size for the RSI was calculated at the
time of receipt of funding for the multicenter stage of
the trial from PCORI (details of the initial sample size
calculation are provided in section 9 of e-Appendix 1).
Based on prior trials in the same settings,4,6 we estimated
that the incidence of all-cause, 28-day in-hospital mor-
tality (primary outcome) in the etomidate group would
be 30%. The patient and clinician partners recommen-
ded that the trial should have adequate statistical power
to detect an absolute difference between groups in mor-
tality of approximately 5 percentage points. This differ-
ence is more conservative than the median of 8
percentage points (interquartile range, 6-10 percentage
TABLE 3 ] Study Outcomes
Primary outcome
All-cause 28-d in-hospital mortality
Secondary outcome
Cardiovascular collapse, a composite of any of the following between induction and 2 min after
intubation: (1) systolic BP < 65 mm Hg, (2) new or increased vasopressor use, (3) cardiac
arrest not resulting in death within 1 h of induction, and (4) cardiac arrest resulting in death
within 1 h of inductiona
Exploratory procedural
outcomes
Cormack-Lehane grade of glottic view
Successful intubation on the ﬁrst attempt, deﬁned as placement of an endotracheal tube in the
trachea with a single insertion of a laryngoscope blade into the mouth and either a single
insertion of an endotracheal tube into the mouth or a single insertion of a bougie into the
mouth followed by a single insertion of an endotracheal tube over the bougie into the mouth
Time from induction to successful tracheal intubation
Lowest oxygen saturation between induction and 2 min after intubation
Lowest oxygen saturation < 80% between induction and 2 min after intubation
Highest and lowest systolic BP from induction to 2 min after intubation
Systolic BP > 180 mm Hg between induction and 2 min after intubation
Systolic BP < 65 mm Hg between induction and 2 min after intubation
New or increased vasopressor use between induction and 2 min after intubation
Cardiac arrest within 2 min of intubation not resulting in death within 1 h of inductiona
Cardiac arrest within 2 min of intubation resulting in death within 1 h of inductiona
Exploratory clinical
outcomes
Ventilator-free days to study day 28
Vasopressor-free days to study day 28
ICU-free days to study day 28
Safety outcomes
Systolic BP at 24 h after induction
Receipt of vasopressors at 24 h after induction
Cardiac arrest receiving CPR between induction and hospital discharge
aCardiac arrest occurring between induction of anesthesia and 2 min after intubation of the trachea will be considered to be a cardiac arrest that occurred
during tracheal intubation. For each case of cardiac arrest occurring during tracheal intubation, we will record whether that cardiac arrest resulted in
death. A cardiac arrest occurring during tracheal intubation will be considered to have resulted in death if the patient died before 1 h after induction.
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points) used as the minimum clinically important differ-
ence in the design of prior randomized trials in critical
care37 and is smaller than the observed difference in
mortality between ketamine and etomidate of 6 to 7 per-
centage points observed in 2 previous trials.24,28 We used
the bsamsize function in R (R Foundation for Statistical
Computing) to calculate that achieving 80% statistical
power at a 2-sided a value of .05 to detect a difference
in mortality of 5.2 percentage points (30.0% in the eto-
midate group vs 24.8% in the ketamine group) would
require enrollment of 2,308 patients. Anticipating that,
like previous Exception from Informed Consent Re-
quirements for Emergency Research trials,38 < 3% of
participants would discontinue follow-up before ascer-
tainment of the primary outcome, we planned to enroll
a total of 2,364 patients (1,182 per group).
Statistical Analysis Principles
Analyses will be conducted following reproducible
research principles using R software. Categorical vari-
ables will be presented as number and percentage.
Continuous variables will be presented as mean (SD)
or median (interquartile range). A 2-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 analyses of secondary and exploratory outcomes,
emphasis will be placed on the magnitude of differences
between groups with 95% CIs (which will not be adjusted
for multiple comparisons), rather than statistical signiﬁ-
cance. P values will not be presented. Templates for the
tables that will be presented in the results manuscript
and supplement for baseline, periprocedural, and in-
hospital outcome variables are provided in e-Tables 1-3.
Main Analysis of the Primary Outcome
The primary analysis will be an intention-to-treat com-
parison of patients randomized to the ketamine group
vs
patients
randomized
to
the
etomidate
group
regarding the primary outcome of all-cause 28-day in-
hospital mortality among all patients in the trial popula-
tion, except those who withdrew from follow-up before
ascertainment of the primary outcome. The primary
outcome will be compared between the 2 trials groups
using a generalized linear mixed-effects model with a
random effect for study site and a ﬁxed effect for group
assignment (ketamine group vs etomidate group). The
absolute difference in percentages, associated 95% CIs,
and a P value for the comparison will be presented. A
rationale for the primary outcome and its analysis can
be found in section 10 of e-Appendix 1.
Additional Analyses of the Primary Outcome
Sensitivity Analyses: We will assess the robustness of the
ﬁndings of the primary analysis in a series of sensitivity
analyses using different approaches to deﬁning and
analyzing the primary outcome. First, we will repeat
the primary analysis among all patients in the trial pop-
ulation, with patients who withdrew from follow-up
before outcome ascertainment treated as (1) all having
experienced the primary outcome or (2) all not having
experienced the primary outcome. Second, we will
repeat the primary analysis using all-cause, all-location
mortality
at
28
days
(ie,
including
available
information
on
deaths
that
occur
after
hospital
discharge). Third, we will repeat the primary analysis
using a c2 test, rather than a generalized linear mixed-
effects model. Fourth, we will compare survival to day
28
between
trial
groups
using
the
Kaplan-Meier
method. Fifth, we will perform an adjusted analysis
comparing the primary outcome between groups using
a
generalized
linear
mixed-effects
model
with
a
random effect for trial site and ﬁxed effects for trial
group
assignment
and
the
following
prespeciﬁed
baseline
variables:
age,
sex,
race,
ethnicity,
Area
Deprivation Index (a proxy for socioeconomic status
and an indicator of neighborhood disadvantage),39
rurality,40 number of comorbidities, and severity of
illness before enrollment as assessed by the Acute
Physiology and Chronic Health Evaluation II score.41
Continuous variables will be modelled assuming a
nonlinear relationship to the outcome using restricted
cubic splines with between 3 and 5 knots.
Analyses of Heterogeneity of Treatment Effect: Heterogene-
ity of treatment effect is nonrandom variation in the
magnitude or direction of the effect of a treatment on
an outcome across levels of a baseline covariate. We
will apply the 3 complementary approaches to analysis
of heterogeneity of treatment effect described in the Pre-
dictive Approaches to Treatment Effect Heterogeneity
Statement:
(1)
traditional
1-variable-at-a-time
subgroup analyses, (2) a risk-modeling approach, and
(3) an effect-modeling approach.42 Complete details of
all 3 approaches are described in section 11 of
e-Appendix 1.
Our subgroup analyses will examine whether prespeci-
ﬁed baseline variables modify the effect of trial group
assignment 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, a random effect for trial site, and in-
dependent variables of trial group, the proposed effect
chestcc.org
7

modiﬁer, and the interaction between the effect modiﬁer
and trial group for each of the following prespeciﬁed
baseline variables: (1) sepsis or septic shock (yes or
no), (2) vasopressor receipt (yes or no), (3) patient loca-
tion (ED or ICU), (4) adrenal insufﬁciency or long-term
receipt of corticosteroids (yes or no), (5) acute neuro-
logic condition (yes or no), (6) active cardiac condition
(yes or no), and (7) baseline risk of the primary outcome
(continuous).
Analysis of the Secondary Outcome
We will perform an unadjusted, intention-to-treat com-
parison of patients randomized to the ketamine group
vs
patients
randomized
to
the
etomidate
group
regarding the secondary outcome of cardiovascular
collapse. A c2 test will be used to generate between-
group differences and the associated 95% CIs.
Analyses of Additional Outcomes
We will conduct unadjusted, intention-to-treat analyses
comparing patients randomized to the ketamine group
vs
patients
randomized
to
the
etomidate
group
regarding
each
prespeciﬁed
exploratory
procedural
outcome,
exploratory clinical outcome,
and
safety
outcome. Between-group differences and the associated
95% CIs will be generated using a c2 test for categorical
outcomes and a Wilcoxon rank-sum test for continuous
outcomes.
Handling of Missing Data
We anticipate that no data on the primary outcome will
be missing except for patients who withdrew from
participation before the collection of the primary
outcome. When data are missing for an outcome, we
will perform complete-case analysis, excluding patients
whose data for the analyzed outcome are missing. In
adjusted analyses, missing data for covariates will be
imputed using multiple imputations. All variables that
included in prespeciﬁed statistical models also will be
included in the imputation model. This allows for the re-
lationships held between the variables of interest to be as
similar as possible with and without imputation. The
speciﬁc method of multiple imputation used in adjusted
analysis uses bootstrapping and predictive mean match-
ing. Samples of nonmissing data are bootstrapped,
then ﬁt to an additive regression model to predict
missing data. Imputation will be performed using the
R statistical software’s aregImpute function from the
Hmisc package.
Discussion
This article reports the rationale, design, and analysis
plan for the RSI, a 2,364-patient randomized trial of
ketamine vs etomidate for induction of anesthesia
among critically ill adults undergoing emergency
tracheal intubation. Several elements of the trial design
warrant discussion.
The RSI was designed to compare ketamine vs etomidate
and does not examine other medications capable of
inducing anesthesia for emergency tracheal intubation,
such as propofol or benzodiazepines. These comparators
were selected for several reasons. First, ketamine and
etomidate are the medications most often used for
emergency tracheal intubation in many EDs14 and
ICUs,5 particularly in the United States.3,43-45 Second,
ketamine and etomidate are the only medications
consistently used for emergency tracheal intubation in
clinical care at the 14 sites participating in the trial.4,6,15
Third, although propofol and benzodiazepines are used
more commonly by some clinical specialties (eg,
anesthesiologists)46,47 and in some clinical settings (eg,
some ICUs outside of the United States),2 observational
studies consistently have reported these medications to
be associated with higher rates of hypotension during
intubation, particularly for patients with preexisting
hemodynamic instability.2,48 We anticipate that
approximately 1 in 4 patients in the RSI will be receiving
vasopressors before enrollment. Thus, we designed the
trial to compare 2 medications with a hemodynamic
proﬁle that permits their use for nearly all critically ill
adults, including those with hypotension or shock before
intubation.
In the RSI, clinicians determine what dose of the assigned
medication each patient receives based on the clinical
condition of the patient using a dosing nomogram
provided by the trial. The nomogram speciﬁes 2 mg/kg of
ketamine and 0.3 mg/kg of etomidate as a full dose.
These are the doses speciﬁed in the US Food and Drug
Administration labeling information for the induction of
anesthesia.33,49 These also are the doses used in 2 of the
largest previous randomized trials comparing ketamine
vs etomidate among critically ill adults.24,28 For patients
who clinicians determine require a lower dose, the
nomogram also provides information on an intermediate
dose (1.5 mg/kg of ketamine or 0.25 mg/kg of etomidate)
and a reduced dose (1.0 mg/kg of ketamine or 0.2 mg/kg
of etomidate) across a range of patient weights.
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The design of the RSI differs from that of previous trials
comparing ketamine vs etomidate in several respects.
First, the planned sample size of 2,364 patients is almost 3
times as large as any prior trial and will permit more
precise estimates of treatment effect.24,28,29,50 Second,
unlike prior trials that excluded patients intubated in the
ED,24 that excluded patients intubated in the ICU,29 or
that enrolled only patients with sepsis,50 the RSI includes a
broad range of patients undergoing emergency tracheal
intubation in an ED or ICU, which increases
generalizability. The only diagnosis excluded from the RSI
is a primary diagnosis of trauma before seeking treatment
in the ED. Because some prior data suggest that ketamine
might increase intracranial pressure51 and the results of 1
prior trial suggested a potential difference in treatment
effect between patients with and without trauma,28 we
determined that the effect of ketamine vs etomidate on
outcomes for patients with trauma was best evaluated in a
separate trial. Third, unlike prior trials that did not collect
procedural outcomes28 or long-term patient-centered
outcomes,24,28,29,50 the RSI collects physiologic outcomes
during the procedure (eg, cardiovascular collapse during
intubation), short-term patient-centered outcomes (eg,
death by day 28), and long-term patient-centered
outcomes (eg, survival and symptoms of posttraumatic
stress disorder at 12 months).
Interpretation
The RSI will provide important evidence regarding the
effect of ketamine vs etomidate on death and other
clinical outcomes among critically ill adults undergoing
emergency tracheal intubation in an ED or ICU. To aid
in the transparency and interpretation of trial results,
this article detailing the protocol and statistical analysis
plan for the RSI has been ﬁnalized before the conclusion
of patient enrollment.
Funding/Support
Research reported in this article was funded by the
Patient-Centered Outcomes Research Institute [Grant
BPS-2022C3-30021) and by the National Heart, Blood,
and Lung Institute [Grant K23HL153584].
Financial/Nonﬁnancial Disclosures
The authors have reported to CHEST Critical Care the
following: All of the authors received support in the
form of grant funding from the Patient-Centered
Outcomes Research Institute (PCORI) for the conduct
of the trial described in this manuscript. M. W. S.
reported having received grant funding from the
National Institute of Health (NIH) and the Department
of Defense (DoD) unrelated to the current work and
compensation from DynaMedex and Baxter Healthcare
unrelated to the current work. K. P. Seitz reported
having received grant funding from the NIH unrelated
to the current work (T32HL087738). S. C. D. reported to
have received grant funding from the NIH unrelated to
the current work (T32GM108554). D. W. R. reported to
have received grant funding from the NIH unrelated to
the current work and compensation from ABSS
solutions inc, Quantum Leap Healthcare Collaborative,
Achieve Life Sciences, Direct Biologics, and UAB Lung
Health Center unrelated to the current work. N. R. A.
reported to have received grant funding from the NIH
unrelated to the current work. T. W. R. reported to have
received funding from the NIH NCATS, PCORI, DoD,
and CDC funding unrelated to the current work, and
compensation from Cumberland Pharmaceutics Inc,
Cytovale Inc, and SanoﬁInc unrelated to the current
work. D. J. D. reported having received grant funding
from the NIH (K23HL165107) unrelated to the current
work.
Acknowledgments
Author contributions: S. C. D., B. I., A. A. L.,
M. W. S., and J. D. C. contributed
substantially to the study concept and design.
S. C. D., B. I., A. A. L., M. W. S., and J. D. C.
were responsible for drafting of the initial
manuscript. S. C. D., B. I., and A. A. L.
contributed equally to this manuscript as ﬁrst
authors. M. W. S. and J. D. C. contributed
equally to this manuscript as senior authors.
All authors critically reviewed the manuscript
for important intellectual content. S. C. D., B.
I., A. A. L., J. D. C., and M. W. S. had ﬁnal
approval and accountabiltiy for integrity of
this manuscript.
Role of sponsors: The sponsor had no role in
the design of the study, the collection and
analysis of the data, or the preparation of the
manuscript.
Disclaimer: The views and statements
presented in this article are solely the
responsibility of the authors and do not
necessarily represent the views of the
Patient-Centered Outcomes Research
Institute or the National Heart, Blood, and
Lung Institute.
Additional information: The e-Appendix
and e-Tables are available online under
“Supplemental Data.”
References
1. Kempker JA, Abril MK, Chen Y,
Kramer MR, Waller LA, Martin GS. The
epidemiology of respiratory failure in the
United States 2002-2017: a serial cross-
sectional study. Crit Care Explor.
2020;2(6):e0128.
2. 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.
3. Casey JD, Janz DR, Russell DW, et al. Bag-
mask ventilation during tracheal
chestcc.org
9

intubation of critically ill adults. N Engl J
Med. 2019;380(9):811-821.
4. Gibbs KW, Semler MW, Driver BE, et al.
Noninvasive ventilation for
preoxygenation during emergency
intubation. N Engl J Med. 2024;390(23):
2165-2177.
5. Wunsch H, Bosch NA, Law AC, et al.
Evaluation of etomidate use and
association with mortality compared with
ketamine among critically ill patients. Am
J Respir Crit Care Med. 2024;210(10):
1243-1251.
6. Prekker ME, Driver BE, Trent SA, et al.
Video versus direct laryngoscopy for
tracheal intubation of critically ill adults.
N Engl J Med. 2023;389(5):418-429.
7. Zane RD. Etomidate or midazolam for
rapid sequence induction in patients with
suspected sepsis? NEJM Journal Watch
website. Accessed December 29, 2021.
https://www.jwatch.org/em20101217
0000001/2010/12/17/etomidate-or-
midazolam-rapid-sequence-induction
8. Chan CM, Mitchell AL, Shorr AF.
Etomidate is associated with mortality and
adrenal insufﬁciency in sepsis: a meta-
analysis. Crit Care Med. 2012;40(11):
2945-2953.
9. Cuthbertson BH, Sprung CL, Annane D,
et al. The effects of etomidate on adrenal
responsiveness and mortality in patients
with septic shock. Intensive Care Med.
2009;35(11):1868-1876.
10. Boonen E, Vervenne H, Meersseman P,
et al. Reduced cortisol metabolism during
critical illness. N Engl J Med. 2013;368(16):
1477-1488.
11. Cooper MS, Stewart PM. Corticosteroid
insufﬁciency in acutely ill patients. N Engl
J Med. 2003;348(8):727-734.
12. Venkatesh B, Finfer S, Cohen J, et al.
Adjunctive glucocorticoid therapy in
patients with septic shock. N Engl J Med.
2018;378(9):797-808.
13. DeMasi SC, Self WH, Jerome RN, et al.
Regulatory approval for the use of
etomidate and ketamine for emergency
tracheal intubation globally. Acad Emerg
Med. 2025;32(S1):8-358.
14. April MD, Arana A, Schauer SG, et al.
Ketamine versus etomidate and peri-
intubation hypotension: a National
Emergency Airway Registry study.
Acad Emerg Med. 2020;27(11):
1106-1115.
15. Upchurch CP, Grijalva CG, Russ S,
et al. Comparison of etomidate and
ketamine for induction during rapid
sequence intubation of adult trauma
patients. Ann Emerg Med. 2017;69(1):
24-33.e2.
16. Khalili-Mahani N, Martini CH, Olofsen E,
Dahan A, Niesters M. Effect of
subanaesthetic ketamine on plasma and
saliva cortisol secretion. Br J Anaesth.
2015;115(1):68-75.
17. Hergovich N, Singer E, Agneter E, et al.
Comparison of the effects of ketamine and
memantine on prolactin and cortisol
release in men. a randomized, double-
blind, placebo-controlled trial.
Neuropsychopharmacology. 2001;24(5):
590-593.
18. Spotoft H, Korshin JD, Sørensen MB,
Skovsted P. The cardiovascular effects of
ketamine used for induction of
anaesthesia in patients with valvular heart
disease. Can Anaesth Soc J. 1979;26(6):
463-467.
19. Pagel PS, Kampine JP, Schmeling WT,
Warltier DC. Ketamine depresses
myocardial contractility as evaluated by
the preload recruitable stroke work
relationship in chronically instrumented
dogs with autonomic nervous system
blockade. Anesthesiology. 1992;76(4):
564-572.
20. Waxman K, Shoemaker WC,
Lippmann M. Cardiovascular effects of
anesthetic induction with ketamine.
Anesth Analg. 1980;59(5):355-358.
21. Gelissen HPMM, Epema AH,
Henning RH, Krijnen HJ, Hennis PJ,
den Hertog A. Inotropic effects of
propofol, thiopental, midazolam,
etomidate, and ketamine on isolated
human atrial muscle. Anesthesiology.
1996;84(2):397-403.
22. Sprung J, Schuetz SM, Stewart RW,
Moravec CS. Effects of ketamine on the
contractility of failing and nonfailing
human heart muscles in vitro.
Anesthesiology. 1998;88(5):1202-1210.
23. Brown CA, Bair AE, Pallin DJ, Walls RM;
NEAR III Investigators. Techniques,
success, and adverse events of emergency
department adult intubations. Ann Emerg
Med. 2015;65(4):363-370.e1.
24. Matchett G, Gasanova I, Riccio CA, et al.
Etomidate versus ketamine for emergency
endotracheal intubation: a randomized
clinical trial. Intensive Care Med.
2021;48(1):78-91.
25. Mohr NM, Pape SG, Runde D,
Kaji AH, Walls RM, Brown CA.
Etomidate use is associated with less
hypotension than ketamine for
emergency department sepsis
intubations: a NEAR Cohort study.
Acad Emerg Med. 2020;27(11):
1140-1149.
26. Dewhirst E, Frazier WJ, Leder M,
Fraser DD, Tobias JD. Cardiac arrest
following ketamine administration for
rapid sequence intubation. J Intensive
Care Med. 2013;28(6):375-379.
27. Koroki T, Kotani Y, Yaguchi T, et al.
Ketamine versus etomidate as an
induction agent for tracheal intubation in
critically ill adults: a Bayesian meta-
analysis. Crit Care. 2024;28(1):48.
28. Jabre P, Combes X, Lapostolle F, et al.
Etomidate versus ketamine for rapid
sequence intubation in acutely ill patients:
a multicentre randomised controlled trial.
Lancet. 2009;374(9686):293-300.
29. Knack SKS, Prekker ME, Moore JC,
et al. The effect of ketamine versus
etomidate for rapid sequence intubation
on maximum Sequential Organ Failure
Assessment score: a randomized clinical
trial. J Emerg Med. 2023;65(5):
e371-e382.
30. Greer A, Hewitt M, Khazaneh PT, et al.
Ketamine versus etomidate for rapid
sequence intubation: a systematic
review and meta-analysis of randomized
trials. Crit Care Med. 2024;53(2):
e374-e383.
31. Chan A-W, Tetzlaff JM, Altman DG, et al.
SPIRIT 2013 statement: deﬁning standard
protocol items for clinical trials. Ann
Intern Med. 2013;158(3):200.
32. US Food and Drug Administration.
Exception from informed consent
requirements for emergency research. US
Food and Drug Administration website.
Accessed November 19, 2024. https://
www.fda.gov/regulatory-information/
search-fda-guidance-documents/
exception-informed-consent-
requirements-emergency-research
33. US Food and Drug Administration,
Ketamine. US Food and Drug
Administration website. Accessed
November 12, 2024. https://www.
accessdata.fda.gov/drugsatfda_docs/
label/2018/016812s040lbl.pdf
34. Semler MW, Janz DR, Russell DW, et al.
A multicenter, randomized trial of ramped
position vs snifﬁng position during
endotracheal intubation of critically ill
adults. Chest. 2017;152(4):712-722.
35. Cormack RS, Lehane JR, Adams AP,
Carli F. Laryngoscopy grades and
percentage glottic opening. Anaesthesia.
2000;55(2):184. 184.
36. Effect of Ketamine And Etomidate During
RSI On Long Term Outcomes (RSI-LTO).
ClinicalTrials.gov identiﬁer:
NCT06179485. Updated January 8, 2025.
http://clinicaltrials.gov/ct2/show/
NCT06179485
37. Yarnell CJ, Abrams D, Baldwin MR, et al.
Clinical trials in critical care: can a
Bayesian approach enhance clinical and
scientiﬁc decision making? Lancet Respir
Med. 2021;9(2):207-216.
38. Silbergleit R, Durkalski V, Lowenstein D,
et al. Intramuscular versus intravenous
therapy for prehospital status epilepticus.
N Engl J Med. 2012;366(7):591-600.
39. Kind AJH, Buckingham WR. Making
neighborhood-disadvantage metrics
accessible—the Neighborhood Atlas.
N Engl J Med. 2018;378(26):2456-2458.
40. US Department of Agriculture Economic
Research Service. Rural-urban commuting
area codes. US Department of Agriculture
Economic Research Service website.
https://www.ers.usda.gov/data-products/
rural-urban-commuting-area-codes/
41. Knaus WA, Draper EA, Wagner DP,
Zimmerman JE. APACHE II: a severity of
disease classiﬁcation system. Crit Care
Med. 1985;13(10):818-829.
42. Kent DM, van Klaveren D, Paulus JK,
et al. The Predictive Approaches to
Treatment effect Heterogeneity (PATH)
statement: explanation and elaboration.
Ann Intern Med. 2020;172(1):W1-W25.
10
Original Research
[ 3 # 3 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 5 ]

43. Ferguson I, Buttﬁeld A, Burns B, et al.
Fentanyl versus placebo with ketamine
and rocuronium for patients undergoing
rapid sequence intubation in the
emergency department: the
FAKT study—a randomized clinical trial.
Acad Emerg Med. 2022;29(6):
719-728.
44. Ferguson I, Alkhouri H, Fogg T,
Aneman A. Ketamine use for rapid
sequence intubation in Australian and
New Zealand emergency departments
from 2010 to 2015: a registry study.
Emerg Med Australas EMA. 2019;31(2):
205-210.
45. Sagarin MJ, Barton ED, Chng Y-M,
Walls RM; National Emergency Airway
Registry Investigators. Airway
management by US and Canadian
emergency medicine residents: a
multicenter analysis of more than
6,000 endotracheal intubation
attempts. Ann Emerg Med. 2005;46(4):
328-336.
46. Wahlen BM, El-Menyar A, Asim M, Al-
Thani H. Rapid sequence induction (RSI)
in trauma patients: insights from
healthcare providers. World J Emerg Med.
2019;10(1):19-26.
47. Sneyd JR, Gambus PL, Rigby-Jones AE.
Current status of perioperative
hypnotics, role of benzodiazepines,
and the case for remimazolam: a
narrative review. Br J Anaesth.
2021;127(1):41-55.
48. Wan C, Hanson AC, Schulte PJ, Dong Y,
Bauer PR. Propofol, ketamine, and
etomidate as induction agents for
intubation and outcomes in critically ill
patients: a retrospective cohort study. Crit
Care Explor. 2021;3(5):e0435.
49. US Food and Drug Administration.
Etomidate. 2024. US Food and Drug
Administration website. Accessed
November 12, 2024. https://www.
accessdata.fda.gov/drugsatfda_docs/
label/2017/018227s032lbl.pdf
50. Srivilaithon W, Bumrungphanithaworn A,
Daorattanachai K, et al. Clinical outcomes
after a single induction dose of etomidate
versus ketamine for emergency
department sepsis intubation: a
randomized controlled trial. Sci Rep.
2023;13(1):6362.
51. Zeiler FA, Teitelbaum J, West M,
Gillman LM. The ketamine effect on ICP
in traumatic brain injury. Neurocrit Care.
2014;21(1):163-173.
chestcc.org
11

 
1
Supplementary file to: 
Protocol and Statistical Analysis Plan for the Randomized Trial of Sedative Choice for 
Intubation (RSI) 
1. List of RSI Investigators 
2 
2. SPIRIT 2013 Checklist 
5 
3. Engagement of Patients, Families, and Community Members 
10 
4. Ethics and Informed Consent Processes 
12 
4.1 Exception from Informed Consent Requirements for Emergency Research (EFIC) 
12 
4.2 Informed Consent Processes in the RSI trial 
13 
4.2.1 Written Informed Consent 
13 
4.2.2 Opportunity to Decline Participation 
14 
4.2.3 Exception from Informed Consent 
14 
5. Group Assignment Sheets with Nomogram (Ketamine) 
15 
6. Group Assignment Sheets with Nomogram (Etomidate) 
16 
7. Definitions of Free-Day Outcomes 
17 
8. Composition and Responsibilities of the Data Safety Monitoring Board 
19 
9. Details of Sample Size Calculation 
20 
10. Rationale for the Choice and Analysis of the Primary Outcome 
22 
11. Effect Modification 
23 
12. Safety Monitoring and Adverse Events 
27 
13. Plan for Communication of Protocol Changes 
28 
14. Patient Privacy, Data Storage, and Sharing 
29 
15. Trial Status 
30 
16. Supplementary Tables 
31 
17. Appendices 
35 
B. Example Informed Consent Document. 
35 
B. Example Notification Document. 
37 
18. References 
37 
 
 
 
 
 

 
2
1. List of RSI Investigators  
Coordinating Center: Clinical Coordinating Center (Vanderbilt University Medical Center, Nashville 
TN) – Jonathan D. Casey, MD MSc* (Director, Coordinating Center); Matthew W. Semler, MD MSc* 
(Chair, Steering Committee); Ariel A. Lewis, MPH, BSN, RN*; Jin H. Han, MD, MSc*; Wesley H. 
Self, MD, MPH*; Todd W. Rice, MD, MSc*; Christopher G. Hughes, MD; Bradley D. Lloyd, RRT-
ACCS*; Karen F. Miller, RN, MPA; Katie S. Gray, BS; Jacob A. Wood, BS; Cheryl L. Gatto, PhD; 
Mary Lynn Dear, PhD; Grace Van Winkle, BA; Sydney Vidrine, MPH; Tiffany L. Israel, MSSW*; 
Elizabeth M. Frawley, BSN RN; Madison E. White, RN; Margaret A. Hays, RN MSN.  Data 
Coordinating Center (Vanderbilt University Medical Center, Nashville TN) – Brant Imhoff, MS*; Li 
Wang, MS*; Matthew S. Shotwell, PhD.  Effect-Modeling Team (University of Wisconsin, Madison, 
WI) – Alexandra Spicer MS, Matt Churpek, MD PhD MPH. 
  
Patient Representatives: Aida Strom (Minneapolis, MN); Barbara Gould (Denver, CO)*; Eileen 
Rubin, (Northbrook, IL); Jasmine McIntosh (Birmingham, AL)*; Patrick Luther (Nashville, TN); 
Sherman Transou (Winston-Salem, NC). 
  
Denver Health Medical Center: Stacy A. Trent, MD MPH*; Carolynn Lyle, PA-C MPH*; L. Jane 
Stewart, MD JD MPH*; Marc Retana Castenada, BS; Sonia Iturrino Rijos, BA. 
  
Hennepin County Medical Center: Brian E. Driver, MD*; Aaron E. Robinson, MD MPH*; Matthew E. 
Prekker, MD MPH*; Greta Kreider Carlson, MD*; Julianna Prohofsky, BS; Joanna Kuo, BS; Kowsar 
Hurreh, BA; Laurynn Giles, BS; Ananya Narayan, BS; Meghana Chimata, BS, BA; Mia Kellman, BS; 
Victoria Stehr; Simon Vergara Santibanez, BS; Shawna Ratanpal, BS; Danielle Laibly, BA; Dawson 
Blankenship, BS; Elijah Hess, BS; Iris Guo; Shivangi Pandey, BS; Spencer Burris-Brown; Stella 
Frangiadakis. 
  

 
3
Wake Forest School of Medicine: Kevin W. Gibbs, MD*; Jessica A. Palakshappa, MD MS*; J. 
Maycee Cain, BS*; John P. Gaillard, MD*; Brianne Redman, MD*; Haileigh Henson, RN; Savanna 
Burgess, RN; Benjamin Richards, RN; Belinda Williamson, RN; Lindsey Nicoletti, RN; Summer 
Usher, RN; Lisa Parks, RN; Leigha Landreth, RN; Katelyn Jimison, PharmD; Alaina Shukdinas, 
PharmD; Christopher Buckley, PharmD; Karl Healy, PharmD MS; Lars Almassalkhi, PharmD MS; 
Hannah Morley, PharmD; Adam Furr, PharmD; Adam Boles, PharmD; Robert Dustin Pippen, 
PharmD. 
  
University of Alabama at Birmingham Medical Center and Heersink School of Medicine: Micah R. 
Whitson, MD*; Logan L. Beach, MD*; Derek W. Russell, MD*; Sheetal Gandotra, MD*; Mary Clay 
Boone, RN BSN; Robert B. Johnson, RRT; Geri-Anne Warman, RN BSN; Jennifer J. Oswald, RN 
BSN; Jerrod Isbell, RRT; Anne Merrill Mason, RN BSN; Gina White, RN BSN; Tyler Greathouse, 
DO; Morgan Locy, MD PhD; Ryan Goetz, MD; Steven Fox, MD; Jonathan Kalehoff, MD; Daniel 
Kelmenson, MD; Meena Sridhar, MD; Ahmed Salem, MD; Aneesah B. Jaumally, MD; Ishan Lalani, 
MD MPH; William S. Stigler, MD; Phillip J. O'Reilly, MD; Donna S. Harris, RN BSN; Cara E. Porter, 
RN ADN; Sonya Hardy, MA; Puneet Aulakh, MD; Joseph B. Barney, MD;  Joseph Chiles III, MD; 
Bryan Garcia, MD; Aditya Kotecha, MD; Abdulhakim Tlimat, MD; Peter Morris, MD; Kinner Patel, 
MD; R. Chad Wade, MD; Carla Copeland, MD; Drew Vestri, RN BSN; Kelsey Jones, RN BSN; 
Regina Oliver, RN BSN CCRN;  Megan Shelton, MSN RN; Reagan Isbell, RN BSN; Lisa Sarratt, RN 
BSN; Sarah W. Robison, MD; Nicole Walker, MS RRT; Stephanie Powell, RRT; Great Peagler-
Mims, MS RRT; Megan Crumpton, MS RRT;  Laquata Boswell, MS RRT; Dianne Freeman, BS 
RRT; Sukhmani Boparai, MD; Parker Hambright, MD; Ivan A. Martinez Avalos, MD; Gary Carbell, 
MD; Nima M. Abdi, MBBS; Hafsa Safdar, MD; Timothy Kennell, MD; Lauren Daley, MD; Victoria 
Smith, MD; William Smith, MD;  Claudia Tejera Quesada, MD; Hongli Liu, MD PhD; William 
Nicolson, MD; Kimberly Okoyeze, MD; Andres J. Gonzales Coba, MD PhD; John Craver, MD; K. 
Cory Guice, DO;  David Page, MD.  
  

 
4
University of Colorado School of Medicine: Adit A. Ginde, MD MPH*; Neil R. Aggarwal, MD MHSc*; 
Carrie Higgins, BSN*; Daniel Resnick-Ault, MD*; Jason C. Brainard, MD*; Cori Withers, BS*; David 
J. Douin, MD MSc*; Kristine Schauer, MBA RN; Amy Sullivan, BA; Andrew Kluemper, PharmD; 
Emily Helmer, BS; Kyle Pickard, BS; Laura G. Murphy, BS; Danielle A. Refvem, BSN; Peter Sottile, 
MD. 
  
Vanderbilt University Medical Center: Stephanie C. DeMasi, MD*; Aaron J. Lacy, MD*; Amelia 
Muhs, MD*; Graham W. W. Van Schaik MD, MBA*; Kevin P. Seitz, MD MSc*; Kristen C. Sherlin, 
PharmD*; LaKeysha C. Wiggins, Gabriel A. Kemp, Ryan C. Dillon, PharmD, Jakea D. Johnson, 
MPH; Linda McLaughlin, PharmD BCPS; Shannon K. Pugh, RN, BSN; Edward T. Qian, MD, MSc; 
Carla M. Sevin, MD; Joanna L. Stollings, PharmD. 
  
*Denotes members of the writing committee who are listed as authors on the manuscript, the 
remainder of the RSI investigators represent collaborators.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
5
 
 
 
 
2. SPIRIT 2013 Checklist 
SPIRIT 2013 Checklist: 
Recommended items to address 
in a clinical trial protocol and 
related documents* 
 
 
 
 
 
 
Section/item 
Item 
No 
Description 
Addressed 
on page 
number 
Administrative information 
 
Title 
1 
Descriptive title identifying the study design, population, 
interventions, and, if applicable, trial acronym 
1 
Trial registration 
2a 
Trial identifier and registry name. If not yet registered, 
name of intended registry 
4, 7 
2b 
All items from the World Health Organization Trial 
Registration Data Set 
1-6 
Protocol version 
3 
Date and version identifier 
NA 
Funding 
4 
Sources and types of financial, material, and other 
support 
2, 12-13 
Roles and 
responsibilities 
5a 
Names, affiliations, and roles of protocol contributors 
1 
5b 
Name and contact information for the trial sponsor 
2 
 
5c 
Role of study sponsor and funders, if any, in study 
design; collection, management, analysis, and 
interpretation of data; writing of the report; and the 
decision to submit the report for publication, including 
whether they will have ultimate authority over any of 
these activities 
1-3, 12 
 
5d 
Composition, roles, and responsibilities of the 
coordinating centre, steering committee, endpoint 
adjudication committee, data management team, and 
other individuals or groups overseeing the trial, if 
applicable (see Item 21a for data monitoring committee) 
1-3 
Section 1 of 
Supplement 

 
6
Introduction 
 
 
 
Background and 
rationale 
6a 
Description of research question and justification for 
undertaking the trial, including summary of relevant 
studies (published and unpublished) examining benefits 
and harms for each intervention 
5-6 
 
6b 
 
Explanation for choice of comparators 
5-7, 19 
Objectives 
7 
Specific objectives or hypotheses 
6 
Trial design 
8 
Description of trial design including type of trial (eg, 
parallel group, crossover, factorial, single group), 
allocation ratio, and framework (eg, superiority, 
equivalence, noninferiority, exploratory) 
7 
Methods: Participants, interventions, and outcomes 
 
Study setting 
9 
Description of study settings (eg, community clinic, 
academic hospital) and list of countries where data will 
be collected. Reference to where list of study sites can 
be obtained 
7, 
Supplement 
Section 1 
Eligibility criteria 
10 
Inclusion and exclusion criteria for participants. If 
applicable, eligibility criteria for study centres and 
individuals who will perform the interventions (eg, 
surgeons, psychotherapists) 
Table 2 
Interventions 
11a 
Interventions for each group with sufficient detail to allow 
replication, including how and when they will be 
administered 
8-9 
11b 
Criteria for discontinuing or modifying allocated 
interventions for a given trial participant (eg, drug dose 
change in response to harms, participant request, or 
improving/worsening disease) 
8-9 
11c 
Strategies to improve adherence to intervention 
protocols, and any procedures for monitoring adherence 
(eg, drug tablet return, laboratory tests) 
NA 
11d 
Relevant concomitant care and interventions that are 
permitted or prohibited during the trial 
9 
Outcomes 
12 
Primary, secondary, and other outcomes, including the 
specific measurement variable (eg, systolic blood 
pressure), analysis metric (eg, change from baseline, final 
value, time to event), method of aggregation (eg, median, 
proportion), and time point for each outcome. Explanation 
of the clinical relevance of chosen efficacy and harm 
outcomes is strongly recommended 
11-12,  
Table 3 

 
7
Participant 
timeline 
13 
Time schedule of enrollment, interventions (including any 
run-ins and washouts), assessments, and visits for 
participants. A schematic diagram is highly recommended 
(see Figure) 
Table 1 
Sample size 
14 
Estimated number of participants needed to achieve study 
objectives and how it was determined, including clinical 
and statistical assumptions supporting any sample size 
calculations 
13-14, 
Supplement 
Section 9 
Recruitment 
15 
Strategies for achieving adequate participant enrollment to 
reach target sample size 
NA 
Methods: Assignment of interventions (for controlled trials) 
 
Allocation: 
 
 
 
Sequence 
generation 
16a 
Method of generating the allocation sequence (eg, 
computer-generated random numbers), and list of any 
factors for stratification. To reduce predictability of a 
random sequence, details of any planned restriction (eg, 
blocking) should be provided in a separate document 
that is unavailable to those who enroll participants or 
assign interventions 
8 
Allocation 
concealment 
mechanism 
16b 
Mechanism of implementing the allocation sequence (eg, 
central telephone; sequentially numbered, opaque, 
sealed envelopes), describing any steps to conceal the 
sequence until interventions are assigned 
8 
Implementation 
16c 
Who will generate the allocation sequence, who will 
enroll participants, and who will assign participants to 
interventions 
8 
Blinding 
(masking) 
17a 
Who will be blinded after assignment to interventions (eg, 
trial participants, care providers, outcome assessors, 
data analysts), and how 
8 
 
17b 
If blinded, circumstances under which unblinding is 
permissible, and procedure for revealing a participant’s 
allocated intervention during the trial 
NA 
Methods: Data collection, management, and analysis 
 
Data collection 
methods 
 
18a 
Plans for assessment and collection of outcome, 
baseline, and other trial data, including any related 
processes to promote data quality (eg, duplicate 
measurements, training of assessors) and a description 
of study instruments (eg, questionnaires, laboratory 
tests) along with their reliability and validity, if known. 
Reference to where data collection forms can be found, if 
not in the protocol 
10-12 
 
18b 
Plans to promote participant retention and complete 
follow-up, including list of any outcome data to be 
collected for participants who discontinue or deviate from 
intervention protocols 
14, 18 

 
8
Data 
management 
19 
Plans for data entry, coding, security, and storage, 
including any related processes to promote data quality 
(eg, double data entry; range checks for data values). 
Reference to where details of data management 
procedures can be found, if not in the protocol 
Supplement 
Section 14 
Statistical 
methods 
20a 
Statistical methods for analysing primary and secondary 
outcomes. Reference to where other details of the 
statistical analysis plan can be found, if not in the 
protocol 
14-17, 
Supplement 
Section 10, 11 
 
20b 
Methods for any additional analyses (eg, subgroup and 
adjusted analyses) 
14-17, 
Supplement 
Section 11 
 
20c 
Definition of analysis population relating to protocol non-
adherence (eg, as randomised analysis), and any 
statistical methods to handle missing data (eg, multiple 
imputation) 
14-17 
Methods: Monitoring 
 
Data monitoring 
21a 
Composition of data monitoring committee (DMC); 
summary of its role and reporting structure; statement of 
whether it is independent from the sponsor and 
competing interests; and reference to where further 
details about its charter can be found, if not in the 
protocol. Alternatively, an explanation of why a DMC is 
not needed 
Supplement 
Section 8 
 
21b 
Description of any interim analyses and stopping 
guidelines, including who will have access to these 
interim results and make the final decision to terminate 
the trial 
12 
Harms 
22 
Plans for collecting, assessing, reporting, and managing 
solicited and spontaneously reported adverse events and 
other unintended effects of trial interventions or trial 
conduct 
Supplement 
Section 12 
Auditing 
23 
Frequency and procedures for auditing trial conduct, if 
any, and whether the process will be independent from 
investigators and the sponsor 
Supplement 
Section 12 
Ethics and dissemination 
 
Research ethics 
approval 
24 
Plans for seeking research ethics committee/institutional 
review board (REC/IRB) approval 
7-8 
Protocol 
amendments 
25 
Plans for communicating important protocol modifications 
(eg, changes to eligibility criteria, outcomes, analyses) to 
relevant parties (eg, investigators, REC/IRBs, trial 
participants, trial registries, journals, regulators) 
Supplement 
Section 13 
Consent or 
assent 
26a 
Who will obtain informed consent or assent from 
potential trial participants or authorised surrogates, and 
how (see Item 32) 
Supplement 
Section 4 

 
9
 
26b 
Additional consent provisions for collection and use of 
participant data and biological specimens in ancillary 
studies, if applicable 
NA 
Confidentiality 
27 
How personal information about potential and enrolled 
participants will be collected, shared, and maintained in 
order to protect confidentiality before, during, and after 
the trial 
Supplement 
Section 14 
Declaration of 
interests 
28 
Financial and other competing interests for principal 
investigators for the overall trial and each study site 
1-3 
Access to data 
29 
Statement of who will have access to the final trial 
dataset, and disclosure of contractual agreements that 
limit such access for investigators 
NA 
Ancillary and 
post-trial care 
30 
Provisions, if any, for ancillary and post-trial care, and for 
compensation to those who suffer harm from trial 
participation 
Supplement 
Section 17 
Dissemination 
policy 
31a 
Plans for investigators and sponsor to communicate trial 
results to participants, healthcare professionals, the 
public, and other relevant groups (eg, via publication, 
reporting in results databases, or other data sharing 
arrangements), including any publication restrictions 
Supplement 
Section 3 
 
31b 
Authorship eligibility guidelines and any intended use of 
professional writers 
NA 
 
31c 
Plans, if any, for granting public access to the full 
protocol, participant-level dataset, and statistical code 
NA 
Appendices 
 
 
 
Informed consent 
materials 
32 
Model consent form and other related documentation 
given to participants and authorized surrogates 
Supplement 
Section 17 
Biological 
specimens 
33 
Plans for collection, laboratory evaluation, and storage of 
biological specimens for genetic or molecular analysis in 
the current trial and for future use in ancillary studies, if 
applicable 
NA 
*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 
Explanation & Elaboration for important clarification on the items. Amendments to the protocol 
should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the 
Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license. 
 
 
 

 
10 
3. Engagement of Patients, Families, and Community Members 
The RSI trial has engaged patients, families, and community members in every phase of the 
research.  Prior to beginning the research, community engagement studios with more than 75 
unique patient, family, community member, and clinician partners first identified the choice between 
ketamine and etomidate as a critical evidence gap and identified mortality as the most relevant and 
important short-term outcomes and symptoms of post-traumatic stress disorder (PTSD) as the most 
important non-mortality long-term outcome. 
Throughout the conduct 
of the RSI trial, engagement 
with patients, families, and 
community partners occurs at 
the four levels of engagement 
shown in the adjacent figure. 
Six Patient Co-investigators, 5 of whom are survivors of emergency tracheal intubation, 
serve on the Steering Committee for the RSI trial, contributing to each monthly meeting as equal 
partners with equal votes. In this role, they have applied their experience building community-
research partnerships to the design of pre-trial Community Consultation, their expertise in lay 
presentation of medical information to optimize the RSI trial’s patient-facing materials and website, 
and the acceptability to ICU survivors of the approach to informed consent and outcome 
assessment. At trial completion, the patient co-investigators will help write publications, design 
dissemination materials, and present the results of the trial to lay and medical audiences. 
A Stakeholder Advisory Council, composed of 15 patient and community stakeholders 
knowledgeable about critical illness and representative of the full diversity of their communities, 
helped design the trial protocol, and meets twice a year with investigators to monitor the impact of 
the trial on participants, review patient-facing materials, inform participant compensation, and 
identify opportunities to disseminate results through community organizations and health systems. 
 

 
11 
In a Community Engagement Studio, a unique panel of 8-12 patients, community 
members, or clinicians (selected for their firsthand knowledge of a particular condition) serve as paid 
experts during a 2-hour face-to-face session with researchers. During the RSI trial, three-yearly 
Community Engagement Studios focus on: Community Consultation; integration of the trial into 
clinical care, retention, and long-term outcome assessments; analysis plan development; and 
interpretation of results, dissemination, and implementation. 
Through Surveys and Town Halls, we have received input on the RSI trial from hundreds of 
patients, caregivers, clinicians, and community members. During pre-trial Community Consultation, 
we conducted in-person surveys with almost 800 patients and family members in ED and ICU 
waiting rooms to solicit input on the conduct of the RSI trial.  ICU survivors, caregivers, and 
community members in our town halls shared what outcomes they valued, how to make enrollment 
represent them, and how to communicate with patients about the trial. Through Facebook ads, we 
solicited input from >1.1 million community members on the trial design.  The full details of the 
Community Consultation and Public Disclosure processes for the RSI trial are publicly available 
through FDA Docket Number 95S-0158 in the Division of Dockets Management (HFA-305) 
(https://www.regulations.gov/document/FDA-1995-S-0036-0230).  The details of the Community 
Consultation and Public Disclosure processes and the feedback received from patients and 
community members for the RSI trial will be published separately. 
 
  
 
 
 
 
 
 

 
12 
4. Ethics and Informed Consent Processes    
4.1 Exception from Informed Consent Requirements for Emergency Research (EFIC) 
The RSI trial has been approved by the institutional review board at Vanderbilt University 
Medical Center (IRB number: 210500) and the US Food and Drug Administration (IND 141424). 
The RSI trial meets all the requirements to enroll patients under 21 CFR 50.24 for emergency 
research in which prospective informed consent is infeasible.1 These requirements include: 
1. Human subjects are in a life-threatening situation, available treatments are unproven or 
unsatisfactory 
2. Obtaining informed consent is not feasible 
3. Participation in the research holds out the prospect of direct benefit to the subjects 
4. The clinical investigation could not practicably be carried out without the waiver 
5. The investigator has committed to attempting to contact a legally authorized representative 
for each subject within that window of time and, if feasible, to asking the legally authorized 
representative contacted for consent within that window rather than proceeding without 
consent 
6. The IRB has reviewed and approved informed consent procedures and an informed consent 
document consistent with 50.25; and 
7. Additional protections of the rights and welfare of the subjects are provided.  
 
Additional protections of the rights and welfare of the subjects in the RSI trial include: 
• 
Completion of consultation with representatives of the communities in which the clinical 
investigation will be conducted and from which the subjects will be drawn (community 
consultation) 
• 
Completion of public disclosure to the communities in which the clinical investigation will be 
conducted and from which the subjects will be drawn, prior to initiation of the clinical 
investigation, of plans for the investigation and its risks and expected benefits 

 
13 
• 
A plan for public disclosure of sufficient information following completion of the clinical 
investigation to apprise the community and researchers of the study, including the 
demographic characteristics of the research population, and its results 
• 
Establishment of an independent data monitoring committee to exercise oversight of the 
clinical investigation; and 
• 
A plan, when feasible, to provide an opportunity for patients, LARs, or family members to 
object to the subject's participation in the clinical investigation when informed consent is not 
feasible;  
 
A summary of the pre-trial community consultation and public disclosure activities is publicly 
available through FDA Docket Number 95S-0158 in the Division of Dockets Management (HFA-305) 
(https://www.regulations.gov/document/FDA-1995-S-0036-0230). 
 
4.2 Informed Consent Processes in the RSI trial 
As required under 21 CFR 50.24,1 the RSI trial uses three approaches to informed consent, 
tailored to the capacity of the patient and the urgency of the intubation procedure.  
 
4.2.1 Written Informed Consent  
When a patient has decisional capacity or a legally authorized representative (LAR) is 
available and the clinical urgency of the procedure permits sufficient time for trial personnel to 
complete an informed consent process, written informed consent is obtained from the patient or 
LAR by trial personnel. The decisional capacity of the patient and the safety and feasibility of 
providing an opportunity for patients or LARs to complete an informed consent process is 
determined by treating clinicians.  

 
14 
4.2.2 Opportunity to Decline Participation 
The RSI trial provides two mechanisms for patients to decline participation.  First, medical 
alert bracelets have been made available prior to and throughout the trial for any community 
members who wishes to opt out of participation in the trial, should they become critically ill and 
require tracheal intubation.  
Second, when the clinical urgency of the intubation procedure precludes completion of a full 
informed consent process but permits a brief discussion of the research prior to the procedure, 
research personnel provide patients, LARs, or family members with an opportunity to express their 
objection to enrollment in the trial.  The decisional capacity of the patient and the safety and 
feasibility of providing an opportunity for patients, LARs, or family members to express their 
objection to research enrollment is determined by treating clinicians.  
 
4.2.3 Exception from Informed Consent  
Because most critically ill patients undergoing emergency tracheal intubation lack decisional 
capacity due to their critical illness, LARs and family members are frequently unavailable, and 
tracheal intubation is a time-sensitive procedure with only minutes between the decision to intubate 
and the completion of the procedure, most patients in the RSI trial are enrolled under EFIC.  When a 
patient is enrolled under EFIC, research personnel notify the patient, LAR, or a family member of 
the patient’s enrolment in the trial at the earliest feasible opportunity and provide an opportunity to 
discontinue participation in the trial.  
 
 
 
 

 
15 
5. Group Assignment Sheets with Nomogram (Ketamine) 
 

 
16 
6. Group Assignment Sheets with Nomogram (Etomidate) 
 
 
 

 
17 
7. Definitions of Free-Day Outcomes 
Ventilator-free days to day 28 (VFDs): VFDs are defined as the number of calendar days, between 
enrollment and 28 days after enrollment, on which the patient is alive and free of invasive 
mechanical ventilation. If a patient is liberated from invasive mechanical ventilation, returns to 
invasive mechanical ventilation and subsequently is liberated from invasive mechanical ventilation 
again prior to day 28, the number of VFDs will be counted from the end of the last period of invasive 
mechanical ventilation to day 28. If the patient is receiving invasive mechanical ventilation at day 28 
or dies prior to day 28, VFDs are 0. If a patient is discharged while receiving invasive mechanical 
ventilation, VFDs are 0. Outcome ascertainment ends at 28 days or hospital discharge, whichever 
occurs first. 
 
ICU-free days to day 28 (ICU-FDs): ICU-FDs are defined as the number of calendar days, between 
enrollment and 28 days after enrollment, on which the patient is alive and not admitted to an 
intensive care unit after the patient’s final transfer out of the intensive care unit. Patients who are 
never transferred out of the intensive care unit receive a value of 0. Patients who die before day 28 
receive a value of 0. For patients who are transferred out of the ICU, return to an ICU, and are 
subsequently transferred out of the ICU again prior to day 28, ICU-free days are counted from the 
date of final transfer out of the ICU. Outcome ascertainment ends at 28 days or hospital discharge, 
whichever occurs first. 
 
Vasopressor-free days to study day 28: Vasopressor-free days are defined as the number of 
calendar days, between enrollment and 28 days after enrollment, on which the patient is alive and 
not receiving vasopressors including days before the first receipt of vasopressors and after the last 
receipt of vasopressors. If a patient is weaned off vasopressors, returns to receiving vasopressors, 
and is subsequently weaned off vasopressors again, vasopressors free days will not include any 
days between the first and last receipt of vasopressors. If the patient is receiving vasopressors at 
day 28 or dies prior to day 28, vasopressor-free days are 0. If a patient is discharged while receiving 

 
18 
vasopressors (e.g., transfer to long-term acute care hospital), vasopressors-free days are 0. 
Outcome ascertainment ends at 28 days or hospital discharge, whichever occurs first. 

 
19 
8. Composition and Responsibilities of the Data Safety Monitoring Board 
 
The Data and Safety Monitoring Board (DSMB) consists of members with expertise in 
bioethics, emergency medicine, pulmonary and critical care medicine, anesthesia, biostatistics, and 
clinical trials.  One patient partner who is a survivor of critical illness requiring emergency tracheal 
intubation serves as a member of the DSMB.  All members of the DSMB are voting members. The 
DSMB developed a charter, approved the trial protocol, approved the patient notification forms, and 
approved the trial monitoring plan prior to trial initiation of enrollment. The DSMB has the ability at 
any point to recommend that the trial end, be modified, or continue unchanged. 
The principal role of the DSMB is to assure the safety of patients in the trial. The DSMB 
monitors data from the trial at semi-annual meetings, reviews and assesses the performance of its 
operations, and makes recommendations to the Steering Committee and Sponsor with respect to:   
• 
Review of adverse events  
• 
Interim results of the study for evidence of efficacy or adverse events  
• 
Possible early termination of the trial because of new external information, early attainment 
of study objectives, safety concerns, or inadequate performance  
• 
Possible modifications in the clinical trial protocol   
• 
Performance of individual centers   
 
 

 
20 
9. Details of Sample Size Calculation  
Initial Sample Size Estimate  
The initial version of the sample size estimate, included in version 1.0 of the trial protocol 
submitted on March 9, 2022, is described here.   
To estimate the expected incidence of in-hospital mortality in the etomidate group of the RSI 
trial, we used data from 656 adults undergoing tracheal intubation for non-traumatic critical illness 
who were recently enrolled from EDs and ICUs in two recent randomized trials.2,3 Among these 
patients, the incidence of 28-day in-hospital mortality was 31%. The minimum clinically important 
difference (MCID) in mortality used in the design of prior critical care RCTs was an absolute risk 
reduction of a median of 8 percent (IQR, 6-10).4 We powered the RSI trial to detect a more 
conservative absolute risk reduction of 6 percent. This equated to an incidence of the primary 
outcome of 25% in the ketamine group and a relative risk of mortality with ketamine compared to 
etomidate of 0.81 – comparable to the relative risk of 0.827 among adults with non-traumatic critical 
illness observed in the only prior RCT comparing ketamine vs etomidate.5 Achieving 80% statistical 
power at a two-sided alpha of 0.05 to detect a 6 percent absolute difference between groups in the 
primary outcome would require enrolling 911 patients per group (1,822 overall). Anticipating that, 
like prior Exception from Informed Consent Requirements for Emergency Research (EFIC) trials, 
less than 5% of patients would discontinue participation after enrollment, we planned to enroll a total 
of 1,900 patients. 
 
Final Sample Size Estimate 
The final version of the sample size estimate, included in the trial protocol on October 18, 
2023, at the time of funding of the multicenter stage of the RSI trial, is described here. 
At the time of funding of the multicenter stage of the RSI trial through a Patient-Centered 
Outcomes Research Institute® Award (BPS-2022C3-30021), the sample size was re-estimated 
using updated estimates of mortality and discontinuation of participation by patients. Based on two 
newly completed trials in the same settings,2,3 we updated our estimate for the incidence of all-

 
21 
cause, 28-day in-hospital mortality (primary outcome) in the etomidate group to 30%. The patient 
and clinician partners who participated in the development of the PCORI® application also 
recommended that, for two common and inexpensive interventions, the trial should have adequate 
statistical power to detect an absolute difference between groups in mortality of approximately 5 
percentage points.  We used the bsamsize R function to calculate that achieving 80% statistical 
power at a two-sided alpha of 0.05 to detect a difference in mortality of 5.2 percentage points 
(30.0% in the etomidate group vs 24.8% in the ketamine group) would require enrollment of 2,308 
patients. Anticipating that, like prior EFIC trials, less than 3% of participants would discontinue follow 
up before ascertainment of the primary outcome, we planned to enroll a total of 2,364 patients 
(1,182 per group). 
 
 

 
22 
10. Rationale for the Choice and Analysis of the Primary Outcome   
Patients, caregivers, and clinicians on our Steering Committee and in our town halls, 
Community Engagement Studios, and surveys consistently identified death as a relevant and 
important outcome of critical illness. Similarly, survival was a universally-recommended outcome in 
recent international surveys of patients,6–9 clinicians,10 and professional societies.11,12 The 1-month 
(28 day) timeframe was chosen because any effects of ketamine vs etomidate on the risk of death 
likely occur over days to weeks, and the risk of death from comorbidities or new health conditions 
unrelated to the initial critical illness increases over time. 
The choice to analyze mortality as a binary variable rather than a time-to-event analysis was 
based on input from patient stakeholders who reported that, for patients on a breathing machine, 
death after a prolonged period on a breathing machine did not represent a better outcome than 
dying sooner.13  This position is consistent with those expressed by patients and caregivers in prior 
studies.14–16   
 

 
23 
11. Effect Modification  
 
We will apply the three complementary approaches to analysis of heterogeneity of treatment 
effect described in the Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: 
(1) traditional one-variable-at-a-time subgroup analyses; (2) a risk-modeling approach; and (3) an 
effect-modeling approach. 
 
Subgroup Analyses. We will examine whether prespecified baseline variables modify the effect of 
trial group assignment 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, a 
random effect for trial site, and independent variables of trial group, the proposed effect modifier, 
and the interaction between the effect modifier and trial group.  For categorical variables, we will 
present the absolute difference 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,17 we have prespecified the following baseline 
variables as potential effect modifiers and hypothesized the direction of effect modification for each: 
1. Sepsis or septic shock (Yes vs No): We hypothesize that the presence of sepsis or septic 
shock at enrollment, assessed using the Third International Consensus Definitions for 
Sepsis and Septic Shock (Sepsis-3) definition,18  will modify the effect of trial group 
assignment on the primary outcome, with a greater decrease in 28-day in-hospital mortality 
in the ketamine group compared to the etomidate group among patients with sepsis or septic 
shock, compared to patients without sepsis or septic shock. This hypothesis is supported by 
inconsistent evidence from prior clinical trials and observational studies suggesting that 
etomidate-induced decreases in cortisol production may have a larger detrimental effect on 
outcomes for patients with sepsis or septic shock.19–26  
2. Vasopressor receipt (Yes vs No): We hypothesize that receipt of vasopressors in the hour 
prior to enrollment will modify the effect of trial group assignment on the primary outcome, 

 
24 
with a greater decrease in 28-day in-hospital mortality in the ketamine group compared to 
the etomidate group among patients receiving vasopressors, compared to patients not 
receiving vasopressors. This hypothesis is supported by secondary outcomes of prior 
randomized trials and observational studies that suggest etomidate may worsen shock 
through causing adrenal insufficiency.26 
3. Patient location (ED vs ICU): We hypothesize that patient location at enrollment will not 
modify the effect of trial group assignment on the primary outcome.  
4. Adrenal insufficiency or chronic receipt of corticosteroids (Yes vs No): We hypothesize that a 
pre-existing diagnosis of adrenal insufficiency or chronic receipt of corticosteroids prior to 
enrollment will modify the effect of trial group assignment on the primary outcome, with a 
greater decrease in 28-day in-hospital mortality in the ketamine group compared the 
etomidate group among patients with adrenal insufficiency or chronic receipt of 
corticosteroids, compared to patients without adrenal insufficiency or chronic receipt of 
corticosteroids. This hypothesis is supported by mechanistic information on the effect of 
etomidate on synthesis of cortisol by the adrenal glands.27  In prior observational and 
interventional studies, the administration of corticosteroids during the acute illness has not 
appeared to affect the association between receipt of etomidate and death.19,28 
5. Acute neurologic condition (Yes vs. No).  We hypothesize that the presence at the time of 
enrollment of an acute neurologic condition associated with an increased risk for elevated 
intracranial pressure, defined as intracranial bleeding, meningitis or encephalitis, or stroke, 
will modify the effect of trial group assignment on the primary outcome, with a lesser 
decrease in 28-day in-hospital mortality in the ketamine group compared to the etomidate 
group among patients with an acute neurologic condition, compared to patients without an 
acute neurologic condition. This hypothesis is supported by inconsistent evidence that 
ketamine may increase intracranial pressure in some patients.29  
6. Active cardiac condition (Yes vs. No).  We hypothesize that the presence at the time of 
enrollment of an active cardiac condition, defined as cardiac arrest, cardiogenic shock, 
congestive heart failure, cardiogenic pulmonary edema, pulmonary hypertension, or 

 
25 
myocardial infarction, will modify the effect of trial group assignment on the primary outcome, 
with a lesser decrease in 28-day in-hospital mortality in the ketamine group compared to the 
etomidate group among patients with an active cardiac condition, compared to patients 
without an active cardiac condition. This hypothesis is supported by inconsistent pre-clinical 
evidence that ketamine may exert a negative ionotropic effect.30,31 
7. Baseline risk of the primary outcome (continuous):  We hypothesize that increased risk of 
death (increased severity of illness), will modify the effect of trial group assignment on the 
primary outcome, with a greater decrease in 28-day in-hospital mortality in the ketamine 
group compared the etomidate group among patients at higher risk of death. This hypothesis 
is supported by prior research suggesting that patients in critical care trials at higher risk of 
an outcome frequently experience a larger absolute treatment effect.32 
 
Risk-modeling approach.  We will examine whether patients’ baseline risk of the primary outcome 
modifies the effect of trial group assignment 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, a random effect for trial site, and independent variables of trial group, patients’ baseline 
risk of the primary outcome, and the interaction between baseline risk of the primary outcome and 
trial group.  Patients’ baseline risk of the primary outcome will be defined using two approaches.  
First, a previously derived and validated multivariable model that uses patient characteristics at the 
time of intubation to predict the probability of 28-day in-hospital mortality for critically ill adults will be 
used to generate a predicted probability of the primary outcome (ranging from 0.0 to 1.0) for each 
patient in the trial.  Second, each patient’s value at enrolment for the APACHE II score will be used 
as a measure of the baseline risk.33 
 
Effect-modeling approach.  The goal of our effect-modeling analyses is to estimate the effect of 
ketamine vs etomidate on 28-day in-hospital mortality for an individual patient based on his or her 
baseline characteristics considered simultaneously (“individualized treatment effect”).34–36  First, in a 
derivation cohort of the initial 1,700 patients enrolled in the trial, we will compare the performance of 

 
26 
candidate effect models using 5-fold cross-validation. Specifically, we will consider X-learners with 
elastic net and random forest base-learners, S-learners with random forest and conditional random 
forest (cforest) base-learners, T-learner with Bayesian Adaptive Regression Trees (BART) as the 
base-learner, R-learner with Extreme Gradient Boosting (Xgboost) as the base-learner, and causal 
forest. The algorithm and base-learner combination resulting in the highest qini coefficient in the out-
of-sample predictions from the 5-fold cross-validation will then be fit using all the derivation data to 
create a final effect model.   
Second, in a validation cohort of the final 664 patients enrolled in the trial, we will validate 
the performance of the individualized treatment effect model.  To do this, we will use the model to 
predict the effect of ketamine vs etomidate on 28-day in-hospital mortality for each of the 664 
patients in the validation cohort (the patient’s predicted individualized treatment effect at the time of 
enrolment). We will compare the treatment effect predicted by the model to the treatment effect 
observed in the validation cohort using the qini coefficient,37 the C statistic for benefit,38 and 
measures of clinical utility, in alignment with the PATH guidelines (examining characteristics by 
quantile of predicted benefit).  The effect-modeling analyses may be presented separately from the 
other trial results if the time required to conduct them or the space required to present them requires 
doing so. 
 
 

 
27 
12. Safety Monitoring and Adverse Events 
 
Ensuring patient safety is an essential component of the RSI trial. Both ketamine and etomidate 
have been approved by the Food and Drug Administration and used in clinical practice for decades 
with an established safety profile.39,40 However, any trial conducted during a high-risk, time-sensitive 
procedure like tracheal intubation of critically ill patients raises unique safety considerations. This 
RSI trial addresses these considerations through:  
1. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse 
events from ketamine or etomidate;  
2. Systematic collection of safety outcomes relevant to use of ketamine and etomidate in this 
setting;  
3. Structured reporting of adverse events. 
 
 

 
28 
13. Plan for Communication of Protocol Changes  
Any changes to the trial protocol, including changes to eligibility, outcomes, and analyses, 
will be implemented via a new version of the full trial protocol, tracked with the date of the update, 
and the version number of the trial protocol. A list summarizing the changes made with each 
protocol revision will be included at the end of each protocol. The updated protocol will be sent to 
the sIRB for approval and tracking prior to implementation of the protocol change. At the time of 
publication, the original trial protocol and the final trial protocol, including the summary of changes 
made with each protocol version, will be included in the supplementary material for publication. 
 
 

 
29 
14. Patient Privacy, Data Storage, and Sharing 
 
Federal regulations 45 CFR 46 111 (a) (7) requires that, when appropriate, there are 
adequate provisions to protect the privacy of patients and to maintain the confidentiality of data. 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. All data collected 
for this study will be entered into a secure online database. Tools within the secure online database 
will be used so that only the coordinating center and investigators from the enrolling site will have 
access to data from patients enrolled at that site. All data will be maintained in the secure online 
database until the time of study publication. At the time of publication, a de-identified version of the 
database will be generated. Deidentified data will be available for sharing following trial publication 
with the requirements and terms of data sharing specified in the trial results manuscript. 
 
 
 
 
 
 
 
 

 
30 
15. Trial Status 
The RSI trial is a pragmatic, multi-center, non-blinded randomized clinical trial comparing the 
use of ketamine vs the use of etomidate for induction of anesthesia during emergency tracheal 
intubation of critically ill adults. Enrollment began on April 6, 2022, and is expected to conclude in 
2025. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
31 
16. Supplementary Tables 
 
Supplementary Table 1. Example of the table of baseline characteristics for the results 
manuscript. 
 
Table 1. Characteristics of the Patients at Baseline 
Characteristic 
Ketamine 
(N=xxx) 
Etomidate 
(N=xxx) 
Age, years – median (IQR)* 
 
 
Female sex – no. (%) 
 
 
Race or ethnic group – no. (%) ** 
 
 
Non-Hispanic White 
 
 
Non-Hispanic Black 
 
 
Hispanic 
 
 
Other 
 
 
Not reported 
 
 
Weight, kg – median (IQR) 
 
 
Body mass index – median (IQR) *** 
 
 
Location of intubation – no. (%) 
 
 
Emergency department 
 
 
Intensive care unit 
 
 
Chronic conditions – no. (%) 
 
 
Adrenal insufficiency or chronic receipt of corticosteroids 
 
 
Cirrhosis 
 
 
Congestive heart failure 
 
 
Coronary artery disease 
 
 
Hypertension 
 
 
Malignancy **** 
 
 
Acute conditions – no. (%) ***** 
 
 
Acute cardiac condition ****** 
 
 
Acute respiratory failure 
 
 
Acute neurologic condition ******* 
 
 
Sepsis or septic shock 
 
 
Glasgow Coma Scale score – median (IQR) 
 
 
APACHE II score – median (IQR) ******** 
 
 
Measurement or treatment within the hour before enrollment 
 
 
Highest heart rate, bpm – median (IQR) 
 
 
Lowest systolic blood pressure, mm Hg – median (IQR)  
 
 
Vasopressor receipt – no. (%) 
 
 
* IQR denotes interquartile range. 
* Race and ethnicity were reported by patients or their surrogates as part of clinical care and 
collected from the electronic medical record by research personnel using fixed categories.  
*** Body-mass index is computed by the weight in kilograms divided by the square of the height in 
meters. 
**** Malignancy is defined as pulmonary/pleural malignancy, active liquid (leukemia or lymphoma), 
or malignancy solid non-pulmonary. 
***** Data on acute conditions were abstracted from the electronic health record and grouped into 
prespecified categories. Patients could have had more than one active condition. 

 
32 
****** Acute cardiac condition is defined as cardiac arrest, cardiogenic shock, congestive heart 
failure, cardiogenic pulmonary edema, pulmonary hypertension, or myocardial infarction present at 
the time of enrolment. 
******* Acute neurologic condition is defined as intracranial bleeding, meningitis or encephalitis, or 
stroke present at the time of enrolment. 
******** Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II range from 0 to 
71, with higher scores indicating a greater severity of illness. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
33 
Supplementary Table 2. Example of the table of characteristics of the intubation procedure 
for the results manuscript.  
 
Table 2. Characteristics of the Intubation Procedure 
Characteristic 
Ketamine 
(N=xxx) 
Etomidate 
(N=xxx) 
Difference 
(95% CI) 
Sedative – no. (%) 
 
 
 
Ketamine 
 
 
 
Etomidate 
 
 
 
Other 
 
 
 
None 
 
 
 
Neuromuscular blocking agent – no. (%) 
 
 
 
Rocuronium 
 
 
 
Succinylcholine 
 
 
 
None 
 
 
 
Measurements or treatments at induction of 
anesthesia 
 
 
 
Oxygen saturation – median (IQR) 
 
 
 
Preoxygenation – no. (%) 
 
 
 
Systolic blood pressure, mm Hg – 
median (IQR) 
 
 
 
Vasopressor bolus or increase – no. 
(%) 
 
 
 
Laryngoscope – no. (%) 
 
 
 
Video 
 
 
 
Direct 
 
 
 
Instrument used on the first attempt — no. (%) 
 
 
 
Endotracheal tube with stylet 
 
 
 
Bougie 
 
 
 
 
 
 

 
34 
Supplementary Table 3. Example of the table of outcomes for the results manuscript.  
 
Outcome 
Ketamine 
(N=xxx) 
Etomidate 
(N=xxx) 
Difference 
(95% CI) 
Primary outcome 
 
 
 
All-cause, 28-day in-hospital mortality – no./total no. (%) 
 
 
 
Secondary outcome 
 
 
 
Cardiovascular collapse between induction and 2 minutes after 
intubation – no./total no. (%) 
 
 
 
Systolic blood pressure < 65 mmHg  
 
 
 
New or increased vasopressor receipt 
 
 
 
Cardiac arrest not resulting in death within 1 hour of 
induction 
 
 
 
Cardiac arrest resulting in death within 1 hour of 
induction 
 
 
 
Procedural outcomes  
 
 
 
Successful intubation on the first attempt – no./total no. (%) 
 
 
 
Median time from induction to intubation (IQR) – seconds  
 
 
 
Lowest oxygen saturation, % – median (IQR) 
 
 
 
Lowest oxygen saturation <80% – no./total no. (%) 
 
 
 
Systolic blood pressure > 180 mm Hg – no./total no. (%) 
 
 
 
Safety outcomes 
 
 
 
Systolic blood pressure at 24 hours, mm Hg – median (IQR) 
 
 
 
Receipt of vasopressors at 24 hours – no./total no. (%) 
 
 
 
Cardiac arrest between induction of anesthesia and hospital 
discharge – no./total no. (%) 
 
 
 
Clinical outcomes* 
 
 
 
Ventilator-free days – median (IQR) 
 
 
 
Vasopressor-free days – median (IQR) 
 
 
 
ICU-free days – median – median (IQR)  
 
 
 
 
 

 
35 
17. Appendices 
B. Example Informed Consent Document. 
An example of the informed consent document used by trial personnel to obtain prospective, written 
informed consent for participation in the RSI trial in instances when a patient or Legally Authorized 
Representative is able to provide informed consent is shown below. 
 
[image redacted for anonymized peer review]  
 
 

 
36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
37 
B. Example Notification Document. 
For patients for whom neither the patient nor a Legally Authorized Representative were able to 
provide prospective, written informed consent for participation in the RSI trial prior to enrolment, an 
example of the notification document used to inform the participant or a Legally Authorized 
Representative of family member of the patient’s enrolment in the trial is shown below. 
 
[image redacted for anonymized peer review] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18. References 
1. FDA Exception from Informed Consent Requirements for Emergency Research (EFIC) 
Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors. Date accessed: 
01/03/2025. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/exception-informed-consent-requirements-emergency-research 

 
38 
2. Gibbs KW, Semler MW, Driver BE, et al. Noninvasive Ventilation for Preoxygenation during 
Emergency Intubation. N Engl J Med. 2024;390(23):2165-2177. doi:10.1056/NEJMoa2313680 
3. Prekker ME, Driver BE, Trent SA, et al. Video versus Direct Laryngoscopy for Tracheal 
Intubation of Critically Ill Adults. N Engl J Med. 2023;389(5):418-429. 
doi:10.1056/NEJMoa2301601 
4. Yarnell CJ, Abrams D, Baldwin MR, et al. Clinical trials in critical care: can a Bayesian approach 
enhance clinical and scientific decision making? Lancet Respir Med. Published online 
November 20, 2020. doi:10.1016/S2213-2600(20)30471-9 
5. Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence 
intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet Lond Engl. 
2009;374(9686):293-300. doi:10.1016/S0140-6736(09)60949-1 
6. Dinglas VD, Chessare CM, Davis WE, et al. Perspectives of survivors, families and researchers 
on key outcomes for research in acute respiratory failure. Thorax. 2018;73(1):7-12. 
doi:10.1136/thoraxjnl-2017-210234 
7. Turnbull AE, Sepulveda KA, Dinglas VD, Chessare CM, Bingham CO, Needham DM. Core 
Domains for Clinical Research in Acute Respiratory Failure Survivors: An International Modified 
Delphi Consensus Study. Crit Care Med. 2017;45(6):1001-1010. 
doi:10.1097/CCM.0000000000002435 
8. Needham DM, Sepulveda KA, Dinglas VD, et al. Core Outcome Measures for Clinical Research 
in Acute Respiratory Failure Survivors. An International Modified Delphi Consensus Study. Am J 
Respir Crit Care Med. 2017;196(9):1122-1130. doi:10.1164/rccm.201702-0372OC 
9. Dinglas VD, Faraone LN, Needham DM. Understanding patient-important outcomes after critical 
illness: a synthesis of recent qualitative, empirical, and consensus-related studies. Curr Opin 
Crit Care. 2018;24(5):401-409. doi:10.1097/MCC.0000000000000533 
10. Hodgson CL, Turnbull AE, Iwashyna TJ, et al. Core Domains in Evaluating Patient Outcomes 
After Acute Respiratory Failure: International Multidisciplinary Clinician Consultation. Phys Ther. 
2017;97(2):168-174. doi:10.2522/ptj.20160196 
11. Mikkelsen ME, Still M, Anderson BJ, et al. Society of Critical Care Medicine’s International 
Consensus Conference on Prediction and Identification of Long-Term Impairments After Critical 
Illness. Crit Care Med. 2020;48(11):1670-1679. doi:10.1097/CCM.0000000000004586 
12. Spruit MA, Holland AE, Singh SJ, Tonia T, Wilson KC, Troosters T. COVID-19: Interim 
Guidance on Rehabilitation in the Hospital and Post-Hospital Phase from a European 
Respiratory Society and American Thoracic Society-coordinated International Task Force. Eur 
Respir J. Published online August 13, 2020:2002197. doi:10.1183/13993003.02197-2020 
13. Rubin EB, Buehler A, Halpern SD. Seriously Ill Patients’ Willingness to Trade Survival Time to 
Avoid High Treatment Intensity at the End of Life. JAMA Intern Med. 2020;180(6):907-909. 
doi:10.1001/jamainternmed.2020.0681 
14. Rubin EB, Buehler AE, Halpern SD. States Worse Than Death Among Hospitalized Patients 
With Serious Illnesses. JAMA Intern Med. 2016;176(10):1557-1559. 
doi:10.1001/jamainternmed.2016.4362 

 
39 
15. Auriemma CL, Harhay MO, Haines KJ, Barg FK, Halpern SD, Lyon SM. What Matters to 
Patients and Their Families During and After Critical Illness: A Qualitative Study. Am J Crit Care 
Off Publ Am Assoc Crit-Care Nurses. 2021;30(1):11-20. doi:10.4037/ajcc2021398 
16. Halpern SD, Temel JS, Courtright KR. Dealing With Death as an Outcome in Supportive Care 
Clinical Trials. JAMA Intern Med. 2021;181(7):895-896. doi:10.1001/jamainternmed.2021.1816 
17. Schandelmaier S, Briel M, Varadhan R, et al. Development of the Instrument to assess the 
Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-
analyses. CMAJ Can Med Assoc J J Assoc Medicale Can. 2020;192(32):E901-E906. 
doi:10.1503/cmaj.200077 
18. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions 
for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. 
doi:10.1001/jama.2016.0287 
19. Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal 
responsiveness and mortality in patients with septic shock. Intensive Care Med. 
2009;35(11):1868-1876. doi:10.1007/s00134-009-1603-4 
20. Lipiner-Friedman D, Sprung CL, Laterre PF, et al. Adrenal function in sepsis: The retrospective 
Corticus cohort study: Crit Care Med. 2007;35(4):1012-1018. 
doi:10.1097/01.CCM.0000259465.92018.6E 
21. Tsai MH, Peng YS, Chen YC, et al. Adrenal insufficiency in patients with cirrhosis, severe 
sepsis and septic shock. Hepatol Baltim Md. 2006;43(4):673-681. doi:10.1002/hep.21101 
22. Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence 
intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet Lond Engl. 
2009;374(9686):293-300. doi:10.1016/S0140-6736(09)60949-1 
23. Mohammad Z, Afessa B, Finkielman JD. The incidence of relative adrenal insufficiency in 
patients with septic shock after the administration of etomidate. Crit Care Lond Engl. 
2006;10(4):R105. doi:10.1186/cc4979 
24. Albert SG, Ariyan S, Rather A. The effect of etomidate on adrenal function in critical illness: a 
systematic review. Intensive Care Med. 2011;37(6):901-910. doi:10.1007/s00134-011-2160-1 
25. Abani O, Abbas A, Abbas F, et al. Tocilizumab in patients admitted to hospital with COVID-19 
(RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet. 
2021;397(10285):1637-1645. doi:10.1016/S0140-6736(21)00676-0 
26. Srivilaithon W, Bumrungphanithaworn A, Daorattanachai K, et al. Clinical outcomes after a 
single induction dose of etomidate versus ketamine for emergency department sepsis 
intubation: a randomized controlled trial. Sci Rep. 2023;13(1):6362. doi:10.1038/s41598-023-
33679-x 
27. de Jong FH, Mallios C, Jansen C, Scheck PA, Lamberts SW. Etomidate suppresses 
adrenocortical function by inhibition of 11 beta-hydroxylation. J Clin Endocrinol Metab. 
1984;59(6):1143-1147. doi:10.1210/jcem-59-6-1143 
28. Wunsch H, Bosch NA, Law AC, et al. Evaluation of Etomidate Use and Association with 
Mortality Compared with Ketamine Among Critically Ill Patients. Am J Respir Crit Care Med. 
Published online August 22, 2024. doi:10.1164/rccm.202404-0813OC 

 
40 
29. Kolenda H, Gremmelt A, Rading S, Braun U, Markakis E. Ketamine for analgosedative therapy 
in intensive care treatment of head-injured patients. Acta Neurochir (Wien). 1996;138(10):1193-
1199. doi:10.1007/BF01809750 
30. Sprung J, Schuetz SM, Stewart RW, Moravec CS. Effects of ketamine on the contractility of 
failing and nonfailing human heart muscles in vitro. Anesthesiology. 1998;88(5):1202-1210. 
doi:10.1097/00000542-199805000-00010 
31. Kongsayreepong S, Cook DJ, Housmans PR. Mechanism of the direct, negative inotropic effect 
of ketamine in isolated ferret and frog ventricular myocardium. Anesthesiology. 1993;79(2):313-
322. doi:10.1097/00000542-199308000-00017 
32. Iwashyna TJ, Burke JF, Sussman JB, Prescott HC, Hayward RA, Angus DC. Implications of 
Heterogeneity of Treatment Effect for Reporting and Analysis of Randomized Trials in Critical 
Care. Am J Respir Crit Care Med. 2015;192(9):1045-1051. doi:10.1164/rccm.201411-2125CP 
33. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease 
classification system. Crit Care Med. 1985;13(10):818-829. 
34. Kent DM, van Klaveren D, Paulus JK, et al. The Predictive Approaches to Treatment effect 
Heterogeneity (PATH) Statement: Explanation and Elaboration. Ann Intern Med. 
2020;172(1):W1-W25. doi:10.7326/M18-3668 
35. Seitz KP, Spicer AB, Casey JD, et al. Individualized Treatment Effects of Bougie vs Stylet for 
Tracheal Intubation in Critical Illness. Am J Respir Crit Care Med. Published online March 6, 
2023. doi:10.1164/rccm.202209-1799OC 
36. Buell KG, Spicer AB, Casey JD, et al. Individualized Treatment Effects of Oxygen Targets in 
Mechanically Ventilated Critically Ill Adults. JAMA. 2024;331(14):1195-1204. 
doi:10.1001/jama.2024.2933 
37. Belbahri M, Murua A, Gandouet O, Nia VP. Uplift Regression: The R Package tools4uplift. :22. 
38. van Klaveren D, Steyerberg EW, Serruys PW, Kent DM. The proposed “concordance-statistic 
for benefit” provided a useful metric when modeling heterogeneous treatment effects. J Clin 
Epidemiol. 2018;94:59-68. doi:10.1016/j.jclinepi.2017.10.021 
39. FDA Ketamine. Date Accessed: 11/12/2024. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016812s040lbl.pdf 
40. FDA Etomidate. Date Accessed: 11/12/2024. November 12, 2024. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018227s032lbl.pdf 
 

Randomized Trial of Sedative Choice for Intubation  
Statistical Analysis Plan Revision Sequence 
 
 
January 18, 2025: Statistical Analysis Plan posted on preprint server 
 
February 7, 2025: Statistical Analysis Plan submitted for publication  
 
April 22, 2025: Statistical Analysis Plan accepted for publication  
 
May 21, 2025: Statistical Analysis Plan* published 
 
August 10, 2025: 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