Protocolized Post-Extubation Respiratory Support (PROPER) Study
Phase: NA
Conditions: Mechanical Ventilation Complication, Acute Respiratory Failure, Intubation Complication
Sponsor: Vanderbilt University Medical Center

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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Protocolized Post-Extubation Respiratory Support 
(PROPER) Study 
 
Version 1.3 
 
 
 
Principal Investigator 
Jonathan D. Casey, MD 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
Faculty Mentors 
Matthew W. Semler, MD, MSc 
& 
Todd W. Rice, MD, MSc 
Department of Medicine 
Division of Allergy, Pulmonary, and Critical Care Medicine 
Vanderbilt University School of Medicine 
 
 
 
 
 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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Table of Contents: 
 
Study Schema 
1.0 
Study Summary 
2.0 
Background 
3.0 
Rationale, Aims, and Hypotheses 
4.0 
Study Description 
5.0 
Inclusion/Exclusion Criteria 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Risks and Benefits 
9.0 
Adverse Events 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Privacy/Confidentiality Issues 
13.0 
Follow-up and Record Retention 
14.0 
References 
 
 
 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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1.0 
Study Summary 
 
Title:  
 
Background:   
Invasive mechanical ventilation is common in the ICU. Approximately 25% of 
patients in the Vanderbilt MICU require invasive ventilation at some point during their 
hospitalization.   Protocols for low tidal volume ventilation, daily spontaneous 
awakening trials, and daily spontaneous breathing trials have significantly shortened the 
duration of mechanical ventilation and improved patient outcomes.  Despite these 
improvements, the period of time following extubation remains high risk.  Around 25% 
of patients develop recurrent respiratory failure after extubation and up to 15% require 
reintubation.  Reintubation is an independent predictor of increased mortality.   
Post-extubation respiratory support with non-invasive ventilation or high flow 
nasal cannula appears to reduce the reintubation rate, but utilization remains low.  
Whether implementation of a protocol identifying patients who may benefit from post-
extubation respiratory support and coordinating with respiratory therapists to deliver 
respiratory support as part of routine protocolized care without a specific physician 
order decreases reintubation rates remain unknown.  To determine the effect on 
reintubation rate of a protocol for post-extubation respiratory support, we propose a 
three phase study: an initial period of observation of current practices; an intervention 
period comparing protocolized post-extubation respiratory support with usual care; and 
(if protocolized post-extubation respiratory support decreases the rate of reintubation) 
a dissemination period during which the protocol will be extended to all patients and 
post-intervention practices and outcomes will be observed.  
 
Primary Aim: 
• To compare the effect of protocolized post-extubation respiratory support, 
versus usual care, on the rate of reintubation within 96 hours (4 days) of 
extubation. 
 
Primary Hypotheses: 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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• Protocolized post-extubation respiratory support will decrease the reintubation 
rate experienced by adults undergoing extubation in the Vanderbilt MICU. 
 
Inclusion Criteria: 
1. Patient is located in Vanderbilt MICU 
2. Patient undergoing extubation from mechanical ventilation  
3. Patient has been receiving mechanical ventilation for at least 12 hours 
4. Age ≥ 18 years old 
 
Exclusion Criteria:  
1. Patient is receiving ventilation via a tracheostomy 
2. Patient is being extubated to comfort measures or has “Do Not Re-intubate” 
order in place at the time of extubation 
3. Patient has required reintubation after a prior attempt at extubation during this 
hospitalization 
4. Unplanned or self-extubation, where immediate reintubation is deemed 
necessary by the clinical team 
 
Consent: Given that (1) all therapies in the protocolized post-extubation respiratory 
support group and usual care group are part of current routine medical care for patients 
undergoing extubation in the Vanderbilt MICU, (2) lack of established risk or benefit of a 
post-extubation respiratory support protocol, (3) provisions allowing treating clinicians 
to employ non-invasive ventilation, high-flow nasal cannula, or any other form of 
respiratory support (regardless of group assignment) when felt to be needed for the 
safe treatment of any specific patient, and (4) the impracticability of obtaining informed 
consent for the implementation of a protocol to all patients cared for by a single 
respiratory therapist, waiver of informed consent will be requested. 
 
Group Assignment:  Patients’ treatment group will be determined by room number, 
with the MICU divided into two clusters, based on geography (front hall and back hall).  
Geographical group assignment is designed to align with the rooms covered by each of 
the two respiratory therapists who staff the unit. Based on MICU admitting protocols, 
patients are arbitrarily assigned to the first available room with no intentional 
movement/placement of patients by severity of illness, amount of nursing needs, or 
other clinical factors.   To control for any potential bias created by geographic 
assignment of the study intervention, the groups will undergo five cross-overs so that 
each bed will spend half of the study in the protocolized post-extubation respiratory 
support group and half in the usual care group. 
 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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Study Interventions: 
• Protocolized post-extubation respiratory support – At the time of extubation, 
all qualifying patients will be initiated on either non-invasive ventilation or high 
flow nasal cannula, which will be continued until the earlier of 5AM the following 
day or ICU transfer.  
• Usual Care – The decision for post-extubation respiratory support will be left to 
the patient’s clinical team.  
 
Primary Endpoint:   
• Reintubation within 96 hours (4 days)  
 
Secondary Endpoints: 
1. All cause in-hospital mortality 
2. ICU-free days 
3. Ventilator-free days 
4. Time to reintubation 
5. Indication for reintubation  
6. Respiratory-caused reintubation 
7. Laryngeal edema requiring reintubation 
8. Delirium within 96 hours of extubation 
9. Agitation within 96 hours of extubation 
10. Lowest S/F ratio at 0-6, 6-12, and 12-24 hours post-extubation 
11. Highest respiratory rate at 0-6, 6-12 and 12-24 hours  
12. Use of HFNC or NIV beyond 24 hours post-extubation 
 
 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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2.0 
Background 
 
Invasive mechanical ventilation is common in the ICU. Approximately, 25% of 
Vanderbilt MICU patients require invasive mechanical intubation at least once during 
their hospitalization.  Protocols for low tidal volume ventilation, daily spontaneous 
awakening trials, and daily spontaneous breathing trials have significantly shortened the 
duration of mechanical ventilation and improved outcomes for these patients.  Despite 
these improvements, the period of time following extubation remains high risk.  Around 
25% of patients experience post-extubation respiratory failure and 11 to 15% of patients 
require reintubation after their first extubation.1–3  In patients identified to be at high 
risk, reintubation rates may be as high as 28%.2,4  Reintubation is associated with 
increased rates of nosocomial infection5 and is an independent predictor of mortality, 
with a relative risk ranging from 3.29-5.34 and an absolute mortality ranging from 19- 
50%.3,6,7  Despite significant improvements in the management of patients receiving 
invasive mechanical ventilation, the rate of reintubation has not changed significantly in 
the last 20 years.8–10 
Based on unadjusted, retrospective data from our ICU, reintubation is associated 
with a relative risk of in-hospital mortality of 4.5 (absolute rate of mortality of 28.8%, 
compared to 6.0%).  The prevention of complications following extubation is a key focus 
of critical care research and quality improvement.1–3,11,12  The only therapy to date 
shown to reduce the rate of reintubation is post-extubation respiratory support with 
either non-invasive ventilation or high flow nasal cannula.  Use of these therapies in 
usual care, however, remains low. 
 
2.1 Prophylactic non-invasive ventilation (NIV) following extubation 
NIV prevents intubation and decreases mortality in patients with respiratory failure 
from COPD.13,14 It also improves the safety of the intubation process.15 In patients who 
experience recurrent respiratory failure after extubation, however, the data have been 
disappointing, with evidence that post-extubation “rescue” NIV (applied when a patient 
develops respiratory failure hours or days after extubation) delays the time to 
reintubation and is associated with an increase in ICU-mortality.11,16  More recent trials 
have explored the use of prophylactic NIV (started at the time of extubation and 
continued for a predetermined period of time).  Two trials of 97 and 162 patients at high 
risk of reintubation, showed that prophylactic NIV for a period of 24 to 48 hours after 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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extubation decreased the rate of post-extubation respiratory failure and the rate of 
reintubation.4,17  A subsequent trial of patients who were hypercarbic on their pre-
extubation spontaneous breathing trial showed that 24 hours of prophylactic NIV 
decreased 90 day mortality from 31% to 11%.18  National guidelines for management 
following extubation were recently updated to include a recommendation for NIV in 
patients at high risk of reintubation.19 
 
2.2 Prophylactic high flow nasal cannula (HFNC) following extubation 
 
HFNC is an apparatus that delivers flow rates up to 60 liters per minute with a 
consistent percent of oxygen that can be finely titrated up to an FIO2 of 1.0.  HFNC has 
been shown to provide patients with a low level of continuous positive airway pressure, 
with dead space washout, decreasing the work of breathing while also improving 
patient comfort and secretion management.20–24  HFNC has been suggested to improve 
mortality in patients with hypoxemic respiratory failure.13  Prophylactic HFNC for 24 to 
48 hours after extubation in non-hypercapneic patients has been demonstrated to 
prevent reintubation in high risk patients, low risk patients, and a general population of 
ICU patients.12,25,26 
 
2.3 Current Utilization of Post-extubation Respiratory Support at Vanderbilt MICU 
 
Prophylactic NIV and HFNC have been shown to improve outcomes following 
extubation in numerous patient populations.  When taken together, these studies 
suggest that all patients might benefit from some form of post-extubation respiratory 
support (NIV or HFNC) – and post-extubation respiratory support has been 
recommended in national guidelines19.  Despite this, the utilization of any form of post-
extubation respiratory support remains low in the Vanderbilt Medical Intensive Care 
Unit. Review of 12 months of data from the Vanderbilt MICU, obtained from a 
prospective trial enrolling a similar patient population, showed that post-extubation 
respiratory support is provided in only 8.3% of extubations.  Several reasons may explain 
the low rate of post-extubation respiratory support provided in the Vanderbilt MICU. 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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First, the existing studies on post-extubation respiratory support were all 
performed in Europe, where practice patterns and patient populations differ 
dramatically from ICUs in the United States. These differences are highlighted by the 
reintubation rates, which in European ICUs have been reported to be 14.4% for “low 
risk” patients25 and 19.1% for “high risk” patients,26 compared to a reintubation rate of 
just 12.1% for all patients in the Vanderbilt MICU.  Second, evidence-based 
recommendations may take as long as 17 years to translate into routine clinical 
practice27.  The majority of trials examining NIV and HFNC after extubation have been 
published in the last 5 years, and these results may not yet have diffused into practice.  
Third, provision of post-extubation respiratory support requires coordination between 
the physicians, nurses, and respiratory therapists.  The results of studies of spontaneous 
awakening and breathing trials suggest that this coordination may be inefficient or 
incomplete in routine care and can be aided by implementation of a structured 
protocol28. 
Implementation of a respiratory therapist driven protocol to provide post-
extubation respiratory support to all patients undergoing extubation in the ICU has the 
potential to improve utilization of recommended respiratory support and decrease the 
rate of reintubation, but currently (1) no validated protocols exist and (2) the effect of 
such a protocol on reintubation in our patient population is unknown. 
We propose a three-phase study: an initial period of observation of current 
practices, an intervention period comparing a respiratory therapist driven protocol for 
post-extubation respiratory support with usual care, and (if protocolized post-
extubation respiratory support decreases the rate of reintubation) a dissemination 
period during which the protocol will be extended to all patients and post-intervention 
practices and outcomes will be observed. 
 
3.0 
Rationale, Aims, and Hypotheses 
 
To determine whether protocolized post-extubation respiratory support (high 
flow nasal cannula or non-invasive ventilation) prevents reintubation compared to usual 
care, a comparative-effectiveness study is needed. 
 
Study Aims: 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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• Primary 
o To evaluate the effect of respiratory therapy driven protocolized post-
extubation respiratory support, compared with usual care, on the rate of 
reintubation of critically ill adults. 
• Secondary 
o To evaluate the effect of the same intervention in the same population 
on clinical outcomes (ventilator-free days, ICU-free days, and in-hospital 
mortality, physiologic outcomes (heart rate, respiratory rate, FIO2, 
SaO2:FIO2 hours post-extubation, arterial pH, and PaCO2) at 0-6, 6-12, and 
12-24 hours post-extubation, procedural outcomes (e.g. indication for 
reintubation), and other ICU-related morbidity (e.g., delirium). 
 
Study Hypotheses: 
• Primary:  
o Respiratory therapy driven protocolized post-extubation respiratory 
support will decrease the incidence of reintubation among patients 
extubated in the medical intensive care unit, compared with usual care.  
 
• Secondary:  
o Protocolized post-extubation respiratory support will increase the 
number of ventilator free days and ICU-free days without affecting in-
hospital mortality. 
 
4.0 
Study Description 
 
To address the aims outlined above, we propose a three-part quality 
improvement study, comprised of an initial observational period, an interventional 
period of cluster-randomized double-crossover design, and a dissemination period of 
post-implementation surveillance.   

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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Period 1:  During the first 3 months of the study, we will prospectively collect 
information on the baseline rates of post-extubation respiratory support and 
reintubation without any intervention.   
Period 2: Over the subsequent 18 months, the intervention will be applied at the 
level of the respiratory therapist. Patients in the MICU are cared for by two respiratory 
therapists, each of whom covers half of the ICU beds, based on geography (front hall, 
back hall).  A protocol for post-extubation respiratory support and education on the 
delivery of NIV and HFNC after extubation will be provided to one of the two respiratory 
therapists.  The delivery of the intervention will include (1) provision of a written 
protocol detailing which patients qualify for post-extubation respiratory support and the 
manner in which post-extubation respiratory support may be delivered, (2) an initial 30 
minute educational session for the respiratory therapist on the techniques and evidence 
surrounding post-extubation respiratory support, (3) bi-weekly five-minute debriefing 
on the experience with and barriers to post-extubation respiratory support, (4) a set of 
physical reminders in the location in which the intervention will be provided, and (5) 
24/7 availability of the study team for questions concerning the provision of post-
extubation respiratory support.  One half of the MICU patients will receive protocolized 
post-extubation respiratory support (from the respiratory therapist using the protocol 
and receiving the educational interventions).  The remaining half of MICU patients, 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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cared for by the respiratory therapist not using the protocol or receiving the educational 
interventions, will serve as a control and receive usual care.  The 18-month 
interventional period will be divided into six blocks of 3 months, with a cross-over 
between the intervention and the usual care group occurring at the end of each block.  
Outcomes will be analyzed at the end of the 18-month intervention period.   
Period 3: If protocolized post-extubation respiratory support decreases the 
reintubation rate, the protocol will be provided to all MICU respiratory therapists and 
applied to all MICU patients.   For 3 months post-implementation, we will monitor the 
compliance with the protocol and reintubation rate, in the absence of ongoing 
education and feedback to capture use of and performance of the protocol during 
routine care.  
 
 
5.0 
Inclusion and Exclusion Criteria 
 
5.1  
Inclusion Criteria: 
1. Patient is located in a participating unit 
2. Patient undergoing extubation from mechanical ventilation  
3. Patient has been receiving mechanical ventilation for at least 12 hours 
4. Age ≥ 18 years old 
 
5.2  
Exclusion Criteria:  
1. Patient is receiving ventilation via a tracheostomy 
2. Patient is being extubated to comfort measures or has “Do Not Reintubate” 
order in place at the time of extubation 
3. Patient has required reintubation after a prior attempt at extubation during this 
hospitalization 
4. Unplanned or self-extubation, where immediate reintubation is deemed 
necessary by the clinical team 
 
6.0 
Enrollment 
 
6.1 
Study Sites:   

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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• Medical Intensive Care Unit at Vanderbilt University Medical Center 
 
6.2  
Study Population:   
 
All adults located in the Vanderbilt MICU who have been receiving mechanical 
ventilation for more than 12 hours via an endotracheal tube and who undergo 
extubation.  Patients will be excluded if they are being extubated to comfort measures 
or have a “Do Not Reintubate” order in place at the time of extubation or if they are 
immediately re-intubated after a self- or unplanned extubation.   
If the clinical team feels that respiratory support is contraindicated, it will be 
withheld, regardless of group assignment, but the patient’s data will be collected and 
included in the intention-to-treat analysis.  Patients will be included regardless of 
gender, race, weight, body mass index, history of underlying lung disease, oxygen 
requirement, or other clinical factors.  
 
6.3  
Enrollment: Patients will be enrolled at the time of extubation if the patient 
meets inclusion but not exclusion criteria. 
 
6.4  
Consent:  
 
Extubation without protocolized respiratory support and a respiratory therapist 
driven protocol guiding respiratory support after extubation are both within the 
spectrum of current routine care in MICUs like Vanderbilt.  All of the interventions 
examined are interventions to which the patient might be exposed to undergoing 
extubation in the MICU outside of the context of a study.  There are no established 
benefits or risks to a post-extubation respiratory support protocol.  In our study, 
treating clinicians will always be allowed to use post-extubation respiratory support in 
the usual care group or no respiratory support in the intervention group, if they feel it is 
necessary for the safe treatment of that individual patient.  For these reasons, we feel 
that this study of a post-extubation respiratory support protocol poses minimal risk. 
 
The intervention in this study is applied at the level of the respiratory therapist 
who will receive education on post-extubation respiratory support, a protocol for 
applying post-extubation respiratory support, and structured feedback on their 
performance. The intervention occurs at a practice level and is applied to every patient 
under that respiratory therapist’s care.  All patients assigned to a respiratory therapist in 
the intervention group will receive protocolized post-extubation respiratory care.  All 
patients in the control arm will be provided usual care by a respiratory therapist who 
will not be using a protocol for post-extubation respiratory support.  Patient-level 
informed consent would cause unacceptable contamination of the study intervention as 
therapists using the protocol on some patients are likely to apply it to other patients for 
whom no protocols are in place.  In such a cluster-level design, enrolling every patient 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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cared for by two respiratory therapists who will be using two different approaches to 
extubation in the ICU, obtaining informed consent from all intubated MICU patients 
would be impracticable. 
Given the minimal risk and impracticability of informed consent, we will request 
waiver of informed consent.  The use of the secure, online database REDCap for the 
collection of any Protected Health Information required for the study minimizes the risk 
to the privacy rights of the individual and the protection of privacy will be not be 
affected by the presence or absence of a waiver of consent. 
 
6.5  
Group Assignment 
 
 
This is a pragmatic, quality improvement study comparing protocolized post-
extubation respiratory support to usual care using a cluster-crossover design.  Patients’ 
treatment group will be determined by their ICU room number. In the VUMC MICU, 
patients are assigned to rooms based on bed availability with no selection preference 
for severity of illness or other clinical criteria.  To control for any potential bias created 
by geographic assignment of the study intervention, the groups will undergo five cross-
overs so that each ICU bed will spend half of the study in the protocolized post-
extubation respiratory support group and half in the usual care group.  The initial group 
assignment will be generated by simple, computerized randomization.  Each cluster will 
then alternate group assignment for each block for the remainder of the study.  Blinding 
of treating providers and nursing staff will not be possible in this study.   
 
  
7.0 
Study Procedures 
 
7.1       Treatment Arms 
 
Protocolized Post-extubation Respiratory Support (Intervention) 
 
All respiratory therapists will be given a 30-minute educational lecture on the 
techniques and evidence base surrounding post-extubation respiratory support before 
the start of the period assigned to implementing the protocol.  During the study period, 
respiratory therapists in the intervention group will be provided with the protocol 
below, which identifies patients who are eligible for post-extubation respiratory support 
group, provides criteria for selection of non-invasive ventilation (NIV) or high flow nasal 
cannula, and provides instructions for the implementation of these interventions: 
 
 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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NIV will be recommended for all patients intubated for a COPD exacerbation and 
for all hypercarbic patients. Hypercarbia will be defined as a partial pressure of arterial 
carbon dioxide (PaCO2) >45 mm Hg on an ABG if one is obtained during a spontaneous 
breathing trial, known chronic hypercarbic respiratory failure, or obesity hypoventilation 
syndrome.  Any patient meeting one of these criteria will be placed on NIV immediately 
following extubation.  Patients with any of the following conditions are felt to have a 
contraindication to non-invasive ventilation, and it will not be provided: 
1. Facial or cranial trauma or surgery, 
2. Recent gastric or esophageal surgery 
3. Inability to protect the airway 
4. Active upper gastrointestinal bleeding 
5. Excessive amount of respiratory secretions 
6. Lack of cooperation 
 
NIV may be discontinued at any point if felt by the clinical team to be impeding 
patient safety.  Patients may take breaks of one hour to eat or drink or for comfort. 
Patients who have one of the contraindications listed above or are unable to tolerate 
NIV for more than 4 hours should be placed on high flow nasal cannula. Sedatives to 
increase tolerance to NIV will be discouraged.  NIV will be continued until 5AM the day 
following extubation (the time at which spontaneous breathing trials are initiated on 
mechanically ventilated patients in our intensive care unit).  If a patient is felt to be 
stable for transfer out of the ICU prior to 5AM the day following extubation, NIV can be 
discontinued at the time of ICU transfer.  Patients who develop respiratory failure 
following the discontinuation of respiratory support can be restarted on NIV or HFNC at 
the discretion of their clinical teams. 
NIV is a routinely employed intervention familiar to clinicians and respiratory 
therapists in the intensive care unit.  In keeping with the pragmatic focus of the study, 
non-invasive ventilation will be delivered by the same clinicians who would perform the 
intervention outside of the research setting.  NIV will be delivered using a full facemask.  
Inspiratory pressure support will be titrated according to standard respiratory protocols 
with a suggestion range of (12–20 cm H2O) and suggested goal respiratory rate less than 
25 breaths per min.  Expiratory pressure and FIO2 will be adjusted to maintain SPO2 of 
greater than 90%.  
HFNC will be recommended for all patients who are not hypercarbic and were 
not intubated for a COPD exacerbation. HFNC will be started immediately following 
extubation and will be continued until 5AM the following day at which time it will be 
weaned according to a pre-existing protocol developed by respiratory therapy.  If a 
patient is felt to be stable for transfer out of the ICU prior to 5AM the day following 
extubation, NIV can be discontinued at the time of ICU transfer.  NIV is an acceptable 
alternative for patients in whom this approach is preferred by the clinical team.  The 
decision to use NIV as a rescue treatment for patients with post-extubation respiratory 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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failure on HFNC will be made by the clinical team but will not be encouraged and will be 
recorded.   
Decisions regarding all other respiratory treatments (diuretics, intravenous 
fluids, antibiotics, corticosteroids, breathing treatments) will be made by the clinical 
team.  The diagnosis of post-extubation respiratory failure and the decision to use 
rescue NIV or reintubate will be made by the treating clinicians. If any healthcare 
provider participating in the patient’s care believes that the study intervention cannot 
be safely provided, the study intervention will be halted and the patient will be provided 
whatever post-extubation respiratory support is felt to be appropriate by the clinical 
team.  
 
 
Usual Care (Control) 
The respiratory therapist will not be provided with a protocol for post-extubation 
respiratory support. Decisions regarding post-extubation respiratory support will be 
made by the patient’s clinical team. NIV and HFNC may be used at the discretion of the 
clinical team as post-extubation respiratory support or as rescue therapy for post-
extubation respiratory therapy.  The use of NIV for the treatment of post-extubation 
respiratory failure will not be encouraged but will be allowed at the discretion of the 
clinical team.  Decisions regarding all other respiratory treatments (diuretics, 
intravenous fluids, antibiotics, corticosteroids, breathing treatments) will be made by 
the treating clinicians as will the diagnosis of post-extubation respiratory failure and the 
decision to use rescue NIV or reintubate.  If NIV or HFNC are given as post-extubation 
respiratory support to a patient in the control arm, we will request that the ordering 
physician and that patient’s respiratory therapist complete a brief data collection sheet 
explaining the type of device planned, home NIV use, the indication for the device, and 
the initial device settings. 
  
7.2  
Blinding 
 
Given the nature of the study intervention, patients, clinicians, and investigators 
will not be blinded to group assignment.   
 
7.3  
Data Collection 
 
Baseline: Age, gender, height, weight, body mass index, race, APACHE II score, length of 
mechanical ventilation (prior to first extubation), active medical problems at the time of 
extubation, mean arterial pressure and vasopressor use prior to extubation, highest FiO2 
delivered in prior 24 hours, lowest oxygen saturation in prior 24 hours, pH, PaO2, PaCO2, 
SaO2:FIO2, indication for intubation, reason for ICU admission.  Date of first spontaneous 
breathing trial. 
 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
 Version Date: 1/4/2019 
Study Title:  Protocolized Post-Extubation Respiratory Support 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
 
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0-96 hours: The need for reintubation within 96 hours (the primary outcome), time to 
reintubation.  Indication for reintubation.  Laryngeal edema requiring reintubation.  The 
amount of time spent receiving HFNC and NIV. Levels of respiratory support provided 
with these devices (flow rate, FIO2, IPAP, EPAP). Respiratory rate, heart rate, pH, PaCO2, 
SaO2, FiO2, at 0-6, 6-12, and 12-24 hours post-extubation.  CAM-ICU score from 0-96 
hours post-extubation.  RAS score from 0 to 96 hours post-intubation.   
 
In-Hospital Outcomes: Rate of reintubation, date of ICU discharge (for ICU-free days), 
date of death, ventilator-free days 
 
7.4 
 Outcome Measures 
 
Primary Endpoint:   
• Reintubation within 96 hours of extubation 
 
Secondary Endpoints: 
1. All-cause in-hospital death 
2. ICU-free days 
3. Ventilator-free days 
4. Time to reintubation 
5. Indication for reintubation  
6. Respiratory-caused reintubation 
7. Laryngeal edema requiring reintubation 
8. Delirium with 96 hours of extubation 
9. Agitation with 96 hours of extubation 
10. Lowest S/F ratio in the first 24 hours 
11. Highest respiratory rate at 0-6, 6-12 and 12-24 hours  
12. Use of HFNC or NIV beyond 24 hours post-extubation 
 
ICU-free days to 28 days after enrollment will be defined as the number of days alive 
and not admitted to an intensive care unit service after the patient’s final discharge 
from the intensive care unit in that hospitalization before 28 days.  Patients who are 
never discharged from the intensive care unit will receive a value of 0.  Patients who die 
before day 28 will receive a value of 0.  For patients who return to an ICU and are 
subsequently discharged prior to day 28, ICU-free days will be counted from the date of 
final ICU discharge.  All data collection will be censored at the first of hospital discharge 
or 28 days. 
 
Ventilator-free days to day 28 will be defined as the number of days alive and with 
unassisted breathing to day 28 after enrollment, assuming a patient survives for at least 
two consecutive calendar days after initiating unassisted breathing and remains free of 
assisted breathing.  If a patient returns to assisted breathing and subsequently achieves 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
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unassisted breathing prior to day 28, VFD will be counted from the end of the last period 
of assisted breathing to day 28.  If the patient is receiving assisted ventilation at day 28 
or dies prior to day 28, VFD will be 0.  If a patient is discharged while receiving assisted 
ventilation, VFD will be 0.   All data collection will be censored at the first of hospital 
discharge or 28 days. 
 
8.0 
Risks and Benefits: 
 
For mechanically ventilated patients who are undergoing extubation in the 
MICU, there are currently no established risks or benefits to protocolized post-
extubation respiratory support. At this time, there is no reason to believe that 
participation in this study would expose patients to greater medical risks or benefits 
than those experienced by critically ill patients undergoing extubation as a part of 
routine care.  The greater benefit of the study would be to society in the form of 
improved understanding of safe and effective patient care for patients following 
extubation. 
 
A potential risk to patients participating in this study involves the collection of 
protected health information (PHI).  In order to limit the associated risks, the minimum 
amount of PHI necessary for study conduct will be collected.  After collection, the data 
will be stored in a secure online database (REDCap) only accessible by the investigators.  
After publication, a de-identified database will be generated to protect participant 
privacy. 
 
 
9.0 
Safety Monitoring and Adverse Events: 
 
9.1 Safety Monitoring 
 
 
This study will take place in the environment of the intensive care unit in which 
each participant will have access to invasive or noninvasive monitoring, and a bed-side 
nurse with high-acuity nurse-to-patient staffing ratio.  During the study, the patient will 
be cared for by a respiratory therapist, a critical care nurse, and usually a pulmonary and 
critical care fellow or attending, in addition to continuous invasive or non-invasive 
monitoring.   
Additionally, study personnel will be readily available to answer questions at any 
time during the study course.  If any healthcare provider participating in the patient’s 
care believes that the study interventions cannot be safely performed, the study 

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intervention will be halted and the patient will be provided whatever post-extubation 
respiratory support is felt to be appropriate by the clinical team.  
 
9.2 Adverse Events 
 
An adverse event is defined as any unexpected and untoward medical 
occurrence in a clinical investigation participant administered an intervention that does 
not necessarily have to have a causal relationship with this treatment.  An adverse event 
therefore can be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an intervention, whether or not the incident is considered 
related to the intervention. 
 
A serious adverse event (SAE) will be defined for this trial as any unexpected and 
untoward medical occurrence that meets any of the following criteria: 
a. Results in death 
b. Is life-threatening (defined as an event in which the participant was at risk of 
death at the time of the event and NOT an event that hypothetically might have 
caused death if it would have been more severe) 
c. Requires inpatient hospitalization 
d. Prolongs an existing hospitalization 
e. Results in persistent or significant disability or incapacity 
f. Results in a congenital anomaly or birth defect 
g. Important medical event that requires an intervention to prevent any of a-f 
above. 
 
 
The Principal Investigator will be responsible for overseeing the safety of this 
trial on a daily basis.  He will be available at any time for questions from the clinical 
team or bedside nurses, who will also be monitoring the patients continuously for 
adverse events and serious adverse events.  Serious and unexpected adverse events 
associated with study interventions will be recorded in a case report form in the study 
record and reported to the IRB within 7 calendar days in accordance with IRB policy.  
Patients who have required mechanical ventilation in the critical care setting are known 
to be at risk for numerous adverse events following extubation including hypoxemia, 
hypercarbia, aspiration, reintubation, hypotension, severe bradycardia, cardiac arrest, 
and death. These events will be recorded as study outcomes and monitored by the 
study personnel.  However, in the absence of an imbalance of the above events 
between study groups, these events are expected in the routine performance of critical 

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care medicine and will not be individually recorded and reported to the IRB as serious 
and unexpected adverse events, unless the investigators or clinical team believe the 
event was related to the study intervention. 
 
10.0 
Study Withdrawal/Discontinuation 
 
Patients can be withdrawn from study participation in the following circumstances: 
• The investigator decides that the patient should be withdrawn for safety 
considerations. 
• There is a significant protocol violation in the judgment of the PI. 
 
The reason and date of every withdrawal will be recorded in the patient study records.  
Follow-up will be performed for all patients who discontinue due to an adverse event or 
any other safety parameter.  Follow-up will also be performed for all patients who end 
participation in the protocol for another reason, but who also have an adverse event or 
other safety parameter that could have led to discontinuation.  Follow-up will be 
conducted until the condition has resolved, until diagnosis of the adverse event or 
safety parameter is deemed chronic and stable, or as long as clinically appropriate.  This 
follow-up will be documented in the patient study record as well.   
 
 
11.0 
Statistical Considerations 
 
SAMPLE SIZE CALCULATION (9/12/17):  
 
Review of 12 months of data obtained during a previous prospective trial 
enrolling a similar population of patients in the same ICU demonstrated a reintubation 
rate of 12.1% within 96 hours, similar to that reported in previous observational studies 
of post-extubation outcomes.1,3  Trials of prophylactic post-extubation NIV have 
suggested that it may reduce the relative risk of reintubation by 49 to 66% in high risk 
patients.4,17  Trials of prophylactic post-extubation HFNC have suggested that it may 
reduce the rate of reintubation by 81% in high risk patients and 60% in low risk patients 
and is non-inferior to NIV in high risk patients12,25,29.   We estimate that the initiation of 
a protocol for post-extubation respiratory support will reduce the relative risk of 
reintubation by 55% (equivalent to an absolute risk reduction of 6.655%).    

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Based on our analysis of retrospective data, we suspect that intra-cluster 
correlation, intra-period correlation, and intra-cluster-intra-period correlation will be 
negligible and will not affect our sample size calculations.  
Using PS version 3.1.2 with the above assumptions and a chi-squared analysis 
with an alpha level of 0.05, we calculated that achieving a statistical power of 0.8 would 
require enrollment of 566 patients.  To account for the low, baseline utilization of post-
extubation respiratory support in the usual care group (8.3% of patients in retrospective 
cohort), which we expect to continue, we estimate that our sample size should be 
increased by 10% to 623 patients.  Based on retrospective data suggesting 35 eligible 
patients are extubated each month, we have planned an 18-month intervention period 
during which we anticipate enrolling 630.  We anticipate observing approximately 105 
extubations during each of the initial observational and the dissemination periods. 
At the end of the third cluster cross-over (12 months), we will examine the 
enrollment rate, the reintubation rate in the usual care arm, and the rate of utilization 
of post-extubation respiratory support in the intervention and control arms.  Using 
these statistics, we will re-calculate the sample size needed for a power of 0.8 and an 
alpha level of 0.5. If appropriate, the principal investigator will have the ability to extend 
the trial by up to 6 months (two additional intervention periods with cross-overs at 
month 18 and 21).   
 
SAMPLE SIZE UPDATE (1/4/19):  
As a cluster-randomized, multiple-crossover trial, the intervention portion of 
PROPER has been designed to enroll for a fixed duration to ensure that each cluster 
spends an equal amount of time receiving each treatment group.  The trial has been 
approved to enroll for 18 months, from 10/1/2017 to 3/31/2019.  The total number of 
patients enrolled will depend on the rates of mechanical ventilation in the MICU during 
the fixed time period of the trial.  Based on retrospective data, we estimated that 
approximately 630 patients would be enrolled under the planned study duration.  The 
number of patients receiving mechanical ventilation in the MICU has increased over the 
duration of the trial, however, and we now anticipate between 720 and 740 patients will 
be enrolled during the planned study period.   
 
 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
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Statistical Analysis: 
 
Trial profile:  
We will present a Consolidated Standards of Reporting Trials diagram to detail 
the movement of patients through the study. This diagram will include total number of 
patients meeting inclusion criteria, number excluded and reason for exclusion, number 
enrolled and randomized in the study, number followed, and number analyzed. 
 
Baseline Characteristics:  
To assess for baseline differences between the groups, we will summarize in 
Table 1 the distribution of baseline variables across the study arms. Categorical variables 
will be reported as frequencies and percentages and continuous variables as either 
means with SDs or medians with interquartile ranges. Variables reported will include 
Demographics (age, gender, race, BMI, co-morbidities), indication for intubation, active 
illnesses at the time of extubation, severity of Illness (APACHE II score), ICU length of 
stay, hospital length of stay, and duration of mechanical ventilation (prior to first 
extubation) 
 
Analyses: 
We will develop and make publicly available prior to the conclusion of enrollment a 
complete statistical analysis plan.  This will detail an approach to the primary analysis 
which adequately accounts for the intra-cluster, intra-period, and intra-cluster-intra-
period correlation observed in the study environment (if applicable).  We will analyze 
the effect of group assignment on all secondary.  We will evaluate for heterogeneity of 
treatment effect between pre-specified baseline variables, group assignment, and 
outcome using formal tests of interaction.  We will perform “per-protocol” and “as-
treated” analyses assessing the impact of contamination. 
 
Presentation of Statistics 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
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Continuous variables will be described as mean and standard deviation or 
median and 25th percentile – 75th percentile or bootstrapped 95% confidence intervals 
as appropriate.  Categorical variables will be given as number and percentage.  All 
between-group comparisons with continuous variables will be performed using Mann-
Whitney U tests; categorical variables will be compared with chi-square testing or 
Fisher’s exact test as appropriate. 
             
12.0 
Privacy/Confidentiality Issues 
At no time during the course of this study, its analysis, or its publication will 
patient identities be revealed in any manner.  The minimum necessary data containing 
patient or provider identities will be collected.  All patients will be assigned a unique 
study ID number for tracking.  Data collected from the medical record will be entered 
into the secure online database REDCap.  All data will be maintained in the secure online 
database REDCap until the time of study publication.  At the time of publication, a de-
identified version of the database will be generated. 
 
13.0 
Follow-up and Record Retention 
Patients will be followed after enrollment for 28 days or until death or hospital 
discharge, whichever occurs first.  Data collected from the medical record will be 
entered into the secure online database REDCap.  Once data are verified and the 
database is locked, all hard copies of data collection forms will be destroyed.  All data 
will be maintained in the secure online database REDCap until the time of study 
publication.  At the time of publication, a de-identified version of the database will be 
generated. 

Principal Investigators: Jon Casey, Todd Rice, Matt Semler            
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1.  
Thille AW, Richard J-CM, Brochard L. The Decision to Extubate in the Intensive 
Care Unit. Am J Respir Crit Care Med 2013;187(12):1294–302.  
2.  
Thille AW, Boissier F, Ben-Ghezala H, et al. Easily identified at-risk patients for 
extubation failure may benefit from noninvasive ventilation: a prospective before-after 
study. Crit Care Lond Engl 2016;20:48.  
3.  
Thille AW, Harrois A, Schortgen F, Brun-Buisson C, Brochard L. Outcomes of 
extubation failure in medical intensive care unit patients. Crit Care Med 
2011;39(12):2612–8.  
4.  
Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent 
respiratory failure after extubation in high-risk patients. Crit Care Med 
2005;33(11):2465–70.  
5.  
Torres A, Gatell JM, Aznar E, et al. Re-intubation increases the risk of 
nosocomial pneumonia in patients needing mechanical ventilation. Am J Respir Crit Care 
Med 1995;152(1):137–41.  
6.  
Frutos-Vivar F, Esteban A, Apezteguia C, et al. Outcome of reintubated patients 
after scheduled extubation. J Crit Care 2011;26(5):502–9.  
7.  
Sellares J, Ferrer M, Cano E, Loureiro H, Valencia M, Torres A. Predictors of 
prolonged weaning and survival during ventilator weaning in a respiratory ICU. Intensive 
Care Med 2011;37(5):775–84.  
8.  
Esteban A, Anzueto A, Frutos F, et al. Characteristics and Outcomes in Adult 
Patients Receiving Mechanical Ventilation: A 28-Day International Study. JAMA 
2002;287(3):345–55.  
9.  
Esteban A, Ferguson ND, Meade MO, et al. Evolution of Mechanical Ventilation 
in Response to Clinical Research. Am J Respir Crit Care Med 2008;177(2):170–7.  
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Esteban A, Frutos-Vivar F, Muriel A, et al. Evolution of Mortality over Time in 
Patients Receiving Mechanical Ventilation. Am J Respir Crit Care Med 
2013;188(2):220–30.  
11.  
Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive Positive-Pressure 
Ventilation for Respiratory Failure after Extubation. N Engl J Med 2004;350(24):2452–
60.  

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12.  
Maggiore SM, Idone FA, Vaschetto R, et al. Nasal high-flow versus Venturi mask 
oxygen therapy after extubation. Effects on oxygenation, comfort, and clinical outcome. 
Am J Respir Crit Care Med 2014;190(3):282–8.  
13.  
Frat J-P, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in 
acute hypoxemic respiratory failure. N Engl J Med 2015;372(23):2185–96.  
14.  
Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute 
exacerbations of chronic obstructive pulmonary disease. N Engl J Med 
1995;333(13):817–22.  
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.  
Keenan SP, Powers C, McCormack DG, Block G. Noninvasive Positive-Pressure 
Ventilation for Postextubation Respiratory Distress: A Randomized Controlled Trial. 
JAMA 2002;287(24):3238–44.  
17.  
Ferrer M, Valencia M, Nicolas JM, Bernadich O, Badia JR, Torres A. Early 
noninvasive ventilation averts extubation failure in patients at risk: a randomized trial. 
Am J Respir Crit Care Med 2006;173(2):164–70.  
18.  
Ferrer M, Sellarés J, Valencia M, et al. Non-invasive ventilation after extubation 
in hypercapnic patients with chronic respiratory disorders: randomised controlled trial. 
The Lancet 2009;374(9695):1082–8.  
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Ouellette DR, Patel S, Girard TD, et al. Liberation from Mechanical Ventilation: 
An Official American College of Chest Physicians/American Thoracic Society Clinical 
Practice Guideline: Inspiratory Pressure Augmentation during Spontaneous Breathing 
Trials, Protocols Minimizing Sedation, and Non-invasive Ventilation Immediately After 
Extubation. Chest 2016; 
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Parke RL, McGuinness SP. Pressures delivered by nasal high flow oxygen during 
all phases of the respiratory cycle. Respir Care 2013;58(10):1621–4.  
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Riera J, Pérez P, Cortés J, Roca O, Masclans JR, Rello J. Effect of high-flow 
nasal cannula and body position on end-expiratory lung volume: a cohort study using 
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Lee JH, Rehder KJ, Williford L, Cheifetz IM, Turner DA. Use of high flow nasal 
cannula in critically ill infants, children, and adults: a critical review of the literature. 
Intensive Care Med 2013;39(2):247–57.  

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Roca O, Riera J, Torres F, Masclans JR. High-flow oxygen therapy in acute 
respiratory failure. Respir Care 2010;55(4):408–13.  
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Mauri T, Turrini C, Eronia N, et al. Physiologic Effects of High-flow Nasal 
Cannula in Acute Hypoxemic Respiratory Failure. Am J Respir Crit Care Med 2016; 
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Hernández G, Vaquero C, González P, et al. Effect of postextubation high-flow 
nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: A 
randomized clinical trial. JAMA 2016;315(13):1354–61.  
26.  
Hernández G, Vaquero C, Colinas L, et al. Effect of Postextubation High-Flow 
Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation 
Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial. JAMA 
2016;316(15):1565–74.  
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Grant J, Cottrell R, Cluzeau F, Fawcett G. Evaluating “payback” on biomedical 
research from papers cited in clinical guidelines: applied bibliometric study. BMJ 
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28.  
Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and 
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(Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet Lond 
Engl 2008;371(9607):126–34.  
29.  
Hernández G, Vaquero C, Colinas L, et al. Effect of Postextubation High-Flow 
Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation 
Respiratory Failure in High-Risk Patients: A Randomized Clinical Trial. JAMA 
2016;316(15):1565–74.  
 
 
PROTOCOL CHANGES BY VERSION 
1. Protocol 1.1 9/12/17 
a. This version of the protocol changes the definition of the primary outcome to 
reintubation within 96 hours, based on newly released research proposing this 
as a new, universal standard 
i. Miltiades A, et al. Cumulative Probability and Time to Reintubation in 
U.S. ICUs.  Crit Care Med. 2017 May;45(5):835-842 
b. This version also updates the sample size calculation based on the new estimate 
of the event rate (which changed from 12.4 to 12.1 with the change in definition 
of the primary outcome). After adjusting sample size to account for 

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contamination in the control arm, the duration of the study remains the same 
(18 months).  We have added plans to recalculate the power/sample size at 12 
months, with the option of extending the trial by up to 6 months if the trial is 
found to be underpowered. 
c. This version describes a new data collection sheet that will be used to collect 
information on patients receiving post-extubation respiratory support in the 
usual care arm.  This data collection sheet will be submitted, along with this 
protocol for IRB approval. 
d. Finally, this form includes additional patient variables to be collected: date of 
first spontaneous breathing trial and RAS score from 0-96 hours post-intubation 
2. Protocol 1.2 12/22/17 
a. This update to the protocol addresses patients who are felt to be stable for 
transfer out of the ICU prior to 5AM the day following extubation (the time at 
which device removal was recommended in the initial protocol).  Neither HFNC 
or NIV are permitted outside of the ICU at VUMC.  The protocol will be updated 
to allow the removal of protocolized post-extubation respiratory support at the 
time of ICU transfer. 
3. Protocol 1.3 1/4/2019 
a. This version reflects an updated estimate of the expected sample size of the 
trial, which as a cluster-randomized multiple crossover trial is designed to enroll 
for a fixed time period (18 months).