Aspiration in Acute Respiratory Failure Survivors
Phase: NA
Conditions: Dysphagia, Aspiration
Sponsor: University of Colorado, Denver

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COMIRB Protocol# 21-3873 
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PROTOCOL #: 21-3873 
COMIRB Protocol   
 
 
 
 
Protocol Version 1, June 1, 2021 
 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD  
CAMPUS BOX F-490   TELEPHONE: 303-724-1055 Fax: 303-724-0990 
   
 
Project Title: Aspiration in Acute Respiratory Failure Survivors 
Principle Investigator:   Marc Moss MD 
 
Objectives:  Hypothesis and Specific Aims 
Aim #1: To determine whether our 5-item decision tree algorithm is a more effective screening test to identify patients at 
high risk for post-extubation aspiration when compared to the 3-WST and the TOR-BSST. 
Aim #2: To identify unique subphenotypes of patients with post-extubation aspiration based upon FEES-related measures 
of upper airway structure and function and determine their trajectories of recovery. 
Aim #3: To determine the effects of ultrasound determined ETT size/tracheal diameter ratio upon post-extubation 
aspiration while accounting for other potential confounders including ETT cuff pressure. 
Hypothesis: We hypothesize that our 5-item decision tree algorithm will more accurately identify ARF survivors at high 
risk for aspiration when compared to two standard tools: the Yale 3-ounce water swallow test (3-WST) and the Toronto 
Bedside Swallowing Screening Test (TOR-BSST), and ratio of ETT size/tracheal diameter determined with ultrasound 
may be a more accurate predictor of aspiration risk than ETT size alone 
Study Design: Prospective cohort study of patients with acute respiratory failure who require mechanical ventilation for 
more than 48 hours.  
 Inclusion Criteria: 
 
1. Admission to an ICU. 
2. Mechanical ventilation with an endotracheal tube for greater than 48 hours.  We will enroll COVID positive patients.  
Please see below for safety procedures.   
 
Exclusion Criteria: 
1. Contraindication to enteral nutrition administration. 
2.  Pre-existing history of dysphagia or aspiration. 
3.  Pre-existing or acute primary central or peripheral neuromuscular disorder.   
4. Presence of a chronic tracheostomy (present prior to ICU admission).  
5. Pre-existing head and neck cancer or surgery.  
6. Coagulopathy resulting in uncontrolled nasal or pharyngeal bleeding.  
7. Delirium for more than 72 hours after extubation as assessed by CAM-ICU.(75,76) 
8. Extubated for greater than 72 hours. 
9. Inability to obtain informed consent from patient or an appropriate surrogate. 
10. Age < 18 years.   
 
For Aim #1: Primary outcome variable: Using a PAS cutoff score of ≥6 on FEES, patients will be stratified by aspiration 
on any of the five consistencies. Sensitivity and negative predictive value will be the co-primary outcomes. 
Statistical analysis: All relevant diagnostic accuracy statistics will be calculated for each screening tool. This includes 
sensitivity (co-primary), specificity, positive predictive value, negative predictive value (co-primary), area under the 
receiver operating characteristic (ROC) curve, and likelihood ratios. 
For Aim #2: Methods: We will use all available patient data with an overall PAS score of 6,7 or 8 (positive for aspiration).  
Longitudinal outcome variables: All study participants will be assessed for the following outcomes during their primary 
hospitalization: 1) time until return to baseline diet (in days), 2) Development of hospital acquired pneumonia according to 
CDC criteria, 3) Re-intubation, 4) Percutaneous feeding tube placement, 5) ICU length of stay, 6) Hospital length of stay, 7) 
Hospital mortality, and 8) Discharge location (home, long term acute care, acute rehabilitation hospital, nursing home, other). 

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For Aim #3: Primary independent variable: ETT size/tracheal diameter ratio. 
Primary Outcome Variable: Aspiration (PAS score of ≥6) on the FEES with any of the feeding consistencies. A PAS score 
of ≥ 6 includes patients with both silent and non-silent aspiration. 
Statistical Analysis: The primary outcome (aspiration) will be modeled using a multivariable logistic regression with ETT 
size/tracheal diameter ratio as one independent variable, and the confounders mentioned in the section above included as 
other predictor variables. 
Overall Sample Size Determination: Based on enrollment data from our R21 grant, 8.8% (22/248) of patients withdrew 
between the non-invasive bedside evaluations and the performance of the FEES examination. An additional 5.2% 
(13/248) of patients had an incomplete FEES that could not be used in the final analysis. Therefore, we will need to 
initially enroll 855 patients, and start the FEES exams on 789 patients to achieve our final sample size of 750 evaluable 
patients. 
For the over 1,000,000 patients that develop acute respiratory failure (ARF) each year, endotracheal tube (ETT) 
placement and mechanical ventilation are life-saving procedures.1 Fortunately, 75% of these patients survive their critical 
illness.2 However, post-extubation aspiration occurs in up to 44% of ARF survivors (330,000) and is associated with 
deleterious consequences including pneumonia, percutaneous feeding tube placement, long-term care admissions, and 
increased hospital mortality.3-7 Our understanding of the epidemiology, screening and diagnosis, mechanisms, and 
therapeutic options for post-extubation aspiration is still in its infancy. Through a multi-faceted approach, this proposal will 
establish the most accurate screening test to identify high-risk patients, facilitate the development of personalized 
therapies for post-extubation aspiration, and identify a novel modifiable risk factor (ETT size) that could dramatically 
improve the intubation process for all ARF patients. 
Our successful NINR-funded R21 award paved the way for this R01 proposal. In our multi-center and multidisciplinary 
prospective study of over 230 ARF survivors, we made three novel discoveries that will allow us to determine how to 
decrease the risk of post-extubation aspiration. First, using non-invasive bedside evaluations performed by speech 
language pathologists and fiberoptic evaluation of swallowing (FEES) examinations, we developed a 5-item screening 
decision tree algorithm that identifies patients at high risk for post-extubation aspiration.8 Second, we identified laryngeal 
structure and swallowing function abnormalities that are associated with post-extubation aspiration, and we identified three 
potentially distinct subphenotypes of ARF survivors.9 Third, we determined that ETT size is associated with an increased 
risk of post-extubation aspiration, and therefore may represent a modifiable risk factor for ARF survivors.10 
 
These promising preliminary observations could pave the way for a 
paradigm shift in the care of ARF survivors.  The crucial next step is a 
more in-depth study to expand upon our novel findings and establish new 
methods to identify, prevent, and treat post-extubation aspiration. Though 
the validity of our decision tree algorithm is promising, its efficacy needs to 
be compared to other currently used screening tools. We hypothesize that 
our 5-item decision tree algorithm will more accurately identify ARF 
survivors at high risk for aspiration when compared to two standard tools: 
the Yale 3-ounce water swallow test (3-WST) and the Toronto Bedside 
Swallowing Screening Test (TOR-BSST).11-14 With FEES as our gold 
standard for detecting aspiration, we will determine the most effective 
method to identify patients at high risk for post-extubation aspiration.15 The 
three ARF subphenotypes we identified may be associated with different  
trajectories of recovery, and represent unique patients who would benefit 
from different personalized therapies.16-19 We will investigate these  
possibilities. Finally, ETT size alone may not represent the spatial  
parameters of the upper airway.20,21 We hypothesize that ratio of ETT  
size/tracheal diameter determined with ultrasound may be a more accurate predictor of aspiration risk than ETT size alone. 
Ultimately, we will identify the most effective method to select the proper ETT size for all ARF patients and decrease the 
risk of post-extubation aspiration.    
 
We are the optimal multi-center research team to perform the proposed studies. Dr. Moss’ interest in aspiration 
began with his 2000 New England Journal of Medicine article identifying the harmful effects of using blue dye to detect 
Figure 1: R01 Proposal Overview: 
 Outer circle represents our multidisciplinary 
and multi-center infrastructure. 

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aspiration in ARF patients.22 Dr. Langmore developed the FEES procedure and is one of the pioneers of dysphagia-
related research.15,23-37 We have already worked collaboratively for many years as a four-center integrated research team 
(Colorado, Boston University, Stanford, Yale), and we will perform a prospective multi-center cohort study of 750 
evaluable ARF survivors to answer three complementary study questions (Figure 1).  
Aim #1: To determine whether our 5-item decision tree algorithm is a more effective screening test to identify patients at 
high risk for post-extubation aspiration when compared to the 3-WST and the TOR-BSST. 
Aim #2: To identify unique subphenotypes of patients with post-extubation aspiration based upon FEES-related measures 
of upper airway structure and function and determine their trajectories of recovery. 
Aim #3: To determine the effects of ultrasound determined ETT size/tracheal diameter ratio upon post-extubation 
aspiration while accounting for other potential confounders including ETT cuff pressure. 
SIGNIFICANCE: Post-extubation dysphagia and aspiration are common in survivors of acute respiratory failure 
(ARF). The care of ARF survivors costs an estimated $19 billion or 8.4% of all hospital expenses.2 Due the COVID 
pandemic, the impact and prevalence of ARF has significantly increased. Up to 50% of hospitalized COVID patients develop 
ARF requiring intubation and mechanical ventilation.38 All ARF survivors cope with a multiple consequences of their critical 
illness.5-7,39-44 As summarized in our two clinical reviews, as many as 44% of ARF survivors develop post-extubation 
aspiration.5,6 However, our understanding of the optimal ways to diagnose and treat post-extubation aspiration are relatively 
unknown.  
There is no standardized method to screen and diagnose post-extubation aspiration. After extubation, ARF patients 
may receive a swallowing screening test to identify those at high risk for aspiration. When the screening test is abnormal, a 
speech language pathologist (SLP) may be consulted to perform a bedside evaluation of swallowing (BSE). Our research 
group and others demonstrated that even the formal BSE does not identify accurately those ARF survivors at high risk for 
post-extubation aspiration.8,14,45-47 Therefore, a new diagnostic algorithm is needed. We developed a five variable BSE-
based decision tree screening algorithm that dramatically improved the detection of post-extubation aspiration. The five 
variables are easy to determine: length of mechanical ventilation, APACHE II score, voice quality, type of ICU, and a 2-
ounce water swallowing assessment.8 Though promising, our algorithm requires validation and comparison to other 
screening tools. The 3-ounce water swallow test (3-WST) and the Toronto Bedside Swallowing Screening Test (TOR-BSST) 
are two of the most used screening tests to identify patients at high risk for aspiration.12-14 We will determine the most 
accurate screening test and establish that test as the standard method to identify patients that require further diagnostic 
testing such as a fiberoptic evaluation of swallowing (FEES) examination. 
The mechanisms responsible for post-extubation aspiration are 
relatively unexplored. The broad post-extubation aspiration definition, 
defined as simply the detection of aspiration, is one barrier to the 
development of effective therapies. Different combinations of demographic 
and physiological factors may naturally cluster into previously undescribed 
subsets or phenotypes that may have different underlying mechanisms and 
may respond differently to treatments.48 Most SLPs treat patients with 
aspiration by restricting oral nutrition, adjusting the consistency of their food 
or liquids, or with different swallowing maneuvers.49-60 These interventions 
limit the chance of aspiration but do not treat the underlying cause of the 
swallowing dysfunction.49-60 Using fluoroscopy, one study of eleven ARF 
survivors demonstrated that those who aspirate manifest a longer time to 
achieve laryngeal closure when compared to normal controls.61 In our large cohort of 213 ARF survivors, we identified 
multiple abnormalities of laryngeal structure and function that were associated with post-extubation aspiration (Figure 2). 
In a preliminary analysis on the 70 ARF survivors with post-extubation aspiration, we identified three unique 
subphenotypes (see Preliminary data). However, 70 patients is insufficient to identify subphenotypes accurately. By 
prospectively following these ARF survivors, we will also determine whether the subphenotypes are associated with 
different trajectories of recovery and identify those patients who benefit from personalized therapies. 
Endotracheal tube (ETT) size is a potentially modifiable factor that has been associated with post-extubation 
laryngeal injury.10,62,63 There is no standard method for selecting the proper endotracheal tube size (diameter) for 
adults.20,64,65 As a result, there is significant variability in the size of the ETT placed during intubation. The placement of a 

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smaller ETT may increase airway resistance, impede weaning from the ventilator, and inhibit the ability to perform 
bronchoscopy. The placement of a larger ETT has been associated with increased rates of laryngeal injury and post-
extubation stridor.62 We identified ETT size as a potential risk factor for post-extubation aspiration in a pilot study and 
replicated these findings in a larger multi-center prospective study.10,63 However, ETT size alone may not be the most 
accurate measure of the spatial parameters of the upper airway and does not account for individual differences in tracheal 
diameter. Ultrasonography is a readily accessible and portable bedside instrument that easily and accurately measures 
tracheal diameter.20,21,66 We hypothesize that a higher ETT/tracheal diameter ratio may more accurately predict post-
extubation aspiration than ETT size alone. If correct, bedside ultrasound could be used prior to intubation to guide the 
selection of ETT size and minimize post-extubation consequences such as stridor and aspiration.  
Levine’s theoretical framework guides our long-term goal to assist ARF survivors return to a full and satisfying life 
within the constraints of their ARF recovery. These conservation principles direct nursing activities and rehabilitation 
efforts to regain the person’s health and wholeness. Levine identified four principles of conservation: energy, structural 
integrity, personal integrity, and social integrity.67,68 
SLPs can improve patient’s structural and personal 
integrity. In addition, the International Classification of 
Function (Figure 3) that highlights the interrelated 
role of generalized impairments (such as weakness) 
on function (in this case dysphagia) also guides this 
proposal. Collectively, this framework demonstrates 
that modifying the influence of personal factors and 
incorporating 
improved 
swallowing 
capabilities 
improves overall function and participation.  Our 
proposal focuses on strategies to reduce the 
development of post-extubation aspiration and 
personalize 
the 
establishment 
of 
effective 
interventions that will prevent and treat post-
extubation aspiration.  
 
INNOVATION: Our research proposal is innovative in five specific ways.  
1) We are the only multi-center and multidisciplinary group studying post-extubation aspiration and dysphagia.  
2) This is the first study to compare different screening tools to detect patients at high risk for aspiration. Our results will 
establish one of these tools as the most clinically useful, and directly improve clinical practice.  
3) We will use novel and innovative statistical techniques. Recursive partitioning analysis was an innovative method to 
develop an effective decision tree algorithm that streamlined the BSE evaluation and accurately identified patients at high 
risk for post-extubation aspiration.69,70 Using the novel statistical approach of a latent class analysis, we will be the first 
group to identify subphenotypes of post-extubation aspiration.16 These subphenotypes likely have different trajectories of 
recovery that are amenable to different interventions.    
4) We will identify one of the first modifiable risk factors (the endotracheal tube/tracheal diameter ratio) for post-extubation 
aspiration, and the first group to utlize an ultrasound measure of laryngeal diameter to improve the selection of the proper 
sized endotracheal tube in adult ARF patients. This observation could dramatically enhance clinical practice for all ARF 
patients by facilitating the placement of the proper sized ETT and decreasing a variety of deleterious consequences such 
as post-extubation aspiration and stridor.  
5) Our study design is innovatively efficient. FEES will serve as the gold standard test for Aims 1 and 3 and identify 
changes in laryngeal structure and function associated with subphenotypes of ARF survivors in Aim 2. 
PRELIMINARY DATA: 
I. General post-extubation data generated by our research group. 
1. Longer duration of mechanical ventilation is associated with dysphagia.71  We conducted a cohort study of 446 
ICU patients who required mechanical ventilation and received a BSE.  On the BSE, dysphagia was present in 84% of 

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patients (mild in 52% and moderate/severe in 48%). Longer duration of mechanical ventilation was independently 
associated with moderate/severe dysphagia (AOR 2.84 [1.78-4.56], p <0.01). 
2. In ARF survivors, dysphagia is associated with prolonged hospitalization and delayed oral nutrition.71 Dysphagia 
was independently associated with the composite outcome of pneumonia, re-intubation, or in-hospital death (AOR 3.31 
[1.78-4.56], p<0.01) (Figure 4 on next page). Dysphagia was 
still present in 55% of patients at hospital discharge. Hospital 
duration was longer in ARF survivors with dysphagia compared 
to those without dysphagia (8 [5-15] days vs 5 [3-8] days after 
the 
BSE 
was 
performed, 
p<0.01). 
Patients 
with 
moderate/severe dysphagia were more likely to be kept NPO 
after the initial BSE (74% vs 15%, p<0.01) and receive a 
surgical feeding tube (15% vs 5%, p<0.01).   
3. Our nationwide survey of SLPs identified current 
practices to diagnose aspiration in ARF survivors. 72  We 
designed, validated, and distributed a survey to 1,966 inpatient 
SLPs. Each survey included questions concerning SLP staffing 
and availability, and methods used in the diagnosis and 
treatment of dysphagia and aspiration.  A total of 836 SLPs 
completed their survey (43%), 801 of whom were actively 
practicing.  This survey represents the largest published study 
to date of SLP practices for ARF survivors.  
4. There are currently no uniformly used diagnostic tests to detect aspiration in ARF survivors.72  Based on our 
national survey, 0nly 29% of hospitals have formal guidelines for when critical care providers should consult SLPs in the 
evaluation of ARF survivors. When consulted, most SLPs performed the BSE on average 24 hours after extubation. 
Importantly, the majority of SLPs (60%) only use the BSE to identify swallowing dysfunction in ARF survivors. Gold standard 
tests (video fluoroscopy-VFSS and FEES) are not commonly used. VFSS and FEES are also more available and more 
utilized at university hospitals when compared to community hospitals (p < 0.01). 
5. With the support from our NINR R21 award, we conducted a prospective multi-center cohort study of ARF 
survivors.  From August 2015 until July 2018, 248 patients were enrolled at the four sites that will be included in this 
proposal (Colorado, Boston University, Yale, and Stanford); with the same investigators and research coordinators. A total 
of 22 subjects withdrew from the study before the FEES was performed, and an additional 13 patients had an incomplete 
FEES exam. Therefore, 213 patients were included in the final analyses. Median age was 57 (interquartile range 47 – 66) 
years, and 62% were male. Median duration of mechanical ventilation was 126 hours (interquartile range 72 – 206). Both 
the BSE and FEES exam were performed in the ICU. Median time from extubation to the BSE was 25 hours, and the FEES 
was completed 1 hour after the BSE.  This 213-patient cohort serves as the foundation for most of the preliminary data 
below.  
II. Data directly relevant to Aim #1: 
6. Silent and non-silent post-extubation aspiration occur in ARF survivors. A total of 33% (70/213, 95%CI=26.6-
39.2%) of patients aspirated on at least one FEES bolus consistency test. Non-silent aspiration (Penetration-Aspiration 
Scale (PAS) score = 6 or 7) was detected in 24% of patients and silent aspiration (PAS = 8) was detected in 14% patients. 
There were 11 patients (5%) with both non-silent and silent aspiration on different consistencies. Five adverse events 
occurred during this study. One patient vomited during FEES, and one vomited the night after the study; both of these 
episodes were considered to be associated with study-related events. Three patients developed transient respiratory failure 
after the FEES that were not considered study-related events. Overall, this study demonstrated that the performance of 
FEES is safe in ARF survivors. 
Figure 4 

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 7. We developed an accurate decision tree algorithm for detecting aspiration in ARF survivors. In order to develop 
a decision tree model, we used a recursive partitioning analysis to predict the development of aspiration on FEES 
examiniation.73,74 To optimize sensitivity, the decision trees were not trimmed by cross-validation. All 175 possible 
demographic and BSE predictor variables were used as candidate predictors for aspiration. When compared to the gold 
standard FEES, the standard BSE detected aspiration with an accuracy of only 52% (95%CI =45-58%), a sensitivity of 83% 
(95%CI =74-92%), and negative predictive value of 81% (95%CI=72-91%). Our decision tree algorithm identified five 
variables for the final model of overall aspiration: 
duration of intubation, APACHE II score, voice quality, 
type of ICU: medical/cardiac vs. other, and a 2-ounce 
water swallowing assessment. Our decision tree 
algorithm improved the sensitivity to 95% (95%CI = 90-
98%), and negative predictive value to 97% (95%CI = 
95-99%). The overall algorithm is displayed in Figure 5 
(next page).  If our diagnostic algorithm was used as a 
screening test, then nearly half (49%) of patients would 
be accurately identified as not being an aspiration risk 
and would require no further diagnostic testing to detect 
aspiration, and the misclassification of these ARF 
patients would decrease by over 30%.  
III. Data directly relevant to Aim #2: 
8. We identified specific abnormalities in laryngeal 
structure that are associated with post-extubation 
aspiration. With over 30 years of FEES experience, Dr. 
Langmore 
independently 
scored 
the 
different 
components of the FEES examination including: velar 
closure, vocal cord/arytenoid mobility, glottic closure, 
epiglottic retroflexion, laryngeal elevation/arytenoid lift, 
base 
of 
tongue 
retraction, 
pharyngeal 
wall 
medialization, secretions, and laryngeal sensation.  Our 
otolaryngologist (Dr. Fink) also scored the FEES for 
vocal fold mobility, laryngeal edema, and vocal cord 
granulation tissue. Each of the variables in the four 
general 
categories 
were 
associated 
with 
post-
extubation aspiration: (1) Laryngeal closure: reduced 
glottic closure, incomplete epiglottic retroflexion, 
decreased arytenoid mobility, and vocal fold immobility. (2) Weakness: reduced pharyngeal medialization. (3) Laryngeal 
sensation: decreased sensation and presence of upper airway secretions. (4) Anatomical: Airway edema (usually 
arytenoid).   
In most cases, the same variables were significantly associated with aspiration, whether the bolus was ice/liquid or 
puree/nectars/solids. In a multivariable analysis, two variables remained significant: pharyngeal medialization (Odds ratio = 
2.57, 95% CI = 1.16-5.84, p = 0.019) and airway edema (Odds ratio = 3.24, 95% CI 1.44-7.66, p = 0.004). 
Figure 5 

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9. Swallowing function is also associated with post-extubation aspiration. For all consistencies, the median overall 
swallowing time was 0-1 second; range from 0-22 seconds for ice/liquids, and up to 240 seconds for solids. The average 
swallowing time for the ice/liquid bolus consistencies was associated with aspiration of the ice/liquid boluses, although not 
significantly, aspiration: 2.6±2.5 seconds vs. not aspiration 2.0 ± 1.8 seconds, p = 0.051. For each consistency, the timing 
of aspiration during the swallow is demonstrated in Table 1.  Reduced sensation was significantly associated with spillage 
of liquids (p= 0.03) and was significantly associated with 
penetration into the laryngeal vestibule before the onset of 
the swallow (p = 0.04). Altered pharyngeal medialization 
was significantly associated with the residue for 
nectar/puree/solid consistencies (p= 0.047). 
10. We identified potential subphenotpyes of ARF 
survivors. For our 213 patients, we examined patient 
demographics, physical exam characteristics, and BSE 
and FEES results. Overall, 63 variables were included as 
predictor variables. Using a forward stepwise multinomial 
regression model, we refined the list of candidate 
predictors for further analysis. Examining the 70 ARF 
survivors with aspiration of any consistency on the FEES 
examination, we identified three potential subphenotypes 
of ARF survivors: 1) patients with more upper airway edema (57%, n=40), 2) patients with predominantly neuromuscular 
weakness (37%, n=26), and 3) patients with focal signs of vocal cord immobility (6%, n=4). The first cluster with upper 
airway edema were younger, more likely to be female, more likely to be non-white, and have lower Charlson scores. The 
second cluster with a predominance of weakness had longer times of mechanical ventilation and higher rates of renal 
disease.  
IV. Data directly relevant to Aim #3: 
11. We identified that ETT size is associated with an increased risk of post-extubation aspiration.10 We first 
conducted a prospective pilot cohort study of 45 ARF survivors to determine the accuracy of the BSE. In the multivariable 
analysis, we identified that ETT size of 8.0 or greater was associated with aspiration, p=0.03. Based on these results, we 
systematically collected information regarding the ETT in our larger prospective cohort study of 213 patients and observed 
similar findings. In both studies, the treating physicians independently selected the ETT size. The distribution of ETT size 
was 8.0 mm or greater (48%), 7.5 mm (35%), 7.0 or smaller (17%). Overall, one third (n=70) of patients aspirated on at 
least one bolus on FEES examination. In the multivariable analysis, ETT size (≤7.5 vs. ≥8.0) was significantly associated 
with patients exhibiting aspiration (p=0.016, OR=2.17, 95% CI=1.14-4.13). 
12. We can measure ETT/tracheal diameter ratio and determined that tracheal diameter does not change during the 
duration of endotracheal intubation. We enrolled six intubated patients within 24 hours of intubation and obtained serial 
tracheal ultrasounds until extubation. The ETT/tracheal diameter appears to be normally distributed and ranges from 0.51-
0.87. Using a paired analysis, there does not appear to be changes in tracheal diameter over time (.70 vs. .67). This study 
is ongoing, and we will add supplemental preliminary data after the primary submission regarding tracheal diameter that is 
permitted due to COVID-19. 
 
Methods:  
Screening and Informed Consent: We created an integrated multi-center network between the Colorado, Boston 
University, Yale, and Stanford that has already performed all aspects of the research proposed in this application. All four 
institutions already had a long history of dysphagia and aspiration research involving critically ill patients. We already 
developed a HIPAA compliant cloud-based system that shares and stores all of the information in the case report forms 
including the FEES videos. A total of 350 ICU beds will be screened on a daily basis. (Table 3). Consecutive patients will 
be screened for enrollment prior to and regardless of whether the SLP service was consulted by the primary team.  Surrogate 
of patients meeting enrollment criteria will be approached for informed consent prior to extubation. 
 
 Tracheal Ultrasound: Part of the study protocol is to obtain a tracheal ultrasound within 72 hours prior to extubation. 
Because it is a very low risk procedure, we propose to be able to perform the tracheal ultrasound with a waiver of informed 
consent if we are unable to consent a surrogate within this time frame. If we are subsequently unable to obtain informed 

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consent for the remaining study procedures or if the surrogate or patient declines enrollment, then we will discard the 
ultrasound images. No other study related procedure would be performed without a signed consent from the patient or their 
surrogate. All patients will be re-consented once they regain cognitive ability and decisional capacity. See Figure 6 for the 
overall study design and flow. 
 
 
 
Collection 
of 
Demographical 
and 
Clinical 
Information: After obtaining informed consent, we will 
collect demographic information, and obtain ETT cuff 
pressures that are collected every 4-6 hours as part of 
standard of care at all four study hospitals. In addition, 
we will record the presence and duration of other oral, 
nasal, and esophageal tubes placed during mechanical 
ventilation.  
 
Performance of the three Screening Tests: The three 
screening tests (outlined below and in Table 4) will be 
performed before the FEES examination. One SLP will 
perform the screening tests. To account for the potential 
learning effect of the patient through participating in one 
of the water swallow tests, the order of the two 2-ounce 
water swallow tests (included in our algorithm and the 
TOR-BSST) and the 3-WST will be performed in random 
order for each study participant. We considered randomizing the order of the screening exams and the FEES examination. 
However, in practice the non-invasive screening tests will always be performed prior to FEES.  
 
Screening Test A. Our five-item decision tree algorithm: Three of the components (length of mechanical ventilation, 
APACHE II score, type of ICU) will be extracted from the medical record. The SLP will then assess the voice quality and 
perform the 2-ounce water consistency assessment.  The voice quality will be scored as (normal vs. abnormal defined as 
aphonic, hoarse, or wet). The 2-ounce water test will be administered via a straw controlled by the patient. The SLP may 
assist in holding the cup. The SLP will wait for 10 seconds following the completion of the trial before recording the results 
for that consistency. Five outcomes (cough, throat clearing, vocal quality change, change in breath sounds, or stridor) will 
be recorded.  
Coughing:  Dichotomized as a single cough within 10 seconds after diet administration (yes/no). 
Throat Clearing:  Dichotomized as a throat clearing sound within 10 seconds after diet administration (yes/no). 
Change in vocal quality:  Baseline vocal quality will be assessed initially 
and dichotomized as normal/abnormal.  Transitions from normal to 
abnormal vocal quality during feeding will be recorded. 
Change in breath sounds:  Breath sounds will be assessed before and 10 
seconds after the examination by auscultating over the larynx at the thyro-
cricoid space during quiet breathing.  Patients will be classified as 
“gurgling” or “non-gurgling.”  Gurgling is a low/medium-pitched rattling 
sound on inhalation or exhalation.81   
Stridor: Dichotomized as present or absent in 10 seconds. 
Screening Test B. Three-Ounce Water Swallow Test (3-WST): Championed in ARF patients by our Yale colleagues, the 3-
WST will be performed according to standard procedures. Patients will receive three ounces of water and will be instructed 
to drink the entire amount, via a cup or straw, completely and without interruption (the cup can be held to the patient’s mouth 
by the SLP).74;76;109 The 3-WST will be scored as pass/fail.  Criteria for failure of the 3-WST are: the inability to drink the 
entire amount, coughing or choking up to 1 minute after completion, or the presence of a wet-hoarse vocal quality.  

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Screening Test C. Toronto Bedside Swallowing Screening Test (TOR-BSST): Though originally developed for stroke 
patients, the TOR-BSST has been used more broadly for other patient populations.12,82,83 More recently, the TOR-BSST 
was studied in critically ill patients (manuscript currently under review). Designed to be administered by nurses, we will have 
our study SLPs complete the 4-hour TOR-BSST training program. Dr. Rosemary Martino (TOR-BSST developer) will 
provide our study SLPs access to the TOR-BSST educational videos and modules to enhance study fidelity (see Dr. 
Martino’s letter of support). For consistency, we will have study SLPs assess each of the four components of the TOR-
BSST; including assessment of baseline voice, tongue movement, ability to swallow water and post-voice quality. The ability 
to swallow water is assessed using the 2-ounce water swallow test according to the TOR-BSST protocol.  
Gold Standard Testing: the FEES Protocol 
Within 4 hours of the completion of the BSE, 
another SLP or investigator who is blinded to the 
results of the three screening tests will administer 
the FEES examination. Vital signs, including blood 
pressure, heart rate, and oxygen saturation will be 
recorded through the entire procedure. Developed 
by Dr. Langmore, the FEES will be performed 
according to her standardized protocol.34,35  Initially, 
the SLP will examine various aspects of upper 
airway structure and function prior to delivering 
liquid or solids. These tasks comprise Part 1 of the 
FEES examination and include structural 
movements that are not visible during swallowing. 
Overall we will assess nine components that will be 
scored similarly to our R21 scoring system: 1. velar 
closure, 2. vocal cord/arytenoid mobility, 3. glottic 
closure, 4. epiglottic retroflexion, 5. laryngeal 
elevation/ arytenoid lift, 6. base of tongue retraction, 7. pharyngeal wall medialization, 8. secretions, and 9. laryngeal 
sensation. Laryngeal sensation will be assessed by observing the laryngeal adductor reflex (LAR): patient response to a 
light touch to the aeryepiglottic folds bilaterally with the tip of the laryngoscope.9 The FEES will also be scored for three 
components of laryngeal function: 1. vocal cord immobility; 2. granuloma formation; and 3. airway edema. Each of these 
functions will be quantified as none, mild, moderate, severe using our previous scoring system.  
Subsequently, the SLP will assess swallowing function with food and liquid trials (Part 2 of the exam). The SLP will 
administer five standard consistencies: ice chips (International Dysphagia Diet Standardization Initiative consistency 
(IDDSI) = starting at 7 and then transition to 0), nectar thin liquids: pre-thickened apple juice (IDDSI = 2), pureed solids: 
applesauce (IDDSI =4), thin liquids: water (IDDSI = 0), and solids: graham cracker (IDDSI =7) in successive boluses that 
increased are in size.84-87 Table 5 outlines the order, type and quantity of each bolus. All boluses will be administered 
unless considered unsafe by the treating SLP. This safety determination will be left to the discretion of the SLP based on 
the patient response to the prior bolus. If there are clinical signs of aspiration with a smaller bolus of one consistency, the 
remaining boluses of that consistency can be skipped. The smallest bolus of the next consistency would then be 
administered.   
Scoring of the FEES Examination:  All FEES examinations will be video and sound recorded and stored in a HIPAA 
compliant cloud-based system. From the recordings, Dr. Langmore will 
perform a blinded review of the determinants of laryngeal structure and 
swallowing function on the FEES examination and determine a 
Penetration Aspiration Scale (PAS) score for each boluses (Table 6).88  A 
PAS score of 6 or greater represents aspiration. A PAS score of 6-7 
represents non-silent aspiration, and a score of 8 represents silent 
aspiration. To obtain an interrater reliability, an experienced SLP at 
Boston University will over read 10% of the FEES. In addition, Dr. Fink will 
score three variables: vocal fold mobility, presence of laryngeal edema, 
and presence of granulation tissue on the vocal cords. The swallowing 
onset time will be determined for each bolus defined as the time from first 
 
Table 6: PAS Scoring 

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bolus visualization until swallow onset. We will assess the residue after each bolus defined as residue in the pharynx/ 
laryngeal vestibule after a swallow. 
How will we ensure our study protocol will be performed safely in COVID positive patients?  Drs. Moss and Langmore were 
part of the multidisciplinary team that developed the International Dysphagia Research Society guidelines for speech 
language pathology related procedures in COVID positive patients.97 When caring for a patient with suspected or known 
COVID-19, we will ensure that personal protective equipment (PPE) is provided to study personnel including an N95 mask, 
a face shield for eye protection, gloves, and an isolation gown. Study personnel will be fitted with PPE in accordance with 
OSHA standards and will receive training to demonstrate competency in properly donning, doffing, and disposing or 
disinfecting PPE equipment. Only the minimal number of essential personnel will be present to perform the screening testing 
and FEES examination while maintaining permissible physical distancing between members during the procedure and 
ideally performing the study procedures in a negative pressure room. 
Monitoring of SLP protocol fidelity: Study fidelity has the dual purpose of monitoring and enhancing both the performance 
of the study and the assessment of the outcome variables.98-100 We will monitor our study in five domains: study design, 
provider training, protocol delivery, receipt, and enactment.  
1. Screening tests and FEES examinations will only be conducted by SLPs that are specifically trained for this study. All of 
the study SLPs will have at least two years of experience in performing bedside evaluations and FEES examinations and 
will have prior experience working with critically ill patients and survivors of ARF. All of the study SLPs participated in our 
R21 protocols. 
2. We already developed a study manual for consistent performance of all study procedures. 
3. All SLPs will undergo formal training in the conduct of all three screening tools including the required 4-hour training for 
the TOR-BSST (see support letter from Dr. Rosemary Martino) 
4. Prior to the start of the study, Dr. Langmore will conduct individual in-person training sessions at each site. She will 
observe each SLP until they are able to implement the protocol independently. During subsequent annual visits, Dr. 
Langmore or her designee will conduct repeat training for all study SLPs. In the event of travel restrictions due to the COVID 
pandemic, we will conduct virtual video conference sessions.  
5.  FEES will be video recorded. Dr. Langmore will review the videos for quality and protocol fidelity to optimize the FEES 
examinations between her annual visits. We will determine the interrater reliability for all components of the FEES by having 
10% of exams over read by a second reader.  
6. We will have monthly calls to review specific cases and videos to assure consistency in the protocol.  
 
Additional Methods for Specific Aim #1: To determine whether our 5-item decision tree algorithm is a more effective 
screening test to identify patients at high risk for post-extubation aspiration when compared to the 3-WST and the TOR-
BSST. 
Primary outcome variable: Using a PAS cutoff score of ≥6 on FEES, patients will be stratified by aspiration on any of the 
five consistencies. Sensitivity and negative predictive value will be the co-primary outcomes. 
Statistical analysis: All relevant diagnostic accuracy statistics will be calculated for each screening tool. This includes 
sensitivity (co-primary), specificity, positive predictive value, negative predictive value (co-primary), area under the receiver 
operating characteristic (ROC) curve, and likelihood ratios. The gold standard outcome will be aspiration as defined by the 
PAS score ≥6 on the FEES. In order to test for differences in diagnostic accuracy statistics between our 5-item decision tree 
algorithm, the 3-WST, and TOR-BSST, we will use paired tests of two proportions (McNemar’s tests). As a secondary 
analysis, we will utilize a multivariable logistic regression with the three screening tools as candidate predictors to infer 
whether the 5-item algorithm adds significantly to the predictive capabilities of either of the two other screening tools.  
Sample Size Calculation and Feasibility: Based on enrollment data from our R21 grant, 8.8% (22/248) of patients 
withdrew between the non-invasive bedside evaluations and the performance of the FEES examination. An additional 5.2% 
(13/248) of patients had an incomplete FEES that could not be used in the final analysis. Therefore, we will need to initially 
enroll 855 patients, and start the FEES exams on 789 patients to achieve our final sample size of 750 evaluable patients. 
Our past success is the best predictor of future study enrollment. During our R21 award, we were able to maintain an 
enrollment rate of one patient/week for each individual site or four patients/week combined, when all four sites were active. 
If we enrolled four patients per week, we would enroll approximately 200 patients per year. Therefore, we will need to enroll 
patients for 4.25 years to enroll 855 patients. On average, there are 5,463 mechanically intubated critically ill patients each 
year at the four hospitals combined. Therefore, we need to enroll 3.6% (one out of 28 patients) of these patients into our 

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study to meet our enrollment criteria. For our budget estimates, we were conservative, and they are based on enrollment of 
210 patients/site or 840 total patients (extra 51 patients) that will start the FEES to achieve 750 evaluable patients.  
Our final sample size of 750 patients who complete the protocol will ensure that the width of the 95% confidence interval (2 
times the margin of error) for each diagnostic accuracy component is at most 5% for especially low/high values (<0.1 or 
>.9), and at most 7.3% for any value between .25 and .75. This sample size yields 80% power to detect a difference of 
0.094 (9.4%) in either the sensitivity or negative predictive value of our 5-item decision tree compared to either screening 
method. This power estimate is based on dual two-sided McNemar tests assuming a 2.5% level of significance (achieves a 
5% family-wise type I error rate), a baseline prevalence of 30% aspiration, and 20% discordant pairs. 
Anticipated Results, Limitations, Additional Considerations, and Future Directions: We anticipate that our algorithm 
will be the most accurate screening test for post-extubation aspiration. Even if this assumption is incorrect, this study will 
establish one of the three tools as the optimal screening test for post-extubation aspiration. The results of this aim will 
enhance clinical practice by improving the screening and diagnosis of post-extubation aspiration and inform SLPs when 
additional studies such as FEES are necessary. We will also be able to determine the interrater reliability of the interpretation 
of the FEES examination. Understanding the areas of the FEES that are most prone to variability will assist in the 
development of improved educational modules for teaching FEES performance and interpretation. Additional considerations 
could include determining if the screening tools accurately predict dysphagia defined as a PAS score of 3-5. The impact of 
COVID-19 on post-extubation aspiration is unknown. In the proposal, we will be able to define the epidemiology of post-
extubation swallowing dysfunction and aspiration in COVID patients who survived their ARF. Future studies could explore 
how to best disseminate and implement the optimal screening tool to enhance its utilization. We will also need to identify 
the optimal healthcare professionals (such as nurses, nursing assistants, or SLPs) who can accurately perform the optimal 
screening test. 
Additional Methods for Specific Aim #2: To identify unique subphenotypes of patients with post-extubation aspiration 
based upon FEES-related measures of upper airway structure and function and determine their trajectories of recovery. 
Methods: We will use all available patient data with an overall PAS score of 6,7 or 8 (positive for aspiration).  
Longitudinal outcome variables: All study participants will be assessed for the following outcomes during their primary 
hospitalization: 1) time until return to baseline diet (in days), 2) Development of hospital acquired pneumonia according to 
CDC criteria, 3) Re-intubation, 4) Percutaneous feeding tube placement, 5) ICU length of stay, 6) Hospital length of stay, 7) 
Hospital mortality, and 8) Discharge location (home, long term acute care, acute rehabilitation hospital, nursing home, other). 
Statistical Analysis: Based our prior studies, we estimate that conservatively 30% of patients will have post-extubation 
aspiration; resulting in a cohort of approximately 225 ARF survivors with aspiration. Baseline clinical and FEES assessments 
of laryngeal structure and pharyngeal/laryngeal function will be considered as class-defining variables in an unsupervised 
clustering/classification framework. Statistical analyses will be conducted using R. We will fit a series of models using all of 
the enrolled subjects, starting with a 1 class solution and sequentially increasing to K classes, where K is the largest number 
supported by the data. Criteria for model selection will based on the Bayesian Information Criteria, the Vuong-Lo-Mendell-
Rubin (VLMR) likelihood ratio test, and the size of the smallest class. The best fitting classification model will be interpreted 
in terms of class homogeneity (i.e., similarity among those assigned to the same class) and separation (i.e., differences 
between those assigned to different classes) and will be inspected for classification certainty by evaluating model entropy 
and the classification probabilities for each class.   
How will we account for missing data? Based on the results of our previous trial, missing data will occur. For example in the 
derivation of our diagnostic algorithm, 25% of patients were missing at least one data point. The majority of missing data 
was from the larger volume liquid and solid consistency trials  in the BSE and FEES when the patients had aspiration 
concerns with lower volumes. Since we will not be performing the BSE, we anticipate have less missing data. We will use 
a modified version of regression-based imputation.101  
1. We will regress the non-missing data against selected predictors from the fields with no missing data. Regression models 
will be selected by forward stepwise selection with AICc as the selection criterion.102 AICc, a sample-size-corrected version 
of AIC, is a fairly liberal model selection criterion compared to BICand variants such as ICL-BIC; the purpose here was to 
ensure that all relevant predictors were included.103 
2. From the regression models, we will predict the missing elements using the corresponding predictor elements. Continuous 
predictions will be rounded as appropriate, and negative predictions will be set to zero since none of the fields in the data 
can take negative values. 

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3. For each regression, we will calculate the pseudo-R^2 value. The pseudo-R^2 will be used in preference to simple R^2 
for the linear regression models to maintain consistency with the multinomial regression models.104 
4. We will calculate a quality score for the fields with imputed values as the product of the pseudo-R^2 and the proportion 
of non-missing elements. Fields with a high regression pseudo-R^2 and few missing elements will be considered more 
reliable for further analysis.  
 
Incorporating outcomes: Once the number of classes are determined, the associations between class and clinical 
outcomes listed on the previous page will be examined using a method that accounts for uncertainty in class specification.105-
108 This method incorporates the degree of uncertainty of class membership. 
Sample size: Preliminary data suggest we should be able to classify patients into 3-4 clusters, and that these clusters will 
be of unequal size. Assuming we arrive at 3 clusters with a class allocation of 1:3:5, our sample size of N=225 will yield 
80% power to detect a standardized effect (Cohen’s f) of f=0.20 in each of our outcomes. If instead we arrive at 4 clusters 
with a class allocation of 1:2:3:4, we will have 80% power to detect a difference of f=0.22 between clusters for each outcome.    
Alternative Analysis: As an alternative analysis to unsupervised clustering approach, we will utilize elastic net penalized 
regression models to assess directly which variables or groups of variables are associated with each of the longitudinal 
outcomes listed above. Models will be tuned using 10-fold cross validation. For these elastic net models, the issue of 
correlated features (of which we expect many) will be mitigated by the ridge (L2) component of the penalty. Features that 
are not at all related to the outcome will be deselected by the L1 (lasso) component of the penalty. This result will yield a 
sparse prediction equation for each outcome.  
Anticipated Results, Limitations, Additional Considerations, and Future Directions: Similar to our preliminary data, 
we anticipate that we will identify at least three distinct phenotypes with different trajectories of recovery. One limitation is 
that we are not performing electrophysiological assessments of swallowing muscles. These procedures are difficult to 
perform and the needle examination would likely decrease participation enthusiasm for the study. If there is a phenotype 
that is more characterized by laryngeal edema, then those ARF survivors should have a more rapid recovery than those 
characterized by weakness. As an additional consideration, we will collect a peripheral neuromuscular examination and 
determine whether peripheral neuromuscular weakness in swallowing (defined as decreased pharyngeal medialization) 
occurs in those patients with peripheral weakness. We could also consider performing diaphragmatic ultrasonography, 
again to see if upper airway neuromuscular weakness is associated with diaphragmatic weakness. We could also perform 
additional analyses for the patients with dysphagia (PAS score of 3-5), to see if subphenotypes exist for the cohort of 
patients with dysphagia but not aspiration. Future studies could determine whether the suphenotypes are stable over time, 
and whether they respond differently to interventions. For example, an edema subphenotype, may be more responsive to 
corticosteroids, and a neuromuscular weakness subphenotype may be more responsive to therapeutic exercises or 
electrical stimulation. 
Additional Methods for Specific Aim #3: To determine the effects of an ultrasound determined ETT size/tracheal 
diameter ratio upon post-extubation aspiration while accounting for other potential confounders. We hypothesize that a 
higher ETT size/tracheal diameter ratio will be associated with an increased risk of post-extubation aspiration. ETT size 
selection will be at the discretion of the treating physician. Based on our two studies involving over 250 patients, there is 
sufficient variability in the ETT size in this patient population (see section 11 of our Preliminary Data).10,63  
Primary independent variable: ETT size/tracheal diameter ratioprior 
to extubation, we will perform an ultrasound to measure tracheal 
diameter. Ultrasonography measurements will be performed in B-
mode with a linear probe (40 mm length, frequencies 7–15 MHz) 
placed on the midline of the anterior neck. To avoid any confusion 
between the cricoid cartilage and a tracheal ring, the procedure will 
begin with the location of the true vocal folds (paired hyperechoic 
linear structures with respiratory and swallowing mobility).20 Then, the 
probe will be moved caudally to visualize the cricoid arch. The 
transverse air-column diameter will be measured at the cephalic half 
of the cricoid cartilage which is narrower than the caudal part (Figure 7) (4,6). We know the external diameter of each of 
the ETTs that will be used in this study (see Table 7). None of the sites use ETTs with externally attached suction ports or 
other specialized ETT. However, if practice changes, we will adjust the external diameter of the ETT accordingly. The 
tracheal diameter and external diameter of the ETT will be measured in millimeters. By dividing the external diameter of 

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the ETT by the external diameter of the trachea, we will determine the ETT/tracheal diameter ratio. For example, if the 
tracheal transverse diameter is 15.1 mm, and the patient has an 8.0 ETT (external diameter of 11.0 mm), the ratio would 
be 11.0/15.1 or 72.8%.To standardize the timing of the ultrasound, all ultrasound images will be obtained prior to 
extubation during a spontaneous breathing trial. We will then upload all images to our already established cloud-based, 
encrypted, HIPAA compliant and University of Colorado information technology approved Citrix ShareFile. 
Strategies to ensure interrater reliability for the ultrasound measurements of tracheal 
diameter: We will utilize similar strategies to our prior FEES training to maintain rigor 
and reproducibility in the ultrasonographic procedure and the tracheal diameter 
measurements across the four sites: 1) Ultrasonography has become a common test 
performed by critical care personnel. We will limit the test performance to a few trained 
ultrasound hospital-certified personnel (mainly the site PIs). 2) A tracheal ultrasound 
manual will be developed. 3. Dr. Moss will conduct individual virtual training sessions 
for each designated investigator. He will observe each investigator until they are able 
to implement the protocol independently. Using the saved images, interrater and intra-
rater reliability will be established among the raters until agreement of at 
least 80% is reached. 4. On our monthly calls, we will review cases and 
videos to assure protocol consistency. 
Additional confounding variables collected as part of this cohort study. 
1. ETT cuff pressures: ETT cuff pressures may be associated with 
post-extubation complications. The ETT cuff pressures are recorded 
every four hours at all study hospitals by respiratory therapists and 
recorded into the medical record. We will classify patients by their 
average daily ETT cuff pressure. 
2. Presence of naso or oral-gastric tube: classified as naso/gastric/none; and type of tube: Dobhoff vs. other. 
3. Presence of esophageal temperature probe, esophageal balloon manometer to measure pleural pressures, 
performance of transesophageal echocardiogram, and other esophageal tubes when placed, such as a Blackmore tube 
for esophageal varices, and EGD examinations: each classified as Yes/no. 
4. We will also examine other medically important variables such as malnutrition at the time of hospital admission using 
the Nutritional Risk Index, recent ICU admission in the prior 3 months, the duration of enteral feeds during the current ICU 
admission, COVID-19 status, and re-intubation.109 
 
Primary Outcome Variable: Aspiration (PAS score of ≥6) on the FEES with any of the feeding consistencies. A PAS score 
of ≥ 6 includes patients with both silent and non-silent aspiration.88 
Secondary Outcomes: 1. Aspiration subsets: We will stratify patients who aspirate into non-silent (PA = 6- 7) and silent 
(PAS=8) aspiration, and also determine maximum PAS scores across bolus and consistency types. 
2. Post-extubation clinical laryngeal edema: We will define laryngeal edema as upper-airway obstruction within 24 hours 
after extubation. Minor laryngeal edema will be defined as stridor associated with a respiratory distress defined as a 
prolonged inspiratory phase and the presence of edema on FEES examination. Major laryngeal edema will defined as 
severe respiratory distress needing tracheal reintubation secondary to upper-airway obstruction that was visualized during 
the FEES examination.62,110 
3. Other standard ICU outcomes: We will also collect the overall length of mechanical ventilation and the length of the 
liberation process from mechanical ventilation (both in days). 
 
Statistical Analysis: The primary outcome (aspiration) will be modeled using a multivariable logistic regression with ETT 
size/tracheal diameter ratio as one independent variable, and the confounders mentioned in the section above included as 
other predictor variables. The endpoint of interest will then be estimated by the odds ratio for a one standard deviation 
increase in the ETT size/tracheal diameter ratio controlling for relevant confounders. Inference will be performed using 
likelihood ratio tests and profile likelihood confidence intervals. If insufficient variation is observed in the confounding 
variables, or if certain confounders are highly correlated creating partial or complete separation in the predictor space, we 
will pre-process these variables as needed prior to including them in the final model. This same modeling framework will be 
used to test the impact of ETT size/tracheal diameter ratio on non-silent and silent aspiration separately. Further, we will 
treat maximum PAS score across boluses and feeding consistencies as an ordinal outcome, modeled using a cumulative 
 
Figure 7: Cricoid cartilage is a round hypoechoic 
structure (the medulla (A)) with hyperechoic 
edges (the internal (B) and external (C) 
perichondrium). The air-column (D) appeared 
hyperechoic and created a posterior acoustic 
shadow. The dotted line represents the 
measured air-column width. 

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link ordinal logistic regression model (CLM). The CLM tests a slightly different hypothesis than our primary analysis, 
estimating the effect of our covariate of interest on the odds of having a more severe aspiration outcome controlling for 
relevant confounders. A similar CLM will be used to model post-extubation clinical laryngeal edema (none, minor, and 
major), as an ordinal outcome with the same covariates. In these CLMs, the proportional odds assumption will be tested 
and relaxed if needed. Finally, we will model the overall length of mechanical ventilation and the length of the liberation 
process from mechanical ventilation using generalized linear models (GLMs), where we will select link functions that are 
best suited to the observed distributions of these variables. All analyses will be performed in the R software (version 4.0+).  
Sample Size: Our data suggest that we can expect an aspiration prevalence of 30%. Assuming 30% aspiration, a 5% level 
of significance, and that the proportion of variance explained (R2) in the primary covariate of interest by the confounders is 
no greater than 50%, our sample of 750 patients with complete outcome data will yield at least 80% power to detect an 
odds ratio of 1.4 or greater for a 1 SD increase in the ETT size/tracheal diameter ratio. If the R2 for ETT size/tracheal 
diameter ratio is 25%, the detectible effect decreases to an odds ratio of 1.3, and if the R2 is 0 (i.e. if the ETT size/tracheal 
diameter ratio is independent from the confounders), we will have 80% power to detect an odds ratio of 1.25 for our primary 
endpoint. These power calculations assume the ETT size/tracheal diameter ratio is approximately normally distributed.  
Anticipated Results, Limitations, Additional Considerations, and Future Directions. We anticipate that a higher ETT 
tube/tracheal diameter ratio will be significantly associated with post-extubation aspiration and possibly with laryngeal 
edema. If we are correct, then tracheal ultrasound could be utilized prior to intubation to measure tracheal diameter and 
select the optimal sized ETT. We will also obtain serial tracheal ultrasound to see if tracheal diameter changes over time. 
We believe that this is unlikely as trachea is a cartilaginous structure. We will determine the effect of ETT cuff pressure 
and the placement of other esophageal devices on post-extubation aspiration. One limitation is we are measuring tracheal 
size, where measures of laryngeal size or diameter may be more relevant. However, tracheal diameter is related to 
laryngeal size. We will consider using ultrasound to measure laryngeal structures and examine the relationship between 
neck circumference or Mallampati scores at the time of intubation on the development of post-extubation aspiration.111,112 
By utilizing tracheal ultrasound prior to intubation, these results would enhance care, reduce deleterious sequelae of 
intubation, and change the practice for all patients that require intubation for ARF. We may also perform neuromuscular 
examinations to determine if peripheral weakness correlates with post-extubation aspiration. If so, then a measure of 
weakness such as dynamometry could screen for post-extubation aspiration. 
This proposal meets the NIH requirements for rigorous and reproducible research. Based on our prior clinical trial 
experience, all four of our research groups maintain excellent protocol compliance and safety of our research subjects. Our 
biostatistician and data managers are integral members of our research team. Our ability to effectively perform the R21 
award demonstrates that we conduct rigorous and reproducible research. In addition, we have developed a comprehensive 
training program in order to maintain excellent protocol fidelity that was implemented in our R21 grant, successfully. Due to 
the sex differences in ARF survivors, the majority of subjects (60%) will be male. We will analyze our data by sex separately 
and report sex differences observed. The 
proposal timeline is displayed in Table 8. 
 
1. Screening and recruitment: 
Patients meeting enrollment criteria will be 
approached for informed consent no later than 72 hours after extubation. Surrogate consent may be used if patients are 
unable to provide their own informed consent. 
 
If patients meet an exclusion criterion, they can be re-evaluated to determine if the exclusion criteria no longer exists; up 
to 72 hours after extubation. The presence of delirium is the one exclusion criterion that is most likely to change over time 
and require repeated assessments. CAM-ICU Flow Sheet is attached as an appendix. 
 
There is no minimal amount of time that is required after extubation to be enrolled into the study (as long as the patient 
meets the inclusion criteria and does not currently meet any of the exclusion criteria.  
After enrollment, the research coordinator should complete the demographic information on the Case Report Forms. No 
fields on the Case Report Forms should be left blank. The research coordinator should also contact and the SLP who will 
perform the BSE screening tests, and the second SLP who will perform the FEES. The research coordinator should 
arrange a specific time that the BSE and FEES will be performed.  

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Screening and recruitment techniques: 
Every new ICU admission receiving mechanical ventilation will be screened. This will include but not be limited to 
admissions from the ED, wards, and operating room. We will also assess patients transferred from outside hospitals. The 
enrollment window for these patients will include the time during admission at the outside hospital and during transfer.  
The research coordinators or site PI will meet with the new incoming groups of ICU residents as part of their unit 
orientation. During this time, the residents will be alerted to each of the study inclusion and exclusion criteria.  We would 
also recommend developing printed laminated cards with important study related and contact for the housestaff and other 
key members of the ICU teams. Each day, the research coordinator will identify each patient who is endotracheally 
intubated and receiving mechanical ventilation for at least 48 hours. Patients will then be followed until they are extubated. 
 
At the time of extubation, the patient by definition meets inclusion criteria for the study. At this point the patient should be 
entered into the screening log in one of several ways 
1. If they meet a permanent exclusion criteria, they should be entered as be excluded from the study 
2. If they meet a potentially transient exclusion (like altered mental status), they should be followed for up to 72 hours after 
exclusion to determine if the exclusion criteria resolves. If it resolves they should approached for enrollment 
3. If the patient meets no exclusion criteria, they should be approached about study participation. 
4. If they agree to participate and sign the consent form then they are enrolled into the study. 
5. If they decline to participate, then they should be entered as an excluded patient. 
 
Inclusion Criteria: 
 
1. Admission to an ICU. 
2. Mechanical ventilation with an endotracheal tube for greater than 48 hours 
Exclusion Criteria: 
1. Contraindication to enteral nutrition administration. 
2.  Pre-existing history of dysphagia or aspiration. 
3.  Pre-existing or acute primary central or peripheral neuromuscular disorder.   
4. Presence of a chronic tracheostomy (present prior to ICU admission).  
5. Pre-existing head and neck cancer or surgery.  
6. Coagulopathy resulting in uncontrolled nasal or pharyngeal bleeding.  
7. Delirium for more than 72 hours after extubation as assessed by CAM-ICU. 
8. Extubated for greater than 72 hours. 
9. Inability to obtain informed consent from patient or an appropriate surrogate. 
10. Age < 18 years.   
 
Informed consent: 
Obtaining informed consent is a process that is reviewed by the appropriate members of our research team on a monthly 
basis. All of the personnel involved in screening and patient identification have successfully completed the on-line course 
on the Responsible Conduct of Research. Informed consent will be obtained from each patient or legally authorized 
representative (LAR) prior to enrollment in the trial. No study procedures will be done prior to obtaining informed consent. 
Permission to approach patients and/or LARs will be requested from the attending physicians. 
If possible, see if one of the patient’s doctors can introduce you to the patient and/or their surrogate decision maker. In 
general our methods for obtaining informed consent include the following: 1. identification and contact of appropriate 
parties to perform informed consent, 2. arrangement of a mutually acceptable meeting time with this party in a private 
conference room or in the patient’s room, and 3. a lengthy discussion between the study investigator and the interested 
party.  The discussion includes an update of the patient’s overall condition justifying the rationale for inclusion of the 
patient into the specific trial.  The consent form is reviewed in detail including the background information and rationale 
regarding the specific intervention of the study, potential risks and options.  Patients or their representatives are informed 
of their rights as a research subject and are informed of their ability to discontinue study participation at any time 
throughout the trial.  Subjects or their representatives are given the opportunity to ask any questions regarding the 
verbally described consent form.  Following this discussion, opportunity is given to privately read the consent form.  If the 
patient or representative is illiterate, the consent form is read to them.  After sufficient time, an additional question and 
answer session is performed if needed.  
 
A few key points to the informed consent process. 

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1. Sit down when you are taking to the patient and/or surrogate. 
2. Explain who you are and that you normally work with patients in the intensive care unit. 
3. Explain that you are here to help determine if the patient is swallowing normally.  
4. Explain that difficulty swallowing is common after being on a breathing machine 
5. State that the standard tests to determine whether someone can swallow properly after being on a breathing machine 
are to have a nurse or speech therapist to observe a person swallow liquids and foods of different consistencies. 
However, these tests are not perfect. Sometimes it appears that the patient can eat normally, and they are actually 
swallowing things down the wrong tube (into their lungs), Other times, it appears that the patient is not swallowing 
properly when they actually are swallowing properly. 
6. In addition to this normal swallowing exam, there is an additional simple test we can do that is above and beyond the 
normal swallowing exam. This additional technique will definitively identify if someone is swallowing normally, and allow 
us to identify the correct strategy for eating. Sometimes we do this test as part of the normal patient swallowing 
evaluation.  
7. The test is simple and down right here in the patient’s room. It takes 5-10 minutes and the patient can watch the test if 
they want. We will put a very small tube (like a very thin straw) down the back of the throat so we can see your vocal 
cords. We will then have you swallow liquids and foods of different consistencies and see if the material is actually going 
down the wrong tube.  
8. Share these results with your doctors so they have the additional information and can use the information to potentially 
take better care of you in regard to your feeding and swallowing.  
 
If the patient agrees to the study, then the coordinator should contact the SLP who will perform the bedside screening 
tests, and the second SLP who will perform the FEES.  
 
 
STUDY PROCEDURES: 
1. Baseline assessments:  
This information will be collected by the study coordinator at the time of enrollment.  
 
Patient Age 
Patient Gender 
Patient Race 
Patient Height 
Patient Weight 
Primary Service 
Hospital Admission Date 
ICU Admission Date 
Intubation Date and Time 
Size of the Endotracheal Tube 
Extubation Date and Time  
Previous reintubation (y/n) 
APACHE II score 
Charlson Comorbidity Index 
 
Next, a SLP will perform three screening tests on each ARF survivor, and a second blinded SLP will perform the FEES to 
determine whether aspiration is truly present. The order of the beside evaluations will be randomized. The reason for the 
random order of the tests is that after several swallows, a patient who has not eaten orally in several days or weeks will 
start to do better as the system “wakes up”.  If one screening test is always performed before the other screening tests, it 
might lead to a false result – it would show more aspiration on the BSE than the FEES.  But it won’t be because the BSE 
was showing a false positive; in fact it is just that the patient started to improve by the time he got the second screening 
test. 
 
2. Bedside Evaluation: 
Screening Test A. Our five-item decision tree algorithm: Three of the components (length of mechanical ventilation, 
APACHE II score, type of ICU) will be extracted from the medical record. The SLP will then assess the voice quality and 

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perform the 2-ounce water consistency assessment.  The voice quality will be scored as (normal vs. abnormal defined as 
aphonic, hoarse, or wet). The 2-ounce water test will be administered via a straw controlled by the patient. The SLP may 
assist in holding the cup. The SLP will wait for 10 seconds following the completion of the trial before recording the results 
for that consistency. Five outcomes (cough, throat clearing, vocal quality change, change in breath sounds, or stridor) will 
be recorded.  
Coughing:  Dichotomized as a single cough within 10 seconds after diet administration (yes/no). 
Throat Clearing:  Dichotomized as a throat clearing sound within 10 seconds after diet administration (yes/no). 
Change in vocal quality:  Baseline vocal quality will be assessed initially 
and dichotomized as normal/abnormal.  Transitions from normal to 
abnormal vocal quality during feeding will be recorded. 
Change in breath sounds:  Breath sounds will be assessed before and 10 
seconds after the examination by auscultating over the larynx at the thyro-
cricoid space during quiet breathing.  Patients will be classified as 
“gurgling” or “non-gurgling.”  Gurgling is a low/medium-pitched rattling 
sound on inhalation or exhalation.81   
Stridor: Dichotomized as present or absent in 10 seconds. 
 
Screening Test B. Three-Ounce Water Swallow Test (3-WST): Championed in ARF patients by our Yale colleagues, the 3-
WST will be performed according to standard procedures. Patients will receive three ounces of water and will be instructed 
to drink the entire amount, via a cup or straw, completely and without interruption (the cup can be held to the patient’s mouth 
by the SLP).74;76;109 The 3-WST will be scored as pass/fail.  Criteria for failure of the 3-WST are: the inability to drink the 
entire amount, coughing or choking up to 1 minute after completion, or the presence of a wet-hoarse vocal quality.  
Screening Test C. Toronto Bedside Swallowing Screening Test (TOR-BSST): Though originally developed for stroke 
patients, the TOR-BSST has been used more broadly for other patient populations.12,82,83 More recently, the TOR-BSST 
was studied in critically ill patients (manuscript currently under review). Designed to be administered by nurses, we will 
have our study SLPs complete the 4-hour TOR-BSST training program. Dr. Rosemary Martino (TOR-BSST developer) will 
provide our study SLPs access to the TOR-BSST educational videos and modules to enhance study fidelity (see Dr. 
Martino’s letter of support). For consistency, we will have study SLPs assess each of the four components of the TOR-
BSST; including assessment of baseline voice, tongue movement, ability to swallow water and post-voice quality. The 
ability to swallow water is assessed using the 2-ounce water swallow test according to the TOR-BSST protocol. 
3. FEES examination: The SLP will review the subject’s medical record and become knowledgeable with the patient’s 
medical history. The FEES examination will be performed by a second SLP who is blinded to the results of the BSE. The 
FEES should be performed within approximately 4 hours of the BSE.  
 
Similar to the BSE, the patient should be seated with the head of the bed as elevated as possible. At the discretion of the 
SLP/investigator, Afrin and Lidocaine spray can be administered into the nasal passage before the laryngoscope is 
inserted. The use of these medications will be noted in the case report form.  
Part 1: First the SLP will perform and videotape the examination of the upper airway. 
Velar closure, base of the tongue retraction, laryngeal elevation, right and left vocal cord/arytenoid mobility, right and left 
pharyngeal wall medialization, epiglottic retroflexion, granuloma formation, and upper airway edema will be assessed. 
Laryngeal sensation will be assessed by observing the laryngeal adductor reflex (LAR) or a patient response to a light 
touch/poke to the aeryepiglottic folds bilaterally with the tip of the laryngoscope, and scored dichotomously. 

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Part 2: Standardized consistency testing: The SLP will then administer five standard consistencies in two trials of each 
consistency with different amounts.106  
Boluses will be administered from lowest to highest aspiration risk: 1) ½ tsp, then  1 tsp ice chips , 2) 1 tsp of nectar thick 
liquids,  then 3 tsp of nectar thick liquids, 3) a 2 ounce patient controlled 
administration of nectar thick liquids, 4) 1 tsp of pureed solids 
(applesauce), then 10 mls of pureed solids (applesauce), 5) 5 mls of thin 
liquids (water or milk),15 mls of  thin liquids (water or milk), and a 2 ounce 
patient controlled administration of thin liquids and 6) ¼ of a graham 
cracker.107 The patient will be instructed to chew the graham cracker 
before swallowing. In order to limit the complexity and duration of our 
consistency testing, honey-thick liquids will be excluded from the protocol.  
After the swallow, the laryngoscope will be advanced to closely view the 
partient’s airway. The SLP will wait for 10 seconds following the completion 
of each individual trial before recording the results for that consistency. If 
necessary, patients will be allowed to drink water between consistency 
tests to clear any remaining residue from their upper airway 
The entire FEES will be video recorded. The SLP will score each of the trials using the PAS score.   
In addition for each of the trials of the consistencies, the SLP will record the following two physiological measures:  
1) Swallowing onset time: The time from first bolus visualization until swallow onset.   
2) Incomplete bolus clearance: leaving residue in the pharynx or laryngeal vestibule after a swallow. 
Using the video recordings, the quantification of the swallowing onset time and incomplete bolus clearance will be 
determined by a single observer. 
The results of the different components of the FEES assessment will be made available to the treating team if requested. 
The coordinator should make sure that the FEES CRF is completely filled out before the SLP who completed the test 
leaves the ICU. See Appendix for FEES evaluation form. 
4. Outcome Assessments 
All patients will be followed for the subsequent outcome assessments. 
Date of ICU discharge 
ICU length of stay 
Date of hospital discharge 
Hospital length of stay 
Discharge location 
Reintubation since enrollment 
 
If yes, date of reintubation 
Died during ICU stay 
Died during hospital stay 
Surgical feeding tube placed? 
 
Human Subjects 
Each study participant or a legally authorized representative (LAR) must sign and date an informed consent form. 
Institutional review board approval will be required before any subject is entered into the study. PETAL will use a central 
IRB. 
Selection of Subjects 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. The ICUs will be screened to determine 
if any patient meets inclusion and exclusion criteria. Data that have been collected as part of the routine management of 
the subject will be reviewed to determine eligibility. No protocol-specific tests nor procedures will be performed as part of 

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the screening process. If any subjects meet criteria for study enrollment, then the attending physician will be asked for 
permission to approach the patient or his/her LAR for informed consent. Study exclusion criteria neither unjustly exclude 
classes of individuals from participation in the research nor unjustly include classes of individuals from participation in the 
research. Hence, the recruitment of subjects conforms to the principle of distributive justice.  
Justification of Including Vulnerable Subjects  
The present research aims to investigate the ability of a bedside evaluation to detect aspiration in acute respiratory failure 
survivors.  Due to the nature of acute respiratory failure and its risk factors (eg, sepsis, trauma), some patients will have 
impaired decision-making capabilities. This study cannot be conducted if limited to enrolling only those subjects with 
retained decision-making capacity. Hence, subjects recruited for this trial are not being unfairly burdened with involvement 
in this research simply because they are easily available. 
Informed Consent 
Federal regulations 45 CFR 46.111(a)(5) require that informed consent will be sought from each prospective subject or 
the subject's legally authorized representative (LAR). As we will enroll patients recovering from acute respiratory failure, 
we anticipate initial informed consent will frequently be obtained from LARs. Consent will be obtained via face-to-face 
meeting.  Patients who survive and regain decision-making capacity before hospital discharge will be approached for re-
consent.  At this point, subjects may choose to continue with study participation or withdraw from the study. Subjects who 
opt not to continue will be asked if their collected data to the point of withdrawal request, may be used in the primary 
analysis. If the subject does not agree, the data will be destroyed. 
The investigator is responsible for ensuring that the LAR understands the risks and benefits of participating in the study, 
answering any questions the LAR may have throughout the study and sharing any new information in a timely manner 
that may be relevant to the LAR's willingness to continue the subject's participation in the trial.  
The study team will make every effort to minimize coercion. All study participants, or their LARs, will be informed of the 
objectives of the study, all procedures, and voluntary nature of participation. The informed consent discussion will be used 
to explain study risks and benefits before the patient is entered into the study and documenting that the LAR is satisfied 
with his or her understanding of these risks and benefits, rights of a participant and consents to participate in the study.   
Continuing Consent 
For subjects for whom consent was initially obtained from a LAR, who subsequently regain decision-making capacity 
while in hospital, all sites will obtain written informed consent for continuing participation, inclusive of continuance of data 
acquisition. The initial consent form signed by the LAR will reflect that such consent will be obtained. 
Withdrawal of Consent 
Patients may withdraw or be withdrawn (by the LAR) from the trial at any time without prejudice. Data recorded up to the 
point of withdrawal will be included in the trial analysis, unless consent to use their data has also been withdrawn. If a 
patient or LAR requests termination of the trial during the study period, the study will be stopped but the patient will 
continue to be followed up as part of the trial. If a patient or LAR withdraws consent during trial treatment, the trial will be 
stopped but permission will be sought to access medical records for data related to the study. If a patient or LAR wishes 
to withdraw from the trial after completion of trial treatment, permission to access medical records for study data will be 
sought.   
Identification of Legally Authorized Representatives 
Many of the patients approached for participation in this research protocol may have limitations of decision-making 
abilities due to their critical illness. Hence, we anticipate most patients will not be able to provide informed consent at time 
of study eligibility.  Accordingly, informed consent will be sought from the potential subject’s legally authorized 
representative (LAR).   
Regarding proxy consent, the existing federal research regulations (‘the Common Rule’) states at 45 CFR 46.116 that “no 
investigator may involve a human being as a subject in research…unless the investigator has obtained the legally 
effective informed consent of the subject or the subject’s legally authorized representative”; and defines at 45 CFR 46 102 
(c) a legally authorized representative (LAR) as “an individual or judicial or other body authorized under applicable law to 

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consent on behalf of a prospective subject to the subject’s participation in the procedures(s) involved in the research.” 
OHRP defined examples of “applicable law” as being state statutes, regulations, case law, or formal opinion of a State 
Attorney General that addresses the issue of surrogate consent to medical procedures. Such “applicable law” could then 
be considered as empowering the LAR to provide consent for subject participation in the research. Interpretation of 
“applicable law” may be state specific and will be addressed by the IRB. 
According to a previous President’s Bioethics Committee (National Bioethics Advisory Committee), an investigator should 
accept as an LAR,a relative or friend of the potential subject who is recognized as an LAR for purposes of clinical decision 
making under the law of the state where the research takes place (National Bioethics Advisory Commitee (NBAC), 1998). 
Finally, OHRP has stated in their determination letters that a surrogate could serve as a LAR for research decision making 
if such an individual is authorized under applicable state law to provide consent for the “procedures” involved in the 
research study (Office of Human Research Protections (OHRP), 2002).      
Each participating site will defer to their institutional requirements for designation of LAR.   
Justification of Surrogate Consent 
According to the Belmont Report, respect for persons incorporates at least two ethical convictions; first, that individuals 
should be treated as autonomous agents, and second, that person with diminished autonomy are entitled to protection. 
One method that serves to protect subjects is restrictions on the participation of subjects in research that presents greater 
than minimal risks. Commentators and Research Ethics Commissions have held the view that it is permissible to include 
incapable subjects in greater than minimal risk research as long as there is the potential for beneficial effects and that the 
research presents a balance of risks and expected direct benefits similar to that available in the clinical setting (Dresser, 
1999). Several U.S. task forces have deemed it is permissible to include incapable subjects in research. For example, the 
American College of Physicians’ document allows surrogates to consent to research involving incapable subjects only  “if 
the net additional risks of participation are not substantially greater than the risks of standard treatment.” (American 
College of Physicians, 1989). Finally, the National Bioethics Advisory Committee (NBAC) stated that an IRB may approve 
a protocol that presents greater than minimal risk but offers the prospect of direct medical benefits to the subject, provided 
that…the potential subject’s LAR gives permission…” (National Bioethics Advisory Committee (NBAC), 1998) 
Consistent with the above ethical sensibilities regarding the participation of decisionally incapable subjects in research 
and the previous assessment of risks and benefits in the previous section, the present study presents a balance of risks 
and potential direct benefits that is similar to that available in the clinical setting.     
Additional Safeguards for Vulnerable Subjects   
The present research will involve subjects who might be vulnerable to coercion or undue influence. As required in 
45CFR46.111(b), we recommend that additional safeguards be included to protect the rights and welfare of these 
subjects. Such safeguards might include, but are not limited to: a) assessment of the potential subject’s capacity to 
provide informed consent, b) the availability of the LAR to monitor the subject’s subsequent participation and withdrawal 
from the study; c) augmented consent processes. The specific nature of the additional safeguards will be left to the 
discretion of the central IRB, in conjunction with the sites.   
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 laboratory specimens, 
evaluation forms, and reports will be identified only by a coded number.  The coded number will be generated by a 
computer, and only the study team will have access to the codes.  All records will be kept in a locked, password protected 
computer.  All computer entry and networking programs will be done with coded numbers only.  All paper case report 
forms will be maintained inside a locked office or electronically secured in a REDCap database.  Study information will not 
be released without the written permission of the patient, except as necessary for monitoring by the National Heart, Lung, 
and Blood Institute, and the PETAL Clinical Coordinating Center. 
Adverse Events 
Safety Monitoring 

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Assuring patient safety is an essential component of this protocol. Each participating investigator has primary 
responsibility for the safety of the individual participants under his or her care. The Investigators will determine daily if any 
adverse events occur during the period from enrollment through study day 2 or ICU discharge, whichever occurs first.   
The following adverse events will be collected in the adverse event case report forms: 
• 
Serious adverse events 
• 
Nonserious adverse events that are considered by the investigator to be related to study procedures or of 
uncertain relationship  
A clinical study adverse event is any untoward medical event associated with the study procedure in humans, whether or 
not it is considered related to a study procedure.   
Adverse events related to protocol procedures must be evaluated by the investigator. If the adverse event is judged to be 
reportable, as outlined above, then the investigator will report to the medical monitor their assessment of the potential 
relatedness of each adverse event to protocol procedure. Investigators will assess if there is a reasonable possibility that 
the study procedure caused the event, based on standard criteria. Investigators will also consider if the event is 
unanticipated or unexplained given the patient’s clinical course, previous medical conditions, and concomitant 
medications.   
If a patient's participation in the study is discontinued as a result of an adverse event, study site personnel must report the 
circumstances and data leading to discontinuation of treatment in the adverse event case report forms.   
Serious Adverse Events 
Serious adverse event collection begins after the patient or surrogate has signed informed consent and has undergone 
study procedures.  If a patient experiences a serious adverse event after consent, but prior to the start of the study, the 
event will NOT be collected unless the investigator feels the event may have been caused by a protocol procedure.  
Study site personnel must alert the medical monitor 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.  
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in one of the following 
outcomes and is not classified as a clinical outcome of acute respiratory failure using the definitions noted above: 
• 
Death  
• 
A life-threatening experience (that is, immediate risk of dying) 
• 
Prolonged inpatient hospitalization or rehospitalization 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if admission to the hospital or 
prolongation of hospitalization was a result of the adverse event. Emergency room visits that do not result in 
admission to the hospital should be evaluated for one of the other serious outcomes (e.g., life-threatening; 
required intervention to prevent permanent impairment or damage; other serious medically important event). 
• 
Persistent or significant disability/incapacity 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if the adverse event resulted 
in a substantial disruption of a person's ability to conduct normal life functions, i.e., the adverse event resulted in a 
significant, persistent or permanent change, impairment, damage or disruption in the patient's body 
function/structure, physical activities and/or quality of life. 
Important medical 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 and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 

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Serious adverse events will be collected during the first 2 study days or until ICU discharge, whichever occurs first, 
regardless of the investigator's opinion of causation. Thereafter, serious adverse events are not required to be reported 
unless the investigator feels the events were related to either study drug or a protocol procedure. 
 
 
 

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APPENDIX: Case Report Forms 
Refer to separate Appendix document:  21-3873 Moss Appendix CRF 07142021.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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