Comparison of Mechanical Ventilation With Low and High Tidal Volumes in Acute Spinal Cord Injury: A Pilot Randomized Comparative Effectiveness Trial
Phase: NA
Conditions: Spinal Cord Injuries
Sponsor: The University of Texas Health Science Center, Houston

  
IRB APPROVAL DATE: 02/23/2023 
01/11/2023 
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Comparison of mechanical ventilation with low and high tidal volumes in acute spinal cord 
injury: A pilot randomized comparative effectiveness trial 
 
NCT04912583   
 
Version Date: 02/23/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
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STUDY PROTOCOL 
 
PROTOCOL NUMBER: 
 
 
PROTOCOL TITLE 1: Comparison of mechanical ventilation with low and high 
tidal volumes in acute spinal cord injury: A pilot randomized comparative 
effectiveness trial 
PROTOCOL TITLE 2: "Effects of mechanical ventilation and tidal volumes on 
inflammatory biomarkers in people with spinal cord injury." 
 
 
VERSION: 
V8 
DATE: 
01/11/2023 
 
CORRESPONDING PRINCIPAL INVESTIGATOR: 
Radha Korupolu, MD, MD 
Associate Professor, Department of Physical Medicine and Rehabilitation 
The University of Texas Health Science Centre 
 
SITE PRINCIPAL INVESTIGATOR: 
Radha Korupolu, MD, MD 
Assistant Professor, Department of Physical Medicine and Rehabilitation 
The University of Texas Health Science Centre 
 
SITE: TIRR Memorial Hermann Hospital, Houston; Craig Hospital, Englewood, CO 
 
COLLABORATORS: 
 
Argyrios Stampas, MD 
Associate Professor, Department of Physical Medicine and Rehabilitation 
The University of Texas Health Science Centre 
 
Marie-Francoise Doursout, PhD 
Professor in the Department of Anaesthesiology 
The University of Texas Health Science Centre 
 
Isaac Hernandez Jimenez, MD 
Assistant Professor, Department of Physical Medicine and Rehabilitation 
The University of Texas Health Science Centre 
 
Andrew Park, MD 
Craig Hospital | Physician Scientist 
CNS Medical Group | Spinal Cord Injury Physician 
University of Colorado Department of Physical Medicine and Rehabilitation | Clinical 
Assistant Professor. 
 
 
 
 
 
IRB NUMBER: HSC-MS-21-0222 

  
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GENERAL INFORMATION 
 
 
Name and address of the sponsor of the study: KL2 Active and Craig. H Neilsen 
Foundation grant: pending 
 
-Craig. H Neilsen Foundation, 16830 Ventura Blvd, Encino, CA 91436 
 
Name and address of the person authorized to sign the protocol and amendments: 
Write the names of all the members of the study team who are authorized to sign protocol 
and amendments. 
Radha Korupolu, Argyrios Stampas, Marie-Francoise Doursout, Isaac Hernandez 
Jimenez 
 
Name and address of study monitor: 
If your study does not have a monitoring plan, state that here. 
No study monitor. 
 
Name, title, address and telephone number(s) of the medical expert for the trial 
 
Radha Korupolu, MD, MS, Associate Professor, Department of Physical Medicine and 
Rehabilitation, 
, 1333 Moursund Street, Houston, Texas 
Ph: 
 
 
Argyrios Stampas, MD, MS, Associate Professor, Department of Physical Medicine and 
Rehabilitation, 1333 Moursund street, Houston, Texas 
Ph: 
 
 
 
Name and title of the investigator(s) and sub-investigators responsible for the trial 
with address and phone number(s) 
 
Radha Korupolu, MD, MS, Assistant Professor, Department of Physical Medicine and 
Rehabilitation, 
 1333 Moursund Street, Houston, Texas 
Ph: 
 
 
Argyrios Stampas, MD, MS, Associate Professor, Department of Physical Medicine and 
Rehabilitation, 1333 Moursund Street, Houston, Texas 
Ph: 
 
 
Isaac Hernandez Jimenez, MD, Assistant Professor, Department of Physical Medicine and 
Rehabilitation, 1333 Moursund Street, Houston, Texas 
Ph: 
 
 
Andrew Park, MD 
Craig Hospital | Physician Scientist 
CNS Medical Group | Spinal Cord Injury Physician 
University of Colorado Department of Physical Medicine and Rehabilitation | Clinical 
Assistant Professor. 
(E) andrew.park@cuanschutz.edu (P) 
 
 
Name and addresses of the clinical laboratories and/or other institutions involved in 
the trial 
IRB NUMBER: HSC-MS-21-0222 
-Centre for Clinical and Translational Sciences KL2 funding, The University of Texas 
Health Science Centre 

  
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Marie-Francoise Doursout, PhD (Dourosut Lab) 
 
Department of Anaesthesiology 
The University of Texas Health Science Centre 
 
 
1. 
BACKGROUND AND RATIONALE 
The annual incidence of SCI in the United States is about 17,810 new cases; cervical 
lesions resulting in complete or incomplete tetraplegia account for 55% of new cases.1 2 In the 
acute phase after SCI up to 74-84% of people will experience respiratory complications such as 
pneumonia, atelectasis and ventilatory failure necessitating mechanical ventilation (MV).1 3-9 
Pneumonia is the leading cause of death after acute spinal cord injury (SCI) and is 
associated with poor neurologic recovery, increased length of stay, and increased mortality.1 10-13 
The impact of infection can be seen with decreased functional gains during acute rehabilitation.14 
Therefore, strategies to mitigate the risk of pneumonia and facilitate early ventilator weaning are 
of primary importance to decrease morbidity and mortality and improve lifelong functional 
outcomes in people with SCI. 
Optimal ventilator settings have been shown to reduce pneumonia and facilitate early 
weaning in people without SCI.15-23 The ventilator settings of interest are tidal volume (Vt) and 
positive end-expiratory pressure (PEEP).  Vt is the volume of air the ventilator provides with 
each “breath” in volume control modes. PEEP is the alveolar pressure above atmospheric 
pressure that is applied at the end of expiration to prevent cyclic opening and closing of alveoli to 
maintain adequate oxygenation.24 
Acute Respiratory Distress Syndrome (ARDS) Network protocol recommends smaller tidal 
volume ≤6 ml/kg predicted body weight (pbw) and positive end-expiratory pressure (PEEP) to 
prevent secondary respiratory complications and decrease mortality in people with ARDS, based 
on robust evidence from multicentre clinical trials.15 16 23 Following the ARDS Network trial, there 
have been several randomized clinical trials (RCTs) conducted in other diagnoses (non-ARDS 
and non-SCI population) in which Vt of greater than 8-12 ml/ kg pbw and less than 6-8 ml/kg pbw 
were compared.17-22 Results from these trials revealed a decreased risk of acute lung injury (ALI) 
and pneumonia in low Vt groups compared to high Vt groups.17-22 
However, current SCI clinical practice guidelines recommend starting Vt of 15 ml/kg pbw 
with an incremental increase in Vt up to 25 ml/kg pbw and weaning off PEEP.4 Unlike the needs 
for MV with pulmonary disease, respiratory function after SCI is limited by low lung volumes due 
to hypoventilation secondary to weakness or paralysis of inspiratory muscles. Therefore, bigger 
“breaths” (high Vt) are recommended to prevent atelectasis and improve lung capacity. In 
preparation for ventilator weaning, Vt is further increased. 4 25 However, in studies comparing 
high vs. low Vt in non-SCI population, low Vt was not associated with a higher risk of 
atelectasis.17 20 21 Importantly, in our cohort study of people with acute SCI, we did not find any 
difference in improvement in breathing capacity or vital capacity with high Vt and moderate Vt 
MV.26 Furthermore, emerging evidence in people with and without SCI suggests that low Vt 
leads to improved respiratory outcomes.17-22 26 27 
The presumed mechanism for worsening morbidity with increased Vt ventilation 
has been called volutrauma- overstretched alveoli leading to disruption of pulmonary epithelium 
and endothelium, lung inflammation, hypoxemia, and the release of inflammatory mediators 
which play a role in the development of pneumonia, lung injury, and sepsis.28 29 These changes 
result in poor pulmonary outcomes such as the prolonged need for mechanical ventilation, and 
increased risk for pneumonia.15 17-20 30 In human RCTs with and without ARDS, lower tidal 
volume ventilation resulted in a greater reduction of inflammatory markers, e.g., tumor necrosis 
factor (TNF) α, IL-6 compared to the higher tidal volume group.15 30-33 
Current evidence in SCI supporting high Vt practice has several limitations.25 34 Current 
guidelines were written based on a small (n=42) retrospective study34 in which vast range of Vts 
of 11.6 to 19.4 ml/kg ideal body weight (IBW) versus 20.3 to 32.2 ml/kg IBW were compared. 
The groups were different at baseline, with the low Vt group having a lower vitIaRlBcaNpUaMcBityERa:t HSC-MS-21-0222 

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admission and other factors suggesting a higher severity of SCI and respiratory impairment. 
This was not taken into consideration during the analysis. Further support for high Vt ventilation 
in SCI comes from a small randomized control trial (n=33) in subacute SCI comparing Vts of 10 
and 20 ml/kg PBW, which did not find a difference in the rate of ventilator-associated pneumonia 
(VAP) and ventilator weaning days between 2 groups.25 This study was limited by an 
underpowered sample size.25 Therefore, the results of this study should be interpreted with 
caution. 
Besides, preliminary results from our cohort studies and survey suggest: 
• 
HVt in the ICU setting with increased probability of ventilator associate pneumonia 
(VAP).27 
• 
HVt in acute rehab is associated with a higher risk of pneumonia and pulmonary adverse 
event compared to moderate Vt.26 
• 
Variation in ventilator settings used for patients with acute SCI in acute care hospital at 
the time of discharge to a rehabilitation facility (Unpublished data). 
• 
Variation in ventilator settings used in acute care hospital and rehabilitation facilities 
across the globe for patients with acute SCI (in press). 
 
This clinically important controversy in acute SCI should be addressed in a large RCT with 
robust power analysis. However, prior to initiating a full-scale randomized clinical trial, a pilot 
comparative effectiveness randomized clinical trial is required to evaluate the outcomes and 
feasibility of recruitment, randomization, retention, and protocol adherence to demonstrate that 
the methods and procedures can work in a large-scale study. This pilot study will also help us 
identify inflammatory markers pertaining to lung injury in people with SCI. 
 
2. 
HYPOTHESIS AND OBJECTIVES 
We propose a pilot randomized comparative effectiveness trial comparing respiratory 
complications and inflammatory markers based on MV settings of 8-10 ml/kg pbw and higher Vt 
of 14-16 ml/kg pbw in people with acute cervical SCI in an acute inpatient rehabilitation hospital. 
Our long-term goal is to study optimal ventilator settings and treatment approaches in acute 
SCI to reduce infections and improve lifelong outcomes. 
 
Objectives: 
 
Objective 1: To compare MV outcomes of high vs. low Vt on the relative risk of pneumonia in 
the acute rehabilitation hospital. 
 
Objective 2: To generate the feasibility data to inform the future RCT design. To achieve 
this objective, we will obtain the following data: a) Recruitment rate: the proportion of eligible 
people who provide consent (b) Adherence rate: the proportion of participants in each group who 
receive assigned intervention per protocol; (c) Retention rate: the proportion of participants in 
each group who complete all study procedures prior to discharge from our hospital; d) Missing 
data: Percentage of missing data in each group. 
 
Objective 3: To analyze MV related lung injury inflammatory biomarkers in relation to tidal 
volume and outcomes. 
 
Hypothesis: 
 
Hypothesis 1: We hypothesize that Bayesian analysis will indicate a>70% probability of lower 
risk of pneumonia in people with acute cervical SCI receiving lower Vt MV than higher Vt. 
 
Hypothesis 2: We hypothesize that we will be able to recruit at least 80% of eligible people 
each year and among recruited subjects, adherence and retention rate will be 80%, with less 
than 10% missing data on outcome measures. 

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Hypothesis 3.1: We hypothesize that MV-related lung injury inflammatory biomarkers (IL-1, IL6, 
IL-8, and tissue necrosis factor α levels) in serum and tracheal aspirate would be lower in the 
low Vt MV group compared to high Vt). 
 
Hypothesis 3.2: People with acute cervical SCI receiving MV will have higher inflammatory 
markers levels than people with acute cervical SCI who do not require mechanical ventilation. 
 
Hypothesis 3.3: People with acute cervical SCI independent of mechanical ventilation status 
who have higher inflammatory marker levels are more likely to develop pneumonia and other 
respiratory complications. 
 
Potential Risks and Benefits: 
 
The overall risk of pulmonary complications in people with acute SCI ranges from 74-84%. The 
proposed study is comparing tidal volume parameters used within current clinical practice. Our 
objective is to find optimal ventilator settings within the current clinical range to lower the current 
risk of pneumonia. Based on current evidence, pneumonia is associated with poor neurological 
recovery. Therefore, any decrease in the incidence of pneumonia can contribute to improved 
neurological recovery. There are no known risks of pulmonary complications due to 
participation in this study. 
 
Risks of a blood draw and tracheal aspirate sample collection: The risks and discomfort of 
drawing blood include temporary discomfort from the needle stick, the possibility of pain or 
bruising at the blood draw site. Similarly, tracheal sample collection can also result in 
temporary discomfort. 
Other Risks: There is a risk that confidentiality will be inadvertently compromised. 
 
 
3. STUDY POPULATION 
Sample Size: We plan to recruit 45 subjects (15 in low Vt, 15 in high Vt, and 15 in the control 
group). We will recruit 30 adults with acute cervical SCI admitted on mechanical ventilation 
from TIRR MHH and Craig Hospital and an additional 15 people with acute cervical SCI not 
dependent on mechanical ventilation at admission to serve as controls from TIRR MHH. 
Criteria for Recruitment: All consecutive patients with SCI admitted to TIRR MHH and Craig 
Hospital will be screened for eligibility based on inclusion and exclusion criteria during the study 
period. The screening will involve the review of history from the patient or primary admitting 
clinician. If a patient meets eligibility criteria, the research coordinator will provide further 
information on the study, answer any questions, and recruit if they are willing to participate and 
provide consent. 
Inclusion Criteria: Subjects must meet all of the inclusion criteria listed below to participate in 
this study. 
• 
Adult patients ≥ 18 years (Lung volumes and ventilator settings are different for 
ages <18 years). 
• 
Acute SCI of duration ≤ four months 
• 
Mechanical ventilation subjects: traumatic or non-traumatic cervical SCI with 
neurological level C1-C5 admitted to our acute inpatient rehabilitation facility (AIR) 
on mechanical ventilation. 
• 
Control subjects: traumatic cervical SCI admitted to 
our acute inpatient rehabilitation facility (AIR) who are not dependent on mechanical 
ventilation. 
Exclusion Criteria: All subjects meeting any of the exclusion criteria listed below at baseline will 
be excluded from participation. 

  
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• 
Severe dysphagia due to concomitant brain stem injury, which increases the risk 
of pneumonia 
• 
Severe brain injury resulting in dysphagia and inability to follow instructions to 
perform vital capacity measurements 
• 
ARDS or severe lung disease (required supplemental oxygen or ventilator prior 
to SCI) at the time of admission (these conditions will not allow patients to 
randomize because target Vt may below) 
• 
Prolonged antibiotics for > 3 weeks at the time of admission due to infection 
(e.g., osteomyelitis, epidural abscess, etc.), 
• 
Presence of diaphragmatic pacemaker. 
Withdrawal Criteria: Possible reasons for discontinuation of study intervention: Intolerance to 
proposed ventilator settings. 
 
Subject Replacement: Subjects who drop out will be replaced by screening the inpatient unit. 
Subjects that drop out will be followed for secondary outcomes collected via the EMR while they 
remain at TIRR. 
 
4. TRIAL SCHEDULE: 
Participants will be enrolled in the study upon consent within 48-72 hrs of admission to TIRR 
MHH or Craig Hospital, and participation will end on discharge from respective hospital. The 
trial will start upon IRB and respective hospital approval on July 1, 2021, and end on June 30, 
2024. 
 
5. STUDY DESIGN 
We propose a randomized comparative effectiveness trial to study systematically current Vt 
ranges to determine optimal settings to improve outcomes. Study participants will be randomly 
assigned to high tidal volume (14-16 ml/kg pbw) or low tidal volume of 8 to 10 ml/kg pbw within 
48 hrs of admission. Subjects will be stratified based vital capacity at admission (≥5.8 cc/kg 
pbw) to ensure equal allocation of those with the most severe respiratory impairment and 
unlikely to wean from the vent. In our experience, vital capacity ≥5.8 cc/kg pbw was associated 
with higher odds of weaning. We will screen and recruit an additional 15 people with acute SCI 
not dependent on mechanical ventilation at admission to serve as controls. We anticipate 3 
years to complete study recruitment. A 1:1 allocation ratio will be applied to the mechanical 
ventilation groups. Participants, principal investigator, outcome assessors, and statistician will 
be blinded to tidal volume assignment. 
 
6. METHODS AND ASSESSMENTS 
Intervention: Lower Vt group will be kept 8- 10 ml/kg pbw with PEEP, and in the high Vt group, 
the participant will receive a tidal volume of 14-16 ml/kg pbw with PEEP. The PEEP will be 
adjusted based on atelectasis on X-ray findings and patient tolerance within 5-10 cm H2O range. 
These thresholds are used based on our cohort study26 and survey data, which suggest the 
current median minimum to maximum Vt range used in rehabilitation hospital setting ranges from 
8-16 ml/kg pbw. Tidal volumes will be increased per our institutional protocol at a rate of 50-100 
ml per day until the target range is achieved. All participants at admission will be switched to 
Assist Control (AC) Mode or synchronized intermittent mandatory ventilation which is the current 
standard of practice in our free-standing acute inpatient rehabilitation unit. We will monitor peak 
and plateau pressures. All study participants will receive standard respiratory care, including 
secretion management using sub-glottic suction, mechanical insufflator-exsufflator, albuterol- 
ipratropium nebulization as-needed medications for thick secretions (e.g., N-acetylcysteine, 
guaifenesin). 
Ventilator weaning Protocol is managed by board-certified SCI medicine rehabilitation 
physicians in our institution. Internal Medicine physicians are consulted on all our mechanically 
ventilated patients, and pulmonologists are available for consultation as needeIRdB.  NTUheMvBeEnRt:ilHatSoCr-MS-21-0222 

  
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weaning protocol begins once the patient is determined to be medically stable by the attending 
physician and satisfies the following institutional criteria: lung auscultation with clear or relatively 
clear breath sounds, vital capacity >10-12 ml/kg pbw measured by Wright’s spirometer via mouth 
or tracheostomy, chest X-ray clear or stable, arterial blood gas analysis on room air within 
normal limits, no active infection, hemoglobin >10 gm/deciliter and should be tolerating 
tracheostomy cuff deflation. The institutional weaning protocol consists of 12-19 days of 
progressive ventilator-free spontaneous breathing.  The weaning schedule is adjusted 
sometimes due to respiratory complications, anxiety, and inability to tolerate protocol. 
 
Control group: Both controls and people in mechanical ventilation groups will receive standard 
comprehensive inpatient rehabilitation services, including physical therapy, occupational therapy, 
speech, and respiratory therapy if needed. 
 
Outcomes: The primary outcome is pneumonia episodes with evidence of new or progressive 
and persistent infiltrate on chest radiograph plus 2 of the following abnormal white blood cell 
count, presence of fever or hyperthermia, purulent sputum, and deterioration in gas exchange. 21 
Any new pneumonia episodes which meet the above criteria and developed 48 hrs after 
achieving target Vt will be recorded. New pneumonia events can only be recorded after 14 days 
from the onset of the first event. 
The secondary outcomes include feasibility outcomes. We will obtain the following data: a) 
Recruitment rate: the proportion of eligible people who provide consent (b) Adherence rate: the 
proportion of participants in each group who receive assigned intervention per protocol; (c) 
Retention rate: the proportion of participants in each group who complete all study procedures 
and d) Missing data: Percentage of missing data in each group. Based on only one RCT25 
performed in SCI comparing high vs. low Vt, we anticipate a total recruitment rate of 80% (i.e., 
that 80% of the eligible would consent for the study), and of those who are enrolled in the study, 
80% adherence and retention rate will be observed. We anticipate <10% missing data. 
Additional outcomes: This data will be collected from the time of admission to our rehabilitation 
hospital until discharge. a) b) Other respiratory complications: The following ventilator- 
associated events will be reported: transfer to acute care hospital due to respiratory 
complications, weaning failure, new pneumothorax, ARDS, pleural effusion, pulmonary 
embolism, atelectasis, and pulmonary edema, and c) total ventilator days, weaning days and 
hospital length of stay. 
We will perform an analysis of MV-related lung injury biomarkers. Blood and tracheal aspirate 
samples will be collected at 3-time points; at baseline within 48 hrs of admission to AIR facility, 
48- 72 hrs after achieving target Vt, and 3rd sample post- weaning or 2 weeks from target Vt. 
Samples will be processed and stored at −80 ° C until use in Dr. Doursout’s laboratory located at 
the Medical School, University of Texas in Houston, TX. We will focus on IL-1, IL-6, IL-8, and 
TNF-α levels. For controls we will obtain blood samples within 48 hrs of admission and 2 weeks 
from baseline. 
Additional data: Additional data collection will include age, sex, weight, height, date of injury, date 
of admission to AIR, time since injury, mechanism of injury, American Spinal Injury Association 
(ASIA) impairment scale (AIS), vital capacity at admission, maximum vital capacity achieved 
during AIR stay, ventilator settings including Vt, peak and plateau pressure, hospital length of stay 
and discharge location. We will also collect information on any other ongoing or new infectious 
events other than pneumonia. 
Randomization: Each subject will be randomized to either a tidal volume of 8-10 ml/kg pbw or 14- 
16 ml/kg pbw within 48 hrs of admission after obtaining consent. A 1:1 allocation ratio will be 
applied with permuted block size to maintain blindness and balance. Subjects will be stratified 
based on C1-C3 AIS A to ensure equal allocation of those with the most severe respiratory 
impairment and unlikely to wean from the vent. In our experience, C1-C3, AIS A was associated 
with lower vital capacity at admission. The study research assistant will randomize subjects in 
the redcap database, and he/she will not be involved in data analysis. 
IRB NUMBER: HSC-MS-21-0222 

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Blinding: The principal investigator (PI), statistician, outcome assessors, and participants will be 
blinded to tidal volume assignment. 
 
Study Visits and Procedures: 
Screening: Patients will be screened at the time of admission to TIRR Memorial Hermann. 
Respiratory therapist and SCI attendings will notify PI or research assistant (RA) regarding 
admits of an SCI patient dependent on mechanical ventilation or cervical SCI patients wo are not 
dependent on MV (controls). PI or RA will discuss eligibility with respiratory therapists or 
attending physicians. PI may review discharge summary from acute care hospital or history and 
physical performed at TIRR admission to determine eligibility. If a person doesn’t meet eligibility 
criteria, we will not save any identified data other than deidentified information on the reason for 
screening failure. 
The screening will require information on age, past medical and surgical history, the duration of 
SCI, etiology of SCI, the dependence on a ventilator, neurological level and current medications. 
Consent: If a subject agrees to participate, then they will be given an IRB-approved consent form 
to review and sign. There will be separate consent forms for MV group and controls due to 
different risks and procedures involved for participation in respective group. Those with 
tetraplegia will unlikely have the ability to sign and we will have a third-party attest to the consent. 
Because of the study's time constraints, they will have 1 day to decide upon whether they will 
participate. 
Study procedures for MV group: 
Day 0-1: screen, approach for informed consent 
Day 1-2: obtain consent and randomization 
Day 1-2: Baseline blood and tracheal specimen for inflammatory marker analysis 
Day 1-4: Titrate tidal volume to achieve respective targets in each group 
Day 4-6: 2nd blood and tracheal specimen (within 48 hrs after achieving target Vt) 
Days 14-18: 3rd sample (post-weaning or 2-week sample) 
Day 0- Discharge: Adverse events monitoring and outcome data collection 
 
Study procedures for control group: 
Day 0-1: screen, approach for informed consent 
Day 1-2: obtain consent 
Day 1-2: Baseline blood specimen for inflammatory marker analysis 
Days 14-18: 2nd sample (2-weeks from baseline) 
Day 0- Discharge: Adverse events monitoring and outcome data collection 
 
 
We will collect demographics, outcome data, and adverse events from electronic medical 
records during their stay at TIRR (day 0- discharge). 
7. TRIAL MATERIALS 
The intervention proposed in this study doesn’t need new equipment. Study intervention 
involves adjusting their current ventilator settings. Clinical outcome measures will be collected 
from electronic medical records in respective hospitals. 
Inflammatory markers will be analyzed from blood and tracheal samples of participants. ELISA 
assays to assess markers of inflammation. A Millipore Multiplex MAP® 37-plex human cytokine 
panel (EMD Millipore, Billerica, MA, USA) will be used. Laboratory supply will include pipettes, 
tubes, reagents, chemicals, and gauze. The majority of the equipment required is provided by 
the institution and/or is part of the standard of care at TIRR Memorial Hermann or available at 
UTHealth for research use. E.g., Office space, computers, and access to MS office software for 
creating data collection report forms. RA or PI will transport samples after collection for storage 
and analysis to Dr. Doursout’s lab. 

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AC 
SIMV 
PS 
CPAP 
TC 
8% 
4% 
30% 
29% 
30% 
40% 
30% 
20% 
10% 
0% 
Ventilator modes used at the time of 
discharge from acute care hospital 
Storage of blood and tracheal specimens: Samples will be processed and stored at −80 ° C 
until use in Dr. Doursout’s laboratory located at the Medical School, University of Texas in 
Houston, TX and Craig Hospital Biorepository laboratory located at Craig Hospital, Englewood, 
CO. 
 
8. TREATMENT 
 
The current clinical practice guidelines recommend a higher tidal volume starting at 15 ml.kg 
predicted body weight (pbw) and upto 25 ml/kg pbw. These guidelines were written based on a 
small retrospective study and biological plausibility. People with SCI suffer hypoventilation due 
to paralysis of the muscle of inspiration. However, current data in people with and without 
ARDs suggests that lower tidal volume lowers the risk of morbidity and mortality and improves 
respiratory outcomes. Cohort study performed at TIRR also suggests that lower tidal volumes 
may lower the risk of pneumonia. 
Our cohort study and a recent survey of physicians managing mechanical ventilators for people 
with SCI suggest practice variation in ventilator settings used for people with SCI. 
 
Data from our center and international survey: 
Variation in ventilator settings used for patients with acute SCI in acute care hospital at 
the time of discharge to a rehabilitation facility (Unpublished data): We collected data on 
91 patients who required mechanical ventilation at the time of admission to acute inpatient 
rehabilitation (AIR) facility from 2015-2019. We noted variation (Figure 1.) in ventilator modes 
and settings used at acute care hospitals at the time of discharge. Median (interquartile range) 
tidal volumes were 7.5 (6.7-8.5) ml/kg pbw on admission to AIR facility or at the time of transfer 
from acute care hospital. 84% of patients were receiving PEEP on admission. After admission 
to the AIR facility, all patients were weaned off PEEP within the next 1-2 days and switched to 
assist control mode. Patients’ tidal volumes were gradually increased to prevent atelectasis per 
SCI clinical practice guidelines.4 As a result, the median (IQR) tidal volumes received in 
rehabilitation hospital were 14 (13-16) ml/kg pbw.  Our data suggest that ventilator settings 
used in acute care hospital and rehabilitation vary. 
Figure 1: Ventilator modes at the time of discharge from acute care hospital 
Abbreviations: Assist control; SIMV: Synchronized intermittent mandatory ventilation; PS: pressure support; CPAP: 
Continuous positive airway 
Variation in ventilator settings used in acute care hospital and rehabilitation facilities 
across the globe for patients with acute SCI (manuscript under review): We conducted an 
international online survey of providers from acute care and rehabilitation hospitals to identify 
practice variations in the management and weaning of mechanical ventilation in patients with 
acute SCI. We received 137 responses from 33 countries.  The highest Vt [median 
(interquartile range)] reported by acute care was 10 (8-10) ml/kg pbw compared to 13 (10-15) 
ml/kg pbw (p=0.001) in the rehabilitation setting. Application of PEEP and keeping the 
tracheostomy cuff inflated are commonly reported practices in acute care, whereas there is 
inconsistency with these practices in the rehabilitation setting. Regarding factors to initiate 
weaning, physicians in acute care mostly relied on arterial blood gas (70%) findings, whereas in 
the rehabilitation setting, physicians relied on vital capacity (73%). We found important 
differences in practices between “acute care and rehabilitation setting” and “within a 
rehabilitation setting.” 

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Investigato
The proposed ventilator settings are within the currently used ventilator settings across the 
globe and in our institution. Our proposed study compares tidal volume ranges of 8-10 ml/kg 
pbw and 14-16 ml/kg pbw. After reviewing our institute's data, current practice (survey results), 
and current literature in the non-SCI population, these settings were proposed. Tidal volumes 
are delivered via a mechanical ventilator used routinely in clinical practice. 
Concomitant therapy: Patients in MV group will undergo ventilator weaning and respiratory 
care for secretion management per institution standard protocol. We will collect information on 
all medications taken by the participant during the study period. Controls will receive medical 
and rehabilitation therapies per current institution standard protocol. 
Blinding: A panel of SCI attendings and a pulmonologist will determine the primary outcome. 
Deidentified data on respiratory events will be discussed with the team to determine if that event 
meets our diagnostic criteria for pneumonia and other ventilator-associated events. Data will be 
collected and presented by RA trained by PI. Inflammatory markers data from MV group and 
controls will be analysed by a blinded assessor. 
 
9. SAFETY MEASUREMENTS 
 
Collecting, Recording and Reporting of Adverse Events 
An adverse event is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of medical treatment or procedure that may or may not be considered 
related to the medical treatment or procedure. 
Outcomes of this comparative effectiveness trial include data collection of adverse events. 
Adverse events include pneumonia and other ventilator-associated events, including acute care 
transfers due to respiratory complications, pneumothorax, transfer to acute care hospital due to 
respiratory complications, weaning failure, new pneumothorax, acute respiratory distress 
syndrome, pleural effusion, pulmonary embolism, atelectasis, and pulmonary edema. 
The Investigators/ RA will be responsible for collecting and reporting adverse events during the 
trial. The investigators/ RA will collect adverse events related to the randomized control trial. 
 
The PI will report problems according to the UTHSC-Houston IRB policy, specifically in the 
event which in the opinion of the PI is both unexpected and related and places subjects or 
others at risk of harm. 
 
An adverse event is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of medical treatment or procedure that may or may not be considered 
related to the medical treatment or procedure. 
Outcomes of this comparative effectiveness trial include data collection of adverse events. 
Adverse events include pneumonia and other ventilator-associated events, including acute care 
transfers due to respiratory complications, pneumothorax, transfer to acute care hospital due to 
respiratory complications, weaning failure, new pneumothorax, acute respiratory distress 
syndrome, pleural effusion, pulmonary embolism, atelectasis, and pulmonary edema. 
The Investigators/ RA will be responsible for collecting and reporting adverse events during the 
trial. The investigators/ RA will collect adverse events related to the randomized control trial. 
 
The PI will report problems according to the UTHSC-Houston IRB policy, specifically in the 
event which in the opinion of the PI is both unexpected and related and places subjects or 
others at risk of harm. 
 
AEs and Reportable Events will be recorded. AE will be recorded on the appropriate case 
report form (CRF) page from the time written informed consent is obtained until completion of 
the study or until resolution of the reportable event. Information to be collected includes the 
description of the AE, date and time of onset, severity, duration, causality, ouItRcBomNeU,MaBnEdR: HSC-MS-21-0222 
relationship to the study procedure.  If an AE is assessed by the 
r IaRsBnAoPtPrReOasVoAnLaDblAyTE: 02/23/2023 

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Page 11 of 15 
 
attributable to study intervention, its occurrence must also be recorded in the source documents 
and reported on the CRF. 
 
Safety Monitoring Plan 
The Data Safety Monitoring Plan (DSMP) for the research study includes statistical analysis on 
rates of morbidity of study participants compared to controls by the PI and the statistician at 
50% recruitment stage. If preliminary results suggest the risk of pneumonia is <25% in one 
group compared to another group, we will stop the study. 
 
We will follow standard clinical procedures in the event of a desaturation episode. The most 
common cause of desaturation is a mucus plug in people with spinal cord injury in the 
rehabilitation setting. We will first suction the patient. If a patient is still not improving with 
suctioning, we will adjust ventilator settings, including tidal volume, to address clinical 
needs.  Given that we have a range of VT in each group, we will first adjust within that 
range if Vt has to be adjusted.  If a person requires further adjustment in Vt, we will allow 
the changes in ventilator settings to meet the patient's needs. We will not remove any 
patient from the study. We will include this data for intent to treat analysis. However, this 
event will be considered a treatment failure, and data will be included to calculate feasibility 
metrics for a larger study. 
 
 
10. 
DATA ANALYSIS 
 
Data Quality Assurance 
The PI will be solely responsible for the accuracy of the data. Single data entry will be 
performed with plans to check 10% of primary variables as a quality control. Single data entry 
error rates are slightly higher than 0.5% when performed by trained staff and the minimally 
improved error rate through double data entry is outweighed by substantial cost savings for 
single data entry. Data anomalies will be reviewed by the PI and clarification and/or correction 
will be performed. Incomplete entries will be reviewed and corrected if information is available. 
 
Data Entry and Storage 
Data will be entered in redcap database accessed through desktop computer of the PI located 
in a locked office in TIRR Memorial Hermann and Craig Hospital. Any paper documents will be 
filed in a study binder in a locked drawer in the office of the PI with HIPPA information removed. 
5 years after manuscript publication, the paper reports will be placed into the shredder bins for 
destruction. 
 
 
11. 
SAMPLE SIZE AND STATISTICAL METHODS 

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Determination of Sample Size: 
The purpose of the proposed pilot trial is to test the feasibility of conducting a randomized 
control trial comparing high vs. low Vt MV. Given the complexity of this study and practice 
variation, it is essential to evaluate recruitment and study procedures. Our cohort study data 
suggest that approximately 19 patients per year will meet eligibility. Based on Fenton et al. 
study comparing high vs. low Vt MV in SCI, we anticipate a total recruitment rate of 80% (i.e., 
that 80% of the eligible would consent for the study), i.e., on average, we are expecting to enroll 
at least 10-12 participants with SCI who are on mechanical ventilation per year for mechanical 
ventilation group and total of 30 subjects for 3 years. 
 
For the control group, we will recruit cervical SCI (neurological level C1-C5) who are not 
dependent on mechanical ventilation at admission to our acute inpatients rehabilitation facility. 
We plan to recruit a total of 15 subjects in 2 years. This is a pilot study based on feasibility of 
completing study within the above time frame this sample size was determined. We will have 
atleast 15 subjects in each group for the analysis. 
 
 
Statistical and Analytical Plans: 
Baseline data and unadjusted analysis of outcome variables will be presented as mean with 
standard deviation (SD) for a continuous variable with normal distribution otherwise as median 
with interquartile range (IQR). Categorical and ordinal data will be reported as totals and 
frequencies for baseline data and unadjusted analysis of outcome variables. 
 
Aim 1: Respiratory outcomes: We will report relative risk with credible interval and posterior 
probability. We will use neutral prior, and for binary outcomes, this will be centered at RR of 1 
with 95% credible interval of 0.3 to 3. Bayesian inference combines a prior or an estimated 
effect distribution based on previous studies and likelihood, which summarizes findings from the 
present study. 35 All Bayesian analyses will use similar models as the frequentist analyses. We 
will report risk ratios with 95% credible intervals and posterior probability of benefit or harm 
associated with the intervention. 
 
Aim 2: The number of patients contacted and recruited per month will be presented, and we will 
use the CONSORT diagram to summarize the numbers and reasons related to recruitment, 
follow-up, and dropout. The main feasibility outcomes include recruitment rate, adherence rate, 
and retention rate. 
We will summarize these outcomes by arm using frequency and percentage. We will inspect 
these percentages relative to our feasibility targets. 
 
Aim 3: Individual inflammatory marker levels will be presented as mean with standard deviation. 
A linear mixed model will be constructed on cytokine levels, adding time and randomization 
group as factors in the model. In this model, the interaction between time and group will be used 
to study differences over time between groups.  A random intercept for the patient will be 
included to account for within-patient correlation. If the residuals are not normally distributed in 
linear mixed model analyses, the data will be transformed (e.g., natural logarithm), or an 
alternative distribution will be used. The relation between cytokine levels and the development of 
pneumonia or pulmonary adverse events will be studied with a multivariate logistic regression 
analysis. A risk ratio with 95% confidence interval (95% CI) will be presented 

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12. 
ETHICAL CONSIDERATIONS 
Informed Consent 
Subjects will be recruited upon admission, meeting the established I/E criteria, and consenting 
to participation. Informed consent will be obtained by the PI and/or the research assistant, and 
they will have one day to decide. All procedures will be fully disclosed, and we will give the 
subjects as much information as possible about the intervention and the data analysis. The 
subjects will be given the opportunity to ask questions. They will be reassured that their 
participation in this study is voluntary, and they have the right to withdraw at any time from the 
study. Any new findings developed during the course of this research that may affect their 
willingness to continue will be provided to subjects. Choosing not to participate or withdrawing 
from this study will not negatively affect subjects’ right to any present or future medical 
treatment or employment to which the subjects are otherwise entitled. Although the PI and 
collaborators may have admitting privileges, they do not have an inpatient service, minimizing 
unperceived coercion, which may be possible if the admitting physicians were directly involved 
in the study. Besides, the subjects will be asked to sign a Research Subject Authorization 
Confidentiality and Privacy Rights form to comply with HIPAA regulations. 
 
IRB review 
This protocol and the associated informed consent documents have been submitted to the IRB 
for review and approval. 
 
Confidentiality of Data and Patient Records 
All patient records will remain confidential. Data with Protected Health Information (PHI) will be 
de-identified and given a subject ID found on the Linking Log. The Linking Log is a 
separate file in a separate folder found on the PI’s desktop computer. 
 
13. 
PUBLICATIONS 
 
We anticipate publication in a peer-reviewed journal within 1 year of completing this study 
describing the effects of high vs. low tidal volume people with acute SCI. 
14. 
RETENTION OF TRIAL DOCUMENTS 
 
All records for all participants, including case report forms (CRFs) and source documentation, 
will be retained by the PI in a binder locked in his office and on his desktop computer locked in 
his office. IRB and 
regulatory records will be placed in a binder along with the mentioned documents and will be 
retained by the PI in his office at TIRR Memorial Hermann, locked in a cabinet. 
 
15. BIOBANKING 
 
In the case of participants from Craig Hospital with a SCI, we will undergo a separate and 
optional consent for participant to authorize the collection and storage leftover blood, urine, or 
tissue clinical samples that may be obtained related to either the primary study or in the future 
as part of the participant’s regular medical care at Craig Hospital. The consent contains 
separate YES/NO Questions to specify consent for collection and storage of leftover research 
and clinically related samples, future permission to contact, and wishes related to incidental 
(unexpected) findings. The participant’s choice will be recorded in a separate biorepository 
database. 

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