Acute Effect of Ventilatory Support During Exercise in Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injury
Sponsor: Spaulding Rehabilitation Hospital

 
PARTNERS HUMAN RESEARCH COMMITTEE 
DETAILED PROTOCOL 
 
PROTOCOL TITLE: 
Ventilatory Support to Improve Exercise Training in High Level Spinal Cord Injury 
 
Clinicaltrials.gov #: NCT02865343 and NCT03267212 
 
Date: 10/17/2017 
 
I. 
BACKGROUND AND SIGNIFICANCE 
 
The cardioprotective effect of regular aerobic exercise in the general population is broadly accepted, but 
its importance for those with spinal cord injury (SCI) may be even greater.1 Although regular aerobic 
exercise with sufficient intensity and duration can improve overall health, daily energy expenditure is low 
in those with SCI, due to lack of both motor function and options for accessible physical activity. To 
overcome this, we developed a unique form of exercise for those with SCI that specifically mirrors 
exercise performed by the able-bodied. Functional Electrical Stimulation Row Training (FESRT) couples 
volitional arm and electrically controlled leg exercise,2 increasing the active muscle and resulting in the 
benefits of large muscle mass exercise. We have found improvements in peak aerobic capacity of up to 
50% with FESRT in these patients.2 However, despite the potential for enhancing aerobic capacity, those 
with high level lesions (C4 to T4) have the greatest denervation of pulmonary muscle and our preliminary 
work suggests this limits the aerobic capacity that can be achieved with FESRT. Despite the ability to 
train the denervated leg skeletal muscle via hybrid FES exercise, the inability to increase ventilation 
beyond limits set by high level SCI restricts aerobic capacity.  
 
Respiratory restriction in SCI reduces inspiratory capacity in direct relation to lesion level,3 and 
those with high level injuries have the greatest compromise. As a result, the increase in ventilatory 
requirements with FES training results in an imbalance between ventilatory capacity and greater whole 
body skeletal muscle demand after FESRT. Hence, external ventilatory support could improve the ability 
to exercise train and hence enhance the adaptations to chronic exercise in high level SCI. In obstructive 
and restrictive pulmonary disorders, non-invasive ventilation (NIV) during exercise training can enhance 
exercise tolerance4, 5 and improve gains in exercise capacity.6, 7 Therefore, we hypothesize that the use 
of NIV during FESRT will reduce ventilatory limits to exercise, leading to greater exercise tolerance and 
increased aerobic capacity in high level SCI. 
 
We have access to a large (N>70) and unique population of individuals with SCI who have been 
enrolled in FESRT for at least 6 months. Roughly half have high level SCI between C4 and T4.  
 
 
 
 
II. 
SPECIFIC AIMS 
 
 
Aim 1: To determine the magnitude of improvement in aerobic capacity after 3 months of 
FESRT+NIV compared to FESRT+shamNIV in high level spinal cord injury. 
 
Aim 2: To examine the relationship among gains in ventilation and increases in the determinants 
of aerobic capacity - maximal cardiac output and arterio-venous oxygen difference after 3 months of 
FESRT+NIV in high level spinal cord injury. 

 
Aim 3: To examine the acute effect of NIV on FES-row VO2max in subjects with both high and 
low level SCI. 
 
 
 
III. SUBJECT SELECTION 
 
FES-Row-Training Group 
Thirty individuals with high level SCI who have FES-row trained for at least 6 months will be randomized 
to (continued) FESRT for 3 months with either NIV or sham NIV. Patients will be medically stable and 
inclusion criteria are SCI at neurological level ≥T4 with American Spinal Injury Association grade A or B 
or C, aged ≥ 18 years of age. Before and after training, we will assess maximal aerobic capacity, 
ventilation, cardiac output, and arterio-venous oxygen difference. Based on our current data, we 
hypothesize that only those randomized to NIV will experience further increases in aerobic capacity and 
that these increases will relate to increased cardiac output and arterio-venous oxygen difference. This 
project will determine the feasibility and effectiveness of this approach to exercise and will lay the 
groundwork for a larger study of the impact of FESRT+NIV to improve health and function in those with 
high level SCI. 
 
 
FES-Row-Exercise Testing Only Group (Cross-Sectional) 
Fifteen individuals with SCI who have FES-row trained for >6 months will perform FES-VO2max row tests 
on separate days with and without the use of NIV to determine maximal aerobic capacity and ventilation. 
Patients will be medically stable and inclusion criteria are SCI at neurological level C5-T12 with American 
Spinal Injury Association grade A or B or C, aged ≥ 18 years of age. In our first four subjects, we have 
observed an increase in maximal aerobic capacity at baseline with NIV assisted increases in ventilation. 
This was unexpected; we hypothesized that we would increase ventilation during the test at baseline, but 
that aerobic capacity would not be higher because it would be proportional to the voluntary (unassisted) 
maximal ventilation. However, this indicates that maximal aerobic capacity in these individuals exceeds 
maximal voluntary ventilation. It will be important to determine the consistency of this response and at 
what level of injury it is not observed.  We have a large population of potential subjects who have 
completed six months of FES-row exercise training across a range of SCI level (C5-T12). Hence, we can 
determine the consistency of the effect and the dependence of the effect on SCI level. (E.g., We could 
obtain data from those with high level SCI who do not want to enroll in 3 months of training with NIV or 
sham NIV.)  
 
 
Exclusion criteria for all subjects are blood pressure>140/90 mmHg, significant arrhythmias, coronary 
disease, chronic respiratory disease, diabetes, renal disease, cancer, epilepsy, current grade 2 or greater 
pressure ulcers at relevant contact sites, other neurological disease, peripheral nerve compressions or 
rotator cuff tears that limit the ability to row, and history of bleeding disorder. 
 
Note: Any changes in cardioactive medications during the exercise testing or training protocols will be 
evaluated by the Principal Investigator and could lead to removal from the study. 
 
 
IV. SUBJECT ENROLLMENT 
 
Research study staff will obtain volunteer consent in accordance with guidelines established by the 
Institutional Review Board during the first visit to the Laboratory. Participants will be sent the consent 

form at least 48 hours in advance so they have ample time to read and ask questions.  Participants are 
encouraged to ask questions and are reminded that participation is strictly voluntary and will not affect 
their current or future care at Spaulding Rehabilitation Hospital or any of its affiliates.  
 
 
 
V. STUDY PROCEDURES 
 
Once recruited for the study the volunteer will visit the laboratory for a health screening session to 
further determine eligibility.  This one-hour session will include obtaining informed consent, detailed 
health history, height and weight measurements, resting blood pressure, resting heart rate and NIV-
device familiarization trial.   
 
Subjects may also be asked to provide additional medical records or may need further testing to 
determine their eligibility and the safety of their participation in this program which includes regular 
vigorous exercise. These additional tests may or may not be covered by insurance. The subjects will be 
responsible for obtaining any additional testing and providing the program with medical records or 
results.  
 
FES-Row-Training Groups and Training Protocols 
 
NIV support. Participants randomized to NIV will perform row training while receiving bi-level positive 
airway pressure ventilation applied through a full-face mask (Phillips Respironics, Murrysville, USA). The 
ventilator will be set in a spontaneous mode with a ramp to reach a minimal pressure of 12 cmH2O during 
inspiration and 4 cmH2O during expiration. A minimal duration for inspiration time may also be imposed 
if the patient desynchronizes with ventilator support. Parameters will then be adapted according to 
participant’s comfort and ventilatory requirement during exercise.  
 
Sham-NIV. In the sham group, similar conditions will be used but the ventilator will be applied with 
maximal pressure support of 5 cmH2O of inspiratory pressure and 2-4 cmH2O of positive end-expiratory 
pressure to overcome the resistance of the breathing circuit. 
 
Subjects in the NIV support group and Sham-NIV group will be blinded to which group they are in and 
how much NIV support they are receiving. 
 
FES-Row Training. The FES row system will optimize the contribution of the pre-trained muscle 
components of quadriceps and hamstrings. To maintain the proper training stimulus at the same 
relative intensity, a maximum FES-rowing test will be performed at baseline for intensity to be 
determined. The goal is for each volunteer to achieve an exercise intensity of 75-85% maintained for at 
least 30 minutes performed three times each week. Measurements of force produced at the foot and 
handle during FES-row training sessions will also be used to monitor training and possibly improve 
rowing technique. Subjects exercise programs will be tailored specifically to their fitness level but 
should progress quickly to the prescribed intensity as all subjects  
 
There is no limit or specific requirement for training sessions that must be attended to continue 
participating in this protocol. Subjects will be encouraged by study staff to attend three training sessions 
per week. Un-reported missed training session will be followed up with a phone call to document why 
the training session was missed and to encourage prompt return to training sessions as soon as 
possible.   
 
Strength Training during FES-RT 
As subjects will already have been participating in FES-row training they will also be given the 

opportunity to continue or start the FES-leg strength training at home concurrently on non FES-rowing 
days (~3 days/week, 30-60 minutes/session). This will be possible after the subjects have 
demonstrated the knowledge and ability of proper use of the stimulation unit for home use. This will be 
closely monitored, as they will also be FES-rowing three times per week at Spaulding Cambridge.  
 
 
Study Assessments  
 
FES-Row Training Group 
All Assessments will be performed at baseline and after three months of FES-row training. There will be 
2 separate FES-VO2max row tests, 2 separate Cardiac Output row tests and 1 Pulmonary Function test 
done at each time point (done at least 48-hours apart). Both NIV Support and Sham-NIV groups will 
perform tests with and without use of the NIV-machine.  
 
FES-Row Exercise Testing Only Group 
Subjects will perform FES-VO2max row tests on separate days with and without the use of NIV to 
determine maximal aerobic capacity and ventilation. Both FES-VO2max Row tests will be performed at 
least 48-hours apart  
 
 
 
Measurements and Testing Protocols: 
 
FES-Row-VO2maxTesting 
Individuals will refrain from eating for 2 hours prior, from caffeine and alcohol for 24 hours prior, and from 
vigorous physical activity for 48 hours prior to testing. Aerobic power will be determined from online 
computer-assisted open circuit spirometry and expired gas analysis will be performed continuously 
throughout the test with the Innocor rebreathing system (Innovision, Odense, Denmark, see details 
below). A heart rate monitor (Suunto, Valimotie 7 FI-01510, Vantaa, Finland) will be used throughout the 
tests. The baseline graded FES row test protocol will be based on each individual’s initial FES row 
response, and 1- to 2-minute workloads well be selected to achieve test protocols of 8 to 12 minutes of 
incremental exercise. The same protocol will be used for the 3-month posttest unless the initial workload 
has become too low to allow proper FES rowing technique. In this case, the initial workload will be the 
second workload from the pretest. To ensure attainment of peak exercise capacity, at least 3 of the 
following criteria must be met: 85% of age predicted maximal heart rate (220 - age), respiratory exchange 
ratio >1.1 at end exercise, plateau in oxygen consumption despite increasing workload, blood lactate 
level (Lactate Plus, Nova Biomedical, Waltham MA) of 8 mM or above, rating of perceived exertion of at 
least 17 on the Borg scale of 6 to 20, and precipitous decline in power >20W during maximal leg 
stimulation. Peak oxygen consumption will be defined as the highest value achieved over 30 seconds. 
 
Immediately after FES-rowing has stopped at the end of the VO2max test, subjects will have a finger tip 
pricked with a safety lancet in order to get a drop of blood that will be used  to measure peak lactate 
levels in whole blood. Peak lactate levels will be used to evaluate exercise intensity as well as to monitor 
training status.  
 
 
 
Cardiac Output Row Testing 
Individuals will refrain from eating for 2 hours prior, from caffeine and alcohol for 24 hours prior, and from 
vigorous physical activity for 48 hours prior to testing. Cardiac output will be measured at rest and during 
a three to six minute FES-row steady state exercise bout at an intensity of 80% of peak heart rate.  

Cardiac Output is measured using the inert gas re-breathing method (Innocor, Innovision, Odense, 
Denmark), a previously validated non-invasive method for rest and exercise measures. Notably, inert gas 
re-breathing measurements of cardiac output do not require steady state conditions and hence can be 
obtained during graded tests. An oxygen-enriched mixture of an inert soluble gas (0.5% nitrous oxide) 
and an inert insoluble gas (0.1% sulphur-hexafluoride) are used to indirectly assess pulmonary blood 
flow and lung volume, respectively. In the absence of pulmonary shunt, cardiac output = pulmonary blood 
flow. Arteriovenous oxygen difference will be derived by applying the Fick principle: arteriovenous oxygen 
difference = oxygen consumption / cardiac output. Subjects will do 2 re-breathing maneuvers at rest and 
2 re-breathing maneuvers once they have achieved target heart rate. 
 
 
Pulmonary Function Tests  
Spirometry will be used to measure lung function, specifically the measurement of the amount (volume) 
and/or speed (flow) of air that can be inhaled and exhaled. Specifically, Forced Volume Vital Capacity 
(FVC) and Maximum Voluntary Ventilation (MVV) tests will be administered. 
 
Regional Cerebral Blood Flow 
A Near-Infrared Spectroscopy (NIRS; PortaLite, Artinis Medical Systems) probe placed on the forehead 
contralateral to the dominant hand will be used to measure blood oxygenation during maximal exercise 
testing. NIRS-derived blood oxygenation levels will be used as a measure of cerebral blood flow at the 
prefrontal cortex. 
 
VI. BIOSTATISTICAL ANALYSIS 
 
This pilot project will employ a simple and straightforward statistical approach to compare changes within 
and between groups. Statistical significance will be set at 0.05, and power at 80%.  Normality and equality 
of variance will be assessed using tests of skewness and kurtosis. Within and between group 
(FESRT+NIV vs. FESRT+shamNIV) comparison of changes will be made using a general linear model 
accounting for potential baseline differences and the intervention effect. Correlations between ventilation, 
aerobic capacity, and hemodynamics variables (cardiac output and arteriovenous oxygen difference) will 
be assessed by Pearson’s or Spearman’s coefficient depending on the normality of the variables. If 
significant relations are found, appropriate regression analyses will be employed. 
 
VII. RISKS AND DISCOMFORTS 
 
Moderate risks are associated with exercise testing and exercise training. Some discomfort and feeling 
of fatigue will be experienced during these tests. There are other risks associated with these tests 
including abnormal blood pressure responses, fainting, irregular, fast or slow heart rhythm, and in rare 
instances, heart attack, stroke, or death. Wearing the face-mask during the VO2max testing and FES-
row training may cause feelings of claustrophobia. Exercise training may induce some muscle or joint 
discomfort when beginning an exercise program and could result in tendonitis and/or musculoskeletal 
overuse injuries over time. Subjects may feel lightheaded or short of breath during use of the NIV machine 
and during the cardiac output measurement. The electrical stimulation unit can cause tingling, pins and 
needles sensations on the skin, skin irritation, increased muscle spasticity and autonomic dysreflexia 
(signs include: headache, nausea, rise in blood pressure, sweating, and goosebumps). There is some 
discomfort with the lancet used on the finger for lactate measurement and there is a small possibility of 
swelling and bruising at the site(s), there is also a slight chance that individuals become dizzy and even 
faint. Subjects may feel lightheaded or short of breath during the pulmonary function tests, there is also 
a slight chance that individuals become dizzy and even faint. 
 
 

 
VIII. POTENTIAL BENEFITS 
 
Volunteers will have the opportunity to participate in a supervised exercise program, which may 
improve their overall cardiovascular fitness and endurance during activities of daily living as well as 
decrease risk of chronic disease. 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
The research coordinator will be responsible for monitoring the completeness of all data and source 
documents. The Principal Investigator will monitor the informed consent procedures in accordance with 
the Informed Consent Compliance Checklist of Partners HealthCare Systems HRQIP. The subject’s 
data/protocol adherence will be monitored by the research coordinator at each step in the study 
including. Checklists and note pages are used to note any deviations or omissions from the protocols. 
The Cardiovascular Research Laboratory Medical Emergency Safety Plan will be followed in the case 
of an adverse medical event. Any clinical/health related issues would be immediately presented to the 
subject (i.e. abnormal EKG, etc) to determine appropriate notification (ie. current physician or 
appropriate specialist)  
 
At each visit, study staff will prompt the participant to report any occurrences of health changes or 
problems. Any serious or non-serious adverse event will be recorded in the participant’s study folder 
and adverse event log and reviewed by the PI. Serious and non-serious adverse events will also be 
reported to the Human Research Committee in accordance with Human Research Committee reporting 
guidelines, following the timeframes specified by the Partners Investigator’s Guidelines. In case of a 
serious adverse event appropriate diagnostic and therapeutic measures will be taken, as determined by 
the investigator.   
 
 
 
 
 
 
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