Respiratory Muscle Strength and Function in Patients With Neuromuscular Disease
Phase: NA
Conditions: Neuromuscular Disease
Sponsor: University of Florida

Respiratory Muscle Strength and Function in Patients With Neuromuscular Disease 
NCT01555905 
Document Date: 07/28/2020 
 
 

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Protocol 
1. Project Title 
 
Respiratory Muscle Strength and Function in Patients with Neuromuscular Disease 
2. Investigator(s): 
 
Barbara Smith, PhD, PT 
Barry Byrne, MD, PhD 
3. Abstract: 
 
Respiratory insufficiency is the most common cause of morbidity and mortality in neuromuscular 
diseases. A hallmark of many neuromuscular diseases is progressive respiratory insufficiency and 
an eventual dependence upon assisted ventilation. Inspiratory muscle training (IMST) is a 
potential treatment option that has been shown to increase strength and ventilatory function in 
critically ill, difficult to wean adults and in patients with mild neuromuscular weakness. However, it 
is poorly understood whether breathing function can be modified by IMST, in patients with 
neuromuscular disease and symptomatic ventilatory insufficiency. The proposed study measures 
IMST-induced changes in ventilatory function in adults with neuromuscular disease, and whether 
strength gains translate to improved resting ventilation. Patients will undergo IMST exercises, 3-5 
days per week for up to 3 months. Outcome variables include measures of change in pulmonary 
function, muscle strength and ventilatory pattern.  
4.  Background: 
 
Inherited neuromuscular diseases (NMDs) include muscular dystrophies, motor neuron 
diseases, metabolic myopathies, or other congenital myopathies. Although the genetic etiology, 
pathophysiology, and disease course varies vastly between the inherited neuromuscular 
diseases, a commonality is a progressive loss of ventilatory muscle function. Respiratory 
muscle dysfunction increases the rate of pulmonary complications and death and is a major 
factor in respiratory failure1, 2. Respiratory failure is the primary cause of mortality for most 
INMDs 3.  
 
Ventilation is a mechanical process, where the respiratory muscles function as a pressure pump 
to drive inspiratory airflow and increase the lung volume. Patients with neuromuscular diseases 
typically present with a restrictive pulmonary pattern, where compliance is reduced by muscle 
weakness and a stiffened chest wall, creating increased mechanical loads at baseline and 
intensifying neuroventilatory drive. When the efferent neuromuscular drive is consistently unmet 
by sufficient ventilatory motor output, the mismatch is perceived as dyspnea 4 and clinically 
appears as hypoventilation and hypercapnia. In chronic, progressive neuromuscular disease, 
the principal determinant of ventilatory insufficiency is weakness of the respiratory muscles. 
 
The principal strategies to attenuate chronic ventilatory insufficiency are to reduce the load of 
breathing, to strengthen the capacity of the respiratory muscles, or a combination of the two 
approaches. Medications, positioning aids or assisted ventilation have been used to reduce 
breathing loads in NMDs 3, 5, 6. With recent advances in pharmacological therapies and the use 
of assisted ventilation, survival to age 30 may exceed 80% in Duchenne muscular dystrophy 

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(DMD) 7. Nevertheless, assisted strategies do not prevent or reverse expected declines in 
longer-term ventilator function that occur over the clinical course of progressive neuromuscular 
disorders. In fact, the preponderance of the literature has shown that MV independently 
facilitates diaphragm muscle atrophy and contractile dysfunction, known as ventilator-induced 
diaphragmatic dysfunction 8, 9.  
 
Alternatively, respiratory muscle training may improve muscle function and delay ventilatory 
decline. It has been previously asserted that inspiratory muscle training (IMT) could overwork 
the respiratory muscles and induce fatigue in patients with neuromuscular compromise 10. 
However, the literature does not support this assumption. Among the NMDs, the majority of IMT 
research has been conducted in children and young adults with DMD who do not require 
assisted ventilation. Training-induced strength gains tend to occur more slowly in patients with 
neuromuscular diseases 11. IMT has shown effective for increasing muscle strength and 
endurance, regardless of disease severity 12. However, patients with the greatest baseline 
ventilatory function make the largest gains in forced expiratory maneuvers 11, 12. Additionally, 
breathing loads are perceived as lighter by patients, following ventilatory muscle training 13. 
Patients with DMD make greater strength gains when training with high-pressure overloads, 
compared to low-modest resistive breathing, and have shown long term improvement in MIP, 
VC, and max ventilation for as long as two years 14. 
 
Because previous research has primarily trained adolescents and young adults, additional 
knowledge is needed regarding the ability of the respiratory muscles to remodel in our youngest 
and older patients. Therefore, we plan to include two separate age cohorts to address these 
gaps. Our team safely incorporated IMST into the clinical care of critically-ill, mechanically 
ventilated infants with and without neuromuscular disease, including a neonate who sustained a 
cerebrovascular accident and an infant with Pompe disease and sepsis. We report that the 
intervention is both feasible and safe in infants (Smith, under review, Phys Ther). Additionally, 
our group has reliably assessed respiratory strength and function in boys with DMD ranging 
from 4 through 10 years of age (Mathur, Physiother Canada, 2009). A key objective of our 
laboratory is to identify the stage of disease where the greatest therapeutic benefit can be 
achieved. The literature suggests this could occur with earlier intervention when possible 
(McCool, 1995, Phys Ther), but older adults with a milder disease phenotype also stand to gain 
from training 15. 
 
While the findings of IMT show initial promise for patients with DMD, less is known about the 
ability of patients with other NMDs to respond to training. In particular, the role of IMT is virtually 
unknown among the rare or orphan neuromuscular diseases (i.e. metabolic and other 
congenital myopathies). Although a common attribute of the neuromuscular compromise is the 
predominance of respiratory insufficiency 16, the pathology, clinical signs, onset and response to 
medical management varies vastly between NMD diagnoses. For example, patients with Pompe 
disease may be distinguished from other NMDs by a relatively earlier involvement of ventilatory 
over limb muscle weakness 17. Moreover, ventilatory muscle weakness and pulmonary function 
correlate poorly with ambulatory function in Pompe disease 18. Therefore, we may not be able to 
apply the research in DMD directly to other progressive neuromuscular disorders. 
 
The pattern of ventilatory muscle weakness especially differs between the NMDs. Pulmonary 
pressures typically decline prior to a loss of forced expiratory volumes in neuromuscular disease 
19, making strength a more sensitive index of pulmonary function. While vital capacity may 
decline by >8% per year in DMD after the age of 12 20, inspiratory strength remains preserved to 
a greater degree than expiratory strength 21, 22. In DMD and amyotrophic lateral sclerosis, 
maximal inspiratory and expiratory pressures correlate equally with unassisted cough peak 

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Fig 2. Respiratory strength improved rapidly in an 
adolescent with nemaline myopathy and post-
operative ventilator failure. She initially required 24-
hour BiPAP, but progressed to night-time only use, her 
baseline breathing status.   
Fig 1. Maximal-effort, unresisted tidal volumes and flows 
are impaired in a young adult male with late-onset Pompe 
disease, compared to a healthy, middle-aged adult. Light, 
added pressure-threshold loads further diminished flow-
volume responses in the patient, but did not vary 
substantially in the healthy adult. 
flows 22, 23. In contrast, the rate of decline in global ventilatory function varies vastly between 
adults with Pompe disease, but is characterized by predominant diaphragm muscle weakness17, 
18, 24. Intercostal and diaphragm muscle involvement are differentially affected among spinal 
muscular atrophy variants25 and may not occur at all in the mildest, adult-onset genotype 26.  
 
Because the inspiratory and expiratory muscles can both be affected by neuromuscular 
disease, the relative roles of training either function may be examined. The expiratory muscles 
primarily influence the effectiveness of cough flows, which are vital for mucociliary clearance 
and prevention of respiratory infection. On the other hand, a functional inspiratory pump is 
necessary in the inspiratory phase of cough, in order to achieve an appropriate cough volume 
23. Moreover, diaphragmatic weakness results in chronic hypoventilation and pre-empts a need 
for ventilatory assist. Because the diaphragm is particularly weakened by assisted ventilation 
and disuse, we propose to conduct a pilot study of the specific role of inspiratory muscle 
strength training (IMST) in respiratory muscle strength, tidal breathing pattern, and forced 
ventilatory function. We have extensive experience 
in evaluating respiratory muscle strength and 
pulmonary function in the laboratory and the 
clinic,27-30 and our group provides clinical post-
operative IMST in difficult to wean infants and 
children with neuromuscular diseases 31.  
 
 
Pilot Data/Preliminary Work 
 
We recently tested respiratory strength and sense 
of breathing effort, on three young adults with late-
onset Pompe disease and symptom-limited 
respiratory function.   Details from a 25 year-old 
male are shown in Fig 1.  Tidal volume and peak 
inspiratory flow were markedly reduced during 
resisted breathing. In addition, the patient’s maximal 
inspiratory pressure (MIP), a non-invasive estimate of 
strength, was 17 cm H2O, which is <20% of the age-
predicted value. This clinical example shows that the 
test procedures are feasible to perform reliably in the 
community or clinic settings. In addition, it illustrates 
the impaired baseline strength and respiratory function 
in patients with late-onset Pompe disease.  
 
We have also prescribed IMST exercises successfully 
for patients with metabolic or other congenital 
myopathies who require assisted ventilation, as part of 
routine clinical care. Fig 2 details the progression of 
strength gains and reduced assisted ventilation over 
two weeks of IMST, in an adolescent with nemaline 
myopathy and postoperative ventilatory insufficiency. 
Her baseline strength was approximately 40% of 
normal for females her age (-35 cm H2O, compared 
to normal values of -80-90 cm H2O). After two weeks 
of IMST, she made significant gains in strength and 
achieved her baseline ventilatory function of BiPAP 
71
2630
508
1665
0
500
1000
1500
2000
2500
3000
Patient 
Healthy
VE (lpm)
VT (mL)

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only during sleep. Importantly, her clinical IMST regime was nearly identical to the proposed 
training, and she experienced no safety events throughout the training period. 
5.  Specific Aims: 
• 
To identify the effect of IMST on the strength of inspiratory and expiratory muscles, in 
patients with neuromuscular disease and ventilatory insufficiency. 
• 
To determine whether IMST-associated changes in strength are associated with 
differences in tidal and forced pulmonary function. 
• 
To compare the rate and extent of training response, based upon disease diagnosis and 
baseline function. 
6. IMST Research Plan: 
Hypothesis  
Inspiratory muscle strength training (IMST) will significantly improve maximal inspiratory 
pressure and pulmonary function in patients with neuromuscular disease and respiratory muscle 
contractile dysfunction.  
 
Design 
Patients will be considered eligible for IMST if they have been diagnosed with an inherited 
neuromuscular disease and show clinical evidence of impaired pulmonary function. Subjects will 
undergo RMST for up to 12 weeks. Pulmonary function and strength testing and a symptom 
questionnaire will be administered before and after IMST. 
 
Study Sample 
This study will consist of two groups of male and female patients aged 6 months-65 years with a 
confirmed diagnosis of a neuromuscular disease. Group 1 will consist of children with earlier-
onset disease, aged 6 months through 11 years of age upon inclusion. Group 2 will consist of 
patients aged 12 through 65 years, which will include both patients with later-stage, early onset 
disease, and those with late-onset, milder disease. The inherited neuromuscular disease 
classifications include: muscular dystrophies, motor neuron diseases, neuromuscular junction 
diseases, peripheral nerve diseases, metabolic myopathies, or other congenital myopathies that 
fall into the NIH classification of a rare/orphan disease. In addition, patients will demonstrate 
evidence of at least one of the following signs of respiratory insufficiency: (1) decreased FVC 
<80% of age and gender-predicted, (2) decreased maximal inspiratory pressure <80% of age 
and gender-predicted, (3) decreased maximal expiratory pressure <80% of age and gender-
predicted, (4) any routine use of supplemental oxygen or mechanically-assisted ventilation, or 
(5) patient report of functionally-limiting dyspnea. 
 
We plan to enroll up to thirty subjects and analyze the data according to baseline disease 
severity (age-predicted pulmonary function). No power calculation is feasible for this pilot trial; 
however, similar studies have found significant training differences in strength with 20-30 patient 
cohorts. Patients will be ineligible to participate if they have required acute antibiotic therapy for 
an acute respiratory infection within 15 days prior to baseline screening, were prescribed 
systemic corticosteroids or neuromuscular blocking agents within 15 days of the baseline 
screening, show laboratory evidence of hepatic or hematologic failure, are currently participating 
in other research studies involving investigational drugs, have a diagnosis of a primary 

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pulmonary disease, use tobacco products, or have any other concurrent medical condition 
which, in the opinion of the investigators, would make the subject inappropriate to participate in 
the respiratory exercises.  
 
Subjects will be recruited from other research studies conducted by the PI and Sub-Is, the 
neuromuscular clinic run by the study team, or by self-referral. The study will be listed on 
ClinicalTrials.gov and the research team’s website. 
 
Study Procedures 
Complete respiratory testing will occur before and after IMST.  In conjunction with respiratory 
testing, baseline and exertional blood pressure, heart and respiratory rate, end-tidal CO2 and 
pulse oximetry will be monitored. The following tests will be completed on all subjects.   
 
Pulmonary Function Tests: Subjects will complete tidal flow-volume assessments and forced 
expiratory maneuvers according to American Thoracic Society guidelines.32 Three to five trials will 
be administered, separated by at least 2 minutes of rest.  
 
Repeated Inspiratory Load Compensation: Subjects will undergo 4 sets of 10 maximal-effort 
breaths against standardized resistances (one set each at 0, 5, 10, and 15 cm H2O).  If a patient 
cannot generate at least 20% of resting tidal volume with one of the lower standardized 
resistances, we will forego testing with any higher loads. Trials will be separated by at least three 
minutes of rest. 
  
Maximal Respiratory Pressures:  Subjects will perform maximal inspiratory and expiratory 
pressure maneuvers, in accordance with American Thoracic Society testing guidelines.32 Trials 
will be administered until 5% variability is achieved between three trials (typically achieved within 5 
trials), and separated by at least 2 minutes of rest. 
 
Every attempt will be made to assist participants and their families to travel to University of 
Florida for respiratory testing. If the study team determines that it is not in the best interest of the 
eligible participant to travel for a test session, the study team will consider the option of 
conducting the requisite tests at a site local to the subject. 
 
Training 
IMST Training: All subjects will receive IMST for up to 3 months, using a commercially-available 
respiratory training device (depending upon initial strength: Threshold PEP or IMT devices, 
Philips-Respironics). Patients and their families will be instructed in the use of the assigned 
training device. Subjects will complete loaded breaths, at an intensity of up to 50% of maximal 
pressure.  In the unlikely event that the subject cannot initially exercise at this intensity, the 
subject will exercise at the highest load that is well-tolerated (determined by full opening of the 
training valve, absence of dyspnea or fatigue, and stable vital signs).   
 
The subject will be instructed to take 8-15 deep, forceful breaths through the Threshold device, 
followed by at least 3 minutes of rest.  The process will be repeated 3 more times for a total of 4 
sets of 8-15 breaths. IMST will be completed three to five days per week, based upon the 
subject’s daily baseline level of fatigue. 
 
Subjects and their families will be directly monitored by telephone during every IMST session for 
the first two weeks and receive real-time feedback to ensure proper technique and provide 
instruction on progression of the training. IMST will routinely occur at home, yet an investigator 
will continue to participate in IMST at least once per week remotely by telephone or video 

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conference. We have experience in remote monitoring of IMST in ventilator-dependent children, 
and remotely-supervised sessions enable investigators to monitor compliance, progress the 
IMST load, and provide feedback. 
 
Statistical Methods  
The primary endpoints for inspiratory muscle training efficacy will include respiratory muscle 
strength. Secondary outcome measures include be respiratory function and breathing pattern 
during loaded breathing. 
 
Changes in strength and respiratory function will be analyzed by repeated measures ANOVA.  
7. Possible Discomforts and Risks: 
Brief periods of loading (<30 seconds) have not been shown to cause clinically significant or 
sustained changes in cardiac function 37.Also, the incidence of blood gas dysfunction is extremely 
rare, due to the limited duration of the testing and training sets. Nevertheless, the protocol 
includes strict limits on baseline and exertional vital signs, end-tidal CO2 and SpO2, in order to 
minimize cardiorespiratory work.  
Inspiratory muscle strength training has been associated with a very low risk of adverse events, 
even in hospitalized patients with cardiovascular impairment, heart failure and ventilator 
dependence. A recent randomized, controlled trial of pre-operative home-based IMST in high-risk 
cardiac surgery patients yielded 0 adverse events among 276 participants 38, while an additional 
20 pre-operative patients awaiting elective aneurysm repair experienced no IMST complications 
39. Moreover, a similar protocol has been used clinically in the Shands surgical ICU to facilitate 
ventilator weaning in well over 100 pediatric and adult patients without any complications 
attributable to IMST. The inspiratory muscle strength training protocol used by our research team 
has been designed to minimize excessive physiological stress, primarily by employing moderate 
intensities, brief training sets, and prolonged rest periods. 
Respiratory testing or training may elicit transient fatigue or shortness of breath that resolves 
within several seconds of completion.  Each training set typically lasts less than 15 seconds, and 
at least two to three minutes of rest will be provided between trials to minimize feelings of exertion, 
and perceived exertion will be monitored during training sessions.   
8. Possible Benefits: 
 
The potential benefit to participants is to determine the feasibility and efficacy of IMST exercises 
that have shown to be effective to increase strength and aid weaning in adults with ventilator 
dependence or to improve strength in mild-severity neuromuscular disease. The training regime 
could provide an adjuvant treatment for symptomatic patients with neuromuscular disease. 
9. Conflict of Interest: 
No conflicts of interest have been identified for any of the investigators in this study.  

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