INTRODUCTION

Patients with neuromuscular disease (NMD) present with specific muscle weakness and fatigue and are largely sedentary and deconditioned (1). This sedentary lifestyle driven by progressive muscle weakness and barriers to accessible means of exercise leads to additional weakness, fatigue, and loss of function (2). This deconditioning cycle results in reduced cardiorespiratory fitness (CRF), which is strongly related to increased risk for cardiovascular and pulmonary diseases (3). Furthermore, people with NMD are living longer with a chronic progressive disease, which may further increase risk of developing these comorbidities over the lifespan (4). These largely preventable comorbidities are the leading causes of morbidity and mortality for those with and without NMD, and the risk for developing them is independently correlated to level of CRF (5). The standard for the assessment of CRF is peak oxygen consumption (peak VO₂), determined with cardiopulmonary exercise testing (CPX). Several small studies have suggested a role for CPX for patients with NMD, and hyperventilatory and hypercirculatory patterns have been observed, but very few have reported on CPX for those with NMD who have more motor impairments or are nonambulatory (1,6–8). CPX is applied by clinical exercise physiologists for exercise prescription as the standard of care, with variables such as percent of peak VO₂ and VO₂ reserve favored for exercise prescription development (9). We report on a specific CPX protocol on a total body trainer for patients with NMD and low mobility.

METHODS

This study was approved by the Institutional Review Board of Stanford University. All research staff were trained in good clinical practice, and all participants provided written informed consent or assent before any study procedures. Patients with NMD were prospectively recruited from the Stanford Neurosciences Health Center at Stanford University. Patients with any NMD and limited mobility were included. Limited mobility was defined as the inability to safely perform treadmill ambulation. Patients were excluded if they could not provide informed consent and assent where appropriate, had performed treadmill or upright cycle ergometry exercise within the last 6 months, or if they were deemed unable to exercise vigorously by the study physicians. Participants in the control group were recruited from the local community, did not have medical diagnoses which would prohibit maximal exercise testing performance, and efforts were made to match for age and sex. Cardiopulmonary exercise tests were performed using a CosMed K5 wearable metabolic system (COSMED USA Inc, Concord, California) and a Keiser wheelchair-accessible total body trainer (Keiser Corporation, Fresno, California) that allowed patients to use lower limb strength in an elliptical pattern with the lower limbs and a rowing pattern with the upper limbs. Additionally, the total body trainer allowed patients who were in wheelchairs to perform the testing without transfering to a bike. Respiratory gas data were collected and analyzed after applying a 30 second rolling average (every 10 seconds) filter. All CPXs were performed by clinical exercise physiologists and physical therapists and monitored by a physician familiar to the patients and the study protocols.

Peak VO₂ and all other respiratory gas metrics were calculated as the highest 30 second average during the last phase of the CPX. Percent of predicted peak VO₂ was calculated using the Fitness Registry and Importance of Exercise National Database (FRIEND) Registry (10). Peak heart rate (HR; b·min⁻¹), rating of perceived exertion (RPE; 6–20), and workload (Watts) were calculated as the highest number recorded during exercise. Oxygen uptake efficiency slope (OUES) was calculated as VO₂ = a logV_E + b, where a = OUES (11). Exercise oscillatory breathing (EOB) was assessed visually by 2 independent investigators with an additional investigator used as a tiebreaker (12). The V_E/VCO₂ slope was calculated for the entire exercise bout (13,14) and to the respiratory compensation point (RCP) to account for nonlinearity, which has been shown to be driven by both CO₂ output and decrease in plasma pH and is related to a decrease in pulmonary perfusion (15–17).

RESULTS

We recruited 37 patients with NMD and 8 non-NMD-affected control participants to the study (see Figure 1, Table 1). Patients were included with facioscapulohumeral muscular dystrophy (n = 12), spinal muscular atrophy type 3 (n = 9), myotonic dystrophy type 1 (n = 9), myotonic dystrophy type 2 (n = 1), Pompe disease (n = 3), limb-girdle muscular dystrophy (n = 2), Duchenne muscular dystrophy (n = 2), dysferlinopathy (n = 1), and dystrophinopathy (n = 1).

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TABLE 1. Patient characteristics.

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We were able to perform high-quality CPX with all participants with no adverse events or safety concerns. Average respiratory exchange ratio (RER) and RPE were 1.08 ± 0.16 and 18 ± 2 compared with 1.16 ± 0.12 and 18 ± 2 for controls, respectively (Table 2). Individuals with NMD presented with reduced exercise performance compared with controls as measured by peak workload (66.0 ± 45.5 W versus 198.6 ± 58.9 W, P < 0.001) and peak VO₂ (20.6 ± 7.10 mL^.kg^−1.min⁻¹ versus 37.5 ± 11.9 mL.kg^−1.min⁻¹, P < 0.001). Disturbed hemodynamic and ventilatory patterns were noted for the NMD group, with borderline chronotropic incompetence and low O₂ pulse, marked ventilatory inefficiency and severely reduced OUES, and a high proportion of patients displaying EOB.

TABLE 2. Results of cardiopulmonary exercise testing. ^a

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The mean V_E/VCO₂ slope for the NMD group was 36.3 ± 7.2, indicating ventilatory inefficiency using a threshold abnormal value of 34 (18). The V_E/VCO₂ slope was also relatively high in the control group (32.2 ± 5.3) and not significantly different from the NMD group (P = 0.13). The use of the entire CPX resulted in higher V_E/VCO₂ slope values due to the inclusion of hyperventilatory data after the RCP (15). There were significant differences noted between the groups (NMD = 31.9 ± 5.6 versus control = 27.0 ± 2.3, P = 0.02), whereby both groups are under the threshold of 34 suggested as the normal hyperventilatory response to high-intensity exercise (16). Importantly, we observed that relative effort as illustrated by equivalent RPE and RER was not significantly different between the groups.

DISCUSSION

This is one of the first reports of quality CPX in patients with a range of NMD from nonambulatory to ambulatory with decreased mobility. We observed significant differences in CPX performance between those with NMD and healthy controls. Patients with NMD had lower peak HR, workload, VO₂, O₂P, and OUES and higher V_E/VCO₂ slope and number of participants presenting EOB. Groups were not significantly different for peak RPE, RER, and %HR.

Some patients with NMD (e.g., patients with spinal muscle atrophy) are not able to safely exercise on a treadmill or cycle ergometer due to muscle weakness and imbalance along proximal and distal muscular distributions. The mode of exercise used in this study is unique as it allowed for indivdiuals with limited mobility to perform testing safely, including while in a wheelchair. Difficulties with CPX testing for NMD include inability to maximally stress the cardiorespiratory system due to muscle fatigue. The total body trainer allows for push and pull exercise which is easier for patients who have shoulder weakness and may not be able to pedal an arm ergometer. Additionally, combining upper and lower body movement allows those with severe proximal weakness to use both upper and lower limbs to attain maximal testing.

Our study is an important contribution to the literature on exercise testing in NMD where there is a need for more studies about the feasibilty of CPX for nonambulatory patients (8). Studies using novel exercise devices may offer an alternative and should be considered in the design of specific CPX protocols for patients with severe motor impairments to allow for adequate testing of CRF. The ability to measure CRF will help improve exercise prescription development and promote an active lifestyle for individuals with NMD, many of whom are at higher risk of other diseases of a sedentary lifestyle (3).

Patients with NMD in the current study had a significantly higher V_E/VCO₂ and lower OUES and O₂P than the control group, and a significantly higher percentage of patients with NMD presented with EOB. These are independent risk factors for poor prognosis of other patient populations, and EOB is a very strong predictor of mortality in heart failure (18). Currently, it is unknown what the relationships of these variables may be on outcome in NMD, and thus, further investigation is warranted to discover their impact (19–24).

Importantly, we were able to show it is possible to perform high-quality CPX, including assessment of peak VO₂, HR, RPE, and ventilatory thresholds in patients with NMD and limited mobility. In addition to investigating its prognotic value, CPX could also be an effective method for prescribing exercise in this population. Establishing effective methods for exercise promotion for patients with NMD has been elusive (25). However, exercise prescription is more effective when combined with CPX, whereby researchers have shown that using ventilatory thresholds adds precision to matching metabolic demands during exercise defined by ventilatory thresholds (26–29). The CPX protocol designed for patients with NMD has the potential to improve on current exercise prescription methods. This is especially important given the ventilatory and hemodynamic limitations in this population, which result in traditional methods of prescription being less effective than in other populations (1). Endurance exercise prescription is inherently difficult in this group; furthermore, specific exercise modes (e.g., Keiser ergometers) and a wide range of diagnoses with large heterogeniety in muscle function require personalization. The traditional barriers to exercise for individuals with NMD may be overcome by the performance of this novel approach to CPX. In the few studies which have assessed the effect of endurance exercise on stronger patients with NMD, training has been observed to increase peak VO₂, workload, and muscle strength by up to 47%, 80%, and 40%, respectively, without causing muscle damage (30–32). As suggested by Siciliano et al. (33,34), proper exercise may improve motor performance in adaptation and response to homeostatic imbalance observed in some patients with NMD. High-quality CPX designed for patients with NMD and lower mobility may promote effective exercise prescriptions.

CONCLUSION

Our data demonstrate that high-quality CPX can be conducted in patients with a broad range of NMD and motor dysfunction. Performing CPX in patients with NMD will delineate distinct physiological profiles that may lead to a better understanding of cardiopulmonary and metabolic pathology in these individuals and improvement in the development of exercise prescription.