Congenital – Original Submission
A Pilot Study of Inspiratory Muscle Training to Improve Exercise Capacity in Patients with Fontan Physiology

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While the Fontan procedure has improved life expectancy, patients with single ventricle physiology have impaired exercise capacity due to limited increase in pulmonary blood flow during activity. Enhancing the “thoracic pump” using inspiratory muscle training (IMT) may ameliorate this impairment. Adult nonsmokers with Fontan physiology were recruited through Boston Children's Hospital's outpatient clinic. Participants underwent cardiopulmonary exercise testing and pulmonary function testing, followed by 12 weeks of IMT and then repeat testing. The primary endpoint was change in % predicted peak oxygen consumption (VO2). Secondary endpoints were changes in other exercise metrics. Eleven patients (6 male) were enrolled. Median ages at time of enrollment and Fontan completion were 28.8 years (25.7, 45.5) and 7.8 years (3.9, 16.5), respectively. Average baseline maximal inspiratory pressure (MIP) was normal; only 2 patients had MIP <70% predicted. Peak work rate improved significantly from baseline after 12 weeks of IMT (116.5 ± 45.0 to 126.8 ± 47.0 W, P = 0.019). Peak VO2 tended to improve (baseline 68.1 ± 14.3, change + 5.3 ± 9.6% predicted, P = 0.12), as did VE/VCO2 slope (34.1 ± 6.7 to 31.4 ± 3.6, P = 0.12). There was no change in peak tidal volume or MIP. In a small cohort of Fontan patients with mostly normal MIP, IMT was associated with significant improvement in peak work rate and a trend toward higher peak VO2 and improved ventilatory efficiency. Larger studies are needed to determine if this reflects true lack of effect or whether this pilot study was underpowered for effect size, and whether IMT is more narrowly useful for patients with impaired MIP.

Introduction

The Fontan operation has greatly improved the life expectancy and long-term outcomes of individuals with single-ventricle anatomy over the last 50 years. As surgical techniques have been refined over time, 10-year survival has increased to over 85%.1 However, individuals with Fontan circulation continue to be limited by impaired exercise function and reduced cardiac output during exercise compared to the general population.2, 3 The primary reason for this limitation is thought to be the absence of a subpulmonary pump to add energy to the circulating blood as it enters the pulmonary vascular bed. Pulmonary blood flow (PBF) is thereby restricted, limiting preload to the systemic ventricle.4

In people with normal biventricular cardiac anatomy, cardiac output is increased by increasing heart rate and left and right ventricular stroke volume, which requires a concomitant increase in ventricular filling. While left ventricular filling depends primarily on increased right ventricular output, right ventricular filling depends on increased venous return. Venous return is normally augmented through several mechanisms including the active relaxation phase of ventricular diastole, atrial systole, generation of negative intrathoracic pressure (the “thoracic pump”), and rhythmic compression of peripheral veins—particularly those in the legs—by the skeletal muscles (the “muscle pump”).

In the absence of a subpulmonary ventricle in individuals who have undergone Fontan palliation, the single, systemic ventricle becomes reliant on the thoracic and muscle pumps to increase venous return and provide systemic preload.5 Weakness of respiratory muscles and of skeletal muscles is common in patients with congenital heart disease, particularly in those with Fontan circulation, and in both cases is associated with decreased exercise capacity.6, 7, 8 Fontan patients also show a high prevalence of reduced lung volume and restrictive spirometry, perhaps related to altered pulmonary blood flow during development, past thoracotomies and sternotomies, other forms of chest wall deformity (eg, scoliosis), and neuromuscular weakness or injury.9, 10 Moreover, there is evidence of abnormal regulation of ventilation, as evidenced by a high prevalence of exercise oscillatory ventilation.11

Exercise training has a beneficial impact on exercise performance in Fontan patients, possibly by increasing skeletal muscle bulk, reducing venous compliance, and increasing the contribution of the “muscle pump” to venous return.12 However, optimal training regimens for patients with Fontan circulation remain uncertain, and adherence with exercise regimens is difficult to maintain.

The potential magnitude of the influence of respiratory mechanics on hemodynamics was suggested by a study which showed a 42% increase in PBF with negative pressure ventilation compared to positive pressure ventilation in a cohort of paralyzed and sedated pediatric Fontan patients.13 In adults without congenital heart disease who have congestive heart failure and inspiratory muscle weakness, inspiratory muscle training (IMT), such as the use of a threshold inspiratory muscle training device (Fig. 1), can improve quality of life and functional capacity, perhaps by reducing inspiratory muscle fatigue and improving peripheral blood flow during exercise.14, 15 Given the high prevalence of inspiratory muscle weakness in patients with complex congenital heart disease and the increased dependence of venous return on the muscle pump and thoracic pump in the Fontan circulation, we surmised that IMT would be particularly beneficial in this population.5, 6

The aim of this study was to explore the tolerability and potential effects of IMT on exercise and pulmonary function parameters in a cohort of adult Fontan patients. We hypothesized that a 12-week program of IMT with an inspiratory impedance threshold device would improve inspiratory muscle function and exercise performance in patients with Fontan physiology.

Section snippets

Patients and Design

A single-center, prospective, single-arm, pilot intervention trial was conducted in adult patients (≥18 years old) with Fontan physiology who were being seen for a routine outpatient clinic visit with cardiopulmonary exercise testing including expiratory gas measurement (CPET) in the cardiology department at Boston Children's Hospital. Potentially eligible subjects were identified prospectively and offered enrollment in the study in advance of their appointment. Patients were excluded if they

Patients

Between April and December 2014, 12 subjects consented to be enrolled in the study. One subject gave consent to enroll and completed the SF-36v2 questionnaire but was unable to complete the baseline CPET due to intolerance of the mouthpiece and was therefore withdrawn from the study. Table 1 describes the clinical characteristics for the remaining subjects. Eleven subjects (6 male) were included in the data analysis. Median ages at enrollment and at Fontan completion were 28.8 years (25.7,

Discussion

The present study demonstrates that IMT is feasible and well tolerated in patients with Fontan circulation. A 12-week course of training was associated with an improvement in peak work rate, but while there was a trend toward improvement, neither change in peak VO2 (the prespecified primary outcome) nor change in VE/VCO2 slope was statistically significant. There was suggestion of improvement in PCS in the SF-36v2, although our small sample size limits robust interpretation.

Studies show that

Conclusions

In a small cohort of Fontan patients with mostly normal MIP, IMT was associated with significant improvement in exercise capacity measured by peak work rate and a trend toward higher peak VO2 and improved ventilatory efficiency. Larger studies are needed to determine if this reflects true lack of effect or whether this pilot study was underpowered for effect size, and whether IMT is more narrowly useful for patients with impaired MIP.

Acknowledgments

We thank Bartolome Celli, M.D, of the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital for lending his valuable expertise in pulmonary physiology.

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    Funding sources: This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers, from the Boston Children's Hospital Innovation & Digital Health Accelerator (IDHA), and from the Dunlevie Fund of the Boston Adult Congenital Heart and Pulmonary Hypertension Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health. (Clinicaltrials.gov NCT number: NCT01977222)

    Conflicts of interest: The authors have no conflicts of interest to disclose.

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