Objective Patients with tetralogy of Fallot (ToF) have limited pulmonary blood flow before corrective surgery and ongoing dysfunction of the pulmonary valve and right ventricle throughout life leading to lower exercise capacity and lung volumes in many patients. Inhalation training can increase lung volumes, improve pulmonary blood flow and consequently exercise capacity. This study tests whether home-based daily breathing training improves exercise capacity and lung volumes.
Methods From February 2017 to November 2018, 60 patients (14.7±4.8 years, 39% female) underwent spirometry (forced vital capacity (FVC); forced expiratory volume in 1 s (FEV1)), cardiopulmonary exercise testing (peak oxygen uptake (peak O2)) and breathing excursion measurement. They were randomised into immediate breathing exercise or control group (CG) and re-examined after 6 months. The CG started their training afterwards and were re-examined after further 6 months. Patients trained with an inspiratory volume-oriented breathing device and were encouraged to exercise daily. The primary endpoint of this study was the change in peak O2. Results are expressed as mean±SEM (multiple imputations).
Results In the first 6 months (intention to treat analysis), the training group showed a more favourable change in peak O2 (Δ0.5±0.6 vs −2.3±0.9 mL/min/kg, p=0.011), FVC (Δ0.18±0.03 vs 0.08±0.03 L, p=0.036) and FEV1 (Δ0.14±0.03 vs −0.00±0.04 L, p=0.007). Including the delayed training data from the CG (n=54), this change in peak O2 correlated with self-reported weekly training days (r=0.282, p=0.039).
Conclusions Daily inspiratory volume-oriented breathing training increases dynamic lung volumes and slows down deconditioning in peak O2 in young patients with repaired ToF.
- heart defects
- tetralogy of Fallot
- cardiac rehabilitation
Data availability statement
No data are available.
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Tetralogy of Fallot (ToF) is the most common cyanotic complex congenital heart disease.1 Corrective surgery is recommended in infancy. Nevertheless, after surgical repair, the malfunction of the pulmonary valve or right ventricle is not rare. This includes, in particular, recurrent stenosis of the pulmonary valve, pulmonary valve regurgitation, dysfunction of the right and/or left ventricle and arrhythmia, or sudden cardiac death.2 Regular monitoring over the long term is recommended including cardiopulmonary exercise testing to objectify exercise performance and to detect deteriorations in the right heart function early.2 3 Exercise capacity of patients with ToF is very variable and on average only about 85% of the peers of the same age.4 Besides, patients’ breathing function is affected, and in many patients, even in young children,4 a restrictive lung function correlates with reduced exercise capacity.5 Regarding this, it has been shown that controlled physical training can increase physical endurance capacity of children and young adults with ToF.6
A few studies are dealing with breathing training in patients with congenital heart disease. Laohachai et al 7 showed an improvement in muscle strength and breathing efficiency in patients with Fontan circulation. Fritz et al 8 showed a significant increase in adult patients with Fontan circulation in oxygen saturation but not in exercise parameters. Both used inspiratory muscle training (IMT). Mereles et al 9 showed a positive effect on exercise capacity via respiratory and exercise training in patients with various kinds of pulmonary arterial hypertension.
The current study tested the hypothesis, whether a home-based volume-oriented inspiratory breathing training increases exercise capacity, expressed as peak oxygen uptake. By improving thoracic mobility, improvement in lung function, and a more homogeneous alveolar oxygen supply, is expected. By the Euler-Liljestrand mechanism,10 this may lead to pulmonary vascular dilatation, improvement of lung perfusion, reduction of right heart afterload and finally to improved exercise performance.
The study was a prospective registered randomised non-blinded clinical trial on breathing exercises. The primary outcome was the improvement of exercise capacity (peak oxygen uptake (peak O2)); secondary outcomes included lung volumes and thoracic flexibility.
The patients’ inclusion started in February 2017 and the last patient was randomised in November 2017.
The study population consisted of patients with repaired ToF including double-outlet right ventricle of Fallot type and pulmonary atresia with ventricular septal defect from 8 to 25 years of age.
Exclusion criteria were obstructive lung function (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score <−1.64), change in medication within the last 3 months, therapeutic catheterisation within the last 6 months, heart surgery within the last 12 months, planned surgery within the next 36 months, severe left heart failure (New York Heart Association classification IV), frequent arrhythmia, a pacemaker or acute lung infection. Potential subjects were recruited from our Munich database for congenital heart defects. There were no public recruiting measures. They were contacted via telephone calls; the information material was sent out, and after some time of reflection (>1 day), patients were invited to an outpatient appointment at our institution. At baseline, all underwent echocardiography, spirometry, breathing excursion and a cardiopulmonary exercise test. Of 75 invited patients, 60 were eligible and randomised. Thirty patients started their training immediately, and 30 patients started their training after 6 months (figure 1). All patients answered a questionnaire after their training that queries if and how often they did the respiratory training.
Cardiopulmonary exercise test
Patients had to undergo an exhausting (respiratory exchange ratio >1.0)11 and symptom-limited cardiopulmonary exercise test (CPET) in an upright position on a bicycle. The highest running 30 s time interval of oxygen uptake during exercise was defined as peak O2. Estimation of ventilatory efficiency ( E/ CO2 slope) was defined manually excluding the values after the respiratory compensation point. All subjects performed a customised ramp-wise protocol aiming at an exercise time of about 8–12 min. As reference values, the height-dependent calculations from Cooper and Weiler-Ravell12 were used, and data were also expressed as a percentage of predicted.
FVC as well as FEV1 were measured just before the CPET to avoid any possible influence on the results due to possible better lung ventilation after maximum physical exertion. The test was done following the American Thoracic Society (ATS) criteria.13 14 Global Lung Initiative (GLI) 2012 references15 were used to calculate z-scores.
Breathing excursion was measured in a supine position with a tape measure at the xiphoid level. Patients’ thoracic circumference was measured after maximal inspiration and expiration. This was done twice, and the larger difference was used for the calculation of breathing excursion.
Four sealed randomisation letter sets were prepared by the Institute for Medical Information Technology, Statistics and Epidemiology, Technical University of Munich, block randomised for males/females and <14/≥14 years of age. They were consecutively opened for every patient after informed consent and after all the baseline investigations.
Inspiratory breathing training
A volume-oriented inspiratory respiratory training was performed with the Coach2 Incentive spirometer lung trainer (Smith Medical ASD Inc, Minneapolis, Minnesota, USA). The device is CE marked for postoperative rehabilitation. It was already used in patients with chronic obstructive airway16 and in patients with thoracic surgery in general to improve their lung re-expansion.17 This device motivates the patient to a constant slow but long inspiration up to a certain inspiration volume without flow resistance. Exhalation is not controlled by the device.
Patients started the training with an inspiration volume of about 40% of their previous measured FVC (L) and trained every day in one to three sets with 10–30 repetitions (following the producer’s recommendations). This wide range was chosen since changes in the volume’s increase take a long time to achieve and patients’ training needs to be adapted also to guarantee personnel success (self-efficacy). Within the first 2 weeks, the patients maintained the volume they had in the beginning, and afterwards, they adapted it individually with the guidance of the study’s supervisor. Each training session endures, depending on the repetitions and individual differences in training, between 5 and 10 min per day. The training should be done once per day in a regular but individual manner (eg, for patients who go to school the afternoon fits better than in patients who are engaged in work). Each patient was encouraged to find his optimal training time within the first 1–2 weeks. Before starting the training, patients were instructed in different breathing techniques and breathing training with the device.
Once a week, the supervisor contacted all patients in training, following a call protocol to get information about training progress, and adapted the inspiration volume, number of sets and number of repetitions per set individually. It was the aim to reach the three sets with 30 repetitions first and then rise slowly the inspiration volume. Possible adverse events were documented.
In advance, case number estimation was performed. In a training study of patients with ToF,18 an increase in peak O2 of 2.14±2.83 mL/kg/min in the training group and 0.35±4.2 mL/kg/min in the control group was measured. Taking the SD from this study and assuming an increase of 3 mL/kg/min for the improvements in haemodynamic is clinically relevant, a case number of 23 patients per randomisation group is obtained with a p<0.05 and a power of >80%. With a drop-out rate of 25%, the inclusion of at least 29 patients per group is necessary. For this purpose, a total of 60 patients are to be recruited.
Descriptive data are expressed in mean±SD (dependent variables in Shapiro-Wilk test p>0.05). Data from the first 6 months were compared between the training group and the delayed training group (no training for this time) by an independent Student’s t-test. The randomised trial was evaluated via intention-to-treat analyses, whereby missing data were imputed by multiple imputation, and inferences were combined by Rubin’s rules. These results are expressed as mean±SEM.
For the correlation with training frequency, data of both groups were merged for their training period. Patients that did not finalise the training and the final questionnaire about training frequency were excluded. To compare data before and after training, the Student’s t-test for dependent samples was used (mean±SD). To correlate the results with training days, Spearman’s correlation was used. All analyses were performed using SPSS (V.25.0, IBM Corporation, Armonk, New York, USA), and a two-tailed probability value <0.05 was considered statistically significant for all tests.
This study was following the Declaration of Helsinki and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice. The study was registered in the ‘Deutsches Register Klinischer Studien’ with the number DRKS00011363. Written informed consent was given by all patients and, if needed, by legal guardians.
Patients’ characteristics of the training and control groups can be seen in table 1.
Initial values did not differ in training and control group (TG and CG, respectively). In three patients, no lung volumes were examined, and further three patients missed the second examination. Their changes in outcomes (Δpeak O2, ΔFVC and ΔFEV1) were calculated via multiple imputations.
As shown in table 2 and figure 2A–C, the training group achieved a significantly more favourable change peak O2 (TG: 0.5±0.6 vs CG −2.1±0.9 mL/min/kg, p=0.011), ΔFVC (TG: 0.18±0.03 vs CG: 0.08±0.03 L, p=0.036) and ΔFEV1 (TG: 0.14±0.03 vs CG: 0.00±0.04 L, p=0.007). Breathing excursion did not show significant improvements.
Correlation with training days/week in the intervention study
Of all patients, six patients were lost to follow-up because they discontinued the study (figure 1). Fifty-four (90%) patients completed the 6-month training and filled in the self-reported training frequency questionnaire. Of these, only 16 patients (30%) trained 7 days per week during the 6 months. Spearman’s correlation shows a positive correlation in self-reported training days/week and Δ peak O2 (r=0.282, p=0.039, figure 3). Merged data from both groups before and after training are shown in table 3.
This study showed that an inspiratory breathing training increases lung volumes and slows down the deconditioning in exercise capacity. The power of improvements depends on exercise frequency.
Only a few published studies consider inspiratory breathing training in patients with congenital heart disease. Laohachai et al 7 treated 23 young Fontan patients with 6-week IMT, which consisted of 30 min of training per day. Their non-randomised study showed improvements in ventilatory efficiency and resting ejection fraction in cardiac MRI. The patient’s exercise capacity and lung function (peak O2, FVC and FEV1) did not change with the training. A recently published paper from Fritz et al 8 investigated adult Fontan patients. This study was randomised with 42 patients. They underwent a 6-month IMT of three sets with 10–30 repetitions per day. They also received weekly calls. In this study, exercise capacity and lung volumes did not change. Only oxygen saturation at rest increased significantly.
Also, there is a prospective non-randomised pilot study19 with 11 adult patients with Fontan circulation who underwent an IMT for 12 weeks. They also reported only a trend in an increased peak O2 and improved E/ CO2 slope.
Nevertheless, these studies investigated a different, very complex congenital heart disease compared with the present study. Fontan patients’ pulmonary blood flow is mainly driven by left heart suction forces and negative intrathoracic pressures during inspiration.8 Patients with repaired ToF have a biventricular circulation, and after the repair, the pulmonary and circulatory is similar to ‘normal’ ones.2 The studies on Fontan patients implement IMT that differs from the training in this study. They used devices with inspiratory resistance that primarily increased ventilator suction capabilities that might be useful in Fontan patients. The present study focused on volume training by deep inhalation using a different training device. We shifted to the new training modality because, first, the durability of the POWERbreathe device was not as expected; second, we saw two previously undiagnosed hiatal hernias in a programme of about 100 patients with IMT that might have been pursued or worsened by the IMT; and third, the haemodynamics of patients with ToF is not dependent on the ventilator pump as it is the Fontan circulation. In the volume-oriented breathing training of the current study, the respiratory muscles are strengthened via deep inspiration, as well as thoracic mobility is improved, despite this could not be shown in our data. Lung volumes are increased leading potentially to better alveolar ventilation. This might improve alveolar ventilation and pulmonary perfusion and finally a right heart afterload reduction. We can only speculate on this physiological pathway, but in the end, exercise capacity was increasing. Unfortunately, no MRI data about right ventricular function at exercise were measured to support the hypothesis of how the improvements in lung volumes result in better exercise capacity in this patient group.
Studies have already shown that there is a correlation between spirometry and exercise capacity.5 By our randomised study, showing that volume-oriented breathing training improves exercise capacity, there is no proof that the reduced exercise capacity is associated with a reduced lung function and is at least in part the result of a decreased lung function. Our volume-oriented inspiratory breathing exercise improves lung function and gives medical doctors and therapists of patients with ToF an option to escape from the status of bad lung function and bad exercise capacity. Our training can potentially improve pulmonary function and at least slow the natural decline in performance in patients with congenital heart disease.20 A decline was already seen in the control group (table 2), but after the training in the control group and merging the training data, the small and now significant increase in exercise capacity becomes obvious (table 3). The lack of an increase in the percentage of predicted peak O2 is most likely due to the decrease in BMI in the training group and the increase in the control group simultaneously (table 2).
Following other studies, the present study underlines the importance of regular training already in infancy and youth21 22 in patients with congenital heart disease, regardless of exactly which training is completed. Patients must have broad and safe opportunities to decide which training fits them best. Since exercise capacity dependents on many factors, a combination of different types of training, which improves or at least maintains the status quo of peak O2 during adolescence and adulthood is recommended.20 A good exercise capacity positively correlates with patients’ quality of life.23 24
Furthermore, this study might focus our interest on the reasons for reduced lung volumes. Finally, it should be the aim to prevent impaired lung volumes. As the number of thoracotomies correlates with a reduced lung volume,25 avoiding thoracotomies by catheter interventions like percutaneous pulmonary valve implantation should be pursued and is nowadays common. Maybe breathing training early after thoracic surgery can improve short-term outcome26 and long-term lung function and exercise capacity. The significant positive correlation between training days/week and increase Δ peak O2 underlies the importance of patients’ compliance. The more often they train, the better the results are. Meyer et al 27 recently published a systematic review on home-based exercise interventions, and they conclude that training compliance seems to be the major challenge. In the present study, 16 patients, as in their self-reported statement, trained 7 days per week during the 6 months of training, which is less than one-third. Four patients (7.4%, figure 3) trained only once or twice a week and two more did not train anyway. These patients need to undergo further investigation to figure out what may help them to increase their compliance in a home-based training or try to implement them to supervised training.
Children and young patients with repaired ToF benefit from a daily 6-month inspiratory breathing training concerning exercise capacity and ventilatory function without any additional exercise practice. However, patients need to be encouraged for frequent training. Further studies need to investigate whether the positive results of the current study of inspiratory volume training in patients with ToF compared with the less favourable results of IMT in Fontan patients are due to the different training modalities or whether they are due to the different haemodynamic situation in these two patients groups.
All patients are in regular tertiary care follow-up in our institution where physical activity and leisure time sports are recommended. It may be that the investigated group is over-represented by very motivated subjects that are possibly highly encouraged in doing sports. The increase of 0.5±0.6 mL/min/kg in peak O2 in the training group in the randomised trial seems to be few. However, it must be interpreted in comparison with the decline of −2.3±0.9 mL/min/kg in the control group, and a total training effect of 2–3 mL/kg/min might indeed represent a clinically relevant treatment option, especially in those patients with an extraordinary response to the training, which still must be outlined.
What is already known on this subject?
Breathing training can influence the exercise capacity in patients with congenital heart defect.
What might this study add?
Inspiratory volume-oriented breathing training in patients with repaired tetralogy of Fallot increases their exercise capacity and lung function significantly.
How might this impact on clinical practice?
An inspiratory volume-oriented breathing training should be offered to patients with repaired tetralogy of Fallot to increase or at least maintain exercise capacity.
Data availability statement
No data are available.
Patient consent for publication
The local ethical board of the Technical University of Munich approved the study (project number: 4/17S).
Contributors JH: conception/design of the study, data collection and analysis, and writing of the manuscript; JR: ideas on testing and critical revision on the manuscript; RO and PE: critical revision of the manuscript and supervision; AH: conception/design of the study, data analysis, writing of manuscript and supervision. All authors approved the final manuscript. JH and AH are responsible for the overall content as guarantors.
Funding The study was funded by an unrestricted grant from the 'Stiftung KinderHerz'. We declare that the results of the study are presented honestly and without fabrication, falsification or inappropriate data manipulation according to the registered protocol. Additionally, we would like to thank the whole team that was crucially responsible for its success. Parts of the study have been presented at the congresses CPX international 2019 and 'Deutsche Gesellschaft für Pädiatrische Kardiologie und Angeborene Herzfehler e.V.' 2020.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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