International Journal of

Environmental Research
and Public Health

Article
Cardiopulmonary Rehabilitation Improves
Respiratory Muscle Function and Functional
Capacity in Children with Congenital Heart Disease.
A Prospective Cohort Study
Francisco José Ferrer-Sargues 1,† , Esteban Peiró-Molina 2,3,† , Pablo Salvador-Coloma 1 ,
José Ignacio Carrasco Moreno 2,3 , Ana Cano-Sánchez 2 , María Isabel Vázquez-Arce 4,5 ,
Beatriz Insa Albert 2 , Pilar Sepulveda Sanchis 3, * and Maria Àngels Cebrià i Iranzo 4,6, *
1 Department of Physiotherapy, Universidad Cardenal Herrera CEU, CEU Universities, 46115 Valencia, Spain;
franciscojose.ferrer@uchceu.es (F.J.F.-S.); pablo.salvador@uchceu.es (P.S.-C.)
2 Pediatric Cardiology Section, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain;
estebanpeiromolina@gmail.com (E.P.-M.); carrasco_jim@hotmail.com (J.I.C.M.);
acano20081976@gmail.com (A.C.-S.); beatriz.insa@gmail.com (B.I.A.)
3 Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe,
46026 Valencia, Spain
4 Rehabilitation and Physical Medicine service, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain;
isabel.vazquez.arce@gmail.com
5 Universidad San Vicente Mártir, 46001 Valencia, Spain
6 Department of Physiotherapy, Universitat de València, 46010 Valencia, Spain
* Correspondence: sepulveda_pil@gva.es (P.S.S.); angeles.cebria@uv.es (M.À.C.I.)
† Authors contributed equally to the work as first co-authors.




Received: 22 May 2020; Accepted: 14 June 2020; Published: 17 June 2020


Abstract: Critical surgical and medical advances have shifted the focus of congenital heart disease
(CHD) patients from survival to achievement of a greater health-related quality of life (HRQoL).
HRQoL is influenced, amongst other factors, by aerobic capacity and respiratory muscle strength,
both of which are reduced in CHD patients. This study evaluates the influence of a cardiopulmonary
rehabilitation program (CPRP) on respiratory muscle strength and functional capacity. Fifteen CHD
patients, ages 12 to 16, with reduced aerobic capacity in cardiopulmonary exercise testing (CPET)
were enrolled in a CPRP involving strength and aerobic training for three months. Measurements
for comparison were obtained at the start, end, and six months after the CPRP. A significant
improvement of inspiratory muscle strength was evidenced (maximum inspiratory pressure 21 cm
H2 O, 23%, p < 0.01). The six-minute walking test showed a statistically and clinically significant rise
in walked distance (48 m, p < 0.01) and a reduction in muscle fatigue (1.7 out of 10 points, p = 0.017).
These results suggest CPRP could potentially improve respiratory muscle function and functional
capacity, with lasting results, in children with congenital heart disease, but additional clinical trials
must be conducted to confirm this finding.

Keywords: congenital heart disease; cardiopulmonary rehabilitation; cardiac rehabilitation; children;

pediatric; respiratory strength; inspiratory pressure; six-minute walking test; physical exercise training

1. Introduction
Congenital heart disease (CHD) is the most frequent form of congenital malformations, enclosing a
third of the congenital anomalies detected during the prenatal and childhood periods [1], with a
global estimated incidence of 8–10% of live births [2]. CHD represents a considerable burden both

Int. J. Environ. Res. Public Health 2020, 17, 4328; doi:10.3390/ijerph17124328 www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2020, 17, 4328 2 of 14

in developed and undeveloped countries [3], and it has substantial economic impact on all health
systems [4].
In the last three decades, critical surgical and medical advances have considerably increased the
survival rates of CHD patients [5], remarkably increasing the number of patients with moderate and
severe forms of CHD that reach adulthood [6]. This “paradigm shift” has repositioned the focus of
interventions, previously centered on increasing survival, and now attempting to achieve a higher
health related quality of life (HRQoL) [7,8].
CHD patients have impaired aerobic capacity and pulmonary function [9] compared to paired age
and gender healthy controls. These impairments have been widely associated with increased morbidity
and mortality [10], and they have been linked to severity of CHD, number of surgical procedures,
surgical complications, and low body mass index (BMI). This last risk factor points to a relationship,
previously described in adult heart failure and CHD, with a lack of respiratory muscle strength [9,11].
Focused on these findings, and their potential improvement, several therapeutic approaches have been
explored in the last decade. Physical activity has proven to be beneficial in improving aforementioned
capacities [12], and subsequent research on the topic of cardiopulmonary rehabilitation specific for
CHD has flourished [13–15].
There is increasingly strong evidence suggesting amelioration of aerobic capacities and HRQoL
following cardiopulmonary rehabilitation programs in children with CHD [14–16], but there is scarce
information about the effects of this intervention on respiratory muscle function, despite the acceptance
of its relation as a risk factor of poor pulmonary function and its association with HRQoL in children [9].
This study evaluates the effect of a cardiopulmonary rehabilitation program, including respiratory
muscle training, on respiratory muscle function, functional capacity, and exercise subjective perception
of children with congenital heart disease.

2. Material and Methods

2.1. Trial Design and Ethics

A single center prospective cohort study was designed and conducted in compliance with the
Good Clinical Practices protocol and Declaration of Helsinki principles. It was approved by the
Hospital Universitari i Politècnic La Fe Ethics Committee (registration number: IIS La Fe - 2017/0506),
on 4 December 2017. The patient information sheet was explained, and all subjects and their legal
guardians gave their informed consent for inclusion before they participated in the study.

2.2. Participants
All patients scheduled for cardiopulmonary exercise tests performed in the pediatric exercise
physiology laboratory of Hospital Universitari i Politècnic La Fe between December 2017 and
January 2020 were screened as potential candidates for the study.
From all patients screened, the inclusion criteria were defined as (1) age between 10 and
16 years; (2) height greater than 135 cm; (3) presence of a significant congenital heart abnormality;
(4) abnormal exercise capacity, defined as a peak oxygen consumption and/or peak oxygen consumption
of less than 80% of the predicted values for age, gender, and height; (5) willingness to be part of the
study and participation commitment from the patients and their parents or legal guardians; and (6)
signature of the informed consent after thorough program and study information. We excluded any
patients presenting (1) personal history of documented life-threatening arrhythmias, (2) inability or
contraindication to perform required physical activity, (3) significant depression of left or right ventricle
function (subjective or left ventricular ejection fraction < 54%), and (4) hypotensive response to exercise
in cardiopulmonary exercise testing (CPET).
Int. J. Environ. Res. Public Health 2020, 17, 4328 3 of 14

2.3. Safety Considerations

All measurements, evaluations, and interventions in the context of the present study were
performed in a safe environment with an emergency resuscitation trolley equipped with a defibrillator,
manual ventilation devices, and CPR medications needed. Patient’s vitals were always continuously
monitored during measurements and rehabilitation and continuous ECG was registered and real-time
visualized by a pediatric cardiologist during training sessions. Real time ECG registry and visualization
was accomplished using Nuubo® wearable ECG technology (Nuubo, 28043, Madrid, Spain).

2.4. Measurements

2.4.1. Anthropometric Characteristics

Before medical anamnesis at the exercise physiology laboratory, anthropometric measurements
were collected in all participants, including weight (kg) and body fat percentage using an electronic
scale TANITA BC-545N (TANITA Corp, Illinois 60005, USA), height (cm) using a manual scale (SECA,
Hamburg 22089, Germany), and skinfolds (triceps, biceps, subscapular, and suprailiac) with a Holtain
Tanner/Whitehouse skinfold caliper (Holtain Ltd. Crosswell, Crymych, Pembs., SA41 3UF, UK.).
BMI (kg/m2 ) was calculated by dividing weight by the square of height in meters. Standard deviation
(SD) scores were calculated for weight, height, and BMI according to the Spanish population standards
recently published by Carrascosa et al. [17].

2.4.2. Baseline Lung Function

Spirometry was performed using a Cortex Metalyzer 3B (CORTEX Medical, Leipzig, Germany)
gas analyzer, and consisted of a flow volume loop recording the forced expiratory volume in 1 second
(FEV1 , L), the forced vital capacity (FVC, L), and the FEV1 /FVC ratio (%). The test was repeated at
least three times to ensure reproducibility, and it was deemed valid after maximality criteria was
fulfilled [18] (generally a difference in values less than 5%). For percent values, we used the prediction
equations by Zapletal et al. [19].

2.4.3. Respiratory Muscle Function

Maximum Static Inspiratory (MIP) and Maximum Static Expiratory (MEP) pressures were
measured in sitting position, using a MicroRPM device (Carefusion, VYAIRE MEDICAL, UK.). In order
to minimize subjects’ training and motivation impact on the results, careful explanation of the test was
carried out, subjects were vigorously encouraged, and MIP and MEP measurements were repeated until
registration of three acceptable and reproducible measurements (difference < 10%), with one minute
rests between them, and the highest value was registered [20,21]. Predicted values were estimated
using the equation proposed by Heinzmann et al. [22] Maximal voluntary ventilation (MVV, L/min)
was estimated from pulmonary function, using the formula FEV1*35 [23].

2.4.4. Functional Capacity

Assessment of functional capacity was carried out using the six minutes walking test (6MWT),
selected by its reproducibility, agreement, and criterion validity shown in pediatric patients with
this particular group of disease [24]. A pulse oximeter, a stopwatch, two cones to mark the end of
the route, a writer Borg scale, and a blood pressure monitor were employed. We registered the
maximum distance in meters covered along a 30 m corridor for six minutes. Standardized phrases
of encouragement were played every minute of the test. Two trials with a 30-min rest between them
were performed after thorough explanation of the procedure in order to minimize the impact of
the training effect on the results, and the highest walking distance was used for analysis. To further
avoid the effect of motivational variation, the physiotherapist responsible for monitoring continuously
inspirited the subject to keep pace and interest. Peripheral oxygen saturation (%), heart rate (HR, bpm),
Int. J. Environ. Res. Public Health 2020, 17, 4328 4 of 14

and dyspnea-muscle fatigue (CR-10) were recorded at rest and the end of the test. For predicted values,
we used the equation proposed by Geiger et al. [25].
All measurements were collected at the beginning of the program (T1), after all programmed
sessions (T2), and six months after conclusion (T3), and all the tests were performed at the same time
of day. We also collected data regarding regular physical activity before and during the program to
account for possible biases.

2.5. Intervention
All subjects were included in a tertiary center pediatric cardiopulmonary rehabilitation program
(CPRP) (IMPROVE project). The IMPROVE intervention was designed following the American
College of Sports Medicine (ACSM) Guidelines for exercise prescription, considering the FITT
(Frequency, Intensity, Type, and Time) principles for cardiac patients and adjusting them to the
pediatric population [26]. Frequency was set to two times per week. Intensity was adjusted from
CPET parameters, regulating endurance training to achieve a HR near VT1 at the beginning of the
program, and progressively moving towards VT2 or a maximal HR of 75% of peak HR. Training was
devised following the Skinner and McLellan model [27]. The type of intervention included endurance
and resistance training. The endurance exercises were conducted in the different modalities of the
continuous training (uniform and variant pace). Each training session lasted for 70 min, and a total of
24 supervised sessions were performed in harmony with the recommendations of previous studies [13].
All subjects were monitored during the session. Peripheral oxygen saturation, heart rate, and
real time ECG were acquired continuously. Blood pressure was measured at the beginning and the
end of sessions with an Omron M6 Comfort Blood Pressure Monitor (Omron Healthcare Europe B.V,
Hoofddorp, The Netherlands). Patients’ perceived exertion was registered using a Borg CR-10 scale at
the beginning, after each training phase, and at the end of each session. Training was always led by
two experienced physiotherapists, and personally supervised by a pediatric cardiologist.
Training sessions were structured in five different phases: (1) Warm-up phase (5 min). This phase
included diaphragmatic breathing, articular mobility exercises, and a light walk. (2) Endurance-training
phase (20 min). Aerobic training was carried out using a treadmill (BH Fitness) and a static bicycle
(BH Rhyno Max H491), including two minutes of warm-up, sixteen minutes of continuous training,
and another two minutes of cool-down, in line with recommendations of endurance training for children
with CHD [28]. We chose the uniform or variant pace based on the progression of the patients during the
intervention. Intensity was set according to previously explained FITT parameters. (3) Resistance-training
phase (20 min). According to the session, the subjects completed three series of four exercises. During the
first sessions, training was done with light and medium resistance bands, emphasizing the analytical
workout of principal muscles (deltoids, biceps brachii, triceps brachii, abdominals, trunk extensors,
quadriceps, hamstrings, and calves). Since session nine, we progressed into a functional training,
using gymnastics equipment as dumbbells, medicine balls, steps, and plyometric workout. They made
10–15 repetitions of each exercise, with a 20 second rest. As a motivational complement, the last sessions
incorporated virtual reality games. (4) Respiratory-training phase (20 min). As a final phase of muscular
training, a specific respiratory muscle workout was conducted using the Threshold® Inspiratory Muscle
Trainer device (Respironics, NJ 07054, USA), adjusting the workload to a minimum of 30% of subject
MIP [29]. Range workload of the IMT device was between 9 to 41 cmH2 O. With all the children
sitting comfortably, the protocol contained 21 min of training divided into seven series, with two
minutes of work and one of rest between series. During this training, a physiotherapist reeducated
the ventilatory pattern, avoiding the use of accessory respiratory musculature and the increase of
respiratory rate and/or tidal volume. To ensure that each patient was training with an appropriate
workload, two intermediate-study MIP measurements were taken (weeks 4 and 8). (5) Cool-down phase
(5 min). It included a light walk and body stretching, especially upper and lower limbs, in order to
normalize vital signs and minimize perceived exertion at the end of the session.
Int. J. Environ. Res. Public Health 2020, 17, 4328 5 of 14

In addition to supervised training sessions, children were encouraged to stay active throughout the
week, participating in physical education at school and non-competitive games. Regarding respiratory
training, as the protocol had to be trained three times a week, two of them were performed during the
sessions, while the other one was carried out at home [30]. Patients received a guide and registered
session completion and incidents.

2.6. Statistical Analysis

All data preparation, exploration, analysis, and plotting were performed using Python
programming language data science open-source libraries including: (1) Numpy (Copyright ©
2020–2020, NumPy Developers), (2) Pandas (Copyright (c) 2008–2011, AQR Capital Management,
LLC, Lambda Foundry, Inc. and PyData Development Team), (3) Matplotlib (Copyright (c)
2012–2013 Matplotlib Development Team), (4) Seaborn (Copyright (c) 2012–2020, Michael L. Waskom),
(5) Scypy (Copyright© 2020–2019 SciPy Developers), and (6) StatsModel (Copyright© 2020–2018
StatsModel Developers). Distribution of quantitative variables was strongly tested for normality
before inferential analysis by performing Shapiro–Wilk, D’Agostino Kˆ2, and Anderson–Darling
tests. Bivariate association was investigated using related and non-related one sample t-test in
case of normally distributed variables, and Mann Whitney U and Wilcoxon signed-rank test for
non-distributed variables depending on data pairing. Bonferroni correction was applied to account for
multiple measurement comparisons potential alpha error. Categorical bivariate association was studied
using Fisher’s exact test. Data are presented as mean values (SD) or median (IQR) in non-normally
distributed variables. A p-value < 0.05 was considered statistically significant. Sample size calculation
for paired mean differences was calculated assuming a level of significance of 0.05, a statistical power
of 70%, and an effect size of 0.6, resulting in a minimum sample size of 15 patients.

3. Results

3.1. Population
A total number of 353 subjects were screened at the exercise physiology laboratory.
Twenty-eight patients fulfilled clinical criteria and were contacted. Participation in the study was
declined by 13 subjects. The main reasons not to participate were geographical limitations and
the time-consuming exigencies of the program, respectively. All demographic characteristics of the
screened patients were documented. Amongst the patients that fulfilled clinical criteria, there were no
significant differences between the ones that accepted and rejected participation in terms of gender,
age, or anthropometric characteristics.
A total of 15 patients were enrolled (mean age 14.4 years, 60% male). All patients had
undergone corrective surgery or heart transplant. Patients diagnoses were Tetralogy of Fallot (6),
Heart transplantation (3), D-Transposition of great arteries (2), Pulmonary Atresia with intact ventricular
septum (1), Pulmonary atresia + VSD (1), repaired VSD (1), and repaired Taussig–Bing anomaly (1).
All patients reported two mandatory sessions per week of light to moderate physical activity in school
class. Two of them performed twice per week sports training (Mitchell class IIB). None of them fulfilled
WHO recommendations for physical activity in children [12].
The demographic and anthropometric features, as well as lung function baseline parameters of
the enrolled population, are described in Table 1. No significant differences were observed between
boys and girls.
Int. J. Environ. Res. Public Health 2020, 17, 4328 6 of 14

Table 1. Demographic, anthropometric, and pulmonary function baseline characteristics of study population.

Total (n = 15) Boys (n = 9) Girls (n = 6)

p-Value
Mean ± SD (range) Mean ± SD (range) Mean ± SD (range)
Demographic/anthropometric
14.4 ± 1.1 14.4 ± 1.3 14.5 ± 0.9
Age (years) 0.43
(12.4–15.7) (12.4–15.7) (13.3–15.8)
161.9 ± 9.9 164.9 ± 10.7 157.4 ± 7.3
Height (cm) 0.05
(143–182) (143–182) (145–165)
52.8 ± 12.5 55.5 ± 12.9 48.9 ± 11.9
Body mass (kg) 0.29
(33–74.2) (41.3–74.2) (33–63)
20 ± 3.5 20.3 ± 3.6 19.5 ± 3.8
BMI (kg/m2 ) 0.11
(14.8–25.4) (14.8–25.4) (15.7–24.3)
Pulmonary function
2.29 ± 0.54 2.34 ± 0.69 2.23 ± 0.23
FEV1 (L) 0.43
(1.26–3.53) (1.26–3.53) (1.89–2.44)
Predicted FEV1 0.77 ± 0.15 0.72 ± 0.17 0.85 ± 0.09
0.05
(%) (0.38–0.93) (0.38–0.90) (0.71–0.93)
2.81 ± 0.72 2.93 ± 0.88 2.64 ± 0.37
FVC (L) 0.30
(1.64–4.15) (1.64–4.15) (2.12–3.09)
Predicted FVC 0.80 ± 0.17 0.75 ± 0.20 0.86 ± 0.10
0.10
(%) (0.40–1.03) (0.40–1.03) (0.72–1.03)
FEV1 /FVC ratio 81.84 ± 5.98 79.86 ± 5.24 84.82 ± 6.20
0.06
(%) (72.0–92.6) (72.00–88.00) (77.00–92.60)
Abbreviations: BMI = Body Mass Index; FEV1 = Forced Expiratory Volume in the 1st second; FVC = Forced
Vital Capacity.

3.2. Program Adherence and Safety

All 15 patients completed the study goal of performing more than 75% of the programmed
training sessions. On average, each patient missed three training sessions (12%, range 1–5). A high
compliance with respiratory home-training protocol was observed (100% of the subjects performed
and registered more than 80% of the programmed home-training sessions). Overall, we experienced
very good predisposition towards the training program and a very thorough completion rate.
Overall, no adverse events were reported during rehabilitation, except for minor muscle stiffness
in the first week of training. ECG continuous monitoring showed no significant arrhythmias,
only registering infrequent and non-perceived monotopic ventricular ectopy in two patients,
already revealed at CPET. No adverse effects were reported during IMT training.

3.3. Respiratory Muscle Function

All participants in the study completed programmed measurements satisfactorily. Individual progression
of respiratory muscle function is summarized in Table 2.
An increase in MIP (mean 94 to 116 cm H2 O, p < 0.01) and percentage of predicted MIP (mean 81%
to 100%, p < 0.01) was observed after rehabilitation. A significant increment (> 20% of predicted) was
not observed more frequently in patients in a worse baseline situation (Fisher’s p = 0.61). This rise
in MIP was maintained in a 6-month follow-up in which the subjects performed no respiratory
training, observing no variation (0.5 cm H2 O) in MIP and percentage of predicted MIP after this time.
A representation of every measure of MIP performed during the program is shown in Figure 1.
 T1 T2 T3 T1 T2 T3 T1 T2 T3
1 40 49 48 70 76 70 53 75 80
2 94 102 100 75 97 102 49 60 62
3 136 112 124 111 106 104 96 99 100
4
Int. J. Environ. Res. Public 1292020, 158
Health 17, 4328 172 121 100 123 98 101 109 7 of 14
5 69 82 93 79 101 114 115 119 117
6 87 123 109 70 79 79 94 96 94
Table 2. Percentage of predicted MIP, MEP, and 6MWT distance of every subject measured before, after,
7 100 95 108 105 116 121 90 101 97
and six months after completion of the training program.
8 56 71 67 76 50 66 93 97 101
Subject 9 MIP (% 59Predicted)
98 107 69
MEP (%83 112
Predicted) 88 6MWT 90 (% Predicted)
93
10T1 91T2 133 T3 129 T1 81 114
T2 102T3 99 T1 101 T2102 T3
11 52 88 86 52 67 70 99 109 116
1 40 49 48 70 76 70 53 75 80
2 1294 82102 111 100100 7575 125
97 107102 103 49 102 60102 62
3 13
136 57112 93 124 87 107
111 98
106 91104 105 96 104 99104 100
4 129
14 72158 77 172 68 121
82 100
79 94123 96 98 124 101104 109
5 1569 9282 154 93 114 79 129 101
138 150114 109 115 109 119107 117
6 87 123 109 70 79 79 94 96 94
Abbreviations:
7 100MIP = Maximum
95 108static Inspiratory
105 Pressure;
116 MEP
121 = Maximum90 static
101 Expiratory
97
Pressure;
8 6MWT
56 = six-minute
71 walking
67 test.76T1: before
50 training;66T2: after93training; 97
T3: six months
101
follow-up.
9 59 98 107 69 83 112 88 90 93
10 91 133 129 81 114 102 99 101 102
An11increase 52 88
in MIP (mean 86 116 cm52
94 to H2O, p <67 0.01) and70percentage 99 of predicted
109 116 (mean
MIP
12 82 111 100 75 125 107 103 102 102
81% to 100%, p < 0.01) was observed after rehabilitation. A significant increment (> 20% of predicted)
13 57 93 87 107 98 91 105 104 104
was not14observed72more frequently
77 in patients
68 82 in a worse
79 baseline94 situation96 (Fisher’s
124 p = 0.61).
104 This
rise in MIP
15 was maintained
92 154in a 6-month
114 follow-up
129 in
138which the
150 subjects109performed109 no respiratory
107
training, observingMIP
Abbreviations: no =variation
Maximum(0.5 cmInspiratory
static H2O) in MIP and percentage
Pressure; MEP = Maximum of predicted MIP after
static Expiratory this time.
Pressure;
6MWT =
A representation of every measure of MIP performed during the program is shown in Figure 1.
six-minute walking test. T1: before training; T2: after training; T3: six months follow-up.

Figure 1. Maximum
Figure 1. MaximumStatic
StaticInspiratory
InspiratoryPressure (MIP)
Pressure measured
(MIP) before
measured training
before (T1),(T1),
training afterafter
the first
the (w4)
first
and second (w8) month of training, at the end of the program (T2), and in a six months follow-up
(w4) and second (w8) month of training, at the end of the program (T2), and in a six months follow- after
finishing the program
up after finishing (T3).
the program (T3).

On the other hand, MEP showed no statistically significant variation (mean 119 to 130 cm H2 O,
p = 0.12) of its absolute value or its percentage of predicted value (mean 87% to 96%, p = 0.11) after
rehabilitation. We observed a slight increment of MEP between the end of the program and the six
months follow-up (mean 130 to 138 cm H2 O). No statistically significant difference was observed after
rehabilitation in MVV (mean 80 to 86 L/min, p = 0.36), despite observing an increment in MVV after
rehabilitation and complete stability during the follow-up period. A comparison of all measures before
and after rehabilitation is represented in Table 3. Differences between measurements at the end of the
program and six months after that point are shown in Table 4.
 months follow-up (mean 130 to 138 cm H2O). No statistically significant difference was observed after
rehabilitation in MVV (mean 80 to 86 L/min, p = 0.36), despite observing an increment in MVV after
rehabilitation and complete stability during the follow-up period. A comparison of all measures
before and after rehabilitation is represented in Table 3. Differences between measurements at the
end of the program and six months after that point are shown in Table 4.
Int. J. Environ. Res. Public Health 2020, 17, 4328 8 of 14
Table 3. Comparison of MIP, MEP, and MVV before and after the program (n = 15). Expressed as
absolute and relative (percentage of predicted values) values.
Table 3. Comparison of MIP, MEP, and MVV before and after the program (n = 15). Expressed as
absolute and relative (percentage of predicted
Before Training values)
After values. Change
Training
Mean
p-Value
(%) Difference
MIP (cm H2O) Before 94.3
Training
± 30.1 After Training
116.1 ± 24.6 Change (%)
23.1 Mean21.8
Difference 0.001p-Value
Predicted
MIP (cm H2 O) MIP (%) 81.4
94.3 ± 30.1± 0.2 100.1 ±
116.1 ± 24.6 0.3 23.1 23 18.7
21.8 0.001 0.001
Predicted
MEPMIP(cm(%)
H2O) ± 0.2± 32.3
81.4119.3 100.1 ±±
130.3 0.331.4 23 9.2 18.7
11 0.12 0.001
MEPPredicted
(cm H2 O) MEP (%) 119.3 87.3± 32.3
± 0.2 130.3 ± 31.4
95.9 ± 0.2 9.29.8 11
8.6 0.11 0.12
Predicted MEP (%) 87.3 ± 0.2 95.9 ± 0.2 9.8 8.6 0.11
MVV (L/min)
MVV (L/min)
80.2 ± 19
80.2 ± 19
85.7 ± 18.2
85.7 ± 18.2 6.8
6.8 5.5 5.5
0.36 0.36
Abbreviations: MIP = Maximum static Inspiratory Pressure; MEP = Maximum static Expiratory
Abbreviations: MIP = Maximum static Inspiratory Pressure; MEP = Maximum static Expiratory Pressure;
MVVPressure;
= Maximum MVVVoluntary
= Maximum Voluntary
Ventilation. Ventilation.
p-values marked p-values
in boldmarked
indicateinnumbers
bold indicate numbers
that are that on a
significant
95% are significant
confidence on a 95% confidence limit.
limit.

Table
Table 4. Comparison
4. Comparison ofofMIP,
MIP,MEP,
MEP,and
andMVV
MVV immediately
immediately after
afterthethe
program andand
program six months after after
six months
completion (n = 15). Expressed as absolute and relative (percentage of predicted values) values.
completion (n = 15). Expressed as absolute and relative (percentage of predicted values) values.
Change Mean
After
After Training Follow-Up
Training Follow-Up Change (%) Mean Differencep-Value
p-Value
(%) Difference
MIPMIP
(cmH 2 O) 2O)
(cmH 116.1 ± 24.6
116.1 ± 24.6 116.6 ± 28.7
116.6 ± 28.7 0.4
0.4 0.5 0.5 0.86 0.86
Predicted MIP (%) 100.1 ± 0.3 101.2 ± 0.3 1.1 1.1 0.88
Predicted MIP (%) 100.1 ± 0.3 101.2 ± 0.3 1.1 1.1 0.88
MEP (cmH2 O) 130.3 ± 31.4 137.7 ± 33.7 5.7 7.4 0.12
MEP (cmH2O) 130.3 ± 31.4 137.7 ± 33.7 5.7 7.4 0.12
Predicted MEP (%) 95.9 ± 0.2 100.8 ± 0.2 5.1 4.9 0.16
MVV (L/min) MEP (%)
Predicted 85.795.9 ± 0.2
± 18.2 100.8
85.9 ± 0.2
± 17.4 5.1
0.2 4.9 0.2 0.16 0.48
MVV (L/min) 85.7 ± 18.2 85.9 ± 17.4 0.2 0.2 0.48
Abbreviations: MIP = Maximum static Inspiratory Pressure; MEP = Maximum static Expiratory Pressure;
MVVAbbreviations: MIP = Maximum
= Maximum Voluntary Ventilation.static Inspiratory Pressure; MEP = Maximum static Expiratory
Pressure; MVV = Maximum Voluntary Ventilation.

3.4. Functional Capacity

3.4. Functional Capacity
All All
subjects completed a valid 6MWT. Figure 2 shows the progression of distance travelled,
subjects completed a valid 6MWT. Figure 2 shows the progression of distance travelled,
muscle fatigue and
muscle fatigue and dyspnea scales
dyspnea previously
scales previouslytotorehabilitation,
rehabilitation, after
after training, and six
training, and sixmonths
monthsafter
after the
end the
of the program. Individual progression in percentage of predicted meters travelled can
end of the program. Individual progression in percentage of predicted meters travelled can be be found
in Table
found 2.in Table 2.

Figure
Figure 2. Representation
2. Representation of six-minute
of six-minute walking
walking test test distance
distance travelled,
travelled, muscle
muscle fatigue
fatigue score,
score, and and
dyspnea
dyspnea
score, score,before
measured measured
(T1),before (T1), immediately
immediately after (T2),after
and(T2), and six months
six months after
after the the program
program (T3). (T3).

A rise in the 6MWT distance travelled (m) was observed after training (mean 642 to 690,
p = 0.001), along with a significant increase in its relation to predicted distances (92% to 99%, p = 0.001).
This improvement was not only statistically but clinically significant, as the change of 48 m after
the intervention exceeded the clinical significance threshold of 30.5 m [31]. No differences were
observed between the end of the program and the six months follow-up (mean 690 to 688, p = 0.60).
Subjects experienced a reduction in Borg muscle fatigue scales (0–10) after training (mean 4.9 to 3.2,
p = 0.017), which presented a significant rebound at six months follow-up (mean 3.2 to 6.3, p = 0.0002).
Although not statistically significant, the Borg dyspnea scale (0–10) showed a decrease after training
(mean 3.9 to 2.8, p = 0.07), which again experienced a rise (mean 2.8 to 4.4, p = 0.03) six months after
training stopped. A summary of the 6MWT distance and scales comparisons pre and post rehabilitation
can be found in Table 5. In Table 6, we show the comparison between the end of the program and the
six months follow-up.
Int. J. Environ. Res. Public Health 2020, 17, 4328 9 of 14

Table 5. Comparison of 6MWT distance, dyspnea score, and muscle fatigue score, before and after the
program (n = 15). Expressed as absolute and relative (percentage of predicted values) values.

Before Training After Training Change (%) Mean Difference p-Value

6MWT distance (m) 642 ± 128 690 ± 115 7 48 0.001
Predicted 6MWT distance (%) 92.5 ± 0.2 99.2 ± 0.1 7.2 6.5 0.001
Dyspnea after 6MWT (0–10) 3.9 ± 3.3 2.8 ± 1.9 28 1.1 0.07
Muscle fatigue after 6MWT (0–10) 4.9 ± 3.1 3.2 ± 1.9 35 1.7 0.017
Abbreviatures: 6MWT = six-minute walking test; Considerations: All Dyspnea and Muscle Fatigues scores at rest
were 0. p-values marked in bold indicate numbers that are significant on a 95% confidence limit.

Table 6. Comparison of 6MWT distance, dyspnea score, and muscle fatigue score immediately after the
program and six months after completion (n = 15). Expressed as absolute and relative (percentage of
predicted values) values.

After Training Follow-Up Change (%) Mean Difference p-Value

6MWT distance (m) 690 ± 115 688 ± 98 −0,9 −2 0.60
Predicted 6MWT distance (%) 99.2 ± 0.1 99.1 ± 0.1 −1 −0.1 0.61
Dyspnea after 6MWT (0–10) 2.8 ± 1.9 4.4 ± 2.1 16 1.6 0.03
Muscle fatigue after 6MWT (0–10) 3.2 ± 1.9 6.3 ± 2.3 20 3.1 0.0002
Abbreviatures: 6MWT= six-minute walking test. p-values marked in bold indicate numbers that are significant on a
95% confidence limit.

4. Discussion
This clinical study demonstrates an improvement of MIP, distance walked, and muscle fatigue
perceived in the 6MWT as surrogate measures of respiratory muscle function and functional capacity
improvement, following a three-month cardiopulmonary rehabilitation program in children with
congenital heart disease. In addition, its results reveal that the achieved benefits are maintained in the
majority of the subjects after a period of six months following rehabilitation, being to our knowledge the
first study to assess persistence of aforementioned benefits. It is arguable that a lack of statistical power
due to small sample size could be potentially obscuring an actual improvement on MEP and perceived
dyspnea in 6MWT, for they border statistical significance, with apparently relevant improvements.

4.1. Respiratory Muscle Function

Global respiratory muscle strength has been shown to be reduced in the CHD population.
This ventilatory limitation has been linked to surgical scarring and thoracic deformation, phrenic nerve
injury, and deconditioning, but it most certainly behaves as a multifactorial phenomenon. In our
study, 46% of participants had a MIP under 80% of their predicted values, in accordance with the high
described prevalence of muscle weakness in this population [11]. However, we observed that despite
prior assumptions of a higher improvement chance in patients with a worse baseline situation [32,33],
respiratory muscle function was improved uniformly amongst the subjects involved in the study,
independently of their starting situation.
We believe that key to this finding is choosing the right intervention protocol. According to
the current evidence, a threshold-type device should be used, with medium intensity workload,
adjusted between 30% and 70% of the baseline MIP. An intensity inferior to 30% does not respect the
principle of overload and does not modify muscle fiber structure. On the other hand, an intensity
greater than 70% can cause muscle fatigue [34]. It is imperative that this load is frequently adjusted to
catalyze improvement. Patients should train at least three times a week for a minimum of eight weeks.
Supervision and instruction prior to home-based training is mandatory.
Paucity of studies and heterogeneity amongst intervention methodologies compromises
comparability of the outcomes amongst them. Laohachai et al. proved that a six-week course of
IMT muscle training for 30 min per day in adolescent/young adult Fontan patients produced a
significant improvement in inspiratory muscle strength, ventilatory efficiency, and resting cardiac
output [29]. In contrast, a pilot study recruited Fontan young adults, showing no improvement in
Int. J. Environ. Res. Public Health 2020, 17, 4328 10 of 14

MIP and MEP after IMT training for 12 weeks. However, the authors postulate that the failure to
improve may be related to inadequate inspiratory load adjustment [35]. More recently, a randomized
controlled trial conducted by Fritz et al. [36] recruited Fontan patients to perform IMT training daily
sessions of 10–30 repetitions of IMT during six months, but the authors state that respiratory muscle
function was not collected as a result. This study showed no improvement on exercise capacity or lung
function. The results of our work are concordant with the data described by Laohachai et al., showing a
considerable and statistically significant increase on MIP after training, with no significant changes in
maximal expiratory pressure.
To our knowledge, this is the first study to evidentiate the preservation of the respiratory muscle
function improvement six months after a rehabilitation program in the CHD population. These results,
however, could be influenced by the follow-up period selected, as it has been previously reported
in different populations that without adherence to IMT, training related gains can be lost within one
year [34]. Additionally, different to previous works focused on the study of Fontan patients, we sought a
more general population in order to test our hypothesis in a more representative group. This approach,
however, must be interpreted carefully, as generalizing with a reduced sample makes it difficult to
extract conclusions for particular cases as is later described in the limitations section.

4.2. Functional Capacity

The six-minute walking test represents a measure of functional capacity, integrating different
physiological aspects and giving a general vision rather than the more precise assessment obtained
in the cardiopulmonary exercise test. Its reliability and criterion validity have been evaluated in the
pediatric population with CHD [24], showing excellent/positive criterion validity and fair agreement,
despite the lack of studies to solidify this evaluation. However, its results must be interpreted and
compared cautiously, as large variations of these test measurement properties exist amongst different
chronic condition groups in children.
Although no minimal clinically important difference has been officially established for children
in the 6MWT, previous works [24] have assumed adult values for adolescents. A systematic review
conducted by Bohannon et al. [31] on adult patients with cardiorespiratory conditions establishes
this difference between 14 and 30.4 m, assuming that a distance exceeding 30.5 m can be considered
clinically meaningful. We find this estimation reasonable for goal-setting in this population considering
our experience and results.
There is wide evidence supporting an inferior aerobic and functional capacity in the CHD
population compared to healthy controls. [37]. Additionally, multiple studies have been conducted
to prove the impact of CPRP in several aerobic capacity indicators. A controlled trial performed by
Rhodes et al. [38] demonstrated an increase in percentage of predicted peak VO2 and peak work
rate after a three months CPRP, as well as the preservation of the exercise function six months after
completion of the rehabilitation program. More recently, a systematic review and meta-analysis by
Gomes-Neto et al. [15] revealed that despite the scarcity and significant heterogeneity of publications,
exercise training may improve peak VO2 in the CHD population, but there are no data about the
repercussion on overall survival.
Most of these studies, however, focus on different outcome measures, although supporting the
same general line of evidence. A study conducted by Moalla et al. [39] on the effects of training in the
six-minute walking test compared CHD with control children (n = 17 vs. 14), and showed a reduction in
baseline distance travelled of CHD children compared to healthy controls and a significant improvement
in distance travelled after training. Despite differences in training protocols and supervision, we believe
that our results show agreement with the data published in this study, observing a similar improvement
of distance travelled, and offering a slightly larger sample (9 vs. 15 patients in the training group).
Careful observation of the six months period after training in our study reveal no improvement
whatsoever in 6MWT performance, compared to the mean 48 m of improvement in the three month
training period, suggesting that despite lack of a formal controlled design, the same subjects experienced
Int. J. Environ. Res. Public Health 2020, 17, 4328 11 of 14

no spontaneous improvement over time. Additionally, our study reveals the persistence of functional
capacity improvement, a new but expected outcome considering previous analysis of aerobic capacity
evolution in time [35]. We found no correlation between 6MWT and respiratory muscle function,
as stated in a previous investigation by Feltez et al. [40]. Concerning perceived fatigue (measured as
muscle fatigue and dyspnea in our study), we found no previous evidence of the impact of exercise
training on this outcome. Our results suggest an improvement of perceived leg fatigue, which has
been shown to be the main exercise-limiting symptom reported by patients in some other chronic
disease groups [41]. Interestingly, worsening of this score occurs after a six months period without
supervised exercise training, possibly pointing out the impact of being active upon the subjective
perception of fatigue.

4.3. Limitations
This study presents multiple limitations that could potentially affect its interpretation. Firstly,
the sample size is small, in accordance with all published literature on the field of cardiac rehabilitation in
children [15]. This limitation is due to the heavy time and resource requirements nature of rehabilitation
programs, both for professionals and for the families. We considered it not advisable to perform
rehabilitation on large groups of children, as the ability of the supervisors to guarantee correct and safe
training and keep the attention of the group declines exponentially as group size grows. Additionally,
the heterogeneity of the group diagnoses, combined with the aforementioned small sample size,
could potentially affect the extrapolation of the results to the wide variety of CHD. This heterogeneity
is caused by the sheer variation in CHD nature, and the rate at which children can be tested with
CPET and screened. We believe a balance between sample size and heterogeneity must be sought.
Another limitation is the lack of a control group, which could potentially affect the ascription of the
effects to the intervention. This is attributable to the scarce number of patients and the difficulty for the
families to attend several visits and measurements without an intervention. To counterweight this
limitation, potential factors of MIP, MEP, and functional capacity improvements were discussed, and the
most relevant were identified as (1) children growth and development during the three-month period
and (2) the effect of training in measuring outcome. To eliminate the first, we compared the predicted
values computing the weight and height at the moment the measurement was taken, accounting for
the potential difference produced by mere growth. In order to minimize the effect of the latter, we
thoroughly trained all children in the measurement methodology before we started data acquisition
and aimed insistently for consistency in the measurements (several readings with < 10% difference).
Lastly, results suggest that the statistical power of the study is limited by the sample size, and it is
plausible that an impact on MEP and MVV would be observed in a larger sample.

5. Conclusions
In summary, we report improvements in inspiratory muscle function, functional capacity,
and muscle fatigue exercise perception after a three months cardiopulmonary rehabilitation program
in children with CHD. Interestingly, improvements in inspiratory muscle function and functional
capacity seem to persist six months after having finished the training. These findings require validation,
and further studies are clearly needed in this direction. These studies must ideally be multicentric,
employ a standardized exercise protocol, and have controlled, ideally randomized design.

Author Contributions: Conceptualization, E.P.-M., F.J.F.-S., M.À.C.I. and P.S.-C.; methodology, F.J.F.-S., M.À.C.I.,
P.S.-C. and E.P.-M; patient selection and recruitment, E.P.-M., J.I.C.M. and A.C.-S.; rehabilitation training, F.F.S.,
M.À.C.I., P.S.-C. and E.P.M.; measures and data acquisition, F.J.F.-S., M.À.C.I. and P.S.-C.; software and statistical
analysis, E.P.-M.; writing (original draft preparation), E.P.-M., F.J.F.-S. and M.À.C.I.; writing (review and editing),
M.À.C.I., P.S.-C., P.S.S., J.I.C.M., A.C.-S., M.I.V.-A. and B.I.A.; resources and logistics, P.S.S., M.I.V.-A. and B.I.A.
All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Int. J. Environ. Res. Public Health 2020, 17, 4328 12 of 14

Acknowledgments: We gratefully acknowledge José Miguel Sáez, Amparo Moya, Eladio Ruiz, Antonio Sánchez,
and Belén Fernández for their support and pediatric cardiology expertise; Enrique Viosca for his support for
the program; Lorena Saiz and Marta Martínez for their extraordinary assistance during exercise testing; Mónica
Orts, Patricia Milotich and Paula Mas for collaborating in the social and psychological aspects of the program;
Ana Bilbao for the nutritional counseling and “Latiendo Juntos” association for their unconditional support to
the program. Lastly we would like to specially thank the families involved in the program for their immense
commitment and their relentless fight to pursue a better health for their children.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations and Acronyms

CHD = Congenital heart disease; CPET = Cardiopulmonary exercise test; CPRP = Cardiopulmonary rehabilitation
program; HRQoL = Health-related quality of life; IMPROVE = Initiative for Monitored Pediatric Rehabilitation
Outlined by Exercise testing. 6MWT = Six-minute walking test.

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