Bongers et al. SpringerPlus 2014, 3:696
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a SpringerOpen Journal
RESEARCH
Open Access
Ventilatory response to exercise in adolescents
with cystic fibrosis and mild-to-moderate airway
obstruction
Bart C Bongers1,2*, Maarten S Werkman2,3, Tim Takken2 and Erik H J Hulzebos2
Abstract
Data regarding the ventilatory response to exercise in adolescents with mild-to-moderate cystic fibrosis (CF) are
equivocal. This study aimed to describe the ventilatory response during a progressive cardiopulmonary exercise test
(CPET) up to maximal exertion, as well as to assess the adequacy of the ventilatory response for carbon dioxide (CO2)
exhalation. Twenty-two adolescents with CF (12 boys and 10 girls; mean ± SD age: 14.3 ± 1.3 years; FEV1: 78.6 ± 17.3%
of predicted) performed a maximal CPET. For each patient, data of a sex- and age matched healthy control was
included (12 boys and 10 girls; mean ± SD age: 14.3 ± 1.4 years). At different relative exercise intensities of 25%,
50%, 75%, and 100% of peak oxygen uptake (VO2peak), breathing pattern, estimated ventilatory dead space ventilation
(VD/VT ratio), minute ventilation (VE) to CO2 production relationship (VE/VCO2-slope), partial end-tidal CO2 tension
(PETCO2), and the VE to the work rate (VE/WR) ratio were examined. VO2peak was significantly reduced in CF patients
(P = 0.01). We found no differences in breathing pattern between both groups, except for a significantly higher VE
at rest and a trend towards a lower VE at peak exercise in patients with CF. Significantly higher values were found
for the estimated VD/VT ratio throughout the CPET in CF patients (P < 0.01). VE/VCO2-slope and PETCO2 values
differed not between the two groups throughout the CPET. VE/WR ratio values were significantly higher in CF during
the entire range of the CPET (P < 0.01). This study found an exaggerated ventilatory response (high VE/WR ratio values),
which was adequate for CO2 exhalation (normal VE/VCO2-slope and PETCO2 values) during progressive exercise up to
maximal exhaustion in CF patients with mild-to-moderate airway obstruction.
Keywords: Pulmonary physiology; Ventilation; Breathing pattern; Children
Background
Peak oxygen uptake (VO2peak) is reported to be limited
in patients with cystic fibrosis (CF) (Bongers et al. 2012;
Hjeltnes et al. 1984; Keochkerian et al. 2008; Shah et al.
1998; Wideman et al. 2009). This reduction seems to have
a multifactorial cause (Selvadurai et al. 2002). Respiratory,
cardiovascular, as well as peripheral muscle function
are reported as potential exercise limiting mechanisms
(Almajed and Lands 2012). In patients with mild to
moderate pulmonary disease, non-pulmonary factors, such
as low muscle mass, impaired skeletal muscle function and
centrally mediated oxygen delivery, seem to predominate
* Correspondence: b.c.bongers-3@umcutrecht.nl
1
Department of Epidemiology, School for Public Health and Primary Care
(CAPHRI), Maastricht University, Maastricht, The Netherlands
2
Child Development & Exercise Center, Wilhelmina Children’s Hospital,
University Medical Center Utrecht, Utrecht, The Netherlands
Full list of author information is available at the end of the article
in limiting exercise capacity (Regnis et al. 1996; Moorcroft
et al. 2005; Saynor et al. 2014). In more severe patients with
CF (forced expiratory volume in one second (FEV1) <60%
of predicted), ventilatory constraints and impaired gas
exchange become more important determinants.
Due to continuous airflow obstruction, as reflected by
a decreased FEV1 and dynamic hyperinflation, adolescents
with CF have been described to develop a rapid shallow
breathing pattern at rest (Hart et al. 2002) and during exercise (Keochkerian et al. 2005). This can be accompanied
with a decreased ventilatory capacity and concomitant
reduced VO2peak (Keochkerian et al. 2008). Children and
adolescents with CF with static hyperinflation at rest (residual volume to total lung capacity ratio (RV/TLC) >30%)
seem to be more prone to a ventilatory limitation during
exercise, which appears to be associated with decreased
© 2014 Bongers et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly credited.
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exercise performance (Sovtic et al. 2013; Werkman et al.
2010).
A recent study found that exercise limitation in adult
patients with CF is multifactorial and that it was dominantly correlated with FEV1 and nutritional and inflammatory status, but also with the magnitude of the overall
ventilatory response during exercise (Pastré et al. 2014).
In patients with severe airway obstruction (FEV1 < 50%
of predicted), multivariate analysis revealed the FEV1 to
be a significant independent predictor of exercise capacity, whereas the ratio between minute ventilation and
carbon dioxide exhalation (VE/VCO2 ratio) at peak exercise was the major determinant of exercise limitation
in patients with mild-to-moderate disease (FEV1 > 50%
of predicted) (Pastré et al. 2014). However, knowledge
about the ventilatory response to exercise in adolescent
patients with mild to moderate CF is ambiguous and
inconclusive. Several studies in mild-to-moderate adolescents with CF describe an exaggerated ventilatory
response with a rapid shallow breathing pattern at rest
(Hart et al. 2002) and during exercise (Keochkerian
et al. 2008). On the contrary, a recent study in adolescents
with mild CF did not find any evidence for a different ventilatory response and/or rapid shallow breathing pattern
during exercise (Borel et al. 2014). As the two studies
demonstrating exaggerated ventilatory responses were
performed in adolescents with CF with lower FEV1 values,
this suggests that the ventilatory response to exercise is at
least partially affected by the degree of airway obstruction.
Moreover, questions can be raised whether the adopted
rapid shallow breathing pattern is beneficial as higher
breathing frequencies seem to increase ventilatory dead
space ventilation (VD/VT ratio), as has been reported in
patients with CF waiting for lung transplantation (Thin
et al. 2004). However, adding additional dead space volume during exercise in patients with mild CF lung disease
had no influence on VO2peak and the duration of the exercise test, and it even increased ventilation which was
attributed to an increased tidal volume with no change in
respiratory rate (Dodd et al. 2006). The increased dead
space volume was accompanied by higher VE/VCO2 ratios
during exercise (Dodd et al. 2006). This finding in patients
with mild CF suggests that the ventilatory response during
exercise in adolescents with CF might differ with healthy
controls and that this might alter during the course of
the disease. Unfortunately the recent study of Borel
et al. (2014), which focussed on ventilation during the
entire range of exercise, only mentioned mechanical
constraints influencing ventilation and did not discuss
metabolic issues related to ventilation. Moreover, they
included small and unequal groups of only prepubertal
children.
As lung function decreases over time in most patients
with CF, exercise capacity eventually becomes limited by
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the lungs reaching their mechanical limits to expand
(approximately at FEV1 values ≤60%pred) (Almajed and
Lands 2012). Insight in the breathing pattern during
progressive exercise in adolescents with CF in a broad
spectrum of lung function deterioration, as well as the
adequacy of this ventilatory response for carbon dioxide
(CO2) exhalation, is clinically relevant for future therapeutic interventions. Therefore, the aim of the current
study was 1) to describe the ventilatory response during
a progressive cardiopulmonary exercise test (CPET) up
to maximal exertion in adolescents with mild-to-moderate
CF and 2) to assess the adequacy of the ventilatory
response for CO2 exhalation (determined from partial
end-tidal carbon dioxide tension (PETCO2)) throughout the CPET in mild-to-moderate patients with CF.
Our hypothesis is that adolescents with CF develop an
obstructive breathing pattern, combined with a relatively
large VD/VT ratio, which limit CO2 wash out.
Methods
Participants
Exercise data of twenty-two adolescents (12 boys and 10
girls from 12 to 17 years of age, mean ± SD age: 14.3 ±
1.3 years) with mild-to-moderate CF were randomly
selected from the exercise database from the CF Center
at the University Medical Center Utrecht. The database
contained anonymous patient data of anthropometry,
lung function and exercise capacity which was measured
as part of usual care at the routine annual check-up.
Therefore, all patients were free from acute pulmonary
or gastrointestinal exacerbation at the time of testing.
Testing procedures used in this study met the assumptions for standard of practice for the routine care of patients with CF. For each patient with CF, an age, sex and
anthropometrically matched healthy control who performed a maximal CPET in our hospital retrospectively
was selected (untrained and normal physical activity
level). All participants and their guardians provided approval for inclusion of the data in research studies. After
evaluation, the medical ethical committee of the University Medical Center Utrecht determined that inclusion
of the data conformed to the regulations of the Dutch
CF Registration and that inclusion of the data in this
study met the ethical polices of the University Medical
Center Utrecht, as well as the regulations of the Dutch
government.
Anthropometric measures
Body mass and body height were determined using an
electronic scale (Seca, Hamburg, Germany) and a stadiometer (Ulmer Stadiometer, Ulm, Germany) respectively.
Body mass index (BMI) was calculated as the body mass
in kilograms divided by the square of the body height in
meters. Standard deviation (SD) scores were calculated
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for body height for age, body mass for age, and BMI for
age using Dutch normative values (Fredriks et al. 2000).
The equation of Haycock et al. (1978), validated in infants, children, and adults, was used to obtain the participants’ body surface area (BSA).
Spirometry and plethysmography
In the patients with CF, spirometry and plethysmography
were performed by qualified lung function analysts of
the CF Center at the University Medical Center Utrecht.
Since the healthy controls were not known with any disease, spirometry and plethysmography was not performed in this group. In order to prevent the potential
influence of bronchial reactivity during exercise, spirometry and plethysmography were performed after
bronchodilation with salbutamol (800 μg). FEV1 was obtained from flow volume curves (Masterscreen, Jaeger,
Würzburg, Germany). Residual volume (RV) and total
lung volume (TLC) were determined in a body plethysmograph (Master Lab system, Jaeger, Würzburg, Germany).
The RV was expressed as a percentage of TLC (RV/TLC
ratio) as well. In order to improve comparative possibilities with the reports of other studies in CF, we used the
commonly used reference values of Zapletal et al. (1987)
to express lung function values as percentage of predicted
values.
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ventilation (VE), oxygen uptake (VO2), VCO2 and RER
from conventional equations. Output from the flow
meter and gas analyzers were averaged over ten-second
intervals and stored for further use. Relative VO2peak
(VO2peak/kg) was calculated by dividing VO2peak by
body mass. HR was monitored continuously by a threelead electrocardiogram (Hewlett-Packard, Amstelveen,
Netherlands) and transcutaneous O2 saturation at the
index finger was measured by pulse oximetry (Nellcor
200 E, Nellcor, Breda, the Netherlands). Peak exercise
parameters were defined as the highest values achieved
within the last 30 seconds prior to exhaustion.
Data analysis
The ventilatory threshold was defined as the point at
which the ventilatory equivalent for oxygen and the partial end-tidal oxygen tension reached a minimum and
thereafter began to rise in a consistent manner, coinciding with an unchanged ventilatory equivalent for carbon
dioxide and a peak in the PETCO2 course (American
Thoracic Society, American College of Chest Physicians
2003; Ohuchi et al. 1996). When this ventilatory equivalents
Table 1 Participant characteristics
Healthy
(n = 22)
Cardiopulmonary exercise test
Sex (boy/girl)
All participants completed a maximal CPET using an
electronically braked cycle ergometer (Jaeger Physis,
Carefusion, Houten, The Netherlands) after bronchodilation with salbutamol. After three minutes of rest
measurements, cycling started at a workload of 0 W.
Then, the work rate (WR) was linearly incremented
with a 15 W∙min−1 ramp protocol (Godfrey 1974) until
the patient stopped due to volitional exhaustion, despite strong verbal encouragement. The test effort was
considered maximal when the participant showed objective (heart rate (HR) at peak exercise (HRpeak) >180
beats · min−1 and/or a respiratory exchange ratio (RER)
at peak exercise (RERpeak) >1.0) (Armstrong and Welsman 2008) and subjective (unsteady biking, sweating,
facial flushing, and clear unwillingness to continue
despite encouragement) signs of maximal effort.
Throughout the CPET, participants breathed through
a facemask (dead space volume 63 or 72 mL, dependent
on size) (Hans Rudolph Inc, Kansas City, MO) that was
connected to a calibrated metabolic cart (Oxycon Pro,
Carefusion, Houten, the Netherlands). Gas analyzers were
calibrated using gases of known concentration, whereas
the flow meter was calibrated using a three-liter syringe
(Hans Rudolph Inc, Kansas City, MO). Expired gas passed
through a flow meter and a gas analyzer connected to a
computer, which calculated breath-by-breath minute
Age (years)
CF
(n = 22)
P-value
12/10
12/10
NA
14.3 ± 1.4
14.3 ± 1.3
0.99
CF mutation class
(I/II/IV/unknown)a
NA
9/27/1/6
NA
PA colonization (never/free
of infection/intermittent/chronic)b
NA
6/1/6/9
NA
1.67 ± 0.10
1.65 ± 0.09
0.61
Body height (m)
c
Body height for age SDS
0.17 ± 0.86
−0.18 ± 0.99
0.24
Body mass (kg)
53.9 ± 12.2
50.2 ± 7.2
0.31
Body mass for age SDSc
0.02 ± 0.83
−0.37 ± 0.64
0.13
BMI (kg · m−2)
19.1 ± 2.6
18.5 ± 2.0
0.51
BMI for age SDSc
−0.09 ± 0.80
−0.34 ± 0.85
0.37
BSA (m2)
1.57 ± 0.22
1.54 ± 0.14
0.72
FEV1 (L)
NA
2.52 ± 0.67
NA
FEV1 (%pred)d
NA
78.6 ± 17.3
NA
RV/TLC (%)
VO2peak/kg (mL · kg−1 · min−1)
NA
33.5 ± 9.3
NA
49.1 ± 7.2
42.4 ± 8.7
<0.01**
Values are presented as mean ± SD.
Abbreviations: BMI body mass index, BSA body surface area, CF cystic fibrosis,
CFTR cystic fibrosis transmembrane conductance regulator, FEV1 forced
expiratory volume in one second, NA not applicable, NS not statistically
significant, RV/TLC residual volume to total lung capacity ratio, SDS standard
deviation score.
**P < 0.01.
a
Based on the classification of CFTR alleles used by Green et al. (2010).
b
Based on the criteria of Lee et al. (2003).
c
Reference values of Fredriks et al. (2000).
d
Reference values of Zapletal et al. (1987).
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method appeared to provide uncertain results for a participant’s ventilatory threshold (n = 4, 18%, in the CF patients,
n = 0 in the healthy controls), the point at which the linear
slope of the relation between the VCO2 and VO2 changed
was taken as the ventilatory threshold, according to the Vslope method (Beaver et al. 1986). The ventilatory threshold (VO2) was expressed as an absolute value, relative
value (VO2 normalized for body mass) and as a percentage of the attained VO2peak. The estimated VD/VT ratio
was calculated by using the PETCO2. The graphical presentation of VE as a function of VCO2 during the progressive CPET was used to determine the point at which VE
increased out of proportion to VCO2, the respiratory compensation point.
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Next to resting values, tidal volume, breathing frequency,
VE, VD/VT ratio, and PETCO2 were determined as an
average of 30 seconds at different exercise intensities of
25%, 50%, 75% and 100% of VO2peak. Both VE and tidal
volume were adjusted for body mass as well. To allow
for fair comparison, resting VO2 was subtracted from
VO2peak. Subsequently, 25%, 50%, 75% and 100% of this
delta VO2 was calculated and summed with the resting
VO2 for each participant (CF patients and healthy controls). Furthermore, we calculated the VE to VO2 relationship (VE/VO2-slope) and the VE to VCO2 relationship
(VE/VCO2-slope) at the same different exercise intensities
by linear regression of the exercise data up to 25%, 50%,
75%, and 100% of VO2peak using the least squares
Table 2 Exercise performance in the healthy adolescents and adolescents with CF
Healthy (n = 22)
CF (n = 22)
P-value
Maximal values
HRpeak (beats · min−1)
RERpeak
192 ± 7
186 ± 8
0.02*
1.15 ± 0.08
1.19 ± 0.09
0.16
WRpeak (W)
222 ± 62
164 ± 32
<0.01**
WRpeak/kg (W · kg−1)
4.2 ± 0.6
3.3 ± 0.5
<0.001***
VO2peak (mL · min−1)
2638 ± 685
2126 ± 516
0.01*
VO2peak/kg (mL · kg−1 · min−1)
49.1 ± 7.2
42.4 ± 8.7
<0.01**
VO2peak/BSA (mL · m2 · min−1)
1667 ± 259
1378 ± 274
<0.01**
VCO2peak (mL · min−1)
2963 ± 871
2409 ± 540
0.03*
VCO2peak/kg (mL · kg · min )
54.9 ± 8.9
48.1 ± 9.7
0.02*
VE @ VO2peak (L · min−1)
89.5 ± 27.2
75.8 ± 18.8
0.08
−1
−1
VE/kg @ VO2peak (L · kg
−1
· min )
−1
Absolute tidal volume @ VO2peak (mL)
Relative tidal volume @ VO2peak (mL · kg )
−1
Breathing frequency @ VO2peak (breaths · min−1)
Estimated VD/VT ratio @ VO2peak (%)
PETCO2 @ VO2peak (mmHg)
VE/WR ratio @ VO2peak (mL · min
−1
·W )
−1
1.7 ± 0.3
1.5 ± 0.3
0.04*
1736 ± 339
1616 ± 373
0.32
32.7 ± 4.8
32.2 ± 6.4
0.98
51 ± 9
48 ± 9
0.25
17 ± 2
21 ± 4
<0.001***
36.3 ± 3.2
38.2 ± 3.7
0.10
399 ± 57
476 ± 71
<0.001***
1439 ± 381
1216 ± 253
0.07
27.1 ± 6.1
24.4 ± 5.1
0.13
Submaximal values
Absolute ventilatory threshold (mL · min−1)
Relative ventilatory threshold (mL · kg−1 · min−1)
Ventilatory threshold (%VO2peak)
PETCO2 @ rest (mmHg)
55 ± 9
58 ± 9
0.32
31.8 ± 2.4
33.5 ± 3.2
0.03*
PETCO2 @ the ventilatory threshold (mmHg)
39.3 ± 3.6
40.0 ± 2.6
0.50
VE/VO2-slope up to the ventilatory threshold
20.5 ± 3.2
23.7 ± 5.1
0.02*
VE/VCO2-slope up to the respiratory compensation point
26.6 ± 2.8
27.1 ± 2.9
0.60
Values are presented as mean ± SD.
Abbreviations: BSA body surface area, CF cystic fibrosis, HRpeak peak heart rate, NS not statistically significant, PETCO2 partial end-tidal carbon dioxide tension,
RERpeak peak respiratory exchange ratio, VCO2peak peak carbon dioxide output, VCO2peak/kg peak carbon dioxide output normalized for body mass, VD/VT ratio
physiological dead space ventilation, VE minute ventilation, VE/kg minute ventilation normalized for body mass, VE/VCO2-slope slope of the relationship between
minute ventilation and carbon dioxide output, VE/VO 2-slope slope of the relationship between minute ventilation and oxygen uptake, VE/WR minute
ventilation to work rate ratio, VO 2peak peak oxygen uptake, VO 2peak/kg peak oxygen uptake normalized for body mass, WR peak peak work rate, WR peak/kg
peak work rate normalized for body mass.
*P < 0.05; **P < 0.01; ***P < 0.001.
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approach. We examined the participants’ response of
the VE to the WR (VE/WR ratio) at similar intensities.
Data from the first minute of exercise were excluded
since the breathing pattern during the first minute of
exercise frequently appears to be unstable.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS, version 15.0; SPSS Inc., Chicago, IL) was used for the dataanalysis. Shapiro-Wilk tests for normality were performed
in order to evaluate the data distribution of each variable.
Differences between adolescents with CF and their healthy
counterparts in anthropometry and in exercise data at different exercise intensities were examined with Mann–
Whitney U tests. Data are presented as mean values ± SD.
A P-value <0.05 was considered as statistically significant.
Results
Anthropometric data for the patients with CF and the
healthy controls are presented in Table 1, with no significant anthropometric between-group differences. Lung
function characteristics of the adolescents with CF are also
shown in Table 1. Patients had mild-to-moderate airway
obstruction (mean FEV1 expressed as a percentage of predicted of 79 ± 17%) and a mild-to-moderate degree of
static hyperinflation (mean RV/TLC ratio of 34 ± 9%).
More specifically, 14 patients (5 boys and 9 girls) had an
absolute RV/TLC ratio greater than 30%, which suggests
static hyperinflation (Eid et al. 2000).
All participants performed a maximal effort during
the CPET (mean test duration of 623 ± 139 and 659 ±
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194 seconds for the CF patients and healthy controls
respectively), and the results are presented in Table 2.
Compared with the healthy controls, adolescents with CF
attained significantly lower values for HRpeak, peak WR
(WRpeak), WRpeak/kg, VO2peak, VO2peak/kg, VO2peak/m2 (normalized for BSA), peak VCO2 (VCO2peak), VCO2peak/kg, and
peak VE (VEpeak) normalized for body mass (VEpeak/kg),
whereas they attained significantly higher values for the
estimated VD/VT ratio at peak exercise, the VE/VO2slope up to the ventilatory threshold, PETCO2 at rest,
and the VE/WR ratio at peak exercise.
Breathing pattern components, tidal volume and breathing frequency, adopted during exercise did not differ significantly between patients with CF and healthy adolescents,
except for a significantly higher breathing frequency at rest
(19 ± 3 versus 22 ± 5 breaths · min−1; P = 0.02) and a trend
for lower absolute tidal volume values at or near maximal
exercise in patients with CF (1.74 ± 0.34 versus 1.62 ±
0.37 L; P = 0.32). Consequently, VE at rest was significantly
higher (11.5 ± 2.1 versus 13.8 ± 3.4 L · min−1; P = 0.02),
whereas VEpeak (75.8 ± 18.8 versus 89.5 ± 27.2 L.min−1;
P = 0.08) tended to be lower in patients with CF. VE normalized for body mass (VE/kg) was significantly higher at
rest (0.2 ± 0.05 versus 0.3 ± 0.06 L · kg−1 · min−1; P < 0.01) and
at 25% of VO2peak (0.4 ± 0.07 versus 0.5 ± 0.08 L · kg−1 · min−1;
P = 0.03) in the patients with CF. Values for breathing frequency divided by the tidal volume (rapid shallow breathing index) tended to be higher in patients with CF at rest
(32 ± 13 versus 38 ± 13; P = 0.14) and at 25% of VO2peak
(27 ± 10 versus 32 ± 15; P = 0.31). Furthermore, estimated
VD/VT ratio values were significantly higher during all
Figure 1 Changes in the estimated VD/VT ratio during exercise at similar percentages of VO2peak in the healthy adolescents and the
adolescents with CF. Dashed lines correspond to the ventilatory threshold in both groups. Abbreviations: CF = cystic fibrosis; VD/VT ratio = physiological
dead space ventilation; VO2peak = peak oxygen uptake. **P < 0.01; ***P < 0.001.
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Figure 2 (See legend on next page.)
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Page 7 of 10
(See figure on previous page.)
Figure 2 Changes in VE/VO2-slope, VE/VCO2-slope, and PETCO2 during exercise at similar percentages of VO2peak in the healthy
adolescents and the adolescents with CF. Dashed lines represent the ventilatory threshold in both groups. Abbreviations: CF = cystic fibrosis;
PETCO2 = partial end-tidal carbon dioxide tension; VE/VCO2-slope = slope of the relationship between minute ventilation and carbon dioxide
output; VE/VO2-slope = slope of the relationship between minute ventilation and oxygen uptake; VO2peak = peak oxygen uptake. *P < 0.05; **P < 0.01.
exercise intensities in patients with CF (see Figure 1, P < 0.01,
P < 0.01, P < 0.01, and P < 0.001 at 25%, 50%, 75%, and
100% of VO2peak respectively).
Figure 2 shows significantly higher VE/VO2-slope
values at 25% (P = 0.01) and 50% (P < 0.01) of VO2peak in
patients with CF, whereas VE/VCO2-slope values differed not significantly between the two groups throughout the entire range of the CPET. Furthermore, Figure 2
demonstrates that, except for resting values (P = 0.03),
PETCO2 values differed not significantly between the two
groups during the CPET.
Figure 3 represents the RER at rest and throughout
progressive exercise in order to elucidate the higher VE/
VO2 ratios during sub-maximal exercise. At rest and during
sub-maximal exercise, patients with CF attained significantly higher RER values (P < 0.001, P < 0.001, P < 0.001,
P < 0.01, and P = 0.26 at rest, 25%, 50%, 75%, and 100%
of VO2peak respectively). The VE/WR ratio depicted in
Figure 4 was significantly higher in CF during the
entire range of the CPET (P < 0.01, P < 0.001, P < 0.001,
and P < 0.001 at 25%, 50%, 75%, and 100% of VO2peak
respectively).
Discussion
The present study aimed to 1) describe the ventilatory
response during a progressive CPET and 2) assess the
adequacy of the ventilatory response for CO2 exhalation
during exercise in mild-moderate adolescents with CF.
First, we found an exaggerated ventilatory response during
exercise. Second, this ventilatory response to exercise seems
to be adequate for CO2 exhalation in patients with
mild-to-moderate CF. The latter is illustrated by a similar course of the VE/VCO2-slope throughout exercise,
higher RER values during sub-maximal exercise, and the
ability to maintain PETCO2 values within normal limits
throughout the entire range of the CPET.
The basic physiological factors that determine and
modify the ventilatory response to exercise are: 1) CO2
output of the exercising muscles, 2) the arterial CO2 setpoint, 3) the VD/VT ratio, and 4) the change in the arterial pressure of CO2 (PaCO2) during exercise (Wasserman
et al. 1996). Several of these concepts are addressed to in
this study. First, muscular CO2 output during (sub-)maximal exercise seems to be increased in patients with CF
(Bongers et al. 2012; Hebestreit et al. 2005; Nguyen et al.
2014), which is illustrated in the current study by a higher
RER. The higher RER in patients with CF is suggested to
reflect a higher reliance on glucose oxidation to meet
energy demands during exercise (Hebestreit et al. 2005;
Nguyen et al. 2014). Altered substrate utilization in CF
(de Meer et al. 1995; Moser et al. 2000; Selvadurai et al.
2003) might explain the increased RER at rest and for
Figure 3 RER during exercise at similar percentages of VO2peak in healthy adolescents and patients with CF. Vertical dashed lines
correspond to the ventilatory threshold in both groups. Abbreviations: CF = cystic fibrosis; RER = respiratory exchange ratio; VO2peak = peak oxygen
uptake. **P < 0.01; ***P < 0.001.
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Figure 4 Changes in the VE/WR ratio during exercise at similar percentages of VO2peak in healthy adolescents and patients with CF.
Dashed lines correspond to the ventilatory threshold in both groups. Abbreviations: CF = cystic fibrosis; VE/WR = minute ventilation to work rate
ratio; VO2peak = peak oxygen uptake. **P < 0.01; ***P < 0.001.
the lower exercise intensities. In addition, slowed VO2
kinetics during exercise and recovery in patients with
CF might also be a possible explanation for an increased
RER during sub-maximal exercise (Kusenbach et al.
1999; Massin et al. 2000; Pouliou et al. 2001; Hebestreit
et al. 2005; Stevens et al. 2009; Saynor et al. 2014). This
results in a greater dependency on glycolytic energy systems at lower exercise intensities resulting in an increased
VCO2. Higher aerobic or anaerobic glycolytic energy
expenditure during exercise increases ventilation as
supported by a study in patients with familial mitochondrial myopathy (Heinicke et al. 2011). The current
study showed an exaggerated VE relative to metabolic
rate, indicated by high VE/VO2-slope values and VE/
WR ratios, as well as an elevated RER, with no apparent signs of pulmonary insufficiency.
Second, the VD/VT was significantly higher at all exercise intensities in patients with CF, which seems to be
exaggerated with disease progression (post-hoc analysis,
data not shown). High VD/VT values during exercise
have previously been reported in patients with CF
(Cerny et al. 1982; Coates et al. 1988; Thin et al. 2004;
Wilkens et al. 2010). This, in combination with the trend
of higher PETCO2 in patients with CF, indicates an
abnormal alveolar dead space ventilation (Wilkens et al.
2010), which might explain the relatively high VE values
at rest and during sub-maximal exercise in patients with
CF. Unfortunately, the exaggerated ventilatory response
we found and the shift from oxidative to glycolytic
energy metabolism, as shown by the attenuation of the
RER slope at exercise intensities above 50% of VO2peak
when compared to healthy controls, seems not to be able
to totally compensate the limited exercise capacity in
patients with CF (significantly reduced VO2peak/kg and
WRpeak/kg). Our results are in agreement with the study
of Borel et al. (2014) who found no effect of mild CF on
breathing pattern and breathing strategy during an incremental CPET. Although breathing pattern and breathing
strategy of adolescents with CF were comparable with
healthy controls, most studies still report a reduced exercise capacity in adolescents with CF (Almajed and Lands
2012; Rand and Prasad 2012; Saynor et al. 2014). Saynor
et al. (2014) recently suggested that centrally mediated
oxygen delivery might be the principally limiting the
aerobic function of pediatric CF patients with mild-tomoderate airway obstruction during ramp incremental
cycling exercise. However, based on the results of the
study of Keochkerian et al. (2008) on the ventilatory response in children with CF, one would still expect that CF
could alter the ventilatory response during a progressive
CPET. The current study demonstrated no significant effect of CF on the ventilatory response for CO2 exhalation
(VE/VCO2-slope and PETCO2) to exercise in patients with
CF with mild-to-moderate airway obstruction.
As described above, we found higher values for RER,
VE/WR, and VE/VO2-slope values during sub-maximal
exercise. These results suggest a higher ventilatory demand rather than a higher ventilatory response during
sub-maximal exercise in patients with mild CF. An explanation for the absence of an impact of CF on the ventilatory
response to exercise is the mild-to-moderate severity of
the lung disease in our population. Keochkerian et al.
(2008) reported that the more severe the airway obstruction, the more rapid and shallow the breathing pattern.
The current study has some limitations. Firstly, by categorizing exercise intensity by %VO2peak, there is no
Bongers et al. SpringerPlus 2014, 3:696
http://www.springerplus.com/content/3/1/696
standardization of exercise intensity relative to the ventilatory response for each participant. However, standardizing
for exercise intensity relative to VO2 (%VO2peak) was also
done by other studies (Borel et al. 2014; Keochkerian et al.
2008). Since the ventilatory threshold occurred at a similar
percentage of VO2peak in the pediatric CF patients and the
healthy controls (58 ± 9% versus 55 ± 9%; P = 0.32), we believe that we did compare groups within the same physiological exercise intensity domain. Secondly, the sample
size was relatively small and included mainly patients with
CF with mild to moderate airflow obstruction. For this
reason, these findings cannot be generalized to patients
with severe airflow obstruction. Nevertheless, the current
study sample is representative for the CF population in a
tertiary CF Center. Thirdly, the estimated VD/VT ratio
cannot be accurately predicted from the PETCO2 in patients with an increased VD/VT ratio due to lung disease
(Wasserman et al. 2005), so caution must be taken with
the interpretation of these results. Fourth, unfortunately
we were not able to correct VO2peak for fat free mass as
this variable was not routineously measured in patients
with CF in the CF Center at the University Medical Center
Utrecht. Finally, the used criteria for a maximal effort are
subject to debate, especially in patients with CF. It has
previously been demonstrated that traditional testing protocols and verification criteria significantly underestimate
VO2peak in both healthy (Barker et al. 2011) and children
with CF (Saynor et al. 2013). We did not verify the attainment of a true VO2peak with a supramaximal exercise testing procedure.
Implications and future research
As a higher ventilatory demand seems to be present during submaximal exercise in mild-moderate patients with
CF, a small decline in ventilatory capacity might hamper
the precarious balance between ventilation and homeostasis with further disease progression in patients with
CF. The main findings presented in this study highlight
the importance for the clinician to aim for attenuation
of lung function decline even in patients with CF with a
relatively preserved lung function (“normal” FEV1). For
future research it would be interesting to evaluate the
latter hypothesis in patients with CF with more severe
airway obstruction. Moreover, the differences we found
during the course of sub-maximal exercise highlight the
importance to evaluate the submaximal exercise response
as well when interpreting a CPET, and not just focus on
peak exercise parameters.
Conclusions
The current study found an exaggerated, but adequate
ventilatory response to exercise for CO2 exhalation in patients with CF with mild-to-moderate airway obstruction.
The higher RER, VE/WR ratios, and VE/VO2-slope values
Page 9 of 10
during sub-maximal exercise point towards a higher ventilatory demand during sub-maximal exercise in patients
with CF and mild-to-moderate lung disease.
Abbreviations
BMI: Body mass index; BSA: Body surface area; CF: Cystic fibrosis; CO2: Carbon
dioxide; CPET: Cardiopulmonary exercise test; FEV1: Forced expiratory volume
in one second; HR: Heart rate; HRpeak: peak heart rate; PETCO2: Partial end-tidal
carbon dioxide tension; RER: Respiratory exchange ratio; RERpeak: Respiratory
exchange ratio at peak exercise; RV: Residual volume; RV/TLC ratio: Residual
volume to total lung capacity ratio; SD: Standard deviation; TLC: Total lung
capacity; VCO2: Carbon dioxide production; VCO2peak: Peak carbon dioxide
production; VD/VT ratio: Ventilatory dead space ventilation ratio; VE: minute
ventilation; VEpeak: peak minute ventilation; VE/VO2-slope: minute ventilation to
oxygen uptake slope; VE/VCO2 ratio: minute ventilation to carbon dioxide
production ratio; VE/VCO2-slope: minute ventilation to carbon dioxide
production slope; VE/WR: minute ventilation to work rate ratio; VO2: Oxygen
uptake; VO2peak: peak oxygen uptake; WR: Work rate; WR: peak work rate.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
BB participated in the design of the study, carried out data analysis and
drafted the manuscript. MW carried out data analysis and drafted the
manuscript. TT and EH participated in the design of the study and helped to
draft the manuscript. All authors read and approved the final manuscript.
Acknowledgements
Dr. Bongers and Dr. Werkman were supported by unconditional research
grants from the Educational Foundation of the University Medical Center
Utrecht (BB) and the Scientific Committee Physiotherapy of the Royal Dutch
Society for Physiotherapy (MW).
Author details
1
Department of Epidemiology, School for Public Health and Primary Care
(CAPHRI), Maastricht University, Maastricht, The Netherlands. 2Child
Development & Exercise Center, Wilhelmina Children’s Hospital, University
Medical Center Utrecht, Utrecht, The Netherlands. 3De Kinderkliniek, Almere,
The Netherlands.
Received: 14 October 2014 Accepted: 14 November 2014
Published: 27 November 2014
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doi:10.1186/2193-1801-3-696
Cite this article as: Bongers et al.: Ventilatory response to exercise in
adolescents with cystic fibrosis and mild-to-moderate airway obstruction.
SpringerPlus 2014 3:696.
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