Pediatric Pulmonology 40:449–456 (2005)

Timing and Driving Components of the Breathing Strategy

in Children With Cystic Fibrosis During Exercise
D. Keochkerian, PhD,1 M. Chlif, PhD,1 S. Delanaud, PhD,2 R. Gauthier, MD,3
Y. Maingourd, MD, PhD,1,4 and S. Ahmaidi, PhD1*
Summary. The aim of this study was twofold: first, to determine the breathing strategies of
children with cystic fibrosis (CF) during exercise, and secondly, to see if there was a correlation with
lung function parameters. We determined the tension-time index of the inspiratory muscles (TT0.1)
during exercise in nine children with CF, who were compared with nine healthy children with a
similar age distribution. TT0.1 was determined as followed TT0.1 ¼ P0.1/PImax
TI/TTOT , where P0.1 is
mouth occlusion pressure, PImax is maximal inspiratory pressure, and TI/TTOT is the duty cycle. CF
children showed a significant decrease of their forced expiratory volume in 1 sec (FEV1), forced
vital capacity (FCV), and FEV1/FVC, whereas the residual volume to total lung capacity ratio (RV/
TLC) ratio and functional residual capacity (FRC) were significantly increased (P < 0.001).
Children with CF showed mild malnutrition assessed by actual weight expressed by percentage of
ideal weight for height, age, and gender (weight/height ratio; 82.3  3.6%). Children with CF
showed a significant reduction in their PImax (69.3  4.2 vs. 93.8  7 cmH2O). We found a negative
linear correlation between PImax and weight/height only in children with CF (r ¼ 0.9, P < 0.001).
During exercise, P0.1, P0.1/PImax, and TT0.1 were significantly higher, for a same percent maximal
oxygen uptake in children with CF. On the contrary, TI/TTOT ratio was significantly lower in children
with CF compared with healthy children. At maximal exercise, children with CF showed a
TT0.1 ¼ 0.16 vs. 0.14 in healthy children (P < 0.001). We observed at maximal exercise that P0.1/
PImax increased as FEV1/FVC decreased (r ¼  0.90, P < 0.001), and increased as RV/TLC
increased (r ¼ 0.92, P < 0.001) only in children with CF. Inversely, TI/TTOT decreased as FEV1/FVC
decreased (r ¼ 0.89, P < 0.001), and TI/TTOT decreased as RV/TLC increased (r ¼ 0.94,
P < 0.001). These results suggest that children with CF adopted a breathing strategy during
exercise in limiting the increase of the duty cycle. Two determinants of this strategy were degrees of
airway obstruction and hyperinflation. Pediatr Pulmonol. 2005; 40:449–456. ß 2005 Wiley-Liss, Inc.

Key words: tension-time index; cystic fibrosis; breathing strategy; inspiratory muscle
performance; exercise.

INTRODUCTION
Cystic fibrosis (CF) primarily affects the respiratory
and digestive systems in children and young adults. In
particular, the bronchial airways of the lungs are blocked
with mucus that impairs breathing and harbors bacteria
and other infectious agents. Children and adolescents with
CF are known to have reduced exercise tolerance. The
precise mechanism of exercise impairment in CF remains
largely unknown, even though nutritional and cardiores-
piratory factors were shown to play an important role.1
An early clinical feature of lung disease is the deve-
lopment of hyperinflation, which increases with further
lung injury.2 Progressive hyperinflation changes the shape
of the thorax, putting the inspiratory muscles (and parti-
cularly the diaphragm) at a mechanical disadvantage.
Additionally, decreased chest wall compliance increases
the energy and oxygen costs of breathing.3 Progressive
airflow obstruction (caused by chronic mucus hyper-
secretion) involves an increase in airflow resistance,4
intrapulmonary gas trapping,5 and ventilation/perfusion
1
EA 3300-APS et Conduites Motrices: Adaptations et Réadaptations,
Université Picardie Jules Verne, Amiens, France.
2
EA 2088-Unité de Recherches sur les Adaptations Physiologiques et
Comporte-mentales, Faculté de Médecine, F-80036, Amiens Cedex,
France.
3
Unité d’Explorations Fonctionnelles Respiratoires Pédiatriques, CHU
Amiens Nord, Amiens, France.
4
Unité d’Explorations Fonctionnelles Cardio-Pédiatriques, CHU Amiens
Nord, Amiens, France.
Grant sponsor: Regional Council of Picardie ‘‘Pôle GBM Périnalité-
Enfance;’’ Grant number: 99/10.
*Correspondence to: Professor Said Ahmaidi, EA 3300-APS et conduites
motrices: Adaptations et Réadaptations, Faculté des sciences du sport,
Université de Picardi Jules Verne, Allée P. Grousset, 80025 Amiens Cedex,
France. E-mail: said.ahmaidi@u-picardie.fr
Received 12 October 2004; Revised 24 February 2005; Accepted 25
February 2005.
DOI 10.1002/ppul.20266
Published online 14 September 2005 in Wiley InterScience
(www.interscience.wiley.com).

ß 2005 Wiley-Liss, Inc.

450 Keochkerian et al.

mismatching.6 These changes may compromise respira- METHODS

tory muscle function, and patients with CF are thus more
Subjects
susceptible to respiratory failure or ventilation limitation
during exercise. Nine children (7 boys and 2 girls, ages 10–14 years),
Respiratory muscle function can be assessed by diagnosed as having CF and who had not been hospitalized
measuring the tension-time index (TTDI) described by for at least 1 month before the study, were compared with
Bellemare and Grassino.7,8 Measurement of TTDI requires 9 healthy children (7 boys and 2 girls, ages 11–14 years)
the use of esophageal and gastric balloons, and is too with a similar age distribution. They were recruited on the
invasive to apply in children. A simplified, noninvasive basis of their willingness to take part in this study. Written
index derived from mouth occlusion pressure (P0.1) was informed consent was obtained from the parents. The
proposed as an alternative method. This noninvasive study was approved by the Medical Ethics Committee of
tension-time index (validated during exercise in healthy the University Hospital (Amiens, France). Spirometrics
individuals and in patients with chronic obstructive and anthropometrics measurements are listed in Table 1.
pulmonary disease) is derived from the equation TT0.1 ¼
P0.1/PImax
TI/TTOT, where PImax is maximal inspiratory Lung Function Data
pressure and TI/TTOT is the duty cycle.9
Spirometry was performed using a pneumotachometer
Previous studies in children with chronic obstructive
(PNT) in a Jaeger Masterscreen body plethysmograph
respiratory disease (COPD)10 or CF11 at rest described a
(Erich Jaeger AG, Würzburg, Germany) by skilled
breathing strategy that avoided inspiratory muscle fatigue
pediatric pulmonary function technicians, who regularly
by limiting the increase in the duty cycle. It was found that
work with children with CF. Calibration was performed
the more the inspiratory demand increased, the more the
daily. Forced expiratory volume in 1 sec (FEV1) and
inspiratory time decreased relative to the total length of the
forced vital capacity (FVC) were measured, and the
breathing cycle.
following European Respiratory Society (ERS)12 criteria
The aims of this study were twofold: first, to determine
were applied for evaluation of FVC and FEV1 reprodu-
the breathing strategy of children with CF during exercise,
cibility: the highest value of FVC and FEV1 ‘‘should not
and second, to establish whether or not there was a corre-
lation between this strategy and children’s lung function
parameters.
TABLE 1— Anthropometric, Spirometric, and Respiratory
Muscle Performance Parameters at Rest in Children With
Cystic Fibrosis and Control Children, Expressed as
Mean  SD1
ABBREVIATIONS
Cystic fibrosis (n ¼ 8) Controls (n ¼ 8)
CF Cystic fibrosis
COPD Chronic obstructive pulmonary disease Age (years) 13.1  1.5 13.3  0.5
f Breathing frequency Height (cm) 157.3  12 162.4  8
FEV1 Forced expiratory volume in 1 sec Weight (kg) 38.1  7.9 55.5  5.4*
FVC Forced vital capacity Wt/Ht (%) 82.3  3.6 107.8  9.7***
FEV1/FVC Forced expiratory volume in 1 sec to forced vital BMI (kg/m2) 15.2  1.4 21.0  0.4***
capacity ratio FEV1 (l) 1.95  0.53 3.28  0.44**
FRC Functional residual capacity FEV1 (% predicted) 68  9 107  7***
P0.1 Mouth occlusion pressure measured 100 msec after FVC (l) 2.87  0.7 3.85  0.55*
onset of inspiration FVC (% predicted) 83  2 107  7***
PImax Maximal inspiratory pressure FEV1/FVC (%) 67  10 85  4***
P0.1/PImax Mouth occlusion pressure to maximal inspiratory FRC (% predicted) 133  19 104  6***
pressure ratio RV/TLC 44  11 22.7  3.8***
PI Mean inspiratory pressure P0.1 (cmH2O) 3.1  0.1 2.0  0.1***
PI/PImax Ratio of the mean inspiratory pressure to maximal PImax (cmH2O) 69.3  4.2 91.0  4.4***
inspiratory pressure P0.1/PImax 0.05  0.004 0.02  0.007***
RV Residual volume TT0.1 0.02  0.002 0.009  0.0006***
TLC Total lung capacity
1
RV/TLC Residual volume to total lung capacity ratio Wt/Ht, ideal weight-to-height ratio; BMI, body mass index; FEV1,
TI Inspiratory time forced expiratory volume in 1 sec; FVC, forced vital capacity; FRC,
TTOT Total duration of respiratory cycle functional residual capacity; RV, residual volume; TLC, total lung
TI/TTOT Duty cycle volume; % predicted, percentage of prediction value; P0.1, mouth
TT0.1 Noninvasive tension-time index occlusion pressure; PImax, maximal inspiratory pressure; TT0.1, tension-
VE Minute ventilation time index.
VT Tidal volume *P < 0.05.
Wt/Ht Ideal weight-to-height ratio **P < 0.01.
***P < 0.001.
 Breathing Strategy in CF Children During Exercise
exceed the next highest one by more than 5% or 0.1 L,
whichever is greater.’’12
The residual volume (RV), total lung volume (TLC),
and functional residual capacity (FRC) were determined
in the body plethysmograph as the mean of three tests.
Predictive value were based on the norm from Zapletal
et al.,13 were used for spirometry and lung volumes.
Malnutrition
Each subject’s weight (Wt) and height (Ht) were
measured. The relative underweight was calculated by
Wt/Ht, which represents the actual weight expressed by
the percentage of ideal weight for height, age, and gender
according to the guidelines of Cystic Fibrosis Foundation
for the nutritional assessment of CF patients. The range of
body size for normal nutritional status is between 90–
100% of ideal weight-for-height. Eighty-five percent to
89% of ideal weight-for-height is defined as underweight
(may indicate early malnutrition), 80–84% is defined as
mild malnutrition, 75–79% is defined as moderate
malnutrition, and <75% is defined as severe malnutrition.
Mouth Occlusion Pressure and
Tension-Time Index
Subjects were asked to breathe quietly, with the nose
occluded, through a mouthpiece connected to the
pneumotachograph (Fleish, Lausanne, Switzerland) with
a two-way low-resistance breathing valve (0.9 cm
H2O l1 sec, dead space of 50 ml, model 9340 occlusion
valve, Hans Rudolph, Inc., Kansas City, MO). During the
exhalation phase of breathing, a balloon was rapidly
inflated in the inspiratory limb of the breathing circuit to
occlude the subsequent inspiratory flow. It was closed
during expiration and automatically opened about
100 msec after onset of the subsequent inspiration.
Occlusion pressure P0.1 was measured with a differential
pressure transducer (50 cmH2O, LPM 9000 series,
Druck, Leicester, UK). The balloon was inflated with
helium from a small gas cylinder, and the valve was
controlled manually with a small switch. The subject was
asked to breathe normally despite the occlusions. Once
this maneuver had been repeated 10–15 times over a
period of 3 min, testing was completed. The subject wore
earplugs to dampen any noise from the switching device
controlling the balloon, and could see neither the
occlusion valve nor the operator and was therefore unable
to anticipate airway occlusion and change his respiratory
pattern. The analysis portion of our computer program
displayed flow, volume, and pressure waveforms and
values. A program was used to identify the onset of
inspiration (where pressure crossed 0 cmH2O) and the
occlusion pressure (P0.1) measured at the mouth 100 msec
after the onset of inspiration was determined. Inspiratory
time (TI) and total time (TTOT) were measured for the
451
breath immediately preceding the occlusion maneuver. A
simplified noninvasive tension-time index can be obtained
with the use of the mouth occlusion pressure (P0.1).9 This
index, validated during exercise in healthy subjects and in
COPD patients, is derived from the equation TT0.1 ¼ P0.1/
PImax
TI/TTOT, where PImax is the maximal inspiratory
pressure and TI/TTOT is the duty cycle.
Maximal Inspiratory Pressure
Maximal inspiratory pressure (PImax) was measured at
functional residual capacity (FRC) on seated subjects at
rest, with a differential pressure transducer (LPM 9000
series, Druck), using the technique of Black and Hyatt.14
Subjects were asked to perform a maximal inspiratory
effort against an occluded airway and to maintain it for at
least 1 sec. The PImax was measured as peak pressure over
1 sec. Maneuvers were performed until three technically
satisfactory and reproducible measurements were
obtained (variation <10%). The best score was kept for
analysis. Great care was taken to fully explain the
maneuvers. This was facilitated by the Labview interface
(Labview, National Instruments Corp., Austin, TX),
which provided a visual feedback to subjects during
maneuvers.
Gas Exchange and Breathing Pattern
Oxygen uptake and carbon dioxide output were
analyzed by a mass spectrometer (Marquette). The mass
spectrometer was calibrated before each test by use of
certified medical gases of known concentrations. Ventila-
tory flow was determined by a turbine flowmeter in a
Ventilatory Measurement Module (Interface Associates,
Inc.) that was calibrated before each test with a 3-l
calibration syringe. From an average of 10 respiratory
cycles, we measured tidal volume (VT), breathing
frequency (f), minute ventilation (VE), and TI/TTOT.
Protocol
All tests were performed at the same time of day. First,
subjects underwent spirometric measurements at rest.
Then they sat on a chair, and after a period of familiar-
ization with the equipment, ventilatory parameters and
mouth occlusion pressure were recorded for 5 min. We
performed at least 10 measurements of P0.1 at the rate of 2
or 3 per minute. Next, our subjects performed measure-
ment of PImax, after 5 min of rest. Then they sat on the
ergocycle (ER 900, Jaeger, Germany) to perform pro-
gressive exercise on an electronically braked cycle
ergometer via a ramp protocol to a symptom-limited
maximum. Work increments were individualized for each
patient based on clinical factors (e.g., history, pulmonary
function test results, and comorbidities),15 to provide an
estimated maximal exercise level which lasted between
8–10 min. When a stable respiratory ration was attained,
452 Keochkerian et al.

subjects started exercise with a 2-min warm-up period. RESULTS

The workload was then increased in steps of 10 or 15 W for
children with CF and 15 or 20 W for control subjects,
every 90 sec, until exhaustion. Two measures of P0.1were
performed during the last 45 sec of each workload. The
test ended when at least three of the following criteria were
observed to demonstrate that they had reached maximal
oxygen uptake:16 1) a stable heart rate close to the
theorical maximal heart rate; 2) respiratory ratio >1.10;
3) an upper limit on VO2 despite the increase of the
workload; and 4) inability of the subject to maintain a
pedalling rate of 60 rpm.
Statistics
Statistical comparisons were performed using StatView
software (Abacus Concepts, Berkeley, CA). Values are
reported as mean  standard deviation (SD). The data at
rest and maximal exercise, compared between CF and
control (C) subjects, were performed using Student’s t-test
when the normality distribution (Kolmogorov-Smirnov
test) and equality of variance (Levene median test) were
verified. When these conditions were not obtained, a
Mann-Whitney rank sum test was used. Exercise data
were compared at the same percent VO2max, using a two-
way analysis of variance for repeated measures
(ANOVA): a fixed factor (group) and a repeated factor
(percent of VO2max), or the ANOVA on ranks test when the
normality test of the distribution failed. When the ANOVA
F ratio was significant (F group, F power, and F group/
power), the post hoc Bonferroni test was used to perform
pairwise multiple comparisons. Linear regression analysis
was performed using the least-squares method. This
analysis was carried out using lung functions and Wt/Ht as
dependent variables, while the possible independent
variables included PImax and TI/TTOT. P < 0.05 was
considered statically significant.
Spirometric and Anthropometric Data
Spirometric and anthropometric data for children with
CF and healthy children are listed in Table 1. CF children
showed a significant decrease of forced expiratory volume
in 1 sec (FEV1), forced vital capacity (FVC), and FEV1/
FVC. The RV/TLC ratio and FRC were significantly
increased in children with CF (P < 0.001), indicating that
they had hyperinflation compared with healthy children.
There was no statistical difference between the two groups
in age and height, but children with CF showed a
significant reduction in weight and Wt/Ht ratio.
Power of Exercise, Gas Exchange,
and Breathing Pattern
Results at rest and for maximal physical performance
are shown in Table 2. At rest, no significant difference was
found in VO2 and VCO2 in both groups. VT did not show
any significant difference in both groups, whereas VE and
f were significantly greater in children with CF compared
with healthy children. Maximal workload reached by
children with CF was significantly lower compared with
healthy children. VO2 and VCO2 reached at maximal
exercise were significantly decreased in children with CF.
They also showed significantly lower VT and VE
compared with healthy children. Only the breathing
frequency did not show a significant difference at maximal
exercise in both groups.
Respiratory Muscle Parameters
At rest, the maximal inspiratory pressure was signifi-
cantly lower in children with CF (Table 1). We found a
negative linear correlation between mean maximal

TABLE 2— Maximal Power of Exercise, Gas Exchange, and Breathing Pattern Parameters
at Rest and Maximal Exercise in Children With Cystic Fibrosis and Healthy Children,
Expressed as Mean  SD1

Rest Maximal exercise

Cystic fibrosis Controls Cystic fibrosis Controls

Power (W) 109  31 181  21***
VO2 (ml
kg
min1) 9.7  1.4 8.6  1 35.2  8.1 49.8  4.6***
VCO2 (ml
min1) 330  10 321  15 1557  46 2797  45***
VE (l
min1) 13.8  1.5 10.1  1.4** 66  22.3 90.3  15.9*
VT (ml) 541  105 550  87 1200  47 1801  22***
VTBW (ml
kg1) 14.2  5.6 9.9  6.8 31.5  10.1 32.6  5.2
f (cyc
min1) 24  4 19  4* 54  7 52  6
1
VO2, oxygen uptake; VCO2, carbon dioxide output; VE, minute ventilation; VT, tidal volume; VTBW, tidal
volume corrected by weight; f, breathing frequency.
*P < 0.05.
**P < 0.01.
***P < 0.001.
 Breathing Strategy in CF Children During Exercise 453

inspiratory pressure (PImax) and RV/TLC only in children DISCUSSION

with CF (PImax ¼ 87.002  (0.4142
RV/TLC), r ¼ 0.87,
P < 0.009). We found a linear correlation between PImax
and Wt/Ht only in children with CF (PImax ¼
 12.027 þ (0.9918
Wt/Ht), r ¼ 0.89, P < 0.001).
When at rest, children with CF showed a significantly
higher P0.1, P0.1/PImax, and TT0.1 (Table 1). On the other
hand, the TI/TTOT ratio was significantly lower in children
with CF compared with healthy children, respectively:
0.38  0.01 vs. 0.42  0.02 (P < 0.05). During exercise,
P0.1 (Fig. 1A), P0.1/PImax (Fig. 1B) and TT0.1 (Fig. 1C)
increased in both groups, and were significantly higher for
the same percentage of VO2max in children with CF
compared with healthy children. On the other hand, the TI/
TTOT ratio was significantly lower in children with CF
compared with healthy children (Fig. 1D). In children with
CF, we found a negative linear correlation between P0.1/
PImax and FEV1/FVC, and a positive linear correlation
between P0.1/PImax and RV/TLC (Fig. 2B), at maximal
exercise. Inversely, TI/TTOT showed a positive linear
relationship with FEV1/FVC (Fig. 2C), and a negative
linear relationship with RV/TLC (Fig. 2D), in children
with CF at maximal exercise. We also observed a negative
correlation between the P0.1/PImax ratio and the TI/TTOT
ratio (Fig. 3).
This study showed that children with CF adopt a
particular breathing strategy in order to counteract lower
levels of inspiratory muscle performance. The noninva-
sive tension-time index TT0.1 is higher in children with CF
than in healthy children, and this is mainly a consequence
of a higher P0.1/PImax ratio. In an attempt to limit the
impact of this elevated TT0.1, children with CF adopt a
specific breathing strategy by limiting the increase in the
duty cycle. We observed that the higher the degree of
airway obstruction and hyperinflation, the higher the P0.1/
PImax ratio at maximal exercise. Conversely, the higher the
degree of airway obstruction and hyperinflation, the lower
the TI/TTOT. For children with CF, we also found that low
nutritional status was associated with a low TI/TTOT ratio.
The scientific literature reported discrepancies in
maximal inspiratory pressure in patients with CF. Most
studies show normal or even above-normal muscle
strength in CF,18,19 although some authors found lower
PImax values in CF sufferers than in healthy sub-
jects.11,19,20 Certain authors suggested that inspiratory
muscle function may be relatively well-preserved due to a
selective ‘‘training stimulus’’ provoked by chronic lung
disease.19 Hart et al. showed that the strength of the

30 0.4
B ***
A
A *** B

0.3 ***
20 ***
P0.1 cmH2O

P0.1/PImax

***
***
*** 0.2 ***
*** ***
10
0.1

0 0.0
20 40 60 80 100 20 40 60 80 100
% VO2max % VO2max

0.18 C
C *** 0.54 D
D ***
**
*** ***
0.12 0.48
TI/TTOT

**
TT0.1

***
*** **
***
0.06 0.42

0.00 0.36
20 40 60 80 100 20 40 60 80 100
% VO2max % VO2max

Fig. 1. A: Mouth occlusion pressure (P0.1). B: Ratio of the mouth occlusion pressure to maximal
inspiratory pressure (P0.1/PImax). C: Tension-time index (TT0.1). D: Ratio of mean inspiratory time to
total time of respiratory cycle (TI / TTOT). Same percentage of VO2max in children with CF (solid
circles) and healthy children (open circles). Values are shown as mean  SD. **P < 0.01,
***P < 0.001.
454 Keochkerian et al.

0.40 0.40
A
A B
B

0.36 0.36

P0.1/PImax
P0.1/PImax
0.32 0.32

0.28 0.28
y = -0.0027x + 0.5184 y = 0.0026x + 0.2239
r = 0.90,
-0.90,p<0.001
p<0.001 r = 0.92, p<0.001
0.24 0.24
40 50 60 70 80 20 30 40 50 60 70
FEV1/FVC RV/TLC

0.50 0.50
y = 0.0009x + 0.4122 y = -0.0009x
0.0009x + 0.5147
r = 0.89, p<00.1 r = -0.94,
0.94,p<00.1
p<00.1
0.49 0.49
TI/TTOT

TI/TTOT
0.48 0.48

0.46 0.46
C
C D
D
0.45 0.45
40 50 60 70 80 20 30 40 50 60 70
FEV1/FVC RV/TLC

Fig. 2. A: Ratio of the mouth occlusion pressure to maximal inspiratory pressure (P0.1/PImax), and
ratio of forced expiratory volume in 1 sec to forced vital capacity (FEV1/FVC) percent predicted in
children with cystic fibrosis (n ¼ 9). B: Ratio of the mouth occlusion pressure to maximal
inspiratory pressure (P0.1/PImax) and residual volume to total lung capacity ratio (RV/ TLC) in
children with cystic fibrosis (n ¼ 9). C: Relationship between ratio of mean inspiratory time to total
time of respiratory cycle (TI / TTOT) and FEV1/FVC percent predicted in children with cystic fibrosis
(n ¼ 9). D: Relationship between ratio of mean inspiratory time to total time of respiratory cycle
(TI / TTOT) and RV/ TLC in children with cystic fibrosis (n ¼ 9).

diaphragm is preserved, using a nonvolitional assessment
of respiratory muscle strength, i.e., magnetic stimulation
of the phrenic nerves.21 Others suggested an effect of
nutritional status on respiratory muscle weakness5 and/or
a consequence of hyperinflation of the pulmonary system
which places inspiratory muscles (and the diaphragm in
particular) at a mechanical disadvantage.20 In our study,
children with CF showed a significantly lower value of
PImax than those usually reported in the literature. Our data
failed to support the notion of compensatory adaptation of
inspiratory muscles, but did emphasize the unfavorable
position of the diaphragm and the severity of malnutrition
in children with CF. Malnutrition is a well-known
complication of CF and is due to malabsorption, reduced
caloric intake, and increased metabolic demand.22 We
found negative correlations between PImax and RV/TLC
(PImax ¼ 87.002  0.4142
RV/TLC, r ¼ 0.87; p < 0.009)
and a positive correlation between PImax and Wt/Ht
(PImax ¼ 12.027 þ 0.9918
Wt/Ht, r ¼ 0.89, p < 0.001).
Children with CF showed mild malnutrition, as evidenc-
ed by the low proportion with ideal weight-for-height
(81.9  3.2%).17 Studies of respiratory muscle function in
CF are difficult to compare because of differences in
subjects’ ages, the methodologies used to assess muscle
function, the severity of airway obstruction and hyper-
inflation, and above all, the extent of malnutrition.
Most previous studies demonstrated a close relationship
between low muscle strength and high P0.1.23,24 Our study
confirmed these previous results: children with CF showed
significantly higher P0.1 values at rest (Table 1) and during
submaximal exercise (Fig. 1A) when compared with
healthy individuals. When muscles fail to generate
tension, the respiratory system detects the muscle
weakness and increases the nervous drive. Ambrosino
et al.23 reported that although P0.1 is used as an index of
neural output to inspiratory muscles in normal subjects,
absolute values of P0.1 may underestimate the effective
neural drive in patients with low inspiratory muscle
strength. Hence, the observation that the P0.1/PImax ratio
constitutes a reliable index is mainly due to the fact that it
eliminates the effect of the greater FRC commonly seen in
CF children. The P0.1/PImax ratio (reflecting the relative
force required for each inspiration25) was considerably
greater during exercise in CF children, compared with
 Breathing Strategy in CF Children During Exercise 455
10
1.0 threshold at maximal exercise. Gautier et al. suggested
that a decreased TI/TTOT at rest was a strategy used by
0.8 children with COPD to stay below the inspiratory
muscles’ fatigue threshold. These authors also observed
that the greater the PI/PImax ratio (ratio of the mean
0.6 inspiratory pressure to maximal inspiratory pressure), the
TI/TTOT

lower the TI/TTOT ratio. The TI/TTOT ratio is an important

0.4 determinant of respiratory fatigue. Bellemare and Grass-
ino31 showed that the TI/TTOT ratio is as important as the
0.2 pressure generated during diaphragmatic contraction (PDI/
TI/TTOT = -0.3222(P0.1/Pimax) + 0.5832 P DImax) in determining diaphragmatic endurance. These
r = -0.93, p<0.0001
authors found that the maximum pressure that can be
0.0
indefinitely sustained decreases when TI/TTOT increases.
0.0 0.2 0.4 0.6 0.8 1.0 Airway obstruction and hyperinflation appear to be major
P0.1/PImax determinants of the lower T /T
I TOT values observed during
exercise in children with CF, compared with healthy
Fig. 3. Relationship between ratio of mean inspiratory time to children. At maximal exercise, we observed that TI/TTOT
total time of respiratory cycle (TI / TTOT) and occlusion pressure to decreased as FEV1/FVC decreased (Fig. 2C), and that TI/
maximal inspiratory pressure (P0.1/PImax) in children with cystic
fibrosis (solid circles) and healthy children (open circles). TT0.1
TTOT decreased as RV/TLC increased (Fig. 2D). Our
isopleth of 0.16 (long-dashed line) represents mean TT0.1 value of present findings suggest that in order to minimize the
CF group at maximal workload, and TT0.1 isopleth of 0.10 (short- unpleasant sensation of flow limitation, children with CF
dashed line) represents mean TT0.1 value of healthy group at use an adaptive breathing strategy during exercise to cope
maximal workload. with the increased work of breathing.
Children with CF showed a significantly higher tension-
healthy subjects (Fig. 1B). We found that the P0.1/PImax time index throughout exercise compared with healthy
ratio was affected by both airway obstruction and children, attesting to the lower levels of inspiratory muscle
hyperinflation (Fig. 2A,B). Hence, children with CF had performance. The significantly higher P0.1/PImax ratio in
less efficient inspiratory muscles but also had a greater children with CF explains the higher TT0.1. In order to
energy demand. Indeed, they used a larger fraction of their prevent fatigue, the children adapted their breathing
inspiratory force reserve, and may therefore be more pattern so as to limit the increase in the duty cycle. We
exposed to respiratory muscle fatigue. The increase in observed that the greater the P0.1/PImax ratio, the lower the
TT0.1 in children with CF (Fig. 1C) could be ascribed to the TI/TTOT ratio at maximal exercise. The extent of airway
P0.1/PImax ratio. The stronger inspiratory demand relative obstruction and hyperinflation appeared to play major
to the inspiratory reserve explains the higher TT0.1, which roles in this strategy: we observed that the higher the
decreases inspiratory muscle performance and could extent of airway obstruction and hyperinflation, the higher
predispose to respiratory fatigue. the P0.1/PImax ratio at maximal exercise. Conversely, the
However, it is known that patients with COPD do not higher the degree of airway obstruction and hyperinfla-
develop diaphragmatic fatigue when exercising to exhaus- tion, the lower the TI/TTOT ratio. We also found that low
tion,26,27 although the reasons for this are not clear. nutritional status in children with CF was associated with a
Possible factors include constraints in ventilatory mecha- low TI/TTOT ratio. The benefit of this strategy is to
nics,28 a higher diaphragmatic mitochondrial content,29 counteract poor levels of inspiratory muscle performance.
and a greater proportion of fatigue-resistant muscle fibers. Nevertheless, such a strategy could predispose the patient
There are also high levels of the slow myofibrillar protein to rapid, shallow breathing,32 which in turn can lead to a
isoforms and low levels of the fast isoforms.30 However, hypoventilation syndrome, hypercapnia, and dyspnea.
children with CF may prevent inspiratory muscle fatigue The latter respiratory factors may in fact constitute the
by adopting a breathing strategy that counteracts an limiting pathological factors during exercise.
excessive decrease in their inspiratory muscle perfor-
mance and/or prevents them from reaching the fatigue
ACKNOWLEDGMENTS
threshold. In our study, children with CF showed a
significantly lower TI/TTOT ratio than healthy children The authors thank the medical staff of the Department
(Fig. 1D). We observed that the greater the P0.1/PImax ratio of Pediatrics (under Dr. Pautard) and Department of
during exercise, the lower the TI/TTOT ratio (Fig. 3). This Pediatric Cardiopulmonary Explorations of the University
negative relationship between TI/TTOT and P0.1/PImax Hospital of Amiens for their technical assistance. We also
suggests that children with CF adopt a breathing pattern thank Eric Saniez for his valuable help in writing for
which keeps inspiratory muscle activity below the fatigue English-language journals.
456 Keochkerian et al.
REFERENCES
1. Shah AR, Gozal D, Keens TG. Determinants of aerobic and
anaerobic exercise performance in cystic fibrosis. Am J Respir
Crit Care Med 1998;157:1145–1150.
2. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir
Crit Care Med 1996;154:1229–1256.
3. Bell SC, Saunders MJ, Elborn JS, Shale DJ. Resting energy
expenditure and oxygen cost of breathing in patients with cystic
fibrosis. Thorax 1996;51:126–131.
4. Corey M, Levison H, Crozier D. Five- to seven-year course of
pulmonary function in cystic fibrosis. Am Rev Respir Dis 1976;
114:1085–1092.
5. Szeinberg A, England S, Mindorff C, Fraser IM, Levison H.
Maximal inspiratory and expiratory pressures are reduced in
hyperinflated, malnourished, young adult male patients with
cystic fibrosis. Am Rev Respir Dis 1985;132:766–769.
6. Dantzker DR, Patten GA, Bower JS. Gas exchange at rest and
during exercise in adults with cystic fibrosis. Am Rev Respir Dis
1982;125:400–405.
7. Bellemare F, Grassino A. Effect of pressure and timing of
contraction on human diaphragm fatigue. J Appl Physiol 1982;
53:1190–1195.
8. Bellemare F, Grassino A. Force reserve of the diaphragm in
patients with chronic obstructive pulmonary disease. J Appl
Physiol 1983;55:8–15.
9. Hayot M, Ramonatxo M, Matecki S, Milic-Emili J, Prefaut C.
Noninvasive assessment of inspiratory muscle function during
exercise. Am J Respir Crit Care Med 2000;162:2201–2207.
10. Gaultier C, Boule M, Tournier G, Girard F. Inspiratory force
reserve of the respiratory muscles in children with chronic obstruc-
tive pulmonary disease. Am Rev Respir Dis 1985;131: 811–815.
11. Hayot M, Guillaumont S, Ramonatxo M, Voisin M, Prefaut C.
Determinants of the tension-time index of inspiratory muscles in
children with cystic fibrosis. Pediatr Pulmonol 1997;23:336–343.
12. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R,
Yernault JC. Lung volumes and forced ventilatory flows. Report
of the Working Party on Standardization of Lung Function Tests,
European Community for Steel and Coal. Official statement of the
European Respiratory Society. Eur Respir J [Suppl] 1993;16:5–40.
13. Zapletal A, Samanek M, Paul T. Lung function in children and
adolescents. Basel: Karger; 1987. p 114–218.
14. Black LF, Hyatt RE. Maximal respiratory pressures: normal
values and relationship to age and sex. Am Rev Respir Dis 1969;
99:696–702.
15. Wasserman K. Principles of exercise testing and interpretation:
including pathophysiology and clinical applications. Philadelphia:
Lippincott Williams & Wilkins; 1999. 556 p.
16. Mahler DA, American College of Sports Medicine. ACSM’s
guidelines for exercise testing and prescription. Philadelphia:
Lippincott Williams & Wilkins; 2000. 368 p.
17. Ramsey BW, Farrell PM, Pencharz P. Nutritional assessment and
management in cystic fibrosis: a consensus report. The Consensus
Committee. Am J Clin Nutr 1992;55:108–116.
18. O’Neill S, Leahy F, Pasterkamp H, Tal A. The effects of chronic
hyperinflation, nutritional status, and posture on respiratory
muscle strength in cystic fibrosis. Am Rev Respir Dis 1983;
128:1051–1054.
19. Lands LC, Heigenhauser GJ, Jones NL. Respiratory and
peripheral muscle function in cystic fibrosis. Am Rev Respir
Dis 1993;147:865–869.
20. Lands L, Desmond KJ, Demizio D, Pavilanis A, Coates AL. The
effects of nutritional status and hyperinflation on respiratory
muscle strength in children and young adults. Am Rev Respir Dis
1990;141:1506–1509.
21. Hart N, Tounian P, Clement A, Boule M, Polkey MI, Lofaso F,
Fauroux B. Nutritional status is an important predictor of
diaphragm strength in young patients with cystic fibrosis. Am J
Clin Nutr 2004;80:1201–1206.
22. Pradal U, Polese G, Braggion C, Poggi R, Zanolla L, Mastella G,
Rossi A. Determinants of maximal transdiaphragmatic pressure in
adults with cystic fibrosis. Am J Respir Crit Care Med 1994;150:
167–173.
23. Ambrosino N, Opasich C, Crotti P, Cobelli F, Tavazzi L,
Rampulla C. Breathing pattern, ventilatory drive and respiratory
muscle strength in patients with chronic heart failure. Eur Respir J
1994;7:17–22.
24. Gorini M, Ginanni R, Spinelli A, Duranti R, Andreotti L, Scano G.
Inspiratory muscle strength and respiratory drive in patients
with rheumatoid arthritis. Am Rev Respir Dis 1990;142:289–
294.
25. Duranti R, Misuri G, Gorini M, Goti P, Gigliotti F, Scano G.
Mechanical loading and control of breathing in patients with
severe chronic obstructive pulmonary disease. Thorax 1995;50:
127–133.
26. Mador MJ, Kufel TJ, Pineda LA, Sharma GK. Diaphragmatic
fatigue and high-intensity exercise in patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2000;
161:118–123.
27. Sinderby C, Spahija J, Beck J, Kaminski D, Yan S, Comtois N,
Sliwinski P. Diaphragm activation during exercise in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2001;
163:1637–1641.
28. Koulouris NG, Dimopoulou I, Valta P, Finkelstein R, Cosio
MG, Milic-Emili J. Detection of expiratory flow limitation
during exercise in COPD patients. J Appl Physiol 1997;82:723–
731.
29. Orozco-Levi M, Gea J, Lloreta JL, Felez M, Minguella J, Serrano
S, Broquetas JM. Subcellular adaptation of the human diaphragm
in chronic obstructive pulmonary disease. Eur Respir J 1999;13:
371–378.
30. Levine S, Kaiser L, Leferovich J, Tikunov B. Cellular adaptations
in the diaphragm in chronic obstructive pulmonary disease.
N Engl J Med 1997;337:1799–1806.
31. Bellemare F, Grassino A. Evaluation of human diaphragm
fatigue. J Appl Physiol 1982;53:1196–1206.
32. Rochester DF. Respiratory muscles and ventilatory failure: 1993
perspective. Am J Med Sci 1993;305:394–402.