- Email: [email protected]
Role of respiratory system impedance in the difference of ventilatory control between children and adults
Respiratory Physiology & Neurobiology 161 (2008) 239–245
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Role of respiratory system impedance in the difference of ventilatory control between children and adults Stefan Keslacy a,∗ , Juliette Carra b , Michele Ramonatxo c a
820 Comstock Avenue, University of Syracuse, Department of Exercise Science, Room 204 Women’s Building, Syracuse, NY 13206, USA Laboratoire Sport Performance Sant´e UPRES EA 2991, Universit´e Montpellier I, 34295 Montpellier, France c Laboratoire de Physiologie des Interactions, Service Central de Physiologie Clinique, Hˆ opital Arnaud de Villeuneuve, 34295 Montpellier, France b
a r t i c l e
i n f o
Article history: Accepted 20 February 2008 Keywords: Children Occlusion pressure Time-constant Peripheral chemoreceptors Exercise
a b s t r a c t How children are able to adapt their ventilation to the intensity of exercise faster than adults remain unclear. We hypothesized that differences of V˙ E observed between children and adults depend on either peripheral chemoreceptors or central command activity. We examined ventilatory control parameters in either normoxic or hypoxic condition (FIO2 = 0.15). We analyzed the adaptability of the respiratory exchanges by (i) the measurement of ventilatory kinetics time-constant and (ii) the central command by the mouth-occlusion pressure (P0.1). A group of nine pre-pubescent children (mean age 9.5 ± 1 years) and a group of eight adults (mean age 24 ± 3.1 years) performed a constant-load exercise. In normoxia, children had significantly shorter time-constant () V˙ CO2 (respectively, 38.5 ± 4.3 and 53.1 ± 5.3 s; P < 0.001), V˙ E (respectively, 52.5 ± 13.1 s vs. 66.1 ± 12.3 s; P < 0.001), and P0.1 (57.4 ± 15.4 and 61.0 ± 12.9 s, respectively; P < 0.001) than adults. In hypoxia, children exhibited shorter P0.1/VT /Ti compare to adults. Reinforced by the significant correlation between V˙ E and P0.1/VT /Ti for children but not adults, we concluded that ventilatory response differences could be due in part to the respiratory system impedance. © 2008 Elsevier B.V. All rights reserved.
1. Introduction The goal of control of ventilation is to maintain pH, oxygen and carbon dioxide partial pressure homeostasis. Feedbacks and feed forwards determining a central command from the respiratory centers, and several peripheral afferents coming from chemical and mechanical receptors allow a very tight regulation of ventilation. In this way, muscular exercise is a model where ventilation needs to answer the metabolic demands. Understand the maturation of control of ventilation represent an important aspect in the comprehension of the development of several respiratory diseases such as asthma cystic fibrosis or sleep apnea in children. It has been shown that pre-pubescent children exhibit faster ventilatory adaptation to a constant-load exercise compare to adults, measured by shorter phase II time-constant of ventilation ( V˙ E ), i.e., the time to reach 63% of the ventilation steady-state value during a moderate intensity exercise (Flandrois et al., 1980; Cooper et al., 1987; Springer et al., 1991; Fawkner et al., 2002). Peripheral chemoreceptors (carotid and aortic bodies) contribute significantly to exercise hyperpnoea, especially in response to variation of PO2 (Wasserman et al., 1975) during phase II of a
∗ Corresponding author. Tel.: +1 315 443 5588; fax: +1 315 443 9375. E-mail address: [email protected] (S. Keslacy). 1569-9048/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2008.02.005
constant-load exercise, they are the primary site of hypoxic ventilatory responsiveness in both children and adults (Springer et al., 1991). To evaluate the contribution of chemoreceptors to ventilatory control during phase II, various investigations have shown that breathing hypoxic gas mixtures stimulates the peripheral chemoreceptors and quickens the ventilatory response to exercise, reflected by a decrease in the ventilatory time-constant ( V˙ E ) (Griffiths et al., 1986). Conversely, breathing hyperoxic gas mixtures inhibited the activity of these chemoreceptors and caused longer V˙ E (Dejours, 1963, 1964), but little is known about the maturation of peripheral chemoreceptors during the growth process of normal children. Ventilation is a parameter that reflects not only the activity of the respiratory centers, but also the impedance (i.e., the ratio between variations of respiratory volumes and flows) of the thoraco-pulmonary system. Thus, to better understand the differences in ventilatory response between children and adults, a parameter that reflects respiratory centers command independently of the mechanical properties needs to be studied. The measure of mouth-occlusion pressure (P0.1), which was introduced by Whitelaw et al. (1975), is a non-invasive technique for assessing the central respiratory command independently of the mechanical properties of the respiratory system. Its relation to mean inspiratory flow (VT /Ti ), allow us to evaluate, in a satisfactory way, the effective impedance of the respiratory system (Derenne et al., 1976).
240
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
Table 1 Anthropometric characteristics and maximal oxygen consumption Subjects
Age (years)
Height (cm)
Weight (kg)
V˙ O2 max (mL min −1 kg−1 ) Air breathing
Hypoxia
Children
Mean S.D.
9.5 1.0
142.0 13.4
37.5 9.5
47.9 3.2
45.2 3.7**
Adults
Mean S.D.
26.9 3.1
176.0 5.6
69.5 7.0
50.7 4.1
45.5 4.7**
V˙ O2 max: maximal oxygen consumption; S.D.: standard deviation, *** P < 0.001 for normoxia compared to hypoxia.
The aim of this study was to determine if a maturation of peripheral chemoreceptors or of respiratory system impedance could explain the difference of control of ventilation between children and adults. We used hypoxic conditions, which stimulates peripheral chemoreceptors, and studied the adaptation of ventilatory parameters (V˙ O2 , V˙ CO2 and V˙ E ), P0.1 and respiratory system impedance (P0.1/VT /Ti ) kinetics in both pre-pubescent children and adults. 2. Methods 2.1. Subjects 9 pre-pubescent children (mean age 9.5 ± 1 years) and a group of 9 young adults (mean age 27 ± 3.1 years) were studied. All were male to avoid gender differences and Table 1 gives the mean values of their physical characteristics and maximal oxygen consumption (V˙ O2 max). The Local Review Board for Research on Human Subjects approved the protocol. After receiving a detailed description of the experimental procedures, all subjects (and the children’s parents) signed an informed consent to participate in a hypoxic breathing experiment. All, however, were unaware of the purpose of the study. Only voluntary pre-pubescent children would take part in the study. All children were free of cardiac and pulmonary diseases. All adults follow the inclusion criteria: age between 20 and 35 years, free of cardiac and pulmonary disease, and practice sports between 2 and 3 h week−1 . 2.2. Protocol We evaluated children and adults under the same protocol and conditions. During the first session, the subjects were familiarized with the equipment and the experimental procedure, particularly with the cycle ergometer in order to be prepared to perform the exercise tests. The study was performed on three different days. For their second and third visit to the laboratory, all subjects underwent a complete medical examination at rest, including an electrocardiogram (ECG), plethysmographic measurements (Table 2), and a pediatrician evaluated children’s pubescent stage according to the Tanner method (Sempe and Capron, 1979). To determined V˙ O 2
max, the subjects randomly and blindly performed an incremental load exercise (in normoxia and hypoxia: 15% O2 ). Finally, for the
fourth visit, they randomly and blindly performed two constantload exercise tests corresponding to 40% of V˙ O2 max, in normoxia and hypoxia; separated by a minimum of 2 h. 2.2.1. Plethysmography For each subject, we assessed plethysmographic measurements (Vmax 229 series Sensormedics) of lung volumes (total lung capacity, TLC) and flows (vital capacity, VC; forced expiratory volume in 1 s, FEV1 ) according to standard techniques and procedures (American Thoracic Society) (Table 2). 2.2.2. Maximal incremental cycling exercise Each subject performed two incremental-load exercises in normoxia and hypoxia. Pedaling frequency was set at 70 rpm. The test began with a 5-min warm-up at 60 W for adults and 10 W for children. The work rate then increased by 30 W for adults and 15 W for children every minute until the subjects reached volitional exhaustion. We considered a value of heart rate (HR) close to the theoretical maximal HR, a respiratory exchange ratio (R) above 1.1 and a plateau for V˙ O2 as criteria of true maximal effort. 2.2.3. Constant-load test Each subject performed two constant-load exercises in normoxia and hypoxia Intervals between the two tests ranged from 2 to 3 h. For each test, subjects completed a 5-min warm-up of unloaded cycling to begin the test with stable ventilatory parameters and R. Then they exercised for 8 min at a power output corresponding to 40% of V˙ O2 max, followed by 10 min of recovery with unloaded cycling. In order to obtain accurate measures, we imposed power output in less than a second. We used a metronome and a speed transducer linked to the computer to maintain the pedaling frequency constant at 70 rpm. 2.3. Measurements The tests were performed on a friction-loaded cycloergometer (Monark 828 E, Stockholm, Sweden) outfitted with a strain gauge (Interface MFG type, Scottsdale, AZ, USA) in a laboratory maintained at 21 ◦ C. The cycloergometer was equipped with speed and force transducers (Electronic Informatics of Pilat, Jonzieux, France) in order to maintain a constant power output. We calibrated the cycloergometer immediately before each test using equipment supplied
Table 2 Pulmonary function data Subjects
FEV1 (L)
FEV1 /VC (%)
TLC (L)
TLC (%)
Children
Mean S.D.
2.2 0.6
FVC (L)
FVC (%) 96.1 9.4
1.8 0.5
86.5 6.4
3.0 0.6
98.9 6.1
Adults
Mean S.D.
5.3 0.5
102.5 12.1
4.3 0.4
81.7 1.2
7.0 0.4
98.9 5.5
FVC: forced vital capacity; FEV1 : force expired volume in 1 s; TLC: total lung capacity in percentage predicted % (Quanjer et al., 1994).
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
by the manufacturer. To obtain an accurate measurement of the friction force, the strain gauge was calibrated with a known mass (10 kg) hung on the friction belt and in an unloaded condition to give a zero value. We used the method proposed by Lakomy (1986) to get an exact measurement of the flywheel inertia. Briefly, the inertia was simply determined from the linear relationship obtained between the free acceleration of the flywheel and the corresponding friction load. V˙ O2 , V˙ CO2 , and V˙ E data were collected continuously, breathby-breath, throughout the tests using an automatic gas exchange system (CPX Medical Graphics, St. Paul, MN, USA) equipped with a zirconium cell for O2 analysis, an infrared cell for CO2 analysis, and a heated pneumotachograph, type Fleish no. 3 (Godart Statham, Holland). We calibrated CO2 and O2 analyzers before each test with gases of known composition (12% O2 and 5% CO2 ). The calibration of the pneumotachograph was carried out using a 3-L syringe. To prevent valve deformation and gas escaping from the inspiratory and expiratory circuits, we reinforced it with a piece of mica. The total dead space was 100 mL. An ear pulse-oximeter measured saturation level continuously during all exercise (Datex Satlite trans, Helsinki, Finland). We used chloroprene weather balloons (1000 g; FD Kaysam, Inc., Totowa, NJ, USA) with a volume greater than 1500 L, for all tests under both conditions: normoxia and hypoxia, which allowed us to run the experiment under the same conditions. Without subjects in the room, we checked balloons for leaks before each test and then inflated them with ambient air for normoxia and a mixture of ambient air and pure nitrogen for hypoxia (15% of O2 ). The catheter of the CPX system allows us to check O2 concentration, temperature and moisture of the balloon’s air. Mouth-occlusions were performed breath-by-breath using a silent electromagnetic valve closed during expiration and opened automatically after 150 ms. The subjects could not see the occlusion valve and therefore were unable to anticipate airway occlusion. P0.1 and ventilatory flow were measured with a transducer Validyne MP 45 and a carrier demodulator model CD 15 (respectively, at ±35 cm H2 O and ±2 cm H2 O). A Biopac system (Biopac System, Inc., Santa Barbara, CA, USA) transformed the electric signal of mouth pressure into analog signals. A processing software (Acqknowledge v3.53) measured and recorded P0.1 and tidal volume (VT ) from these signals by integration of the flow and respiratory time. For the constant-load exercise tests, we measured P0.1 every two cycles at rest and every cycle during exercise in order to obtain a kinetic. Breath-by-breath data for V˙ O2 , V˙ CO2 , V˙ E , VT , P0.1 and P0.1/VT /Ti , respiratory frequency (f), inspiratory time (Ti ) and expiratory time (Te ) were collected continuously throughout testing. An electrocardiogram measured heart rate with standard bipolar electrode placement.
241
P0.1/VT /Ti that were greater than three standard deviations from the modeled V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti were considered outliers and were removed, in line with a previous work (Carra et al., 2003; Keslacy et al., 2005). These outlier values, assumed to be due to shallow breaths or breathe holding represented less than 1% of the total data collected. Model parameters were determined with an iterative procedure by minimizing the sum of the mean squares of the differences between the estimated V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti based on the model and the measured parameters. Iterations continued until successive repetitions reduced both the sum of the residuals by <10−6 and the correlation coefficient of the relationship between residuals and time by <10−4 . To assess the validity of the model parameters, coefficients of variation were computed using the bootstrap method (Black et al., 1969; Eastwood and Hillman, 1995). Briefly, this consisted of re-sampling the original data set with replacements to create a number of “bootstrap replicate” data sets of the same size as the original data set. For each replicate set, model parameters estimated following the same procedures as for original data. This operation was repeated 1000 times. 2.5. Statistical analysis For all subjects, ventilation and pulmonary gas exchange timeconstants expressed as means and standard deviation (m ± S.D.). The Fisher test determined the model’s degree of significance. The quality of the adjusted model was assessed by the coefficient of determination (r2 ) obtained between the modeled and measured V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti values. Linear and nonlinear regressions checked the random distribution of the model according to time. The Shapiro-Wilk test was used to determine the normality of the distribution of the studied parameters. Paired t-tests were used to compare the model parameters between the two experimental conditions. The relationship between V˙ E and P0.1/VT /Ti assessed by Pearson’s correlation coefficients in the two experimental conditions. Differences were declared to be significant for P < 0.05. 3. Results 3.1. Incremental-load test During incremental-load exercise in hypoxia, the children demonstrated 5.6% reduction in V˙ O2 max (45.2 ± 3.7 mL min−1 kg−1 vs. 47.9 ± 3.2 mL min−1 kg−1 ; P < 0.001) and adults 11.4% reduction (45.5 ± 4.7 mL min−1 kg−1 vs. 50.7 ± 4.1 mL min−1 kg−1 ; P < 0.001). The maximal power reached at V˙ O2 max decreased from 160 to 153 W for exercise in hypoxia for children and from 273 to 262 W for adults.
2.4. Data analysis
3.2. Constant-load test
We used a nonlinear regression techniques to fit V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti raw data with an exponential function. The mathematical model consisted of an exponential term, which represent phase II. The exponential term constrained to start only at the “inflection point” of the response thanks to a time delay and an amplitude (Whipp et al., 1982):
No significant relationships between residuals and time in either experimental condition were identified, suggesting random distribution of the residuals and a model adapted to describe the kinetics of ventilatory parameters under the two conditions (normoxia vs. hypoxia). Model parameters adjustment led to coefficients of determination that ranged between 0 and 1 (mean value of 0.92 ± 0.08). The Fisher test indicated the model’s high degree of significance for all subjects (P < 0.001) (Borrani et al., 2001).
Y (t) = Yb + A[1 − e−(t−td1/t) ] where Y(t) is the parameter variation (V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti ), Yb is the unloaded cycling baseline value, A is the asymptotic values for the exponential term, and is the timeconstant. The values of the measured V˙ O2 , V˙ CO2 , V˙ E , P0.1 and
3.3. Steady-state values during phase III As shown in Table 3 for steady-state values during a constantload exercise, hypoxia induced a significant decrease in oxygen
242
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
Table 3 Comparison of steady-state values of different parameters between children and adults during exercise in normoxia and hypoxia Hypoxia
Normoxia −1
V˙ E (L min−1 )
−1
Power (W)
SAO2 (%)
HR (b min
V˙ E (L min−1 )
Power (W)
SAO2 (%)
HR (b min
Children Mean S.D.
98.5 0.5
148.7 8.5
39.3 6.0
61.7 6.1
87.5 1.7
159.7 6.5
41.2 6.6
60.4 4.6
Adults Mean S.D.
98.4 0.9
112.0 9.1
42.8 4.4
92.5 4.6
89.0 1.6
124.6 8.9
45.8 4.9
89.4 3.2
)
)
SAO2 : oxygen saturation; HR: heat rate and V˙ E ventilation.
saturation around 11% for children (87.8 ± 1.7% vs. 98.5 ± 0.5% O2 ) and adults (89.0 ± 1.6% vs. 98.4 ± 0.9% O2 ). The values of heart rate during exercise in hypoxia increased significantly by 7.4% (160 ± 6 bpm vs. 149 ± 8 bpm; P < 0.001) for children, and by 10.4% (125 ± 9 bpm vs. 112 ± 9 bpm; P < 0.001) for adults. The steady-state value of V˙ E during phase III of the constant-load exercise increased significantly during hypoxic breathing for children (+4.4%) (41.2 ± 6.6 L min−1 vs. 39.3 ± 6.0 L min−1 ; P < 0.01) and adults (+6.5%) (45.8 ± 4.9 L min−1 vs. 42.8 ± 4.5 L min−1 ; P < 0.01). 3.4. Phase II kinetics: comparison of time-constant between children and adults in normoxia During exercise in normoxia, the mean time-constant for V˙ O2 was similar for children and adults (respectively, 28.9 ± 4.2 and 33.2 ± 5.8 s). However, children compared to adults, had significantly shorter V˙ CO2 (respectively, 38.5 ± 4.3 and 53.1 ± 5.3 s; P < 0.001), V˙ E (respectively, 52.5 ± 13.1 s vs. 66.1 ± 12.3 s; P < 0.001) and VT /Ti (respectively, 51.2 ± 10.8 s vs. 66.0 ± 13.8 s; P < 0.001). P0.1 was shorter for children compare to adults (57.4 ± 15.4 and 61.0 ± 12.9 s, respectively; P < 0.05). Lastly, we observed that P0.1/VT /Ti was about 45.7% shorter for children compared to adults (26.9 ± 3.4 and 39.2 ± 3.5 s, respectively; P < 0.001) (Fig. 1). 3.5. Comparison of the effect of hypoxia on time-constant between children and adults In response to hypoxia, there was an increase in V˙ O2 of 25.9% for children, from 28.5 ± 3.9 to 35.9 ± 3.0 s (P < 0.001), and of 16.9% for adults, from 33.7 ± 8.6 to 39.4 ± 7.9 s (P < 0.001) (Fig. 2C). Furthermore, under the same condition, V˙ E and V˙ CO2 significantly decreased in both groups. For children, mean V˙ E decreased from
52.5 ± 12.8 to 36.8 ± 8.3 s (29.9%) (P < 0.001), and mean V˙ CO2 decreased from 38.0 ± 4.1 to 36.5 ± 4.0 s (3.9%) (P < 0.01) (Fig. 2A and B). For adults, mean V˙ E decreased from 66.0 ± 12.3 to 48.9 ± 10.0 s (25.9%) (P < 0.001), and mean V˙ CO2 decreased from 53.0 ± 8.0 to 50.7 ± 7.7 s (4.3%) (P < 0.01) (Fig. 2A and B). Decrease of V˙ E and V˙ CO2 were similar for children and adults. In hypoxia, P0.1 decreased in the same manner for children from 57.4 ± 15.4 to 52.0 ± 15.5 s (P < 0.001) and for adults, from 61.0 ± 12.9 to 49.9 ± 12.4 s (P < 0.001) (Fig. 3A). P0.1/VT /Ti decreased for children from 26.9 ± 3.4 to 23.8 ± 3.5 s (11%) (P > 0.001) and were stable for adults from 39.2 ± 3.3 to 40.5 ± 3.7 s (P > 0.001) (Fig. 3C). We found significant correlations between time-constants of V˙ E and P0.1 for adults in normoxia (y = 0.8974x + 11.326; R2 = 0.89) and in hypoxia (y = 0.8043x + 8.72; R2 = 0.98) (Fig. 4A), as well as for children in normoxia (y = 0.712x + 9.65; R2 = 0.93) and in hypoxia (y = 0.475x + 12.11; R2 = 0.90) (Fig. 4C). No correlations between time-constant of V˙ E and P0.1/VT /Ti were observed for adults in normoxia (y = 0.974x + 9.56; R2 = 0.14) or hypoxia (y = 1.326x + 14.01; R2 = 0.12) (Fig. 4B). However, time-constant of V˙ E and P0.1/VT /Ti were significantly correlated for children in normoxia (y = 3.4457x − 42.04; R2 = 0.8166) and hypoxia (y = 2.3595x − 23.97; R2 = 0.8488) (Fig. 4D). 4. Discussion This study compared the adaptation of the intensity of exercise for ventilation, respiratory exchanges, mouth-occlusion pressure and respiratory system impedance during constant-load exercise of moderate intensity between children and adults. We also compared normoxic and hypoxic exercise to better evaluate the contribution of the peripheral chemoreceptors. Our results showed that in normoxia children had significantly shorter V˙ E and V˙ CO2 than adults, and kinetics of P0.1. In response to hypoxia, V˙ E , V˙ CO2 and P0.1 decreased in the same manner in both groups. The main result of this study is the faster adaptation of the respiratory system impedance ( P0.1/VT /Ti ) for children compare to adult, which correspond to the faster V˙ E . 4.1. Methodological considerations
Fig. 1. Comparison of ventilatory parameters time-constant between () adults and ( ) children with ventilation (V˙ E ), oxygen consumption (V˙ O2 ), carbon dioxide output (V˙ CO2 ), mouth-occlusion pressure (P0.1), inspiratory ramp (VT /Ti ) and respiratory system impedance (P0.1/VT /Ti ).
We chose to assess the central command by measuring P0.1 because this measurement is non-invasive. This parameter is particularly interesting for experimental conditions when the impedance of the thoraco-pulmonary system differs among subjects (Whitelaw and Derenne, 1993), which is the case between children and adults (Ramonatxo et al., 1986). This parameter is independent of the resistance and compliance of the respiratory system and does not depend on respiratory muscle properties, except in some pathology. At the functional residual capacity (FRC), the respiratory muscles develop the measured pressure because the elastic
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
243
Fig. 2. Effect of hypoxia on individual values of (A) ventilation ( V˙ E ), (B) carbon dioxide output ( V˙ CO2 ) and (C) oxygen consumption ( V˙ O2 ). The inspiratory fraction of O2 (FIO2 ) is shown on the x-axis, with ( ) hypoxia at 15% O2 (FIO2 = 15%) and () normoxia (FIO2 = 21%) (*** P < 0.001).
recoil of the thoraco-pulmonary system is negligible. As pulmonary volume is stable, there are no vagal influences related to the HeringBreuer reflex. Last, during an occluded inspiration, the force–speed relationship has low importance. Caution is required, however, when interpreting P0.1 responses to exercise. Indeed, since functional residual capacity decreases
from rest to exercise, the inspiratory muscles, depending on their length–tension characteristics, could generate more force in response to a given neural drive and induce an increase in P0.1. In this study, we do not know whether that ventilatory level modification was identical for pre-pubescent children and adults. However, the relative resting volumes, i.e., functional residual capacity/total
Fig. 3. Effect of hypoxia on individual values of (A) mouth-occlusion pressure ( P0.1), (B) inspiratory ramp ( VT /Ti ) and (C) respiratory system impedance ( P0.1/VT /Ti ). The inspiratory fraction of O2 (FIO2 ) is shown on the x-axis, with ( ) hypoxia at 15% O2 (FIO2 = 15%) and () normoxia (FIO2 = 21%) (*** P < 0.001; NS: non-significant).
244
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
Fig. 4. Correlation between individual values in adults of (A) V˙ E and P0.1, and (B) V˙ E and P0.1/VT /Ti ; and in children of (C) V˙ E and P0.1, and (D) V˙ E and P0.1/VT /Ti during exercise ( ) in normoxia and () in hypoxia.
lung capacity (FRC/TLC), do not change in relation to age and in normal children, P0.1 during exercise is a good indicator of the central inspiratory command, despite changes in the ventilation level. Furthermore, as shown by several studies (Cha et al., 1987; Henke et al., 1988) the decrease in FRC is moderate and relatively constant during progressive exercise. Therefore, a difference in FRC, could play a role to explain the observed differences, but does not seem sufficient to solely account for the faster ventilatory kinetic in children compare to adults. The continuous measurement of P0.1, i.e., cycleby-cycle, does not affect flow or ventilation, particularly when the measurement is taken from rest (Ward et al., 1981; Larsson et al., 1993), as in our study. Thus, P0.1 appears to be a good reflect of the central command. To our knowledge, it is the only non-invasive method to assess it.
4.2. Do differences in central command or peripheral chemoreceptors activity explain the faster ventilatory kinetics in children? The hypoxic condition at 15% O2 induced a decrease in SaO2 and an increase in HR and V˙ E in both the children and adults during steady-state phase III of exercise, as expected and showed in previous studies (Springer et al., 1989, 1991). Time-constants values of V˙ O2 , V˙ CO2 , and V˙ E measured during exercise in normoxia for children and adults corresponded to those measured by others (Flandrois et al., 1980; Springer et al., 1989, 1991). We found that children showed V˙ CO2 similar to adults, but they had shorter V˙ CO2 and V˙ E , i.e., they exhibited faster responses than adults did during constant-load exercise below the ventilatory threshold. To our knowledge, it is the first study that measured P0.1 cycleby-cycle during a constant-load exercise and compare children vs. adult. The values of P0.1 time-constants were close to those of ventilation and VT /Ti in both groups. Furthermore, we found significant correlations between P0.1 and V˙ E during exercise in normoxia and hypoxia for both children and adults. This reflects the normal close coupling between central command and ventilation. The main
result was that P0.1 time-constants decreased in the same manner for children and adults in hypoxia. Thus kinetic of central command during phase II of a constant-load exercise were the same, we can assume that there is no maturation of this command with age. Thus, the faster ventilatory responses that we observed for children compare to adults were not due to a difference in the central command. Exercise in hypoxia allows us to stimulate peripheral chemoreceptors and assess their contribution to control of ventilation. We found that V˙ E decreased for children in the same manner as in adults. This reflects that hypoxia stimulates carotid bodies with the same amplitude for children and adults. Our results show that the faster ventilatory kinetic observed between children and adults in normoxia could not be due to different peripheral chemoreceptor activity. On the other hand, Springer et al. (1989) studied the reactivity of the carotid bodies to hyperoxia inhibition. They measured the fall in V˙ E during a hyperoxic switch (i.e., the sudden imposition of 80% oxygen during steady-state exercise) to decrease importance of carotid body input. In normoxia, they found no difference in Peripheral Chemoreceptor Tone (PCT) between children and adults, whereas during hypoxia (15% O2 ), they found a PCT greater in children than in adults (+50%). This study is not in contradiction with our results. We assume that the contribution of peripheral chemoreceptors to the ventilatory adaptation to exercise intensity (phase II) is different compare to steady state (phase III). Thus, the maturation process is certainly complex enough to induce difference in peripheral chemoreceptor contribution to ventilatory kinetic phase II and phase III of a constant-load exercise. Muscle CO2 storage capacity could also be taking into account. Springer et al. (1989) explained the time-constant differences in V˙ E by the relative size of the CO2 storage capacity for children compared to adults. The lower quantity of CO2 stored at the onset of exercise for children could explain the more rapid arrival of metabolically produced CO2 to the respiratory centers, which induces a faster ventilatory response to exercise. However, although this mechanism may play a role, it does not seem to be the main mechanism to explain the difference in the V˙ E time-constants of children and adults since our results show no difference in central command contribution.
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
The fact that the time-constants of ventilation were different between children and adults, whereas the time-constants of P0.1 were the same, brings us to study the respiratory system impedance kinetic. Since we showed that P0.1/VT /Ti , which indicates adaptation of the respiratory system impedance to exercise, was faster for children compare to adults, we can assume that the faster adaptation of ventilation during phase II in the children was due in part to a faster adaptation of the respiratory system impedance. One explanation for this is that the compliance of the thoraco-pulmonary system decreased with growth (Gaultier et al., 1982). Children thus present a more compliant respiratory system, which seems to adapt more quickly to a signal from the central command, as reflected by the faster P0.1/VT /Ti kinetics. A more compliant lung could respond to exercise with a more rapid change in mean volume, thus for the same central command, faster ventilatory adaptation to exercise could be due, in part, to mechanical advantage of respiratory system. We cannot exclude also that differences in circulatory dynamics could account for the faster ventilatory kinetics in children. The shorter vascular pathways in children could allow a faster equilibration of blood gases and thus of the ventilatory parameters time-constants. We could speculate that inhibitory afferences from the respiratory system such as Golgi organs, pulmonary stretch receptors or neuromuscular spindles (Keslacy et al., 2005) could mature with age. In conclusion, our study showed that the central command adaptation and the speed-up of ventilatory kinetic in response to hypoxia during sub-maximal exercise do not differ between children and adults. Thus, maturation of peripheral chemoreceptors or central command is unlikely to fully regulate the ventilatory response to a constant-load exercise during the transition from puberty to adulthood. Faster kinetic of respiratory impedance could explain in part the faster V˙ E for children. It seems that inhibitory afferents from the respiratory system mature during growth and their role may increase with age. This result may be important to better understand respiratory disease evolution with age. Further studies need to be done to assess the contribution of respiratory impedance in respiratory disease development. References Black, L.E., Hyatt, R.E., 1969. Maximal respiratory pressures: normal values and relationship to age and sex. Am. Rev. Respir. Dis. 99, 696–702. Borrani, F., Candau, R., Millet, G.Y., Perrey, S., Fuchslocher, J., Rouillon, J.D., 2001. Is the VO2 slow component dependent on progressive recruitment of fast-twitch fibers in trained runners? J. Appl. Physiol. 90, 2212–2220. Carra, J., Candau, R., Keslacy, S., Giolbas, F., Borrani, F., Millet, G.P., Varray, A., Ramonatxo, M., 2003. Addition of inspiratory resistance increases the amplitude of the slow component of O2 uptake kinetics. J. Appl. Physiol. 94, 2448– 2455. Cha, E.J., Sedlock, D., Yamashiro, S.M., 1987. Changes in lung volume and breathing pattern during exercise and CO2 inhalation in humans. J. Appl. Physiol. 62, 1544–1550.
245
Cooper, D.M., Kaplan, M.R., Baumgarten, L., Weiler-Ravell, D., Whipp, B.J., Wasserman, K., 1987. Coupling of ventilation and CO2 production during exercise in children. Pediatr. Res. 21, 568–572. Dejours, P., 1963. The regulation of breathing pattern during muscular exercise in man: a neuro-humoral theory. In: Cunninghman, D.J.C., Lloyd, B.B. (Eds.), The Regulation of Human Respiration. Blackwell, Oxford, pp. 535– 547. Dejours, P., 1964. Control of respiration in muscular exercise. In: Fenn, W.O., Rahn (Eds.), Hand Book of Physiology Section 3. Respiration. Vol I. American Physiological Society, Washington, DC, pp. 631–649. Derenne, J.P., Couture, J., Iscoe, S., Whitelaw, A., Milic-Emili, J., 1976. Occlusion pressures in men rebreathing CO2 under methoxyflurane anesthesia. J. Appl. Physiol. 40, 805–814. Eastwood, P.R., Hillman, D.R., 1995. A threshold loading device for testing of inspiratory muscle performance. Eur. Respir. J. 8, 463–466. Fawkner, S.G., Armstrong, N., Potter, C.R., Welsman, J.R., 2002. Oxygen uptake kinetics in children and adults after the onset of moderate-intensity exercise. J. Sports Sci. 20, 319–326. ´ H. Flandrois, R., Grandmontagne, M., Mayet, M.H., 1980. In: Shepard, R., Lavallee, (Eds.), Adaptation cardio-respiratoire au debut de l’exercise musculaire chez ´ l’enfant. Universite´ du Quebec, pp. 319–328. Gaultier, C., Perret, L., Boule, M., Baculard, A., Grimfeld, A., Girard, F., 1982. Occlusion pressure and breathing pattern in children with chronic obstructive pulmonary disease. Bull. Eur. Physiopathol. Respir. 18, 851–862. Griffiths, T.L., Henson, L.C., Whipp, B.J., 1986. Influence of inspired oxygen concentration on the dynamics of the exercise hyperpnoea in man. J. Physiol. 380, 387–403. Henke, K.G., Sharratt, M., Pegelow, D., Dempsey, J.A., 1988. Regulation of endexpiratory lung volume during exercise. J. Appl. Physiol. 64, 135–146. Keslacy, S., Matecki, S., Carra, J., Borrani, F., Candau, R., Prefaut, C., Ramonatxo, M., 2005. Effect of inspiratory threshold loading on ventilatory kinetics during constant-load exercise. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1618–R1624. Lakomy, H.K., 1986. Measurement of work and power output using friction-loaded cycle ergometers. Ergonomics 29, 509–517. Larsson, H., Hellstrom, L.G., Linnarsson, D., 1993. Breath-by-breath determination of inspiratory occlusion pressure. Clin. Physiol. 13, 133–142. Quanjer, P.H., Tammeling, G.J., Cotes, J.E., Pedersen, O.F., Peslin, R., Yernault, J.C., 1994. Lung volumes and forced ventilatory flows. Work Group on Standardization of Respiratory Function Tests. European Community for Coal and Steel. Official position of the European Respiratory Society. Rev. Mal. Respir. 11 (Suppl. 3), 5–40. Ramonatxo, M., Mercier, J., el-Fassi-Ben Abdallah, R., Vago, P., Prefaut, C., 1986. Breathing pattern and occlusion pressure during exercise in pre- and peripubertal swimmers. Respir. Physiol. 65, 351–364. Sempe, M., Capron, J.P., 1979. “Chronos”: analysis of bone maturation by an automated numerical method. Pediatrie 34, 833–845. Springer, C., Barstow, T.J., Cooper, D.M., 1989. Effect of hypoxia on ventilatory control during exercise in children and adults. Pediatr. Res. 25, 285–290. Springer, C., Barstow, T.J., Wasserman, K., Cooper, D.M., 1991. Oxygen uptake and heart rate responses during hypoxic exercise in children and adults. Med. Sci. Sports Exerc. 23, 71–79. Ward, S.A., Agleh, K.A., Poon, C.S., 1981. Breath-to-breath monitoring of inspiratory occlusion pressures in humans. J. Appl. Physiol. 51, 520–523. Wasserman, K., Whipp, B.J., Koyal, S.N., Cleary, M.G., 1975. Effect of carotid body resection on ventilatory and acid-base control during exercise. J. Appl. Physiol. 39, 354–358. Whipp, B.J., Ward, S.A., Lamarra, N., Davis, J.A., Wasserman, K., 1982. Parameters of ventilatory and gas exchange dynamics during exercise. J. Appl. Physiol. 52, 1506–1513. Whitelaw, W.A., Derenne, J.P., Milic-Emili, J., 1975. Occlusion pressure as a measure of respiratory center output in conscious man. Respir Physiol 23, 181–199. Whitelaw, W.A., Derenne, J.P., 1993. Airway occlusion pressure. J. Appl. Physiol. 74, 1475–1483.
Contents lists available at ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Role of respiratory system impedance in the difference of ventilatory control between children and adults Stefan Keslacy a,∗ , Juliette Carra b , Michele Ramonatxo c a
820 Comstock Avenue, University of Syracuse, Department of Exercise Science, Room 204 Women’s Building, Syracuse, NY 13206, USA Laboratoire Sport Performance Sant´e UPRES EA 2991, Universit´e Montpellier I, 34295 Montpellier, France c Laboratoire de Physiologie des Interactions, Service Central de Physiologie Clinique, Hˆ opital Arnaud de Villeuneuve, 34295 Montpellier, France b
a r t i c l e
i n f o
Article history: Accepted 20 February 2008 Keywords: Children Occlusion pressure Time-constant Peripheral chemoreceptors Exercise
a b s t r a c t How children are able to adapt their ventilation to the intensity of exercise faster than adults remain unclear. We hypothesized that differences of V˙ E observed between children and adults depend on either peripheral chemoreceptors or central command activity. We examined ventilatory control parameters in either normoxic or hypoxic condition (FIO2 = 0.15). We analyzed the adaptability of the respiratory exchanges by (i) the measurement of ventilatory kinetics time-constant and (ii) the central command by the mouth-occlusion pressure (P0.1). A group of nine pre-pubescent children (mean age 9.5 ± 1 years) and a group of eight adults (mean age 24 ± 3.1 years) performed a constant-load exercise. In normoxia, children had significantly shorter time-constant () V˙ CO2 (respectively, 38.5 ± 4.3 and 53.1 ± 5.3 s; P < 0.001), V˙ E (respectively, 52.5 ± 13.1 s vs. 66.1 ± 12.3 s; P < 0.001), and P0.1 (57.4 ± 15.4 and 61.0 ± 12.9 s, respectively; P < 0.001) than adults. In hypoxia, children exhibited shorter P0.1/VT /Ti compare to adults. Reinforced by the significant correlation between V˙ E and P0.1/VT /Ti for children but not adults, we concluded that ventilatory response differences could be due in part to the respiratory system impedance. © 2008 Elsevier B.V. All rights reserved.
1. Introduction The goal of control of ventilation is to maintain pH, oxygen and carbon dioxide partial pressure homeostasis. Feedbacks and feed forwards determining a central command from the respiratory centers, and several peripheral afferents coming from chemical and mechanical receptors allow a very tight regulation of ventilation. In this way, muscular exercise is a model where ventilation needs to answer the metabolic demands. Understand the maturation of control of ventilation represent an important aspect in the comprehension of the development of several respiratory diseases such as asthma cystic fibrosis or sleep apnea in children. It has been shown that pre-pubescent children exhibit faster ventilatory adaptation to a constant-load exercise compare to adults, measured by shorter phase II time-constant of ventilation ( V˙ E ), i.e., the time to reach 63% of the ventilation steady-state value during a moderate intensity exercise (Flandrois et al., 1980; Cooper et al., 1987; Springer et al., 1991; Fawkner et al., 2002). Peripheral chemoreceptors (carotid and aortic bodies) contribute significantly to exercise hyperpnoea, especially in response to variation of PO2 (Wasserman et al., 1975) during phase II of a
∗ Corresponding author. Tel.: +1 315 443 5588; fax: +1 315 443 9375. E-mail address: [email protected] (S. Keslacy). 1569-9048/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2008.02.005
constant-load exercise, they are the primary site of hypoxic ventilatory responsiveness in both children and adults (Springer et al., 1991). To evaluate the contribution of chemoreceptors to ventilatory control during phase II, various investigations have shown that breathing hypoxic gas mixtures stimulates the peripheral chemoreceptors and quickens the ventilatory response to exercise, reflected by a decrease in the ventilatory time-constant ( V˙ E ) (Griffiths et al., 1986). Conversely, breathing hyperoxic gas mixtures inhibited the activity of these chemoreceptors and caused longer V˙ E (Dejours, 1963, 1964), but little is known about the maturation of peripheral chemoreceptors during the growth process of normal children. Ventilation is a parameter that reflects not only the activity of the respiratory centers, but also the impedance (i.e., the ratio between variations of respiratory volumes and flows) of the thoraco-pulmonary system. Thus, to better understand the differences in ventilatory response between children and adults, a parameter that reflects respiratory centers command independently of the mechanical properties needs to be studied. The measure of mouth-occlusion pressure (P0.1), which was introduced by Whitelaw et al. (1975), is a non-invasive technique for assessing the central respiratory command independently of the mechanical properties of the respiratory system. Its relation to mean inspiratory flow (VT /Ti ), allow us to evaluate, in a satisfactory way, the effective impedance of the respiratory system (Derenne et al., 1976).
240
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
Table 1 Anthropometric characteristics and maximal oxygen consumption Subjects
Age (years)
Height (cm)
Weight (kg)
V˙ O2 max (mL min −1 kg−1 ) Air breathing
Hypoxia
Children
Mean S.D.
9.5 1.0
142.0 13.4
37.5 9.5
47.9 3.2
45.2 3.7**
Adults
Mean S.D.
26.9 3.1
176.0 5.6
69.5 7.0
50.7 4.1
45.5 4.7**
V˙ O2 max: maximal oxygen consumption; S.D.: standard deviation, *** P < 0.001 for normoxia compared to hypoxia.
The aim of this study was to determine if a maturation of peripheral chemoreceptors or of respiratory system impedance could explain the difference of control of ventilation between children and adults. We used hypoxic conditions, which stimulates peripheral chemoreceptors, and studied the adaptation of ventilatory parameters (V˙ O2 , V˙ CO2 and V˙ E ), P0.1 and respiratory system impedance (P0.1/VT /Ti ) kinetics in both pre-pubescent children and adults. 2. Methods 2.1. Subjects 9 pre-pubescent children (mean age 9.5 ± 1 years) and a group of 9 young adults (mean age 27 ± 3.1 years) were studied. All were male to avoid gender differences and Table 1 gives the mean values of their physical characteristics and maximal oxygen consumption (V˙ O2 max). The Local Review Board for Research on Human Subjects approved the protocol. After receiving a detailed description of the experimental procedures, all subjects (and the children’s parents) signed an informed consent to participate in a hypoxic breathing experiment. All, however, were unaware of the purpose of the study. Only voluntary pre-pubescent children would take part in the study. All children were free of cardiac and pulmonary diseases. All adults follow the inclusion criteria: age between 20 and 35 years, free of cardiac and pulmonary disease, and practice sports between 2 and 3 h week−1 . 2.2. Protocol We evaluated children and adults under the same protocol and conditions. During the first session, the subjects were familiarized with the equipment and the experimental procedure, particularly with the cycle ergometer in order to be prepared to perform the exercise tests. The study was performed on three different days. For their second and third visit to the laboratory, all subjects underwent a complete medical examination at rest, including an electrocardiogram (ECG), plethysmographic measurements (Table 2), and a pediatrician evaluated children’s pubescent stage according to the Tanner method (Sempe and Capron, 1979). To determined V˙ O 2
max, the subjects randomly and blindly performed an incremental load exercise (in normoxia and hypoxia: 15% O2 ). Finally, for the
fourth visit, they randomly and blindly performed two constantload exercise tests corresponding to 40% of V˙ O2 max, in normoxia and hypoxia; separated by a minimum of 2 h. 2.2.1. Plethysmography For each subject, we assessed plethysmographic measurements (Vmax 229 series Sensormedics) of lung volumes (total lung capacity, TLC) and flows (vital capacity, VC; forced expiratory volume in 1 s, FEV1 ) according to standard techniques and procedures (American Thoracic Society) (Table 2). 2.2.2. Maximal incremental cycling exercise Each subject performed two incremental-load exercises in normoxia and hypoxia. Pedaling frequency was set at 70 rpm. The test began with a 5-min warm-up at 60 W for adults and 10 W for children. The work rate then increased by 30 W for adults and 15 W for children every minute until the subjects reached volitional exhaustion. We considered a value of heart rate (HR) close to the theoretical maximal HR, a respiratory exchange ratio (R) above 1.1 and a plateau for V˙ O2 as criteria of true maximal effort. 2.2.3. Constant-load test Each subject performed two constant-load exercises in normoxia and hypoxia Intervals between the two tests ranged from 2 to 3 h. For each test, subjects completed a 5-min warm-up of unloaded cycling to begin the test with stable ventilatory parameters and R. Then they exercised for 8 min at a power output corresponding to 40% of V˙ O2 max, followed by 10 min of recovery with unloaded cycling. In order to obtain accurate measures, we imposed power output in less than a second. We used a metronome and a speed transducer linked to the computer to maintain the pedaling frequency constant at 70 rpm. 2.3. Measurements The tests were performed on a friction-loaded cycloergometer (Monark 828 E, Stockholm, Sweden) outfitted with a strain gauge (Interface MFG type, Scottsdale, AZ, USA) in a laboratory maintained at 21 ◦ C. The cycloergometer was equipped with speed and force transducers (Electronic Informatics of Pilat, Jonzieux, France) in order to maintain a constant power output. We calibrated the cycloergometer immediately before each test using equipment supplied
Table 2 Pulmonary function data Subjects
FEV1 (L)
FEV1 /VC (%)
TLC (L)
TLC (%)
Children
Mean S.D.
2.2 0.6
FVC (L)
FVC (%) 96.1 9.4
1.8 0.5
86.5 6.4
3.0 0.6
98.9 6.1
Adults
Mean S.D.
5.3 0.5
102.5 12.1
4.3 0.4
81.7 1.2
7.0 0.4
98.9 5.5
FVC: forced vital capacity; FEV1 : force expired volume in 1 s; TLC: total lung capacity in percentage predicted % (Quanjer et al., 1994).
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
by the manufacturer. To obtain an accurate measurement of the friction force, the strain gauge was calibrated with a known mass (10 kg) hung on the friction belt and in an unloaded condition to give a zero value. We used the method proposed by Lakomy (1986) to get an exact measurement of the flywheel inertia. Briefly, the inertia was simply determined from the linear relationship obtained between the free acceleration of the flywheel and the corresponding friction load. V˙ O2 , V˙ CO2 , and V˙ E data were collected continuously, breathby-breath, throughout the tests using an automatic gas exchange system (CPX Medical Graphics, St. Paul, MN, USA) equipped with a zirconium cell for O2 analysis, an infrared cell for CO2 analysis, and a heated pneumotachograph, type Fleish no. 3 (Godart Statham, Holland). We calibrated CO2 and O2 analyzers before each test with gases of known composition (12% O2 and 5% CO2 ). The calibration of the pneumotachograph was carried out using a 3-L syringe. To prevent valve deformation and gas escaping from the inspiratory and expiratory circuits, we reinforced it with a piece of mica. The total dead space was 100 mL. An ear pulse-oximeter measured saturation level continuously during all exercise (Datex Satlite trans, Helsinki, Finland). We used chloroprene weather balloons (1000 g; FD Kaysam, Inc., Totowa, NJ, USA) with a volume greater than 1500 L, for all tests under both conditions: normoxia and hypoxia, which allowed us to run the experiment under the same conditions. Without subjects in the room, we checked balloons for leaks before each test and then inflated them with ambient air for normoxia and a mixture of ambient air and pure nitrogen for hypoxia (15% of O2 ). The catheter of the CPX system allows us to check O2 concentration, temperature and moisture of the balloon’s air. Mouth-occlusions were performed breath-by-breath using a silent electromagnetic valve closed during expiration and opened automatically after 150 ms. The subjects could not see the occlusion valve and therefore were unable to anticipate airway occlusion. P0.1 and ventilatory flow were measured with a transducer Validyne MP 45 and a carrier demodulator model CD 15 (respectively, at ±35 cm H2 O and ±2 cm H2 O). A Biopac system (Biopac System, Inc., Santa Barbara, CA, USA) transformed the electric signal of mouth pressure into analog signals. A processing software (Acqknowledge v3.53) measured and recorded P0.1 and tidal volume (VT ) from these signals by integration of the flow and respiratory time. For the constant-load exercise tests, we measured P0.1 every two cycles at rest and every cycle during exercise in order to obtain a kinetic. Breath-by-breath data for V˙ O2 , V˙ CO2 , V˙ E , VT , P0.1 and P0.1/VT /Ti , respiratory frequency (f), inspiratory time (Ti ) and expiratory time (Te ) were collected continuously throughout testing. An electrocardiogram measured heart rate with standard bipolar electrode placement.
241
P0.1/VT /Ti that were greater than three standard deviations from the modeled V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti were considered outliers and were removed, in line with a previous work (Carra et al., 2003; Keslacy et al., 2005). These outlier values, assumed to be due to shallow breaths or breathe holding represented less than 1% of the total data collected. Model parameters were determined with an iterative procedure by minimizing the sum of the mean squares of the differences between the estimated V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti based on the model and the measured parameters. Iterations continued until successive repetitions reduced both the sum of the residuals by <10−6 and the correlation coefficient of the relationship between residuals and time by <10−4 . To assess the validity of the model parameters, coefficients of variation were computed using the bootstrap method (Black et al., 1969; Eastwood and Hillman, 1995). Briefly, this consisted of re-sampling the original data set with replacements to create a number of “bootstrap replicate” data sets of the same size as the original data set. For each replicate set, model parameters estimated following the same procedures as for original data. This operation was repeated 1000 times. 2.5. Statistical analysis For all subjects, ventilation and pulmonary gas exchange timeconstants expressed as means and standard deviation (m ± S.D.). The Fisher test determined the model’s degree of significance. The quality of the adjusted model was assessed by the coefficient of determination (r2 ) obtained between the modeled and measured V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti values. Linear and nonlinear regressions checked the random distribution of the model according to time. The Shapiro-Wilk test was used to determine the normality of the distribution of the studied parameters. Paired t-tests were used to compare the model parameters between the two experimental conditions. The relationship between V˙ E and P0.1/VT /Ti assessed by Pearson’s correlation coefficients in the two experimental conditions. Differences were declared to be significant for P < 0.05. 3. Results 3.1. Incremental-load test During incremental-load exercise in hypoxia, the children demonstrated 5.6% reduction in V˙ O2 max (45.2 ± 3.7 mL min−1 kg−1 vs. 47.9 ± 3.2 mL min−1 kg−1 ; P < 0.001) and adults 11.4% reduction (45.5 ± 4.7 mL min−1 kg−1 vs. 50.7 ± 4.1 mL min−1 kg−1 ; P < 0.001). The maximal power reached at V˙ O2 max decreased from 160 to 153 W for exercise in hypoxia for children and from 273 to 262 W for adults.
2.4. Data analysis
3.2. Constant-load test
We used a nonlinear regression techniques to fit V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti raw data with an exponential function. The mathematical model consisted of an exponential term, which represent phase II. The exponential term constrained to start only at the “inflection point” of the response thanks to a time delay and an amplitude (Whipp et al., 1982):
No significant relationships between residuals and time in either experimental condition were identified, suggesting random distribution of the residuals and a model adapted to describe the kinetics of ventilatory parameters under the two conditions (normoxia vs. hypoxia). Model parameters adjustment led to coefficients of determination that ranged between 0 and 1 (mean value of 0.92 ± 0.08). The Fisher test indicated the model’s high degree of significance for all subjects (P < 0.001) (Borrani et al., 2001).
Y (t) = Yb + A[1 − e−(t−td1/t) ] where Y(t) is the parameter variation (V˙ O2 , V˙ CO2 , V˙ E , P0.1 and P0.1/VT /Ti ), Yb is the unloaded cycling baseline value, A is the asymptotic values for the exponential term, and is the timeconstant. The values of the measured V˙ O2 , V˙ CO2 , V˙ E , P0.1 and
3.3. Steady-state values during phase III As shown in Table 3 for steady-state values during a constantload exercise, hypoxia induced a significant decrease in oxygen
242
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
Table 3 Comparison of steady-state values of different parameters between children and adults during exercise in normoxia and hypoxia Hypoxia
Normoxia −1
V˙ E (L min−1 )
−1
Power (W)
SAO2 (%)
HR (b min
V˙ E (L min−1 )
Power (W)
SAO2 (%)
HR (b min
Children Mean S.D.
98.5 0.5
148.7 8.5
39.3 6.0
61.7 6.1
87.5 1.7
159.7 6.5
41.2 6.6
60.4 4.6
Adults Mean S.D.
98.4 0.9
112.0 9.1
42.8 4.4
92.5 4.6
89.0 1.6
124.6 8.9
45.8 4.9
89.4 3.2
)
)
SAO2 : oxygen saturation; HR: heat rate and V˙ E ventilation.
saturation around 11% for children (87.8 ± 1.7% vs. 98.5 ± 0.5% O2 ) and adults (89.0 ± 1.6% vs. 98.4 ± 0.9% O2 ). The values of heart rate during exercise in hypoxia increased significantly by 7.4% (160 ± 6 bpm vs. 149 ± 8 bpm; P < 0.001) for children, and by 10.4% (125 ± 9 bpm vs. 112 ± 9 bpm; P < 0.001) for adults. The steady-state value of V˙ E during phase III of the constant-load exercise increased significantly during hypoxic breathing for children (+4.4%) (41.2 ± 6.6 L min−1 vs. 39.3 ± 6.0 L min−1 ; P < 0.01) and adults (+6.5%) (45.8 ± 4.9 L min−1 vs. 42.8 ± 4.5 L min−1 ; P < 0.01). 3.4. Phase II kinetics: comparison of time-constant between children and adults in normoxia During exercise in normoxia, the mean time-constant for V˙ O2 was similar for children and adults (respectively, 28.9 ± 4.2 and 33.2 ± 5.8 s). However, children compared to adults, had significantly shorter V˙ CO2 (respectively, 38.5 ± 4.3 and 53.1 ± 5.3 s; P < 0.001), V˙ E (respectively, 52.5 ± 13.1 s vs. 66.1 ± 12.3 s; P < 0.001) and VT /Ti (respectively, 51.2 ± 10.8 s vs. 66.0 ± 13.8 s; P < 0.001). P0.1 was shorter for children compare to adults (57.4 ± 15.4 and 61.0 ± 12.9 s, respectively; P < 0.05). Lastly, we observed that P0.1/VT /Ti was about 45.7% shorter for children compared to adults (26.9 ± 3.4 and 39.2 ± 3.5 s, respectively; P < 0.001) (Fig. 1). 3.5. Comparison of the effect of hypoxia on time-constant between children and adults In response to hypoxia, there was an increase in V˙ O2 of 25.9% for children, from 28.5 ± 3.9 to 35.9 ± 3.0 s (P < 0.001), and of 16.9% for adults, from 33.7 ± 8.6 to 39.4 ± 7.9 s (P < 0.001) (Fig. 2C). Furthermore, under the same condition, V˙ E and V˙ CO2 significantly decreased in both groups. For children, mean V˙ E decreased from
52.5 ± 12.8 to 36.8 ± 8.3 s (29.9%) (P < 0.001), and mean V˙ CO2 decreased from 38.0 ± 4.1 to 36.5 ± 4.0 s (3.9%) (P < 0.01) (Fig. 2A and B). For adults, mean V˙ E decreased from 66.0 ± 12.3 to 48.9 ± 10.0 s (25.9%) (P < 0.001), and mean V˙ CO2 decreased from 53.0 ± 8.0 to 50.7 ± 7.7 s (4.3%) (P < 0.01) (Fig. 2A and B). Decrease of V˙ E and V˙ CO2 were similar for children and adults. In hypoxia, P0.1 decreased in the same manner for children from 57.4 ± 15.4 to 52.0 ± 15.5 s (P < 0.001) and for adults, from 61.0 ± 12.9 to 49.9 ± 12.4 s (P < 0.001) (Fig. 3A). P0.1/VT /Ti decreased for children from 26.9 ± 3.4 to 23.8 ± 3.5 s (11%) (P > 0.001) and were stable for adults from 39.2 ± 3.3 to 40.5 ± 3.7 s (P > 0.001) (Fig. 3C). We found significant correlations between time-constants of V˙ E and P0.1 for adults in normoxia (y = 0.8974x + 11.326; R2 = 0.89) and in hypoxia (y = 0.8043x + 8.72; R2 = 0.98) (Fig. 4A), as well as for children in normoxia (y = 0.712x + 9.65; R2 = 0.93) and in hypoxia (y = 0.475x + 12.11; R2 = 0.90) (Fig. 4C). No correlations between time-constant of V˙ E and P0.1/VT /Ti were observed for adults in normoxia (y = 0.974x + 9.56; R2 = 0.14) or hypoxia (y = 1.326x + 14.01; R2 = 0.12) (Fig. 4B). However, time-constant of V˙ E and P0.1/VT /Ti were significantly correlated for children in normoxia (y = 3.4457x − 42.04; R2 = 0.8166) and hypoxia (y = 2.3595x − 23.97; R2 = 0.8488) (Fig. 4D). 4. Discussion This study compared the adaptation of the intensity of exercise for ventilation, respiratory exchanges, mouth-occlusion pressure and respiratory system impedance during constant-load exercise of moderate intensity between children and adults. We also compared normoxic and hypoxic exercise to better evaluate the contribution of the peripheral chemoreceptors. Our results showed that in normoxia children had significantly shorter V˙ E and V˙ CO2 than adults, and kinetics of P0.1. In response to hypoxia, V˙ E , V˙ CO2 and P0.1 decreased in the same manner in both groups. The main result of this study is the faster adaptation of the respiratory system impedance ( P0.1/VT /Ti ) for children compare to adult, which correspond to the faster V˙ E . 4.1. Methodological considerations
Fig. 1. Comparison of ventilatory parameters time-constant between () adults and ( ) children with ventilation (V˙ E ), oxygen consumption (V˙ O2 ), carbon dioxide output (V˙ CO2 ), mouth-occlusion pressure (P0.1), inspiratory ramp (VT /Ti ) and respiratory system impedance (P0.1/VT /Ti ).
We chose to assess the central command by measuring P0.1 because this measurement is non-invasive. This parameter is particularly interesting for experimental conditions when the impedance of the thoraco-pulmonary system differs among subjects (Whitelaw and Derenne, 1993), which is the case between children and adults (Ramonatxo et al., 1986). This parameter is independent of the resistance and compliance of the respiratory system and does not depend on respiratory muscle properties, except in some pathology. At the functional residual capacity (FRC), the respiratory muscles develop the measured pressure because the elastic
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
243
Fig. 2. Effect of hypoxia on individual values of (A) ventilation ( V˙ E ), (B) carbon dioxide output ( V˙ CO2 ) and (C) oxygen consumption ( V˙ O2 ). The inspiratory fraction of O2 (FIO2 ) is shown on the x-axis, with ( ) hypoxia at 15% O2 (FIO2 = 15%) and () normoxia (FIO2 = 21%) (*** P < 0.001).
recoil of the thoraco-pulmonary system is negligible. As pulmonary volume is stable, there are no vagal influences related to the HeringBreuer reflex. Last, during an occluded inspiration, the force–speed relationship has low importance. Caution is required, however, when interpreting P0.1 responses to exercise. Indeed, since functional residual capacity decreases
from rest to exercise, the inspiratory muscles, depending on their length–tension characteristics, could generate more force in response to a given neural drive and induce an increase in P0.1. In this study, we do not know whether that ventilatory level modification was identical for pre-pubescent children and adults. However, the relative resting volumes, i.e., functional residual capacity/total
Fig. 3. Effect of hypoxia on individual values of (A) mouth-occlusion pressure ( P0.1), (B) inspiratory ramp ( VT /Ti ) and (C) respiratory system impedance ( P0.1/VT /Ti ). The inspiratory fraction of O2 (FIO2 ) is shown on the x-axis, with ( ) hypoxia at 15% O2 (FIO2 = 15%) and () normoxia (FIO2 = 21%) (*** P < 0.001; NS: non-significant).
244
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
Fig. 4. Correlation between individual values in adults of (A) V˙ E and P0.1, and (B) V˙ E and P0.1/VT /Ti ; and in children of (C) V˙ E and P0.1, and (D) V˙ E and P0.1/VT /Ti during exercise ( ) in normoxia and () in hypoxia.
lung capacity (FRC/TLC), do not change in relation to age and in normal children, P0.1 during exercise is a good indicator of the central inspiratory command, despite changes in the ventilation level. Furthermore, as shown by several studies (Cha et al., 1987; Henke et al., 1988) the decrease in FRC is moderate and relatively constant during progressive exercise. Therefore, a difference in FRC, could play a role to explain the observed differences, but does not seem sufficient to solely account for the faster ventilatory kinetic in children compare to adults. The continuous measurement of P0.1, i.e., cycleby-cycle, does not affect flow or ventilation, particularly when the measurement is taken from rest (Ward et al., 1981; Larsson et al., 1993), as in our study. Thus, P0.1 appears to be a good reflect of the central command. To our knowledge, it is the only non-invasive method to assess it.
4.2. Do differences in central command or peripheral chemoreceptors activity explain the faster ventilatory kinetics in children? The hypoxic condition at 15% O2 induced a decrease in SaO2 and an increase in HR and V˙ E in both the children and adults during steady-state phase III of exercise, as expected and showed in previous studies (Springer et al., 1989, 1991). Time-constants values of V˙ O2 , V˙ CO2 , and V˙ E measured during exercise in normoxia for children and adults corresponded to those measured by others (Flandrois et al., 1980; Springer et al., 1989, 1991). We found that children showed V˙ CO2 similar to adults, but they had shorter V˙ CO2 and V˙ E , i.e., they exhibited faster responses than adults did during constant-load exercise below the ventilatory threshold. To our knowledge, it is the first study that measured P0.1 cycleby-cycle during a constant-load exercise and compare children vs. adult. The values of P0.1 time-constants were close to those of ventilation and VT /Ti in both groups. Furthermore, we found significant correlations between P0.1 and V˙ E during exercise in normoxia and hypoxia for both children and adults. This reflects the normal close coupling between central command and ventilation. The main
result was that P0.1 time-constants decreased in the same manner for children and adults in hypoxia. Thus kinetic of central command during phase II of a constant-load exercise were the same, we can assume that there is no maturation of this command with age. Thus, the faster ventilatory responses that we observed for children compare to adults were not due to a difference in the central command. Exercise in hypoxia allows us to stimulate peripheral chemoreceptors and assess their contribution to control of ventilation. We found that V˙ E decreased for children in the same manner as in adults. This reflects that hypoxia stimulates carotid bodies with the same amplitude for children and adults. Our results show that the faster ventilatory kinetic observed between children and adults in normoxia could not be due to different peripheral chemoreceptor activity. On the other hand, Springer et al. (1989) studied the reactivity of the carotid bodies to hyperoxia inhibition. They measured the fall in V˙ E during a hyperoxic switch (i.e., the sudden imposition of 80% oxygen during steady-state exercise) to decrease importance of carotid body input. In normoxia, they found no difference in Peripheral Chemoreceptor Tone (PCT) between children and adults, whereas during hypoxia (15% O2 ), they found a PCT greater in children than in adults (+50%). This study is not in contradiction with our results. We assume that the contribution of peripheral chemoreceptors to the ventilatory adaptation to exercise intensity (phase II) is different compare to steady state (phase III). Thus, the maturation process is certainly complex enough to induce difference in peripheral chemoreceptor contribution to ventilatory kinetic phase II and phase III of a constant-load exercise. Muscle CO2 storage capacity could also be taking into account. Springer et al. (1989) explained the time-constant differences in V˙ E by the relative size of the CO2 storage capacity for children compared to adults. The lower quantity of CO2 stored at the onset of exercise for children could explain the more rapid arrival of metabolically produced CO2 to the respiratory centers, which induces a faster ventilatory response to exercise. However, although this mechanism may play a role, it does not seem to be the main mechanism to explain the difference in the V˙ E time-constants of children and adults since our results show no difference in central command contribution.
S. Keslacy et al. / Respiratory Physiology & Neurobiology 161 (2008) 239–245
The fact that the time-constants of ventilation were different between children and adults, whereas the time-constants of P0.1 were the same, brings us to study the respiratory system impedance kinetic. Since we showed that P0.1/VT /Ti , which indicates adaptation of the respiratory system impedance to exercise, was faster for children compare to adults, we can assume that the faster adaptation of ventilation during phase II in the children was due in part to a faster adaptation of the respiratory system impedance. One explanation for this is that the compliance of the thoraco-pulmonary system decreased with growth (Gaultier et al., 1982). Children thus present a more compliant respiratory system, which seems to adapt more quickly to a signal from the central command, as reflected by the faster P0.1/VT /Ti kinetics. A more compliant lung could respond to exercise with a more rapid change in mean volume, thus for the same central command, faster ventilatory adaptation to exercise could be due, in part, to mechanical advantage of respiratory system. We cannot exclude also that differences in circulatory dynamics could account for the faster ventilatory kinetics in children. The shorter vascular pathways in children could allow a faster equilibration of blood gases and thus of the ventilatory parameters time-constants. We could speculate that inhibitory afferences from the respiratory system such as Golgi organs, pulmonary stretch receptors or neuromuscular spindles (Keslacy et al., 2005) could mature with age. In conclusion, our study showed that the central command adaptation and the speed-up of ventilatory kinetic in response to hypoxia during sub-maximal exercise do not differ between children and adults. Thus, maturation of peripheral chemoreceptors or central command is unlikely to fully regulate the ventilatory response to a constant-load exercise during the transition from puberty to adulthood. Faster kinetic of respiratory impedance could explain in part the faster V˙ E for children. It seems that inhibitory afferents from the respiratory system mature during growth and their role may increase with age. This result may be important to better understand respiratory disease evolution with age. Further studies need to be done to assess the contribution of respiratory impedance in respiratory disease development. References Black, L.E., Hyatt, R.E., 1969. Maximal respiratory pressures: normal values and relationship to age and sex. Am. Rev. Respir. Dis. 99, 696–702. Borrani, F., Candau, R., Millet, G.Y., Perrey, S., Fuchslocher, J., Rouillon, J.D., 2001. Is the VO2 slow component dependent on progressive recruitment of fast-twitch fibers in trained runners? J. Appl. Physiol. 90, 2212–2220. Carra, J., Candau, R., Keslacy, S., Giolbas, F., Borrani, F., Millet, G.P., Varray, A., Ramonatxo, M., 2003. Addition of inspiratory resistance increases the amplitude of the slow component of O2 uptake kinetics. J. Appl. Physiol. 94, 2448– 2455. Cha, E.J., Sedlock, D., Yamashiro, S.M., 1987. Changes in lung volume and breathing pattern during exercise and CO2 inhalation in humans. J. Appl. Physiol. 62, 1544–1550.
245
Cooper, D.M., Kaplan, M.R., Baumgarten, L., Weiler-Ravell, D., Whipp, B.J., Wasserman, K., 1987. Coupling of ventilation and CO2 production during exercise in children. Pediatr. Res. 21, 568–572. Dejours, P., 1963. The regulation of breathing pattern during muscular exercise in man: a neuro-humoral theory. In: Cunninghman, D.J.C., Lloyd, B.B. (Eds.), The Regulation of Human Respiration. Blackwell, Oxford, pp. 535– 547. Dejours, P., 1964. Control of respiration in muscular exercise. In: Fenn, W.O., Rahn (Eds.), Hand Book of Physiology Section 3. Respiration. Vol I. American Physiological Society, Washington, DC, pp. 631–649. Derenne, J.P., Couture, J., Iscoe, S., Whitelaw, A., Milic-Emili, J., 1976. Occlusion pressures in men rebreathing CO2 under methoxyflurane anesthesia. J. Appl. Physiol. 40, 805–814. Eastwood, P.R., Hillman, D.R., 1995. A threshold loading device for testing of inspiratory muscle performance. Eur. Respir. J. 8, 463–466. Fawkner, S.G., Armstrong, N., Potter, C.R., Welsman, J.R., 2002. Oxygen uptake kinetics in children and adults after the onset of moderate-intensity exercise. J. Sports Sci. 20, 319–326. ´ H. Flandrois, R., Grandmontagne, M., Mayet, M.H., 1980. In: Shepard, R., Lavallee, (Eds.), Adaptation cardio-respiratoire au debut de l’exercise musculaire chez ´ l’enfant. Universite´ du Quebec, pp. 319–328. Gaultier, C., Perret, L., Boule, M., Baculard, A., Grimfeld, A., Girard, F., 1982. Occlusion pressure and breathing pattern in children with chronic obstructive pulmonary disease. Bull. Eur. Physiopathol. Respir. 18, 851–862. Griffiths, T.L., Henson, L.C., Whipp, B.J., 1986. Influence of inspired oxygen concentration on the dynamics of the exercise hyperpnoea in man. J. Physiol. 380, 387–403. Henke, K.G., Sharratt, M., Pegelow, D., Dempsey, J.A., 1988. Regulation of endexpiratory lung volume during exercise. J. Appl. Physiol. 64, 135–146. Keslacy, S., Matecki, S., Carra, J., Borrani, F., Candau, R., Prefaut, C., Ramonatxo, M., 2005. Effect of inspiratory threshold loading on ventilatory kinetics during constant-load exercise. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1618–R1624. Lakomy, H.K., 1986. Measurement of work and power output using friction-loaded cycle ergometers. Ergonomics 29, 509–517. Larsson, H., Hellstrom, L.G., Linnarsson, D., 1993. Breath-by-breath determination of inspiratory occlusion pressure. Clin. Physiol. 13, 133–142. Quanjer, P.H., Tammeling, G.J., Cotes, J.E., Pedersen, O.F., Peslin, R., Yernault, J.C., 1994. Lung volumes and forced ventilatory flows. Work Group on Standardization of Respiratory Function Tests. European Community for Coal and Steel. Official position of the European Respiratory Society. Rev. Mal. Respir. 11 (Suppl. 3), 5–40. Ramonatxo, M., Mercier, J., el-Fassi-Ben Abdallah, R., Vago, P., Prefaut, C., 1986. Breathing pattern and occlusion pressure during exercise in pre- and peripubertal swimmers. Respir. Physiol. 65, 351–364. Sempe, M., Capron, J.P., 1979. “Chronos”: analysis of bone maturation by an automated numerical method. Pediatrie 34, 833–845. Springer, C., Barstow, T.J., Cooper, D.M., 1989. Effect of hypoxia on ventilatory control during exercise in children and adults. Pediatr. Res. 25, 285–290. Springer, C., Barstow, T.J., Wasserman, K., Cooper, D.M., 1991. Oxygen uptake and heart rate responses during hypoxic exercise in children and adults. Med. Sci. Sports Exerc. 23, 71–79. Ward, S.A., Agleh, K.A., Poon, C.S., 1981. Breath-to-breath monitoring of inspiratory occlusion pressures in humans. J. Appl. Physiol. 51, 520–523. Wasserman, K., Whipp, B.J., Koyal, S.N., Cleary, M.G., 1975. Effect of carotid body resection on ventilatory and acid-base control during exercise. J. Appl. Physiol. 39, 354–358. Whipp, B.J., Ward, S.A., Lamarra, N., Davis, J.A., Wasserman, K., 1982. Parameters of ventilatory and gas exchange dynamics during exercise. J. Appl. Physiol. 52, 1506–1513. Whitelaw, W.A., Derenne, J.P., Milic-Emili, J., 1975. Occlusion pressure as a measure of respiratory center output in conscious man. Respir Physiol 23, 181–199. Whitelaw, W.A., Derenne, J.P., 1993. Airway occlusion pressure. J. Appl. Physiol. 74, 1475–1483.