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1 Laboratoire de Physiologie Respiratoire, Faculté de Médecine, St.-Antoine, Université Pierre et Marie Curie, 75012 Paris, France; and 2 Institute of Pathological Physiology, Charles University, Prague, Czech Republic
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We
investigated whether an hypoxia-induced increase in airway resistance
mediated by vagal efferents participates in the increase in
end-expiratory lung volume (EELV) observed in hypoxia. We also assessed
the contribution of the end-expiratory activity of the diaphragm
(DE) to this phenomenon.
Therefore, we measured EELV, total lung resistance
(RL), dynamic lung compliance
(Cdyn), DE, and minute
ventilation (
E) in anesthetized rats
during normoxia and hypoxia (10%
O2) before (control) and after
administration of atropine or saline. In the control group, hypoxia
increased EELV, Cdyn, DE, and
E but slightly decreased
RL. These changes were
unaffected by saline or atropine, except that, in the atropine-treated rats, hypoxia did not change RL.
These results suggest that 1) the
increase in EELV observed in hypoxia cannot result from an increase in
airway resistance; 2) the increased
and persistent activity of inspiratory muscles during expiration is the
most likely cause of the increase in EELV during hypoxia; and
3) the decrease in
RL induced by hypoxia could
result from the increase in lung volume including EELV.
total lung resistance; dynamic lung compliance; end-expiratory activity of the diaphragm; postinspiratory inspiratory activity; atropine; braking of expiratory airflow
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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HYPOCAPNIC HYPOXIA has been reported to increase the end-expiratory lung volume (EELV) in several species (1, 6, 8, 14, 34), although the mechanism involved is not clearly defined. It has been suggested that the increased activity of inspiratory muscles during expiration may contribute to this phenomenon (6). Indeed, hypoxia increases the postinspiratory inspiratory activity (PIIA) of the diaphragm (4, 30), reducing the expiratory airflow (6, 15). When the diaphragmatic activity persists up to the end of expiration, as recently shown in cats and rats (6, 7, 33), it should prevent the thorax from collapsing to its relaxed position and, therefore, increase EELV. Indeed, we have recently shown that concomitant changes in the diaphragmatic activity at the end of expiration (DE) and EELV induced by various levels of oxygenation are clearly correlated (6).
This increased EELV observed in hypoxia has often been described in
intubated animals, implying that a braking of the upper airways cannot
contribute to this phenomenon (2). However, hypoxia is also known to
induce an increase in lower airway resistance mediated by vagal
efferents through cholinergic pathways (25). Such bronchoconstriction
should reduce the expiratory airflow and, thus, contribute to the
increase in EELV. If this mechanism is involved, the pharmacological
suppression of bronchoconstriction should attenuate the hypoxia-induced
increase in EELV, whereas the increase in the end-expiratory activity
of the diaphragm should remain the same. To test this hypothesis, we
have examined the changes in ventilation
(E), EELV, total lung resistance
(RL), and dynamic lung
compliance (Cdyn) in response to hypoxia before and after the
intravenous administration of atropine, which has been shown to block
the increase in lung resistance induced by hypoxia (19). In addition,
to assess the contribution of the activity of inspiratory muscles
during expiration, we have measured the expiratory flow-volume curves
and DE in response to hypoxia. The flow-volume curves would show the braking effect of PIIA during expiration, whereas an increased
DE would suggest an increase in
thoracic volume at the end of expiration. Finally, because our results
did not show the expected increase in lung resistance during hypoxia,
we extended our study by estimating the changes in airway resistance
from the passive relaxation curve (15) in paralyzed animals during
normoxia and hypoxia.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies were performed in 27 adult male Wistar rats with an average
body weight of 243.8 ± 26.4 (SD) g. A first group of 22 rats was
used to assess the effects of hypoxia on
E, diaphragmatic activity, and EELV
before and after administration of atropine. A second group of five
rats was used to elicit the effects of hypoxia on expiratory braking
and airway resistance. The techniques used for the surgery and
postsurgical care of the animals were compatible with National
Institutes of Health guidelines.
Protocol 1
Preparation. Under brief halothane anesthesia, a midline abdominal incision was made, and two electrodes (multistrand Teflon-coated wires) were implanted in the costal part of the right hemidiaphragm. A third electrode (used as a ground) was tied into the neck muscles. All the wires were tunneled subcutaneously and exteriorized at the back of the neck. Ten milliliters of glucose (5%) were administered to maintain the hydric equilibrium, and the animals were allowed to recover for at least 3 days. Each rat was then anesthetized with pentobarbital sodium (40 mg/kg ip), and a short cannula (ID 1.7; OD 2.3 mm) was inserted into the trachea just below the larynx.
Measurements.
E was measured by direct
plethysmography. The pressure signal due to breathing was monitored by
a differential pressure transducer (Elema-Schonander EMT 32). The
diaphragm electromyographic (EMG) signal was recorded by connecting the
bared terminal part of the wires to the amplifier (Grass P15 AC
preamplifier). The signal was filtered (30-1,000 Hz), sampled at
25 kHz, rectified, and integrated by a computer program over 100-ms
intervals every 10 ms.
E, Cdyn, and
RL, and instantaneous values of
integrated diaphragmatic EMG at the trough, which corresponds to the
end of expiration (DE).
Recordings. The animal was placed in a 5.6-liter Plexiglas chamber in a prone position, and the tracheal tube was connected to an external circuit. The experiments were carried out at a mean ambient temperature of 24.9 ± 1.8°C, and the mean colonic temperature of the animals was 37.2 ± 0.9°C. When breathing was stable, ventilation, diaphragmatic activity, and EELV were measured in normoxia [inspiratory O2 fraction (FIO2) = 0.21] at 5 and 10 min, in hypoxia (FIO2 = 0.10) at 5 and 10 min, and again in normoxia at 10 and 15 min. This protocol was performed in 22 rats as control animals and then repeated in 11 of these rats after intravenous injection of atropine (1 mg/kg, 0.1 ml/100 g) and in the other 11 animals after intravenous injection of saline (0.1 ml/100 g). The effectiveness of atropine was tested by the absence of pupillary constriction in response to light.
Protocol 2
The animals were anesthetized, instrumented, and the ventilatory and EMG parameters were measured as described in protocol 1.The flow-volume curves were obtained from the plethysmographic record of volume and its derivation into flow. VT, flow, and DE were recorded during spontaneous and relaxed expirations in normoxia and spontaneous expirations after 10 min of hypoxia (10%). The relaxed expiration was obtained by occluding the airway at the end of tidal inspiration, the occlusion being maintained until the rat relaxed its respiratory muscles.
Then the animals were paralyzed with succinylcholine iodide (2 mg/kg) and artificially ventilated. The lungs were inflated to six different volumes, and the passive collapse time (TE) was determined as the time required for expiratory flow to return to a value indistinguishable from zero. The VT-TE relationships during these inflations were measured in normoxia and after 10 min of hypoxia.
Data Analysis and Statistics
Each variable ofE and diaphragmatic
activity was averaged over five consecutive respiratory cycles. EELV
values were the mean of three consecutive measurements made at a time
interval of 10 s. Results are presented as means ± SE. Statistical
analysis was done by using nonparametric tests, because they do not
assume a normal distribution. The Wilcoxon test and Friedman two-way analysis of variance with multiple comparisons were used to compare the
data with their own control values. Differences were considered significant when P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Protocol 1
Control responses to hypoxia.
Table 1 shows the mean values of
respiratory variables for control animals in normoxia, hypocapnic
hypoxia, and after recovery in normoxia. Hypoxia induced a marked
increase in E (+60.5% of normoxic
control values) because of a slight increase in
VT (+10.9%) and a marked
increase in f (+44.9%). The increase in f is due to a shortening
mainly of TE and, to a lesser
extent, to a shortening of TI.
All these ventilatory parameters returned to control normoxic levels
after 15 min of recovery in normoxia.
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17.4%), whereas Cdyn slightly increased
(+21.2%) and remained transiently elevated also at 10 min of recovery
in normoxia; after 15 min of recovery, both
RL and Cdyn values returned to
control levels. Because the hypoxia-induced increase in Cdyn was
relatively small compared with that of EELV, the Cdyn-to-EELV ratio was
significantly decreased by hypoxia.
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E, EELV, and
DE and slightly decreased
RL.
Effects of atropine.
As shown in Table 2, the
administration of saline or atropine during normoxia did not affect any
of the ventilatory parameters. For saline- and atropine-treated rats,
exposure to hypoxia produced a marked increase in
E, mainly because of a large
increase in f induced by the reduction in both
TI and
TE. The ventilatory responses to
hypoxia in saline- and atropine-treated rats did not differ
significantly.
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Protocol 2
Expiratory flow-volume curves.
In spontaneously breathing animals, expiratory flow is driven by the
elastic recoil of the respiratory system and opposed by its resistance
to airflow plus the PIIA of inspiratory muscles. Thus
expiratory flow-volume curves can be used as an index of the quantity
of PIIA: at a given volume, the higher the PIIA, the lower the flow. To
illustrate the effect of the PIIA of inspiratory muscles on the braking
of expiratory airflow, we used the method of Zin et al. (37). We
compared the flow-volume curves recorded during the relaxed expiration
of an occluded breath in normoxia, and during a spontaneous breath in
normoxia and hypoxia (Fig. 4). In normoxia,
the flow at a given volume was much lower during spontaneous than
during relaxed expiration. Because the occlusion maneuver blocked the
PIIA, the difference between the relaxed and spontaneous breath shows
the presence of PIIA in normoxia. Similarly, during spontaneous
breathing, the lower flow in hypoxia than in normoxia, particularly at
the beginning of expiration, reflects the increased PIIA in hypoxia and
suggests that the braking of expiratory airflow was more intense in
hypoxia. These changes occurred in 9 of the 12 animals.
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VT-TE
relationship.
Hypoxia did not increase but slightly decreased total
RL during the control
measurement. To substantiate this finding, we tried to assess the
changes in airway resistance by comparing the
VT-TE
relationships during passive relaxation of the respiratory system in
normoxia and hypoxia in paralyzed rats. Under this experimental condition, all the respiratory muscles were inactivated and, thus, expiratory flow was driven only by the elastic recoil of the
respiratory system. Therefore, any increase in airway resistance should
prolong the time required to return to EELV from the same
VT. Figure
5 shows similar
VT-TE
relationships in normoxia and hypoxia, suggesting that hypoxia did not
increase airway resistance. In fact, similar VT-TE
relationships in normoxia and hypoxia associated with the hypoxia-induced increase in Cdyn (Fig. 2) imply a decrease in resistance to flow in hypoxia.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of our study demonstrate that 1) hypoxia slightly decreased RL and, therefore, the hypoxia-induced increase in the EELV cannot result from an increased RL; 2) the similar VT-TE relationships in normoxia and hypoxia together with an hypoxia-induced increase in Cdyn support our finding of a decrease in RL during hypoxia; 3) the increased and persistent activity of the diaphragm during expiration in hypoxia reduces the expiratory airflow and thus should contribute to the increase in EELV; and 4) the hypoxia-induced decrease in RL observed in control animals was not observed in the atropine-treated rats.
Methodology
Measurement of EELV and RL in animals requires the use of general anesthesia, which is known to depress respiratory function. In particular, it has been shown that various anesthetics decreased the bronchoconstrictor responses induced by the electrical stimulation of efferent vagal fibers (18). However, under barbiturate anesthesia, such an effect is observed only with high additional doses of pentobarbital sodium. Moreover, in decerebrate nonanesthetized cats, the hypoxia-induced bronchoconstriction was not affected by the administration of subanesthetic doses of pentobarbital sodium (19).Besides the effect of anesthesia, the control values of DE and EELV could have been influenced by the position of the animal (21) and tracheal intubation (3). However, these conditions did not change during the experiments and thus could not have affected the relative changes induced by hypoxia. In addition, baseline values of DE and EELV in any single animal were stable.
We ascertained the EELV changes by the manometric method because this method allows repeated measurements within a short period of time. Our EELV values, therefore, include intrathoracic gas, which does not communicate with the atmosphere and may be also indirectly affected by the decompression of abdominal gas. However, values obtained by manometric and nitrogen-dilution methods correlate very closely (27), suggesting that neither trapped air nor the abdominal gas content has any substantial impact.
Also, the increased negativity of intrapulmonary pressure during inspiratory efforts after airway occlusion likely causes chest wall distortion and thus could stimulate lung and thoracic receptors. However, there were no consistent changes in the pattern of breathing, Cdyn, RL, and EELV immediately after the occlusion, probably because of its short duration (2.09 ± 0.04 s).
We measured RL because this
parameter has been previously used to show the hypoxia-induced
bronchomotor response in dogs and cats (19, 25). The water-filled
catheter used for the esophageal measurement was reported to have an
adequate frequency response in both magnitude and timing. The accuracy
of this method was checked by comparing the value of a known resistance
added to the tracheal tube (0.10 cmH2O · ml
1 · s)
with the measured increment (0.11 cmH2O · ml1 · s).
Although our control values of
RL were similar to those reported in rats (9, 11), the unexpected decrease in
RL observed in hypoxia led us to
perform a complementary study. We have, therefore, assessed the effect
of hypoxia on airway resistance by measuring the
VT-TE
relationship in paralyzed rats.
Changes in ventilatory parameters and DE. The ventilatory response to hypoxia observed in the present study was essentially similar to that found in anesthetized rats by other authors (10, 32). Our finding that EELV was increased during acute hypoxia has also been reported in several species (1, 6, 8, 14, 28, 34). Also, the hypoxia-induced increase in DE is in agreement with the prolongation of diaphragmatic postinspiratory activity during hypoxia in dogs (30) and confirmed our previous results (4-7, 33).
Nevertheless, the increase in DE and EELV during hypoxia may be partly generated by hypoxia per se and partly by the effect of the accompanying hypocapnia. Indeed, the diaphragm was more active during expiration in hypocapnic than in normocapnic hypoxia (4-6, 30), and EELV increased more in hypocapnic than in normocapnic hypoxia (6). The administration of intravenous atropine in normoxia did not affect any of the ventilatory parameters. In humans, De Troyer et al. (13) have found that an atropine-induced vagal blockade during air breathing slightly increased functional residual capacity (+7%) because of a reduction in lung recoil pressure. Such an effect has not been observed in our anesthetized rats. Similarly, these authors reported that atropine reduced airway resistance and increased Cdyn. In the present study, RL and Cdyn were unaffected by atropine, probably because of a long-lasting reduction in bronchomotor tone caused by a previous hypoxic test. In several studies performed in anesthetized and paralyzed dogs or cats, an hypoxia-induced increase in RL was reduced by the intravenous injection of atropine or by cooling or sectioning of the vagus nerves, showing the participation of vagal cholinergic pathways (17, 19, 25, 31). Other authors suggested that the bronchoconstriction observed in hypoxia may be mediated by local histamine release (29, 31). In the present study, these mechanisms could not be involved because RL was not increased by hypoxia and atropine did not significantly affect RL.Changes in lung mechanics. Our finding that hypoxia slightly decreased RL is in agreement with the hypoxic bronchodilation elicited by morphometric methods in humans (20) and minipigs (35). However, other studies have found that hypoxia either had no effect (12, 16, 28, 29, 36) or increased RL (17, 19, 25, 31). Similarly, conflicting results are reported concerning the effect of hypoxia on Cdyn (12, 17, 19, 28, 29).
The interpretation of all these works is complicated because of differences in the species studied and in the experimental procedures used (awake or anesthetized, intact or intubated, hypo- or isocapnic hypoxia, different severity and duration of hypoxia). Indeed, the increased RL reported in dogs (25) could be partly due to the effect of hypocapnia accompanying hypoxia (26), whereas the unchanged or decreased RL reported in nonintubated humans or sheep (12, 20, 28) could be partly due to the effect of hypoxia on upper airway resistance (2). In addition, in anesthetized animals the time of recording after the induction of hypoxia may affect the results (18). Finally, the measurement of RL reflects resistive elements in large and small airways and in tissues, whereas the morphometric methods measure only the caliber of large airways. Our finding of a decrease in RL observed during hypoxia in anesthetized rats was supported by the measurement of the VT-TE relationships during passive collapse of the respiratory system in paralyzed animals by using the method described by Gautier et al. (15). Under the latter experimental condition, expiration is driven only by the elastic recoil of the respiratory system, and thus an increase in flow resistance cannot be counteracted by the activity of respiratory muscles during expiration. Consequently, if the respiratory system of the same compliance is inflated to the same volume, an increase in resistance will prolong the expiration. In our paralyzed rats, the VT-TE relationships were similar in normoxia and in hypoxia, which suggests that airway resistance did not change. However, as hypoxia increased Cdyn, the elastic recoil of the respiratory system at a given volume was smaller in hypoxia. Therefore, the pressure driving the expiratory airflow was lower in hypoxia, which implies a decrease in resistance to flow. It should be noted that most of the studies that reported an increase in RL in hypoxia have been performed in paralyzed animals (17, 19, 25, 31), whereas those that failed to find any effect of hypoxia on RL were performed in humans (28), in awake or in anesthetized but spontaneously breathing animals (12, 36) as in the present study. In paralyzed animals, hypoxia cannot induce the increase in EELV previously described (6) insofar as such an effect likely depends on the inspiratory muscle activity during expiration. Now, the increase in lung volume is well known to decrease the flow resistance. Again, Ludwig et al. (22) recently reported that increasing lung volume caused a significant fall in the lung and airway resistances previously increased by vagal stimulation. Thus the lack of increased EELV in hypoxia in paralyzed animals could explain the discrepancy in the RL response to hypoxia between paralyzed and spontaneously breathing animals. Therefore, in our nonparalyzed rats, the increase in EELV and VT during hypoxia may be responsible for the decrease in RL. Together, these different results suggest that the effect of hypoxia on lung resistance could result from two opposing effects: a primary increase in airway and/or tissue resistance, possibly originating from peripheral chemoreceptors (25), followed by a compensatory increase in lung volume and EELV that decreases the airway resistance.Mechanism of the increase in EELV. Our results showed that the increase in EELV in hypoxia cannot be related to an increase in airway resistance. At the same time, hypoxia has been found to enhance the braking of the expiratory airflow, although this effect was less pronounced than in cats (6). Such expiratory braking resulted from the slowing down of the collapse of the thorax, likely due to an increase in PIIA of inspiratory muscles. In addition, the fact that hypoxia increased DE suggests that the diaphragm, and probably other inspiratory muscles, keep the EELV at a higher level in hypoxia than in normoxia.
However, the increased EELV could also stem from a reduction in the expiratory duration. Nevertheless, in anesthetized rats, during control air breathing, there is a slight delay between the end of the expiratory flow and the beginning of the next inspiration, which generally disappears in hypoxia; thus the shortening of expiration in hypoxia does not necessarily affect the time available for the collapse of the respiratory system. Moreover, as previously shown, TE is decreased in both hypoxia and hypercapnia, whereas EELV is increased only in hypoxia (6, 33). Smith et al. (30) suggested that the effect of TE shortening on EELV is compensated for, in hypercapnia, by the increased expiratory muscle activity and reduced PIIA, whereas, in hypocapnic hypoxia the reduced TE in addition to the absence of expiratory muscle activation and prolonged PIIA resulted in the increase in EELV. Also, the increase in the Cdyn in hypoxia may participate in the increase in EELV, but this effect was too small to have played a major role. Indeed, the increase in Cdyn related to the interpleural pressure at the end of expiration (~1.5 cmH2O) can explain only ~10% of the change in EELV we have found. In conclusion, these results strongly suggest that the increase in EELV observed during hypoxia is mainly due to the increase in PIIA, which brakes the expiratory airflow, and to the remaining DE, which prevents the thorax from collapsing to its relaxed position. The increase in EELV may compensate for the increase in RL caused by the hypoxia-induced bronchoconstriction.| |
ACKNOWLEDGEMENTS |
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The authors thank J. Chandellier for preparing the illustrations.
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FOOTNOTES |
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M. Bonora was the recipient of a fellowship as part of a joint program between l'Université Pierre et Marie Curie, Paris, and Charles University, Prague. This work was also supported by Grant GAUK 27/1998.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. Bonora, Laboratoire de Physiologie Respiratoire, Faculté de Médecine St-Antoine, 27, rue de Chaligny, 75012 Paris, France.
Received 8 December 1998; accepted in final form 19 March 1999.
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TOP
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METHODS
RESULTS
DISCUSSION
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