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Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Simon, B. A., P. B. Zanaboni, and D. P. Nyhan. Effect
of hypoxia on respiratory system impedance in dogs. J. Appl. Physiol. 83(2): 451-458, 1997.
The effects of hypoxia on lung and airway
mechanics remain controversial, possibly because of the confounding
effects of competing reflexes caused by systemic hypoxemia. We compared
the effects of systemic hypoxemia with those of unilateral alveolar
hypoxia (with systemic normoxemia) on unilateral respiratory system
impedance (Z) in intact, anesthetized dogs. Independent lung
ventilation was obtained with a Kottmeier endobronchial tube.
Individual left and right respiratory system Z was measured during
sinusoidal forcing with 45 ml of volume at frequencies of 0.2-2.1
Hz during control [100% inspired
O2 fraction
(FIO2)], systemic
hypoxemia (10% FIO2), and
unilateral alveolar hypoxia (0%
FIO2 to left lung, 100%
FIO2 to right lung). During
systemic hypoxemia, there was a mean Z magnitude increase of 18%. This
change was entirely attributable to a decrease in the imaginary
component of Z; there was no change in the real component of Z. Administration of atropine (0.2 mg/kg) did not block the increase in Z
with systemic hypoxemia. In contrast, there was no change in Z in the
lung subjected to unilateral alveolar hypoxia. We conclude that
alveolar hypoxia has no direct effect on lung mechanical properties in
intact dogs. In contrast, systemic hypoxemia does increase lung
impedance, apparently through a noncholinergic mechanism.
hypoxic pulmonary vasoconstriction; lung mechanics; resistance; compliance; hypoxemia; atropine
INTRODUCTION HYPOXIC PULMONARY vasoconstriction (HPV) is a
well-known regional mechanism in the lung for regulating the
distribution of pulmonary blood flow and optimizing
ventilation-perfusion matching. In a complementary fashion, alveolar
hypocapnia causes regional pneumoconstriction, which distributes
ventilation away from a hypoperfused region (20). The effect of
regional hypoxia on lung and airway mechanics, however, remains
controversial for several reasons. There appears to be considerable
variability among different species and different experimental
preparations. For example, there is evidence of airway constriction to
hypoxemia in intact dogs (18, 26) but bronchodilation in minipigs (33). In humans, hypoxia has been reported to cause bronchoconstriction (25),
to cause bronchodilation (10), and to have no effect (8). Furthermore,
there is poor agreement between in vivo and in vitro results. In vitro
studies of airway rings or smooth muscle show a consistent relaxation
response to hypoxia in tissue from dogs and pigs (5, 6, 24, 28). One
possible explanation for these disparities is that systemic hypoxemia
may cause variable activation of sympathetic, vagal, and other reflex
responses, which could vary among species or preparations and could
cloud the interpretation of direct lung effects.
To investigate whether alveolar hypoxia alters regional lung mechanics,
we developed a model in which the left and right lungs can be
independently ventilated and their individual mechanical properties
measured. We then used this model to compare the effects of systemic
hypoxemia with the effects of unilateral alveolar hypoxia
[maintaining normal systemic
PO2 and normal alveolar PCO2
(PACO2)] on unilateral
respiratory system impedance in intact, anesthetized dogs. Finally,
because vagal reflexes have been implicated in the mechanical response
of the lung to hypoxemia in the dog (18), we examined the effect of atropine on the hypoxemic response.
MATERIALS AND METHODS
P, and
F) as follows
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] and hypoxemia (H1: 10%
FIO2 to both lungs; 
).
Values are means ± SE. * P < 0.05.
RESULTS
) in two animals during left
lung hypoxia suggest that the
PAO2 is in equilibrium with
the mixed venous blood (Table 2). In
addition, although we did not quantify ventilation, it was necessary to significantly decrease the ventilation to the left lung relative to the
right lung during unilateral hypoxic ventilation to maintain the
PETCO2 in the desired range.
All blood-gas values returned to control levels after unilateral or
bilateral hypoxia was terminated.
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), and hypoxemia after atropine
(H2, ). Values are means ± SE.
* P < 0.05 for
hypoxemia effect after atropine.
Traditional compliance and resistance parameters for the respiratory system are presented in Fig. 3 for the hypoxemia protocol. Compliance, calculated by fitting C =
(2
fIm{Z})
1
(where C is compliance and f is
frequency) to the data (assuming negligible inertance at these
frequencies), decreased similar amounts during both hypoxemia trials
(H1/C1 and H2/C3 = 0.91 ± 0.03 and 0.87 ± 0.03 before and after
atropine, respectively; P < 0.05)
and increased with administration of atropine (C3/C2 = 1.07 ± 0.03, P < 0.05). Airway resistance,
approximated as Re{Z} at the highest frequency (2.1 Hz),
did not change significantly with hypoxemia but fell 30% after
atropine administration.
P < 0.05 vs. C2;
§ P < 0.05 vs. C3.
Unilateral alveolar hypoxia. There were no changes in |Z|, Im{Z}, Re{Z}, or compliance at any frequency in the hypoxic left or control right lung during unilateral alveolar hypoxic ventilation (Fig. 4).
) and unilateral hypoxic ventilation (100%
FIO2 to right lung, 0%
FIO2 to left lung; ).
Values are means ± SE.
DISCUSSION
Hypoxia is a life-threatening challenge to an organism and results in a variety of homeostatic neural and endocrine responses. The extent and net effect of these responses may depend on several factors, including the severity and duration of the hypoxemia, use of and type of anesthetic agents, particular experimental conditions, and particular species studied. These responses may have primary or secondary effects on the lung and airways, and the net effects are unpredictable. For example, sympathetic responses and catecholamine release would tend to bronchodilate, whereas vagal responses cause constriction. In addition, changing metabolic conditions (acidosis, hypercarbia) may also have an effect. Thus studies attempting to determine the effects of hypoxia on airway function have yielded results that are inconsistent among species (18, 26, 33), within species with different experimental protocols (8, 10, 25), and between in vivo and in vitro preparations (5, 6, 24, 28). To distinguish the direct effects of alveolar hypoxia on lung and airway mechanical function from the confounding effects of systemic hypoxemia, we have used a model in which the lungs of anesthetized dogs can be independently ventilated with different gas mixtures and the respiratory system impedance of each side can be determined separately. We then used this model to compare the effects of systemic hypoxemia with the effects of unilateral alveolar hypoxia (maintaining normal systemic PO2 and normal PACO2). We found a significant increase in respiratory system impedance during systemic hypoxemia. This increase was primarily in the imaginary component of impedance, which reflects lung elastance. During unilateral hypoxic ventilation, however, there was no change in lung mechanical behavior. The response to hypoxemia was not affected by intravenous atropine. These results suggest that isolated alveolar hypoxia does not affect airway or lung mechanics, and in this model the constriction to hypoxemia is via a nonvagal mechanism.
Methodological considerations. The technique of lung isolation and independent ventilation to separate the effects of systemic from local lung interventions has been used by many investigators for the study of the pulmonary circulation and the airways (9, 12, 20). An important advantage of this approach is that it allows survivable studies in intact, minimally instrumented animals. However, the measurement of input impedance from airway opening pressure and flow only provides information about total respiratory system impedance. To separate lung properties from chest wall properties, a measurement of pleural pressure must be obtained. The most commonly used estimate of pleural pressure changes is esophageal pressure, but this measurement is a poor reflection of regional pleural pressure when lung mechanical properties are nonuniform (9, 14). Methods for measuring regional pleural pressure tend to be invasive (17, 35) and not compatible with survival experiments. Thus these impedance measurements are limited by the presence of the chest wall, which although pharmacologically relaxed and presumably constant throughout the experiments, may cause the measurement to be less sensitive to subtle changes in lung properties than open-chest approaches. Barnas et al. (1), using a similar oscillatory forcing technique on the whole lungs of intact dogs, found that the chest wall contributed ~50% of the respiratory system elastance over this frequency range. Relative contributions of lung and chest wall to respiratory system resistance (Rrs), on the other hand, varied with frequency. The chest wall contributed 60-70% of the resistance at frequencies <1 Hz, contributions of lung and chest wall were about equal at 1 Hz, and the lung contributed 60% of Rrs at 2 Hz. Thus the lung contributes 40-60% of the total respiratory system input impedance over the frequency range studied. If it is assumed that there are no changes in the mechanics of the relaxed chest wall, the changes in input impedance reported here are therefore conservative estimates of the mechanical effects on the lung itself. However, it is possible that subtle changes in lung properties, particularly those of the tissue component of resistance, which would be seen at low frequency when chest wall effects are greatest, are masked by this limitation. A second aspect of this preparation that potentially complicates the interpretation of the data is that the contralateral lung is left open to atmosphere during the ipsilateral impedance measurement. This creates a slightly different configuration than is found in the conventional measurement of "respiratory system" properties, with the lung of interest now in series with the parallel combination of the ipsilateral chest wall and contralateral lung. Furthermore, the chest wall contribution to the measured impedance may be different when only one lung is oscillated and the chest wall expands inhomogeneously. It is not possible to separate the individual contribution of each of these elements without regional pleural pressure measurements. As a result, it is possible that changes in the unilateral impedance measurement could be due in part to changes in the contralateral lung pathway rather than the lung of interest. However, in another study using this method, impedance measurements on the control side did not change when the contralateral lung underwent a 50% increase in |Z| during unilateral hypocapnia from pulmonary artery occlusion (22), suggesting that this effect is small. Thus, again, barring changes in the properties of the relaxed chest wall, changes in impedance measured with this method should still primarily reflect changes in the ipsilateral lung. We chose to use a relatively small, constant-amplitude volume across the frequency range for our impedance measurement, an approach that can potentially exaggerate the effect of airway resistance at higher frequencies because of the higher peak flows obtained. However, data from Barnas et al. (1), examining impedance changes from 50 to 100 ml of VT in intact dogs (corresponding to ~25-50 ml of VT per single lung) would suggest that one would expect at most a 10-15% fall in chest wall elastance, no change in lung elastance, and minimal changes in chest wall resistance, pulmonary resistance, and Rrs. Thus the choice of constant amplitude is not likely to have caused any significant difference from the alternative approach of constant peak flow (i.e., falling amplitude as frequency increases). Over the course of a measurement run, mean airway pressure typically fell 0.5-1 cmH2O. This was probably due to O2 uptake from the closed system and corresponds to a volume loss of ~30 ml. This would cause the lung volume to be slightly smaller at the higher-frequency measurements than at the outset, which could cause a small increase in resistance and compliance compared with conditions in which volume remained exactly constant. However, because this effect was similar for all runs, it is not likely a cause of significant error in evaluating changes between conditions. Effect of atropine. The administration of intravenous atropine caused a 9% decrease in |Z|. Re{Z} fell significantly only at the higher frequencies, consistent with an effect on airway resistance. By use of high-resolution computed tomography, this dose of atropine was found to maximally dilate large airways (3), although airways <1 mm could not be measured. In addition, there was a fall in Im{Z} of ~7% across all frequencies or, equivalently, an increase in compliance. These results correspond to the inverse of the increased resistance and decreased compliance in dogs during vagal stimulation (13). In humans, intravenous atropine has been shown to cause a decrease in airway resistance (~50%) and an increase in lung compliance (~18%), along with a 7% increase in FRC (4). We cannot distinguish whether our findings are due to relaxation of vagally mediated smooth muscle/airway tone (with or without an increase in FRC from resulting decreased lung recoil) or recruitment of additional lung volume, although there is no reason to suspect the latter. In any event, these results confirm the sensitivity of this technique to detect relatively small changes in Z. Hypoxemia. The primary effect of hypoxemia on lung mechanics was to cause a decrease in compliance, as evidenced by the changes in Im{Z}. There was no change in the Re{Z}. Again, this finding could result from a loss of ventilated lung volume or a fall in FRC. To avoid this, volume history was standardized and large inflations were given to prevent progressive atelectasis over time. Furthermore, the changes in Z occurred rapidly and completely returned to baseline during the repeat control measurement. VT was maintained in this protocol, as opposed to the unilateral hypoxic ventilation series, in which VT to the hypoxic lung was decreased to maintain PETCO2. One would expect to see a greater fall in lung volume and increase in impedance under conditions of reduced VT due to increased atelectasis, but none was found. Finally, previous experience using this closed-chest model to measure changes in unilateral respiratory system impedance during hypocapnia induced by unilateral pulmonary artery occlusion, in which lung volumes were measured using helium dilution, showed no changes in FRC with considerably stronger hypocapnic constrictions (46% increase in |Z|) (22). Thus we consider a decrease in FRC due to passive atelectasis to be an unlikely cause of the observed changes. The lack of effect of atropine on the response to hypoxemia was somewhat surprising, particularly in light of the well-known results of Nadel and Widdicombe (18), in which cooling of the vagi prevented the increase in lung resistance and decrease in tracheal volume seen with hypoxemia. As discussed above, this dose of atropine has been shown to maximally dilate large airways and caused a measurable fall in Z, so it is unlikely that the preserved response was due to inadequate cholinergic blockade. Other investigators have found responses to hypoxemia unaffected by intravenous atropine. Sterling (25) found that atropine had no effect on the decrease in specific airway conductance in awake humans breathing 10-12% O2, although the response could be blocked by inhaled
-agonists. This was interpreted to mean that
hypoxia acts directly on bronchial smooth muscle. Strieder
et al. (26), working in intact dogs, found that hypoxemia caused an
increase in lung recoil, which was not blocked by atropine but was
decreased by the antihistamine promethazine, and an increase in lung
resistance, which was prevented by atropine administration. These
authors proposed that hypoxemia causes smooth muscle contraction in the small airways and periphery mediated by local release of histamine. Our
results are also consistent with the hypothesis that systemic hypoxemia
increases Z via a noncholinergic mechanism that primarily affects small
airways and peripheral smooth muscle. In our model there is no
significant cholinergic response and no change in the resistance of the
large airways. There are changes in compliance and Im{Z},
presumably reflecting changes in lung tissue or peripheral smooth
muscle properties similar to those seen by Strieder et al.
Possibly, a technique in which tissue resistance could be separated
from large airway properties would show changes as well.
Unilateral hypoxia.
Unilateral hypoxic ventilation had no effect on respiratory system
input impedance, despite evidence for a brisk HPV response, as
indicated by the decreased CO2
output of the hypoxic lung. One possible explanation for this finding
is that the PAO2 was
not low enough to trigger a response. The limited
data from two dogs
suggest that the PAO2 is in
equilibrium with the . Our
mean PAO2 during hypoxic
ventilation was 58 ± 4.4 Torr. Although it is not as low as the
PAO2 of 25-35 Torr
achieved during hypoxemia, this value is below the
FIO2 of 10-12%
(PO2 = 70-80 Torr)
typically used in hypoxemia studies in which an effect was noted (18,
25, 26). Furthermore, because the average systemic
PO2 was only 110 ± 15 Torr,
further reduction of the
FIO2 to the right lung to
reduce the would have
resulted in hypoxemia in several of the animals. Although it is
difficult to imagine a physiologically relevant situation in which
ventilated alveoli have a PO2 <60
Torr, it is possible that this delivery of
O2 to the alveoli by mixed venous
blood prevented a local hypoxic response.
Another possible explanation for the lack of a response to unilateral
hypoxic ventilation involves the bronchial circulation, which may be
very important in modulating regional lung mechanical responses.
Whereas changes in bronchial blood flow do not appear to directly
affect airway caliber or resistance (2), the bronchial blood flow has
been shown to modulate airway responses through delivery or clearance
of substances that may constrict or relax bronchial smooth muscle (31).
Recently, it was demonstrated that up to 90% of the airway response to
an intravenous injection of methacholine occurs via the bronchial
circulation (32). Decreasing the PO2
of bronchial blood has been shown to trigger HPV in the absence of
alveolar or systemic hypoxia (16), and maintenance of bronchial blood
flow has been shown to decrease ischemia-reperfusion lung injury (19).
Because the bronchial blood flow increases during hypoxia (30), it is
possible that the delivery of this normoxic systemic blood to the
airways prevented the constriction response to hypoxic ventilation.
Further studies of the effects of changing the
O2 concentration of the bronchial blood flow on the lung mechanical response to hypoxemia and regional alveolar hypoxia are necessary to determine the importance of this
interaction.
Another difference between the unilateral hypoxic and hypoxemic
conditions relates to the pulmonary circulation. During unilateral hypoxia there is pulmonary vasoconstriction and shunting of pulmonary blood flow to the nonhypoxic lung, but pulmonary arterial pressures do
not increase very much because of the reserve capacity of the contralateral pulmonary circulation (11). With hypoxemia, however, the
entire pulmonary bed constricts, but because cardiac output is
maintained, pulmonary arterial pressure increases dramatically (15). It
is possible that this constricted and high-pressure perfused state of
the pulmonary vasculature has a mechanical correlate in increased input
impedance. Interdependence between the pulmonary vessels and the
airways may affect airway caliber as pulmonary vascular pressures
increase by mechanical "crowding" within a fixed volume sheath
and/or by causing airway edema and wall thickening (34).
Alternatively, changes in lung mechanics may be due to stiffening of
the vascular tree or alveolar wall with vascular congestion (7).
Alveolar hypocapnia due to pulmonary artery occlusion has been shown to
cause a significant pneumoconstriction, with increased lung resistance
and decreased compliance, such that ventilation is redistributed away
from the hypoperfused region (20, 23). An interaction between hypoxia,
HPV, and hypocapnic constriction may be responsible for some of the
effect seen here. Traystman et al. (27) showed that collateral
resistance, measured with the wedged bronchoscope method, increased
when the distal airways were infused with 5%
O2. This increase was prevented
when 5% CO2 was added to the
infused gas mixture. They speculated that the hypoxic gas caused local
HPV, decreasing CO2 delivery to
the region with resultant local hypocapnia and constriction. We
decreased ventilation to the hypoxic lung to maintain normal
PETCO2 during unilateral
hypoxia and prevent alveolar hypocapnia, which would have prevented
this constrictor response. However, this does not explain the lung
impedance increases during systemic hypoxemia, during which
PACO2 was also normal.
Recently, Venegas et al. (Ref. 29 and personal communication) presented data showing a large increase in lung perfusion heterogeneity during
hypoxia measured using positron imaging. One could speculate that
hypoxemia with continued ventilation resulted in areas of regional
hypoperfusion and regional hypocapnic constriction, but net
CO2 elimination was unchanged,
since the entire cardiac output must still pass through the lungs and
ventilation was maintained. These constricted regions resulted in a
measurable increase in lung impedance, and this response would be
expected to primarily affect the imaginary component. During unilateral
hypoxic ventilation, however, the blood flow could be uniformly shunted
to the other lung, and the regional hypocapnia could be avoided.
Further studies in which perfusion distribution during unilateral
hypoxia vs. hypoxemia is characterized are required to determine
whether this hypothesis is valid.
In summary, we have demonstrated that hypoxemia, but not unilateral
alveolar hypoxic ventilation, causes an increase in respiratory system
input impedance in anesthetized dogs. This finding suggests that
alveolar hypoxia, unlike alveolar hypocapnia (20), has no direct effect
on lung or airway mechanical properties. The response to hypoxemia is
not blocked by prior administration of intravenous atropine and is
characterized primarily by a change in lung compliance, consistent with
previous findings in anesthetized dogs (26). These results are
consistent with the hypothesis that hypoxemia results in an active
increase in peripheral or small airway smooth muscle contraction,
perhaps due to the release of histamine (26) or some other
noncholinergic reflex or mediator.
ACKNOWLEDGEMENTS
The authors thank Rosie Cousins for technical support, Dr. Charles Rohde (Dept. of Biostatistics, Johns Hopkins School of Public Health) for statistical consultation, and Mansheung Fung for assistance with data analysis and computer programming.
FOOTNOTES
Address for reprint requests: B. Simon, Dept. of Anesthesia, Tower 711, Johns Hopkins Hospital, Baltimore, MD 21287-8711.
Received 20 August 1996; accepted in final form 21 March 1997.
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M. Bonora and M. Vizek Lung mechanics and end-expiratory lung volume during hypoxia in rats J Appl Physiol, July 1, 1999; 87(1): 15 - 21. [Abstract] [Full Text] [PDF]
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H. Sakai, M. Fukui, Y. Nakano, K. Endo, T. Hirai, Y. Oku, and M. Mishima Acute response of the lung mechanics of the rabbit to hypoxia J Appl Physiol, January 1, 1999; 86(1): 306 - 312. [Abstract] [Full Text] [PDF]
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