Gas Exchange during Acute Experimental Canine Asthma12 A. R. RUBINFELD,3 P. D. WAGNER,.and J. B. WEST, with the technical assistance of R. C. MATTHEWS
SUMMARY. The inert gas infusion technique was used to recover distributions of ventilation-perfusion ratios in anesthetized dogs during 17 episodes of acute asthma produced experimentally by bronchoprovocation with aerosolized Ascaris suum extract, methacholine, or histamine. Regardless of the agent used, 2 general patterns of ventilation/perfusion maldistribution were observed. During mild attacks of bronchospasm, a broadening of the normal unimodal distribution of ventilationperfusion ratios occurred. During more severe attacks, the ventilation/perfusion distributions were clearly bimodal (with true right-to-left shunt of more than 4 per cent present on only one occasion), suggesting that there are, in general, 2 populations of gas-exchanging units in the lung under these conditions. One population has approximately normal ratios of ventilation to blood flow. T h e second is a population centered on a low ventilation-perfusion ratio (average, 0.14) that can be explained by ventilation of lung units with completely obstructed bronchi via collateral pathways. The postmortem appearances of the lungs and the time course of the gas-exchange abnormalities suggest that the chief cause of the bronchial occlusion responsible for the low ventilation-perfusion units was excessive mucus in the lumen. T h e presence of collateral pathways of ventilation in the canine lung appeared to protect the animals from developing areas of true shunt under these conditions. T h e ventilation/perfusion distributions were similar to those seen in human patients with bronchial asthma.
Introduction U n t i l recently, 2 m a i n approaches have b e e n used to study the abnormalities of p u l m o n a r y gas exchange d u r i n g asthma. Using the RileyCournand (1) analysis, n u m e r o u s studies have confirmed that the arterial h y p o x e m i a in this c o n d i t i o n is caused by a c o m b i n a t i o n of ventilation-blood flow ( \ ^ A / Q ) m i s m a t c h i n g a n d true right-to-left s h u n t (2-7). I n most pa(Received in original form March 22, 1978 and in revised form June 19,1978) 1 Supported by Grants No. HL17731 and HL00111 from the National Institutes of Health and the Parker B. Francis Foundation. 2 Requests for reprints should be addressed to John B. West, M.D., Ph.D., School of Medicine, Department of Medicine M-013, University of California at San Diego, La Jolla, Ca. 92093. 3 Overseas Fellow of the Royal Australasian College of Physicians.
tients the s h u n t fraction is small, b u t u n d e r some circumstances it may exceed 17 p e r cent of the cardiac o u t p u t (2). I n addition, t o p o g r a p h i c studies of p u l m o n a r y ventilation a n d perfusion d u r i n g asthma have also d e m o n s t r a t e d that mald i s t r i b u t i o n of each of these tends to be patchy a n d evanescent (8-10). Each of these approaches is limited in its ability to quantify accurately the degree of V A / Q m i s m a t c h i n g in the lung. T h e Riley-Cournand technique, because of its 3-compartment l u n g model, has the a d v a n t a g e of simplicity, b u t it does n o t provide a detailed p i c t u r e of the d i s t r i b u t i o n of V A / Q w i t h i n the lung. T h e t o p o g r a p h i c approach is limited by the resolution of external c o u n t i n g techniques t h a t average the radioactivity t h r o u g h a given l u n g field. I n d e e d , the r a n g e of V A / Q measured in such studies is less t h a n that which actually exists in the n o r m a l l u n g (11). Recently W a g n e r a n d associates (12, 13) have
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 118, 1978
525
526
RUBINFELD, WAGNER, AND WEST
introduced an inert gas-elimination technique, which has the potential to define more accurately the gas-exchange characteristics of the lung than either of the approaches described previously. Preliminary data from such studies performed in 7 asthmatic subjects have been presented (14). T h e results showed that there were 2 populations of gas-exchanging units present in the lung, one centered around a normal X^A/Q of 1.0, and a second population centered around a low V A / Q between 0.01 and 0.1. True shunting, i.e., V A / Q of zero, was not observed. T h e possible presence of 2 discrete populations of gas-exchanging units is intriguing and requires explanation on an anatomic basis. T h e present study sought to explore these original findings by studying gas exchange in the canine model of experimental asthma and relating these findings to postmortem pathologic changes. T h e advantages of this model are: (1) it has been well characterized (15, 16); (2) the animals are readily available; (3) the animals can be studied on more than one occasion; (4) the animals may have a broader range of induced bronchospasm than is reasonable in human volunteers and (5) the animals can be killed during bronchospasm, permitting immediate examination of the lungs. Materials and Methods Nine healthy mongrel dogs weighing 22 to 30 kg were studied during 17 attacks of induced bronchospasm. Each animal was anesthetized with 30 mg of sodium pentobarbital per kg of body weight given intravenously, paralyzed with 1.5 mg of gallamine per kg of body weight, and intubated with a lowpressure cuff Portex endotracheal tube. Ventilation was maintained with a Harvard pump (Millis, Mass.) so as to maintain a baseline end-tidal Pco 2 of approximately 30 mm Hg (measured with a Perkin-Elmer MGA-1100 mass spectrometer). A sigh to a transpulmonary pressure (Ptp) of 20 cm H 2 0 was given every 15 min. Transpulmonary pressure was measured with a Sanborn 267B differential transducer; one side was attached to a balloon catheter placed at mid-esophageal level; the other side, to a multi-side-holed catheter introduced via the endotracheal tube, just proximal to the main carina. Airflow was measured with a no. 2 Fleisch pneumotachograph and a Statham PM15 differential transducer. Tidal volume was recorded as the electronically integrated flow signal. All signals were recorded on a Brush multichannel recorder (Gould Instruments, Ohio). Airflow resistance was calculated by measuring Ptp, subtracting the elastic component of this pressure, and dividing by the instantaneous flow (17). The results reported are the mean values
of estimates made during 8 to 10 consecutive breaths at an inspiratory flow of 0.25 liter per sec. When required, functional residual capacity (FRC) was measured by a closed-circuit helium (He) technique. The animal was separated from the respirator, and at the end-expiratory lung volume, a 1,830-ml syringe filled with a H e - 0 2 mixture was connected to the endotracheal tube. Syringe ventilation was maintained until fluctuations in He concentration were less than 1 per cent of the initial value. The He concentration was measured with the mass spectrometer and was recorded on a Brush recorder. The formula used for calculation of FRC was as follows: FRC = [(1,830 X initial He)/ final He] - 1,830 ml. The FRC was measured in triplicate, and results were accepted only if they agreed within 5 per cent. Blood samples were taken, and vascular pressures were measured through a large-bore femoral artery cannula and a no. 7 Swan-Ganz double-lumen catheter (Edwards Labs, Ca.) inserted into the-pulmonary artery. Vascular pressures were measured with BiotecBT70 (Pasadena, Ca.) and Statham P23BB (Oxnard, Ca.) pressure transducers. Blood pH, Po 2 , and Pco 2 were measured with Radiometer BMS3, Mk 2 (Copenhagen) electrodes. The bronchial challenge procedures entailed a 60sec administration of either aerosolized 0.1 or 0.5 per cent methacholine hydrochloride (Sigma), 1 or 2 per cent histamine diphosphate (Sigma), or Ascaris suum extract (Greer Labs, N. C.) in dilutions between 1:1,000 and 1:10 (weight/vol). Aerosols were delivered via a Bird Mark VII (Palm Springs, Ca.) respirator and micronebulizer. In some experiments, 0.5 per cent isoproterenol aerosol (Winthrop) was delivered for 60 sec using the same respirator circuit. The challenges administered to each animal are shown in table 1. Duplicate samples for inert gas studies were collected at the height of the attacks, which occurred approximately 10 min after chal-
TABLE1 BRONCHOPROVOCATION A N D S E V E R I T Y OF RESULTING ATTACKS OF A S T H M A FOR EACH A N I M A L TESTED Ascaris Dog
Mild
1 2 3
2 1 1
5 6 7 8 9
*
Severe
Methacholine Mild
Severe
Histamine Mild
Severe
1 2 1
*
1*
*
1 1
1 1* 1 1*
Shunt developed after provocation (see text for further discussion).
527
GAS EXCHANGE IN EXPERIMENTAL ASTHMA
lenge with Ascaris and approximately 3 to 6 min after challenge with methacholine and histamine. Resumption of a steady state of gas exchange after the challenge was checked by measuring end-tidal Po 2 and Pco 2 , breath-by-breath, with the mass spectrometer and by monitoring Ptp, heart rate, pulmonary arterial pressure, and systemic blood pressure. T h e inert gas technique, used to recover distributions of V A / Q , has been described in detail elsewhere (12, 13). In brief, 6 inert gases (sulfahexafluoride [SFJ, ethane, cyclopropane, halo thane, ether, and acetone) were dissolved in isotonic saline, which was infused into a peripheral vein at a rate of 2.4 ml per min with a Harvard infusion pump. After a 30-min equilibration period, simultaneous 5- to 10ml samples of arterial and mixed venous blood and mixed expired gas were collected. These were analyzed for their inert gas contents by chromatography (18), and a retention value (ratio of mixed arterial to mixed venous partial pressure) and an excretion value (ratio of mixed expired to mixed venous partial pressure) were calculated for each gas. From these data and from minute ventilation, cardiac output was derived using the Fick principle. Retention and excretion data were processed by a digital computer to yield representative distributions of V A / £ ) (12,13). Such distributions are obtained by least-squares best-fit analysis using a 50-compartment lung model. The number of compartments used is large enough to approximate numerically a continuous curve, but is otherwise unimportant. T h e least-squares best fit is performed by a standard quadratic programming technique known as ridge regression (19). This approach involves enforced smoothing of sufficient magnitude that when random experimental error is added to the data several times, the resulting recovered distributions do not differ significantly from one another. T h e proper interpretation of these distributions requires an additional analysis that explores the variability of distributions that are compatible with the measured set of data (19). Several sets of the data in this study were subjected to this analysis.
d a n d e r extracts of 3 animals n o t bronchoreactive to t h e antigens p r o d u c e d n o a l t e r a t i o n in the V A / Q distributions originally recovered. Similarly, arterial P o 2 (Pao 2 ), arterial P c o 2 (Pacc>2)> airflow resistance, a n d h e m o d y n a m i c variables r e m a i n e d u n c h a n g e d . Mild asthma. I n k e e p i n g with c u r r e n t usage, we will refer to the bronchospasm that followed aerosol challenges as asthma; however, we are aware that differences exist between this a n i m a l model of the disease a n d h u m a n asthma (20). Seven attacks of bronchospasm were induced with either relatively d i l u t e Ascaris extracts ( 1 : 1,000 or 1:100, weight/vol), 0.1 p e r cent methacholine, or 1 p e r cent h i s t a m i n e (table 1). T h e s e attacks were accompanied by only modest changes in airflow resistance a n d P a o 2 (table 2). T y p i cal examples of recovered distributions of V A / Q are shown in figure 2 for each agent at the height of the attacks. T h e m a i n features of these distributions were c o m m o n to each p r o v o k i n g agent used. I n each case, the previously narrow u n i m o d a l distributions of V A / Q became broader, w i t h o u t developing 2 clear-cut modes, alt h o u g h there was sometimes a t r e n d toward bimodality, as shown in figure 2b. S h u n t d i d n o t develop. T h e broadness of the distributions indicates that significantly m o r e blood flow t h a n n o r m a l was associated with areas of low V A / Q , a n d this accounted for the degree of h y p o x e m i a seen u n d e r these circumstances.
§
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o | ^*-J Results Control experiments. A representative distribution of V A / Q in o n e d o g u n d e r baseline conditions is illustrated in figure 1. B o t h ventilation a n d blood flow are p l o t t e d against V A / Q o n a log scale. T h e d i s t r i b u t i o n of each is n a r r o w a n d u n i m o d a l , i.e., p u l m o n a r y blood flow is dist r i b u t e d to l u n g units w i t h V A / Q r a n g i n g from a p p r o x i m a t e l y 0.25 to 2.0 a n d centered a r o u n d a V A / Q of 0.85. T h e r e is n o s h u n t ( V A / Q = zero). T h e s e results are similar to those r e p o r t e d earlier in n o r m a l anesthetized dogs (13). Provocation with aerosolized Ascaris
or cat
Z
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_
0.2
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/
y,
,
,
J
L
p-
-f
1
0 0.01 0.1 1.0 10.0 100.0 \/ENTILATION / PE RF USION RATIO
Fig. 1. Distributions of ventilation and blood flow versus the ratio of ventilation to perfusion ( V A / Q ) in a normal dog under baseline conditions. The distribution of each is narrow and unimodal. The range of V A / Q is from 0.25 to 2.0.
528
RUBINFELD, WAGNER, AND WEST
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SUMMARY. The inert gas infusion technique was used to recover distributions of ventilation-perfusion ratios in anesthetized dogs during 17 episodes of acute asthma produced experimentally by bronchoprovocation with aerosolized Ascaris suum extract, methacholine, or histamine. Regardless of the agent used, 2 general patterns of ventilation/perfusion maldistribution were observed. During mild attacks of bronchospasm, a broadening of the normal unimodal distribution of ventilationperfusion ratios occurred. During more severe attacks, the ventilation/perfusion distributions were clearly bimodal (with true right-to-left shunt of more than 4 per cent present on only one occasion), suggesting that there are, in general, 2 populations of gas-exchanging units in the lung under these conditions. One population has approximately normal ratios of ventilation to blood flow. T h e second is a population centered on a low ventilation-perfusion ratio (average, 0.14) that can be explained by ventilation of lung units with completely obstructed bronchi via collateral pathways. The postmortem appearances of the lungs and the time course of the gas-exchange abnormalities suggest that the chief cause of the bronchial occlusion responsible for the low ventilation-perfusion units was excessive mucus in the lumen. T h e presence of collateral pathways of ventilation in the canine lung appeared to protect the animals from developing areas of true shunt under these conditions. T h e ventilation/perfusion distributions were similar to those seen in human patients with bronchial asthma.
Introduction U n t i l recently, 2 m a i n approaches have b e e n used to study the abnormalities of p u l m o n a r y gas exchange d u r i n g asthma. Using the RileyCournand (1) analysis, n u m e r o u s studies have confirmed that the arterial h y p o x e m i a in this c o n d i t i o n is caused by a c o m b i n a t i o n of ventilation-blood flow ( \ ^ A / Q ) m i s m a t c h i n g a n d true right-to-left s h u n t (2-7). I n most pa(Received in original form March 22, 1978 and in revised form June 19,1978) 1 Supported by Grants No. HL17731 and HL00111 from the National Institutes of Health and the Parker B. Francis Foundation. 2 Requests for reprints should be addressed to John B. West, M.D., Ph.D., School of Medicine, Department of Medicine M-013, University of California at San Diego, La Jolla, Ca. 92093. 3 Overseas Fellow of the Royal Australasian College of Physicians.
tients the s h u n t fraction is small, b u t u n d e r some circumstances it may exceed 17 p e r cent of the cardiac o u t p u t (2). I n addition, t o p o g r a p h i c studies of p u l m o n a r y ventilation a n d perfusion d u r i n g asthma have also d e m o n s t r a t e d that mald i s t r i b u t i o n of each of these tends to be patchy a n d evanescent (8-10). Each of these approaches is limited in its ability to quantify accurately the degree of V A / Q m i s m a t c h i n g in the lung. T h e Riley-Cournand technique, because of its 3-compartment l u n g model, has the a d v a n t a g e of simplicity, b u t it does n o t provide a detailed p i c t u r e of the d i s t r i b u t i o n of V A / Q w i t h i n the lung. T h e t o p o g r a p h i c approach is limited by the resolution of external c o u n t i n g techniques t h a t average the radioactivity t h r o u g h a given l u n g field. I n d e e d , the r a n g e of V A / Q measured in such studies is less t h a n that which actually exists in the n o r m a l l u n g (11). Recently W a g n e r a n d associates (12, 13) have
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 118, 1978
525
526
RUBINFELD, WAGNER, AND WEST
introduced an inert gas-elimination technique, which has the potential to define more accurately the gas-exchange characteristics of the lung than either of the approaches described previously. Preliminary data from such studies performed in 7 asthmatic subjects have been presented (14). T h e results showed that there were 2 populations of gas-exchanging units present in the lung, one centered around a normal X^A/Q of 1.0, and a second population centered around a low V A / Q between 0.01 and 0.1. True shunting, i.e., V A / Q of zero, was not observed. T h e possible presence of 2 discrete populations of gas-exchanging units is intriguing and requires explanation on an anatomic basis. T h e present study sought to explore these original findings by studying gas exchange in the canine model of experimental asthma and relating these findings to postmortem pathologic changes. T h e advantages of this model are: (1) it has been well characterized (15, 16); (2) the animals are readily available; (3) the animals can be studied on more than one occasion; (4) the animals may have a broader range of induced bronchospasm than is reasonable in human volunteers and (5) the animals can be killed during bronchospasm, permitting immediate examination of the lungs. Materials and Methods Nine healthy mongrel dogs weighing 22 to 30 kg were studied during 17 attacks of induced bronchospasm. Each animal was anesthetized with 30 mg of sodium pentobarbital per kg of body weight given intravenously, paralyzed with 1.5 mg of gallamine per kg of body weight, and intubated with a lowpressure cuff Portex endotracheal tube. Ventilation was maintained with a Harvard pump (Millis, Mass.) so as to maintain a baseline end-tidal Pco 2 of approximately 30 mm Hg (measured with a Perkin-Elmer MGA-1100 mass spectrometer). A sigh to a transpulmonary pressure (Ptp) of 20 cm H 2 0 was given every 15 min. Transpulmonary pressure was measured with a Sanborn 267B differential transducer; one side was attached to a balloon catheter placed at mid-esophageal level; the other side, to a multi-side-holed catheter introduced via the endotracheal tube, just proximal to the main carina. Airflow was measured with a no. 2 Fleisch pneumotachograph and a Statham PM15 differential transducer. Tidal volume was recorded as the electronically integrated flow signal. All signals were recorded on a Brush multichannel recorder (Gould Instruments, Ohio). Airflow resistance was calculated by measuring Ptp, subtracting the elastic component of this pressure, and dividing by the instantaneous flow (17). The results reported are the mean values
of estimates made during 8 to 10 consecutive breaths at an inspiratory flow of 0.25 liter per sec. When required, functional residual capacity (FRC) was measured by a closed-circuit helium (He) technique. The animal was separated from the respirator, and at the end-expiratory lung volume, a 1,830-ml syringe filled with a H e - 0 2 mixture was connected to the endotracheal tube. Syringe ventilation was maintained until fluctuations in He concentration were less than 1 per cent of the initial value. The He concentration was measured with the mass spectrometer and was recorded on a Brush recorder. The formula used for calculation of FRC was as follows: FRC = [(1,830 X initial He)/ final He] - 1,830 ml. The FRC was measured in triplicate, and results were accepted only if they agreed within 5 per cent. Blood samples were taken, and vascular pressures were measured through a large-bore femoral artery cannula and a no. 7 Swan-Ganz double-lumen catheter (Edwards Labs, Ca.) inserted into the-pulmonary artery. Vascular pressures were measured with BiotecBT70 (Pasadena, Ca.) and Statham P23BB (Oxnard, Ca.) pressure transducers. Blood pH, Po 2 , and Pco 2 were measured with Radiometer BMS3, Mk 2 (Copenhagen) electrodes. The bronchial challenge procedures entailed a 60sec administration of either aerosolized 0.1 or 0.5 per cent methacholine hydrochloride (Sigma), 1 or 2 per cent histamine diphosphate (Sigma), or Ascaris suum extract (Greer Labs, N. C.) in dilutions between 1:1,000 and 1:10 (weight/vol). Aerosols were delivered via a Bird Mark VII (Palm Springs, Ca.) respirator and micronebulizer. In some experiments, 0.5 per cent isoproterenol aerosol (Winthrop) was delivered for 60 sec using the same respirator circuit. The challenges administered to each animal are shown in table 1. Duplicate samples for inert gas studies were collected at the height of the attacks, which occurred approximately 10 min after chal-
TABLE1 BRONCHOPROVOCATION A N D S E V E R I T Y OF RESULTING ATTACKS OF A S T H M A FOR EACH A N I M A L TESTED Ascaris Dog
Mild
1 2 3
2 1 1
5 6 7 8 9
*
Severe
Methacholine Mild
Severe
Histamine Mild
Severe
1 2 1
*
1*
*
1 1
1 1* 1 1*
Shunt developed after provocation (see text for further discussion).
527
GAS EXCHANGE IN EXPERIMENTAL ASTHMA
lenge with Ascaris and approximately 3 to 6 min after challenge with methacholine and histamine. Resumption of a steady state of gas exchange after the challenge was checked by measuring end-tidal Po 2 and Pco 2 , breath-by-breath, with the mass spectrometer and by monitoring Ptp, heart rate, pulmonary arterial pressure, and systemic blood pressure. T h e inert gas technique, used to recover distributions of V A / Q , has been described in detail elsewhere (12, 13). In brief, 6 inert gases (sulfahexafluoride [SFJ, ethane, cyclopropane, halo thane, ether, and acetone) were dissolved in isotonic saline, which was infused into a peripheral vein at a rate of 2.4 ml per min with a Harvard infusion pump. After a 30-min equilibration period, simultaneous 5- to 10ml samples of arterial and mixed venous blood and mixed expired gas were collected. These were analyzed for their inert gas contents by chromatography (18), and a retention value (ratio of mixed arterial to mixed venous partial pressure) and an excretion value (ratio of mixed expired to mixed venous partial pressure) were calculated for each gas. From these data and from minute ventilation, cardiac output was derived using the Fick principle. Retention and excretion data were processed by a digital computer to yield representative distributions of V A / £ ) (12,13). Such distributions are obtained by least-squares best-fit analysis using a 50-compartment lung model. The number of compartments used is large enough to approximate numerically a continuous curve, but is otherwise unimportant. T h e least-squares best fit is performed by a standard quadratic programming technique known as ridge regression (19). This approach involves enforced smoothing of sufficient magnitude that when random experimental error is added to the data several times, the resulting recovered distributions do not differ significantly from one another. T h e proper interpretation of these distributions requires an additional analysis that explores the variability of distributions that are compatible with the measured set of data (19). Several sets of the data in this study were subjected to this analysis.
d a n d e r extracts of 3 animals n o t bronchoreactive to t h e antigens p r o d u c e d n o a l t e r a t i o n in the V A / Q distributions originally recovered. Similarly, arterial P o 2 (Pao 2 ), arterial P c o 2 (Pacc>2)> airflow resistance, a n d h e m o d y n a m i c variables r e m a i n e d u n c h a n g e d . Mild asthma. I n k e e p i n g with c u r r e n t usage, we will refer to the bronchospasm that followed aerosol challenges as asthma; however, we are aware that differences exist between this a n i m a l model of the disease a n d h u m a n asthma (20). Seven attacks of bronchospasm were induced with either relatively d i l u t e Ascaris extracts ( 1 : 1,000 or 1:100, weight/vol), 0.1 p e r cent methacholine, or 1 p e r cent h i s t a m i n e (table 1). T h e s e attacks were accompanied by only modest changes in airflow resistance a n d P a o 2 (table 2). T y p i cal examples of recovered distributions of V A / Q are shown in figure 2 for each agent at the height of the attacks. T h e m a i n features of these distributions were c o m m o n to each p r o v o k i n g agent used. I n each case, the previously narrow u n i m o d a l distributions of V A / Q became broader, w i t h o u t developing 2 clear-cut modes, alt h o u g h there was sometimes a t r e n d toward bimodality, as shown in figure 2b. S h u n t d i d n o t develop. T h e broadness of the distributions indicates that significantly m o r e blood flow t h a n n o r m a l was associated with areas of low V A / Q , a n d this accounted for the degree of h y p o x e m i a seen u n d e r these circumstances.
§
1.0 r
o -J LL
Q O O
a\
BASELINE
0.8
'
f
IA J
_i
Ifl
Scae
o | ^*-J Results Control experiments. A representative distribution of V A / Q in o n e d o g u n d e r baseline conditions is illustrated in figure 1. B o t h ventilation a n d blood flow are p l o t t e d against V A / Q o n a log scale. T h e d i s t r i b u t i o n of each is n a r r o w a n d u n i m o d a l , i.e., p u l m o n a r y blood flow is dist r i b u t e d to l u n g units w i t h V A / Q r a n g i n g from a p p r o x i m a t e l y 0.25 to 2.0 a n d centered a r o u n d a V A / Q of 0.85. T h e r e is n o s h u n t ( V A / Q = zero). T h e s e results are similar to those r e p o r t e d earlier in n o r m a l anesthetized dogs (13). Provocation with aerosolized Ascaris
or cat
Z
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_
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"
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/
y,
,
,
J
L
p-
-f
1
0 0.01 0.1 1.0 10.0 100.0 \/ENTILATION / PE RF USION RATIO
Fig. 1. Distributions of ventilation and blood flow versus the ratio of ventilation to perfusion ( V A / Q ) in a normal dog under baseline conditions. The distribution of each is narrow and unimodal. The range of V A / Q is from 0.25 to 2.0.
528
RUBINFELD, WAGNER, AND WEST
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