Gas Exchange in the Pulmonary Collateral Circulation of Dogs Effects of Alveolar Hypoxia and Systemic Hypoxemia 1 - 3
E. S. LILKER and E. J. NAGY
SUMMARY __________________________________________________________ The left main pulmonary artery was ligated in 7 fully grown dogs. This resulted in an enlarged pulmonary collateral (systemic) flow to the left lung. By collecting gas from each lung separately, gas exchange in the pulmonary collateral circulation was studied and compared to that in the normal contralateral side. Studies were done repeatedly during a period of 3 years. Compared to that in the preoperative period, the ligated (left) side showed a decrease in ventilation (42.5 to 34.5 per cent of total), a marked increase in wasted ventilation (0.30 to 0.55), and a marked decrease in 0 2 uptake (45 to 1!.2 per cent of total) and C0 2 production (27.5 to 15.3 per cent of the total). There were no changes in arterial blood gases or pH. A significant, sustained, systemic hypertension was noted in all dogs in which the left main pulmonary artery was ligated (190 /120). The mean blood flow through the pulmonary collateral circulation of the left lung with the dogs breathing room air was estimated to be 94 ml per min. When the dogs were made hypoxemic by breathing 12 per cent 0 2 through the normal right lung, there was a marked increase in pulmonary collateral (systemic) flow to the contralateral side (194 ml per min). This resulted in an increase in 0 2 consumption (29.4 per cent of total) and C0 2 production (23.1 per cent of total) of the left lung. When the dogs were given 12 per cent Ory to breathe through the ligated left lung, there was no change in arterial Po 2 . There was a significant increase in blood flow through the pulmonary collateral circulation to 136 ml per min. Because of the gradient of 0 2 between the blood flowing into the left lung and that present in the alveoli, there was a net production of 0 2 from the left lung of 4.5 ml per min. When the pulmonary systemic circulation participates in gas exchange, it appears to increase during hypoxemia as well as during alveolar hypoxia.
Introduction
The contribution of the pulmonary collateral (systemic) circulation (PCC) to gas exchange in normal persons is negligible; however, it may become important in patients with conditions that occlude pulmonary arteries, such as (Received in original form December 26, 1974 and in revised form May 29, 1975) l From the Department of Medicine and the Respiratory Unit, St. Josephs' Hospital, University of Toronto, Toronto, Ontario, Canada. 2 Supported by the Ontario Thoracic Society and St. Josephs' Hospital Research Foundation.
congenital heart disease, pulmonary emboli, and certain chronic inflammations, such as tuberculosis and bronchiectasis (l-3). The vasomotor response of the pulmonary circulation to alveolar hypoxia and hypoxemia is now well established (4-1 0), but there are no data available on the reactivity of PCC to similar stimuli. This study was undertaken to study how the PCC (systemic circulation) responds to hypoxemia and alveolar hypoxia. The PCC increases when the pulmonary ar2 Requests for reprints should be addressed to Dr. E. S. Ulker, Suite 607, 170 St. George St., Toronto, Ontario, Canada.
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tery is ligated. We used this model in dogs to produce an enlarged PCC in the left lung only. The pulmonary systemic circulation is normally probably less than I per cent of total cardiac output in humans (1); measuring changes accurately is difficult, because the sensitivity of the methods is less than the oscillations of cardiac output (11 ). One of the advantages of the present model is a greater ratio of signal to noise because of the expansion of the systemic circulation. Another advantage is that the contralateral lung serves as the control lung during experiments. We have shown that the PCC is capable of gas exchange, with the respiratory quotient greater than that via the pulmonary circulation. Whereas the pulmonary circulation constricts in response to alveolar hypoxia, the systemic circulation dilates. During hypoxemia, there is a marked increase in PCC flow. Materials and Methods We produced permanent intrapericardial left pulmonary arteryligation in 7 fully grown dogs (mean weight: 30 ± 8 kg). Special care was taken to preserve all nerves, lymphatics, and vessel structures in the operated lungs. The physiologic studies were started 3 to 6 months postoperatively. Angiograms were done to confirm the occlusion of the left pulmonary artery from 6 to 12 months after surgery. Before each experiment, the dogs were anesthetized; anesthesia was maintained with 2 per cent pentobarbital. A tracheal divider (modified Benfield) was introduced into the airways. Correct placement and presence of leaks were checked by ventilating one lung with 10 per cent helium and 90 per cent 0 2, and monitoring the expired gas from the contralateral lung. The same procedure was repeated at the end of each experiment. An arterial cannula was placed in the femoral artery. The dogs were breathing spontaneously while end·tidal C0 2 concentrations were continuously monitored using an LB·I Beckman Analyzer and recorded on a Grass multichannel .recorder. The expired gas from each lung was collected separately using Douglas bags. Concentrations of 0 2 and C0 2 in the bags were measured using a microScholander apparatus. Arterial pH, arterial Po 2 (Pao 2) and arterial Pco 2 (Paco 2 ) were measured by an Instrumentation Laboratories microelectrode system. Minute ventilation CVE) was measured by passing the total expired gas collected through a wet gas meter (Precision Scientific Co., Chicago, III.) and dividing by time. The dogs were studied under 3 different experimental conditions: both lungs inhaling room air; right lung inhaling 12 per cent 0 2 and 88 per cent N2 • and left lung inhaling room air; right lung in-
haling room air, and left lung inhaling 12 per cent 0 2 and 88 per cent N 2 . All experiments were done in a steady state, which was defined as stable end-tidal Pco 2 , pulse rate, and blood pressure for I min. Douglas bags were flushed for approximately 15 min with expired gas before collection, which was subsequently continued for 10 min. Arterial blood for measurement of pH, Pao 2 • and Paco 2 was collected in duplicate samples during gas collection. Blood pressure was recorded by a Statham arterial pressure transducer attached to the arterial cannula and was recorded on the Grass polygraph. · From the data collected, we calculated VE, tidal v?lume (Vr), 0 2 uptake ('Vo 2 ), C0 2 output (Vco 2 ), and wasted ventilation (Vn) by the standard Bohr equation, and alveolar Po2 (PAo 2 ) for each lung separately. Blood flow through the left lung (systemic circulation) was estimated by the Fick principle, using C0 2 as the indicator gas, using the foll~wing expression: QL = Vco 2 jCaco2 - Ccco 2, where QL =left lung perfusion in liter per min; Vco 2 = C0 2 output of the left lung; Caco 2 =arterial C0 2 content, calculated from Paco 2 and pH using the C0 2 dissociation curve by the Severinghaus slide rule; Ccco 2 = end-capillary C0 2 content, calculated from the C0 2 dissociation curve using end-tidal Pco 2 and assuming pH to be the same as arterial pH. All experiments were done in duplicate on different days. With the exception of QL, all measurements were also obtained in 4 of the dogs I to 6 weeks before surgery. All results were evaluated by a paired t test (12), because the dogs served as their own contro!"subjects. Results The effects of permanent ligation of the left main pulmonary artery on arterial blood gases, arterial blood pressure, and gas exchange of the left lung are shown in table l. All studies were performed in a steady state with both lungs inhaling room air. There were no changes in arterial blood gases. The systolic and diastolic blood pressures were significantly increased postoperatively. The left lung showed a decreased, but measurable, gas exchange, although there was more C0 2 excretion than 0 2 uptake. The VofVr was markedly increased, and VE, expressed as a percentage of the total, was significantly decreased, indicating a shift of ventilation to the contralateral lung. The mean ± SD values shown in table 1 were calculated by using data for all of the dogs and experiments indicated. For statistical analysis of the data in table 1, a paired t test was used to compare the values obtained in the 4 dc.gs studied before surgery to the values obtained in these dogs after surgery.
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TABLE 1 EFFECTS OF PERMANENT LIGATION OF THE LEFT MAIN PULMONARY ARTERY ON ARTERIAL BLOOD GASES, BLOOD PRESSURE, AND GAS EXCHANGE IN DOGS* Before Surgery No. of dogs No. of experiments VE, left lung as% total VD/VT, left lung Vo2, left lung as% total VC02, left lung as% total PAo 2 (left lung). mm Hg Arterial pH, units Pao 2 , mm Hg Paco 2 • mm Hg Arterial blood pressure, mm Hg Systolic Diastolic
4 8 42.5 ± 10 0.30±0.16 45 ± 6.2 37.5 ± 4.9 93.5 ± 12.8 7.29 ± 0.05 73 ±8.3 37.5 ±5.5 145 ± 15 85 ± 35
After Surgery 7 18 34 ± 5.6t 0.55 ±0.18t 11.2 ± 3.1t 15.3±2.1t 130 ± 7.9t 7.30 ± 0.04 70 ± 4.6 38 ±5.3 190 ± 32t 120±31t
• Data were obtained while both lungs were breathing room air, before and at least 6 months after left main pulmonary artery ligation. All data are expressed as mean± SD. tp < 0.05 compared to preoperative value.
Gas exchange and blood flow (QL) through the left lung (systemic) during 3 experimental situations are summarized in table. 2 In the control experiment, both lungs inspired room air. When the. dogs were made hypoxemic by inhaling 12 per cent 0 2 and 88 per cent N 2 through the normal right lung, and room air through the left lung, there was a marked decrease in Pao 2, as well as a slight decrease in Paco 2 and arterial pH. Although there was a decrease in total Vo2 , the absoiute amount of Vo 2 by the left lung actually increased. There was also an absolute increase in the amount of C0 2 produced through the left lung. The calculated QL of the left lung was markedly increased compared to the control lung. No significant change in blood pressure or heart rate was noted. When the left lung inhaled a hypoxic mixture of 12 per cent 0 2 and 88 per cent N 2 , and the right lung, room air, there were no definite changes in arterial blood gases. The only questionable change was an increase in Pao 2 . The total oxygen consumption of the dogs actually decreased, probably because 0 2 was actually excreted through the left lung, because the inflowing Pao 2 was higher than P Ao 2 • Despite these changes, there was an estimated increase in QL compared to the control value. No changes in heart rate or blood pressure were noted. When the dogs were studied repeatedly during a period of 3 years, there was no consistent change in any of the parameters of lung func-
tion or blood flow. Several dogs tended to show a decrease in QL with age. Discussion
The tracheal divider may result in a slight interference with the shift of ventilation away from the underperfused areas of the lung (12). This probably had no significance in our studies, because it has been shown that even I per cent C0 2 can block a shift in ventilation. In all of our experiments, there was more than I per cent C0 2 in both right and left lungs. All of the data presented for these dogs were obtained under the same anesthetic conditions and with pentobarbital. We have subsequently performed 2 complete experiments (under all 3 sets of conditions) using pentobarbital and one complete experiment using chloralose and were unable to note any differences in the ventilation, gas exchange, or cardiovascular data. The use of C0 2 to calculate blood flow through the PCC by the Fick principle has been described previously (1). Because the C0 2 produced by the left lung was only from the systemic circulation, the Vco 2 in the expression is valid and truly reflects systemic blood flow. Because the blood flowing into the left lung is systemic, we assumed that sampling more distally in the femoral artery would not be significantly different from sampling at the arch of the aorta, where the PCC originates. The major problem in using the Fick equation as described is finding the most reliable way of calculating Ccco 2 . When we as-
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TABLE 2 GAS EXCHANGE AND BLOOD FLOW DATA (MEAN± SD) OBTAINED UNDER 3 SETS OF EXPERIMENTAL CONDITIONS IN DOGS 6 MONTHS TO 3 YEARS AFTER LIGATION OF THE LEFT MAIN PULMONARY ARTERY Both Lungs Breathing Room Air (Control Experiment) No. of dogs No. of experiments VE, left lung as% total VD/VT,Jeft lung V02, left lung, ml/min V02, left lung as% total VC02, left lung, ml/min VC02, left lung as% total PAo 2 • left lung, mm Hg V02, right and left lung, ml/min Arterial pH, units Pa 02 , mm Hg ~ac 02 , mm Hg OL, ml/min Arterial blood pressure, mm Hg Systolic ·Diastolic Heart rate, beats/min •p
< 0.05
7
Right Lung Breathing 12 % 02, 88% N2; Left Lung, Room Air
6 15 38.5 ± 7.6 0.54 ±0.14 30 ±6* 29.4* 36 ± 7* 23.1
18 34.5 ±5.6 0.55 ±0.18 20 ±8 11.2 28 ±9 15.3 130 ± 7.9 180 7.30 ± 0.04 70 ± 4.6 38 ±5.3 94 ±34
132 ± 5.8 102* 7.25 ±0.08* 49 5.6*. 31.5±5.1* 194 ±96*
190 ± 32 120 ± 31 134 ±48
200 ±39 126 ± 36 141 ±52
±
Right Lung Breathing Room Air; Left Lung, 12% 02,88% N2
6 12 36.2 ± 6.1 0.54 ±0.14 -4.5 ± 2* -3.95* 32.9 ± 2* 15.1 60 ± 20* 160.5* 7.28 ±0.06 79 ± 8.3 38.5 ± 6.7 136±41* 194 ± 30 124 ± 30 136 ± 21
compared to control value.
sumed end-tidal Pco2 to equal end-capillary Pco2 , we had to assume that wasted ventilation was negligible. This was not so; in fact, wasted ventilation in the left lung was very large. This "dilution" effect by the large wasted ventilation of the left lung results in an underesti· mation of the true end-capillary Pco 2 • A higher end-capillary Pco 2 results in a large C0 2 content and thus, a higher QL. Thus, we probably considerably underestimated QL. There have been many studies showing the anatomic and physiologic consequences of chronic pulmonary artery occlusion in dogs and man (I, 7, 13). We confirm the findings of others and have shown that during a steady-state determination, there is measurable gas exchange through the expanded PCC. The higher respiratory quotient through the PCC compared to the pulmonary circulation preoperatively was probably chiefly due to the fact that there was less C0 2 in the alveolus sup· plied by .the PCC, and thus there was a higher driving pressure (alveolar-arterial Pco 2 difference). The low oxygen uptake by the PCC is chiefly a function of the small pressure gradient of 0 2 between the inflowing blood (systemic arterial) and the alveolus. The increase seen in systemic arterial blood pressure after pulmonary artery ligation has not been described previous-
ly. This increase in blood pressure was first noted 3 to 6 months postoperatively .and persisted in all dogs for the entire 3 years of the study. The mechanism of the hypertension is currently being investigated. When we produced hypoxemia by ventilating the normal right lung (pulmonary circulation) with a hypoxic mixture, Vo 2 and Vco2 of that lung decreased. This indicates vasoconstriction of the pulmonary circulation and has been described previously (4-IO). Vo 2 and Vco 2 increased through the PCC and the estimated QL increased. This increased flow through the systemic circulation of the lung could not be due to a passive shift of blood flow away from the hypoxic lung, because the two. circulations are in series. Thus, it must mean that there was vasodilatation of the systemic blood vessels in the lung. The systemic arterial anoxia could result in increased Vo 2 through the PCC merely by increasing the driving pressure for 0 2 between the alveolus and the inflowing systemic blood. This, however, would not account for the increase in Vco 2, which must reflect increased perfusion. Because there was no consistent change in arterial blood pressure during hypoxemia, it is unlikely that the increased PCC flow was partly
GAS EXCHANGE IN PULMONARY COLLATERAL CIRCULATION OF DOGS
due to this increase in pressure in the aorta. This mechanism has been described previously as an important factor in the regulation of the pulmo· nary collateral blood flow in dogs (14). The effect of alveolar hypoxia on PCC had not been studied previously. \'\fe have shown that alveolar hypoxia of the left lung results in an increase in estimated QL. The two known physiologic methods of increasing PCC are by increasing systemic blood pressure and by inducing hypoxemia. Because there was no change in arterial blood pressure, this could not have been a method of changing the QL. The Pao 2 was not significantly changed. The gradient of 0 2 from the alveolus and the infiowing arterial blood was actually reversed, resulting in 0 2 production through the left lung (PCC). The increase in QL thus must have been due to a direct vasadilating effect of the alveolar hypoxia. Unilateral breathing of hypoxic mixtures appears to constrict the pulmonary arterioles and to dilate PCC. This study further supports the view that the anatomic site of hypoxic pulmonary artery constriction is probably the pulmonary arteriole, rather than the pulmonary vein or capillary. Thus, as special care was taken to preserve all nerves and lymphatics of the left lung during surgery, and assuming that the only difference between two lungs was the precapillary arterial supply, the difference in response to alveolar hypoxia in the left and right lungs must reflect the type of blood vessel supplying the alveoli. The decrease in total 0 2 uptake when the dogs were inhaling a hypoxic mixture through the PCC was probably due to the fact that the difference between alveolus and inflowing blood was reversed; thus, there was a net production of 0 2 from the left lung. The very marked decrease in total 0 2 consumption when the dogs were inhaling a hypoxic mixture through the normal pulmonary circulation is difficult to explain. It may be due to vasoconstriction (which is known to occur to a certain extent) sufficient to decrease the diffusing capacity for 0 2 and, thus, to limit Vo 2 . It might also have been partly due to a mechanical problem, in that we used expired, rather than inspired, volumes to calculate Vo 2 • It is known that the inspired volume does not always equal the expired volume. This might have led to considerable underestimation of the Vo 2 of the pulmonary circulation. The clinical relevance of this model is complicated by the fact that these dogs all developed systemic arterial hypertension. It is not known
619
whether hypertensive systemic vessels (PCC) respond to ·hypoxia and hypoxemia in the same way that nonhypertensive vessels respond. In disease states, portions of lung may derive their blood supply at the gas exchange level through the systemic circulation (PCC). If P Ao 2 were decreased in these areas, such as might occur in airway obstruction, the vascular supply might actually increase (vasodilatation in response to alveolar hypoxia). This would be opposite to what would happen in a normal part of the lung supplied by pulmonary circulation. In the presence of systemic hypoxemia, there would also be an increase in PCC. Acknowledgment
The writers thank Mr. Tony Reolada and Mr. Lionel Caplan for their technical assistance; Dr. E. Phillipson, Dr. N. Zamel, and Dr. A. C. Bryan, for their helpful criticism. References l. Cudkowicz, L.: The Human Bronchial Circula-
tion in Health and Disease, Williams and Wilkins, Baltimore, 1968, p. 105. 2. Miyazawa, K., Katori, R., Ishikawa, K., Yamaki, M., Kobayashi, Y., Tsuiki, K., Matsunaga, A., and Nakamura, T.: Selective bronchial arteriography and bronchial blood flow: Correlative study, Chest, 1970,57 416. 3. Viola, A. R., and Abbate, E. H.: Respiratory function and effective collateral flow, 8 years after ligation of the left pulmonary artery, Am Rev Respir Dis, 1973, 108, 1216. 4. Hales, C. A., and Kazemi, H.: Hypoxic vascular response of the lung: Effect of aminophylline and epinephrine, Am Rev Respir Dis, 1974, 110, 126.
5. Fishman, A. P.: Respiratory gases in the regulation of the pulmonary circulation, Physiol Rev, 1961, 41,214.
6. Fishman, A. P.: Dynamics of the pulmonary circulation, Circulation, 1963,2, 1667. 7. Duke, H. N.: Observations on the effects of hypoxia on the pulmonary vascular bed., J Physiol, 1957' 45, 135.
8. Aviado, D. M.: Pharmacology of the pulmonary circulation, Pharmacal Rev, 1960, 12, 189. 9. Borst, H. G., Whitten berger, J. L., Berglund, F., and McGregor, M.: Effects of unilateral hypoxia and hypercapnia on pulmonary blood flow distribution in the dog, Am J Physiol, 1957, 191, 446. 10. Day, I. deB., and Hebb, C.: Pulmonary and
Bronchial Vascular Systems, Williams and Wilkins, Baltimore, 1966, p. 29. 11. Burton, A. C.: Physiology and Biophysics of the Circulation, Yearbook Medical Publishers Inc.,
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Chicago, 1965, p. 159. 12. Snedecor, G. W., and Cochran, W. G.: Statistical Methods, ed. 6, Iowa State University Press, Ames, 1967, p. 92. 13. Severinghaus, ]. W., Swenson, E. W., Finley, T ... Lategola, M. T., and Williams, J.: Unilateral hypoventilation produced in dogs by occluding one pulmonary artery, J Appl Physiol, !961, 16, 53.
14. Williams, H. N., Jr., and Towbin, E. J.: Magnitude and time of development of the collateral circulation to the lung after occlusion of the left pulmonary artery, Circ Res, 1955,3,422. 15. Auld, P. A. M., Rudolph, A. M., and Golinko, R. J.: Factors affecting bronchial collateral blood flow to the dog, Am J Physiol, 1960, 198, ll66.
E. S. LILKER and E. J. NAGY
SUMMARY __________________________________________________________ The left main pulmonary artery was ligated in 7 fully grown dogs. This resulted in an enlarged pulmonary collateral (systemic) flow to the left lung. By collecting gas from each lung separately, gas exchange in the pulmonary collateral circulation was studied and compared to that in the normal contralateral side. Studies were done repeatedly during a period of 3 years. Compared to that in the preoperative period, the ligated (left) side showed a decrease in ventilation (42.5 to 34.5 per cent of total), a marked increase in wasted ventilation (0.30 to 0.55), and a marked decrease in 0 2 uptake (45 to 1!.2 per cent of total) and C0 2 production (27.5 to 15.3 per cent of the total). There were no changes in arterial blood gases or pH. A significant, sustained, systemic hypertension was noted in all dogs in which the left main pulmonary artery was ligated (190 /120). The mean blood flow through the pulmonary collateral circulation of the left lung with the dogs breathing room air was estimated to be 94 ml per min. When the dogs were made hypoxemic by breathing 12 per cent 0 2 through the normal right lung, there was a marked increase in pulmonary collateral (systemic) flow to the contralateral side (194 ml per min). This resulted in an increase in 0 2 consumption (29.4 per cent of total) and C0 2 production (23.1 per cent of total) of the left lung. When the dogs were given 12 per cent Ory to breathe through the ligated left lung, there was no change in arterial Po 2 . There was a significant increase in blood flow through the pulmonary collateral circulation to 136 ml per min. Because of the gradient of 0 2 between the blood flowing into the left lung and that present in the alveoli, there was a net production of 0 2 from the left lung of 4.5 ml per min. When the pulmonary systemic circulation participates in gas exchange, it appears to increase during hypoxemia as well as during alveolar hypoxia.
Introduction
The contribution of the pulmonary collateral (systemic) circulation (PCC) to gas exchange in normal persons is negligible; however, it may become important in patients with conditions that occlude pulmonary arteries, such as (Received in original form December 26, 1974 and in revised form May 29, 1975) l From the Department of Medicine and the Respiratory Unit, St. Josephs' Hospital, University of Toronto, Toronto, Ontario, Canada. 2 Supported by the Ontario Thoracic Society and St. Josephs' Hospital Research Foundation.
congenital heart disease, pulmonary emboli, and certain chronic inflammations, such as tuberculosis and bronchiectasis (l-3). The vasomotor response of the pulmonary circulation to alveolar hypoxia and hypoxemia is now well established (4-1 0), but there are no data available on the reactivity of PCC to similar stimuli. This study was undertaken to study how the PCC (systemic circulation) responds to hypoxemia and alveolar hypoxia. The PCC increases when the pulmonary ar2 Requests for reprints should be addressed to Dr. E. S. Ulker, Suite 607, 170 St. George St., Toronto, Ontario, Canada.
AMERICA:\ REVIEW OF RESPIRATORY DISEASE, VOLUME 112, 1975
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tery is ligated. We used this model in dogs to produce an enlarged PCC in the left lung only. The pulmonary systemic circulation is normally probably less than I per cent of total cardiac output in humans (1); measuring changes accurately is difficult, because the sensitivity of the methods is less than the oscillations of cardiac output (11 ). One of the advantages of the present model is a greater ratio of signal to noise because of the expansion of the systemic circulation. Another advantage is that the contralateral lung serves as the control lung during experiments. We have shown that the PCC is capable of gas exchange, with the respiratory quotient greater than that via the pulmonary circulation. Whereas the pulmonary circulation constricts in response to alveolar hypoxia, the systemic circulation dilates. During hypoxemia, there is a marked increase in PCC flow. Materials and Methods We produced permanent intrapericardial left pulmonary arteryligation in 7 fully grown dogs (mean weight: 30 ± 8 kg). Special care was taken to preserve all nerves, lymphatics, and vessel structures in the operated lungs. The physiologic studies were started 3 to 6 months postoperatively. Angiograms were done to confirm the occlusion of the left pulmonary artery from 6 to 12 months after surgery. Before each experiment, the dogs were anesthetized; anesthesia was maintained with 2 per cent pentobarbital. A tracheal divider (modified Benfield) was introduced into the airways. Correct placement and presence of leaks were checked by ventilating one lung with 10 per cent helium and 90 per cent 0 2, and monitoring the expired gas from the contralateral lung. The same procedure was repeated at the end of each experiment. An arterial cannula was placed in the femoral artery. The dogs were breathing spontaneously while end·tidal C0 2 concentrations were continuously monitored using an LB·I Beckman Analyzer and recorded on a Grass multichannel .recorder. The expired gas from each lung was collected separately using Douglas bags. Concentrations of 0 2 and C0 2 in the bags were measured using a microScholander apparatus. Arterial pH, arterial Po 2 (Pao 2) and arterial Pco 2 (Paco 2 ) were measured by an Instrumentation Laboratories microelectrode system. Minute ventilation CVE) was measured by passing the total expired gas collected through a wet gas meter (Precision Scientific Co., Chicago, III.) and dividing by time. The dogs were studied under 3 different experimental conditions: both lungs inhaling room air; right lung inhaling 12 per cent 0 2 and 88 per cent N2 • and left lung inhaling room air; right lung in-
haling room air, and left lung inhaling 12 per cent 0 2 and 88 per cent N 2 . All experiments were done in a steady state, which was defined as stable end-tidal Pco 2 , pulse rate, and blood pressure for I min. Douglas bags were flushed for approximately 15 min with expired gas before collection, which was subsequently continued for 10 min. Arterial blood for measurement of pH, Pao 2 • and Paco 2 was collected in duplicate samples during gas collection. Blood pressure was recorded by a Statham arterial pressure transducer attached to the arterial cannula and was recorded on the Grass polygraph. · From the data collected, we calculated VE, tidal v?lume (Vr), 0 2 uptake ('Vo 2 ), C0 2 output (Vco 2 ), and wasted ventilation (Vn) by the standard Bohr equation, and alveolar Po2 (PAo 2 ) for each lung separately. Blood flow through the left lung (systemic circulation) was estimated by the Fick principle, using C0 2 as the indicator gas, using the foll~wing expression: QL = Vco 2 jCaco2 - Ccco 2, where QL =left lung perfusion in liter per min; Vco 2 = C0 2 output of the left lung; Caco 2 =arterial C0 2 content, calculated from Paco 2 and pH using the C0 2 dissociation curve by the Severinghaus slide rule; Ccco 2 = end-capillary C0 2 content, calculated from the C0 2 dissociation curve using end-tidal Pco 2 and assuming pH to be the same as arterial pH. All experiments were done in duplicate on different days. With the exception of QL, all measurements were also obtained in 4 of the dogs I to 6 weeks before surgery. All results were evaluated by a paired t test (12), because the dogs served as their own contro!"subjects. Results The effects of permanent ligation of the left main pulmonary artery on arterial blood gases, arterial blood pressure, and gas exchange of the left lung are shown in table l. All studies were performed in a steady state with both lungs inhaling room air. There were no changes in arterial blood gases. The systolic and diastolic blood pressures were significantly increased postoperatively. The left lung showed a decreased, but measurable, gas exchange, although there was more C0 2 excretion than 0 2 uptake. The VofVr was markedly increased, and VE, expressed as a percentage of the total, was significantly decreased, indicating a shift of ventilation to the contralateral lung. The mean ± SD values shown in table 1 were calculated by using data for all of the dogs and experiments indicated. For statistical analysis of the data in table 1, a paired t test was used to compare the values obtained in the 4 dc.gs studied before surgery to the values obtained in these dogs after surgery.
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TABLE 1 EFFECTS OF PERMANENT LIGATION OF THE LEFT MAIN PULMONARY ARTERY ON ARTERIAL BLOOD GASES, BLOOD PRESSURE, AND GAS EXCHANGE IN DOGS* Before Surgery No. of dogs No. of experiments VE, left lung as% total VD/VT, left lung Vo2, left lung as% total VC02, left lung as% total PAo 2 (left lung). mm Hg Arterial pH, units Pao 2 , mm Hg Paco 2 • mm Hg Arterial blood pressure, mm Hg Systolic Diastolic
4 8 42.5 ± 10 0.30±0.16 45 ± 6.2 37.5 ± 4.9 93.5 ± 12.8 7.29 ± 0.05 73 ±8.3 37.5 ±5.5 145 ± 15 85 ± 35
After Surgery 7 18 34 ± 5.6t 0.55 ±0.18t 11.2 ± 3.1t 15.3±2.1t 130 ± 7.9t 7.30 ± 0.04 70 ± 4.6 38 ±5.3 190 ± 32t 120±31t
• Data were obtained while both lungs were breathing room air, before and at least 6 months after left main pulmonary artery ligation. All data are expressed as mean± SD. tp < 0.05 compared to preoperative value.
Gas exchange and blood flow (QL) through the left lung (systemic) during 3 experimental situations are summarized in table. 2 In the control experiment, both lungs inspired room air. When the. dogs were made hypoxemic by inhaling 12 per cent 0 2 and 88 per cent N 2 through the normal right lung, and room air through the left lung, there was a marked decrease in Pao 2, as well as a slight decrease in Paco 2 and arterial pH. Although there was a decrease in total Vo2 , the absoiute amount of Vo 2 by the left lung actually increased. There was also an absolute increase in the amount of C0 2 produced through the left lung. The calculated QL of the left lung was markedly increased compared to the control lung. No significant change in blood pressure or heart rate was noted. When the left lung inhaled a hypoxic mixture of 12 per cent 0 2 and 88 per cent N 2 , and the right lung, room air, there were no definite changes in arterial blood gases. The only questionable change was an increase in Pao 2 . The total oxygen consumption of the dogs actually decreased, probably because 0 2 was actually excreted through the left lung, because the inflowing Pao 2 was higher than P Ao 2 • Despite these changes, there was an estimated increase in QL compared to the control value. No changes in heart rate or blood pressure were noted. When the dogs were studied repeatedly during a period of 3 years, there was no consistent change in any of the parameters of lung func-
tion or blood flow. Several dogs tended to show a decrease in QL with age. Discussion
The tracheal divider may result in a slight interference with the shift of ventilation away from the underperfused areas of the lung (12). This probably had no significance in our studies, because it has been shown that even I per cent C0 2 can block a shift in ventilation. In all of our experiments, there was more than I per cent C0 2 in both right and left lungs. All of the data presented for these dogs were obtained under the same anesthetic conditions and with pentobarbital. We have subsequently performed 2 complete experiments (under all 3 sets of conditions) using pentobarbital and one complete experiment using chloralose and were unable to note any differences in the ventilation, gas exchange, or cardiovascular data. The use of C0 2 to calculate blood flow through the PCC by the Fick principle has been described previously (1). Because the C0 2 produced by the left lung was only from the systemic circulation, the Vco 2 in the expression is valid and truly reflects systemic blood flow. Because the blood flowing into the left lung is systemic, we assumed that sampling more distally in the femoral artery would not be significantly different from sampling at the arch of the aorta, where the PCC originates. The major problem in using the Fick equation as described is finding the most reliable way of calculating Ccco 2 . When we as-
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TABLE 2 GAS EXCHANGE AND BLOOD FLOW DATA (MEAN± SD) OBTAINED UNDER 3 SETS OF EXPERIMENTAL CONDITIONS IN DOGS 6 MONTHS TO 3 YEARS AFTER LIGATION OF THE LEFT MAIN PULMONARY ARTERY Both Lungs Breathing Room Air (Control Experiment) No. of dogs No. of experiments VE, left lung as% total VD/VT,Jeft lung V02, left lung, ml/min V02, left lung as% total VC02, left lung, ml/min VC02, left lung as% total PAo 2 • left lung, mm Hg V02, right and left lung, ml/min Arterial pH, units Pa 02 , mm Hg ~ac 02 , mm Hg OL, ml/min Arterial blood pressure, mm Hg Systolic ·Diastolic Heart rate, beats/min •p
< 0.05
7
Right Lung Breathing 12 % 02, 88% N2; Left Lung, Room Air
6 15 38.5 ± 7.6 0.54 ±0.14 30 ±6* 29.4* 36 ± 7* 23.1
18 34.5 ±5.6 0.55 ±0.18 20 ±8 11.2 28 ±9 15.3 130 ± 7.9 180 7.30 ± 0.04 70 ± 4.6 38 ±5.3 94 ±34
132 ± 5.8 102* 7.25 ±0.08* 49 5.6*. 31.5±5.1* 194 ±96*
190 ± 32 120 ± 31 134 ±48
200 ±39 126 ± 36 141 ±52
±
Right Lung Breathing Room Air; Left Lung, 12% 02,88% N2
6 12 36.2 ± 6.1 0.54 ±0.14 -4.5 ± 2* -3.95* 32.9 ± 2* 15.1 60 ± 20* 160.5* 7.28 ±0.06 79 ± 8.3 38.5 ± 6.7 136±41* 194 ± 30 124 ± 30 136 ± 21
compared to control value.
sumed end-tidal Pco2 to equal end-capillary Pco2 , we had to assume that wasted ventilation was negligible. This was not so; in fact, wasted ventilation in the left lung was very large. This "dilution" effect by the large wasted ventilation of the left lung results in an underesti· mation of the true end-capillary Pco 2 • A higher end-capillary Pco 2 results in a large C0 2 content and thus, a higher QL. Thus, we probably considerably underestimated QL. There have been many studies showing the anatomic and physiologic consequences of chronic pulmonary artery occlusion in dogs and man (I, 7, 13). We confirm the findings of others and have shown that during a steady-state determination, there is measurable gas exchange through the expanded PCC. The higher respiratory quotient through the PCC compared to the pulmonary circulation preoperatively was probably chiefly due to the fact that there was less C0 2 in the alveolus sup· plied by .the PCC, and thus there was a higher driving pressure (alveolar-arterial Pco 2 difference). The low oxygen uptake by the PCC is chiefly a function of the small pressure gradient of 0 2 between the inflowing blood (systemic arterial) and the alveolus. The increase seen in systemic arterial blood pressure after pulmonary artery ligation has not been described previous-
ly. This increase in blood pressure was first noted 3 to 6 months postoperatively .and persisted in all dogs for the entire 3 years of the study. The mechanism of the hypertension is currently being investigated. When we produced hypoxemia by ventilating the normal right lung (pulmonary circulation) with a hypoxic mixture, Vo 2 and Vco2 of that lung decreased. This indicates vasoconstriction of the pulmonary circulation and has been described previously (4-IO). Vo 2 and Vco 2 increased through the PCC and the estimated QL increased. This increased flow through the systemic circulation of the lung could not be due to a passive shift of blood flow away from the hypoxic lung, because the two. circulations are in series. Thus, it must mean that there was vasodilatation of the systemic blood vessels in the lung. The systemic arterial anoxia could result in increased Vo 2 through the PCC merely by increasing the driving pressure for 0 2 between the alveolus and the inflowing systemic blood. This, however, would not account for the increase in Vco 2, which must reflect increased perfusion. Because there was no consistent change in arterial blood pressure during hypoxemia, it is unlikely that the increased PCC flow was partly
GAS EXCHANGE IN PULMONARY COLLATERAL CIRCULATION OF DOGS
due to this increase in pressure in the aorta. This mechanism has been described previously as an important factor in the regulation of the pulmo· nary collateral blood flow in dogs (14). The effect of alveolar hypoxia on PCC had not been studied previously. \'\fe have shown that alveolar hypoxia of the left lung results in an increase in estimated QL. The two known physiologic methods of increasing PCC are by increasing systemic blood pressure and by inducing hypoxemia. Because there was no change in arterial blood pressure, this could not have been a method of changing the QL. The Pao 2 was not significantly changed. The gradient of 0 2 from the alveolus and the infiowing arterial blood was actually reversed, resulting in 0 2 production through the left lung (PCC). The increase in QL thus must have been due to a direct vasadilating effect of the alveolar hypoxia. Unilateral breathing of hypoxic mixtures appears to constrict the pulmonary arterioles and to dilate PCC. This study further supports the view that the anatomic site of hypoxic pulmonary artery constriction is probably the pulmonary arteriole, rather than the pulmonary vein or capillary. Thus, as special care was taken to preserve all nerves and lymphatics of the left lung during surgery, and assuming that the only difference between two lungs was the precapillary arterial supply, the difference in response to alveolar hypoxia in the left and right lungs must reflect the type of blood vessel supplying the alveoli. The decrease in total 0 2 uptake when the dogs were inhaling a hypoxic mixture through the PCC was probably due to the fact that the difference between alveolus and inflowing blood was reversed; thus, there was a net production of 0 2 from the left lung. The very marked decrease in total 0 2 consumption when the dogs were inhaling a hypoxic mixture through the normal pulmonary circulation is difficult to explain. It may be due to vasoconstriction (which is known to occur to a certain extent) sufficient to decrease the diffusing capacity for 0 2 and, thus, to limit Vo 2 . It might also have been partly due to a mechanical problem, in that we used expired, rather than inspired, volumes to calculate Vo 2 • It is known that the inspired volume does not always equal the expired volume. This might have led to considerable underestimation of the Vo 2 of the pulmonary circulation. The clinical relevance of this model is complicated by the fact that these dogs all developed systemic arterial hypertension. It is not known
619
whether hypertensive systemic vessels (PCC) respond to ·hypoxia and hypoxemia in the same way that nonhypertensive vessels respond. In disease states, portions of lung may derive their blood supply at the gas exchange level through the systemic circulation (PCC). If P Ao 2 were decreased in these areas, such as might occur in airway obstruction, the vascular supply might actually increase (vasodilatation in response to alveolar hypoxia). This would be opposite to what would happen in a normal part of the lung supplied by pulmonary circulation. In the presence of systemic hypoxemia, there would also be an increase in PCC. Acknowledgment
The writers thank Mr. Tony Reolada and Mr. Lionel Caplan for their technical assistance; Dr. E. Phillipson, Dr. N. Zamel, and Dr. A. C. Bryan, for their helpful criticism. References l. Cudkowicz, L.: The Human Bronchial Circula-
tion in Health and Disease, Williams and Wilkins, Baltimore, 1968, p. 105. 2. Miyazawa, K., Katori, R., Ishikawa, K., Yamaki, M., Kobayashi, Y., Tsuiki, K., Matsunaga, A., and Nakamura, T.: Selective bronchial arteriography and bronchial blood flow: Correlative study, Chest, 1970,57 416. 3. Viola, A. R., and Abbate, E. H.: Respiratory function and effective collateral flow, 8 years after ligation of the left pulmonary artery, Am Rev Respir Dis, 1973, 108, 1216. 4. Hales, C. A., and Kazemi, H.: Hypoxic vascular response of the lung: Effect of aminophylline and epinephrine, Am Rev Respir Dis, 1974, 110, 126.
5. Fishman, A. P.: Respiratory gases in the regulation of the pulmonary circulation, Physiol Rev, 1961, 41,214.
6. Fishman, A. P.: Dynamics of the pulmonary circulation, Circulation, 1963,2, 1667. 7. Duke, H. N.: Observations on the effects of hypoxia on the pulmonary vascular bed., J Physiol, 1957' 45, 135.
8. Aviado, D. M.: Pharmacology of the pulmonary circulation, Pharmacal Rev, 1960, 12, 189. 9. Borst, H. G., Whitten berger, J. L., Berglund, F., and McGregor, M.: Effects of unilateral hypoxia and hypercapnia on pulmonary blood flow distribution in the dog, Am J Physiol, 1957, 191, 446. 10. Day, I. deB., and Hebb, C.: Pulmonary and
Bronchial Vascular Systems, Williams and Wilkins, Baltimore, 1966, p. 29. 11. Burton, A. C.: Physiology and Biophysics of the Circulation, Yearbook Medical Publishers Inc.,
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Chicago, 1965, p. 159. 12. Snedecor, G. W., and Cochran, W. G.: Statistical Methods, ed. 6, Iowa State University Press, Ames, 1967, p. 92. 13. Severinghaus, ]. W., Swenson, E. W., Finley, T ... Lategola, M. T., and Williams, J.: Unilateral hypoventilation produced in dogs by occluding one pulmonary artery, J Appl Physiol, !961, 16, 53.
14. Williams, H. N., Jr., and Towbin, E. J.: Magnitude and time of development of the collateral circulation to the lung after occlusion of the left pulmonary artery, Circ Res, 1955,3,422. 15. Auld, P. A. M., Rudolph, A. M., and Golinko, R. J.: Factors affecting bronchial collateral blood flow to the dog, Am J Physiol, 1960, 198, ll66.
