Pulmonary circulation in embolic pulmonary edema

The ultrasonic method was used in acute experiments on cats with open chest under artificial lung ventilation to obtain blood flow in low-lobar pulmonary artery and vein, the blood pressure in pulmonary artery, as well as the left atrial pressure in fat (olive oil) and mechanical (Lycopodium spores) pulmonary embolism. It is shown that pulmonary embolism produces the decrease in the blood flow in pulmonary artery and vein, the increase of the pressure in pulmonary artery and left atria, the increase of lung vessels resistance. The decrease is observed of systemic arterial pressure, bradycardia, and extrasystole. After 5-10 min the restoration of arterial pressure and heart rhythm occur and partial restoration of blood flow in pulmonary artery and vein. In many experiments the blood flow in vein outdoes that in the artery--it allows to suppose the increase of the blood flow in bronchial artery. After 60-90 min there occur sudden decrease of systemic arterial pressure, the decrease of the blood flow in pulmonary artery and vein. The pressure in pulmonary artery and resistance of pulmonary vessels remain high. Pulmonary edema developed in all animals. The death occurs in 60-100 min after the beginning of embolism.     

Pulmonary circulation in experimental toxic edema of the lungs

By means of ultrasonic method used in acute experiments on cats with open chest under artificial lung ventilation the authors studied the blood flow in low-lobar pulmonary artery and the vein, the blood pressure in pulmonary artery as well as the balance between output of right and left ventricles in experimental pulmonary edemas caused by intravenous infusion of mixture fatty acids. It was shown, that acute injury of lungs vessels produces redistribution of blood flow to the lesser circulation, increases the pressure in pulmonary artery. The pattern of pulsating blood flow in lobar artery and vein changes. The authors assume that in situation, when lung vessels permeability is already deranged redistribution of the blood to the lesser circulation aggravates the degree of edema.     

Effects of diverse regimes of artificial respiration on the course of experimental toxic pulmonary edema

In acute experiments on cats with closed chest the author studied the influence of artificial ventilation of increased frequency or volume on the pulmonary edema degree, foam formation intensity, pulmonary gas exchange and the animals survival in experimental pulmonary edema caused by intravenous infusion of mixture fatty acids. It was shown, that artificial ventilation of increased frequencies or volumes in pulmonary edema reduces the increase of the pulmonary coefficient and edema liquid quantity at the beginning of edema and it does not become stronger in following stages. Artificial ventilation of increased regimes decreases the foam formation, increases survival of the animals, delays the arterial pressure decrease, improves the pulmonary gas exchange. Artificial ventilation of increased frequency is more effective then ventilation of increased volume decreases foam formation and improves gas exchange in the lungs.     

Acute increases in anastomotic bronchial systemic to pulmonary blood flow due to generalized lung injury

Since pulmonary blood flow to regions involved in adult respiratory disease syndrome (ARDS) is reduced by hypoxic vasoconstriction, compression by cuffs of edema, and local thromboses, we postulated that the bronchial circulation must enlarge to provide for the inflammatory response. We measured anastomotic bronchial systemic to pulmonary blood flow [QBr(s-p)] serially in a lung lobe in 31 open-chest dogs following a generalized lobar injury simulating ARDS. The pulmonary circulation of the weighed left lower lobe (LLL) was isolated and perfused (zone 2) with autologous blood in anesthetized dogs. QBr(s-p) was measured from the amount of blood which overflowed from this closed vascular circuit corrected by any changes in the lobe weight. The LLL was ventilated with 5% CO2 in air. The systemic blood pressure (volume infusion), gases, and acid-base status (right lung ventilation) were kept constant. We injured the LLL via the airway by instilling either 0.1 N HCl or a mixture of glucose and glucose oxidase or via the pulmonary vessels by injecting either alpha-naphthylthiourea or oleic acid into the LLL pulmonary artery. In both types of injury, there was a prompt rise in QBr(s-p) (mean rise = 247% compared with control), which was sustained for the 2 h of observation. The cause of this increase in flow was studied. Control instillation of normal saline into the airways or into the pulmonary vessels did not change QBr(s-p) nor did a similar increase in lobar fluid (weight) due to hydrostatic edema. Neither cardiac output nor systemic blood pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of lung volume and alveolar pressure on reverse pulmonary venous blood flow.

We have reported that left atrial blood refluxes through the pulmonary veins to gas-exchanging tissue after pulmonary artery ligation. This reverse pulmonary venous flow (Qrpv) was observed only when lung volume was changed by ventilation. This was believed to drive Qrpv by alternately distending and compressing the alveolar and extra-alveolar vessels. Because lung and pulmonary vascular compliances change with lung volume, we studied the effect of positive end-expiratory pressure (PEEP) on the magnitude of Qrpv during constant-volume ventilation. In prone anesthetized goats (n = 8), using the right lung to maintain normal blood gases, we ligated the pulmonary and bronchial arterial inflow to the left lung and ventilated each lung separately. A solution of SF6, an inert gas, was infused into the left atrium. SF6 clearance from the left lung was determined by the Fick principle at 0, 5, 10, and 15 and again at 0 cmH2O PEEP and was used to measure Qrpv. Left atrial pressure remained nearly constant at 20 cmH2O because the increasing levels of PEEP were applied to the left lung only. Qrpv was three- to fourfold greater at 10 and 15 than at 0 cmH2O PEEP. At these higher levels of PEEP, there were greater excursions in alveolar pressure for the same ventilatory volume. We believe that larger excursions in transpulmonary pressure during tidal ventilation at higher levels of PEEP, which compressed alveolar vessels, resulted in the reflux of greater volumes of left atrial blood, through relatively noncompliant extra-alveolar veins into alveolar corner vessels, and more compliant extra-alveolar arteries.     

Pulmonary hemodynamics and gas exchange properties during progressive edema

In this investigation we have studied the effect of increments of pulmonary edema on pulmonary hemodynamics, and physiological and hemodynamic shunt in an isolated lung preparation. Hemodynamic shunt was defined by the slope of the relationship between pulmonary arterial and airway pressures; when the slope decreases, there is a greater degree of shunt. Cardiovascular changes were analyzed using a Starling resistor model of the pulmonary circulation where the effective downstream pressure to flow as seen from the pulmonary artery exceeds the pulmonary venous outflow pressure. This effective downstream pressure is referred to as the critical pressure (Pc), and at low lung inflation the locus of this critical pressure is in extra-alveolar vessels. With 3-4 h of progressive edema to an average of 185% initial lobe weight we found a progressive rise in pulmonary arterial pressure (Ppa) from 12.1 to 21.5 cmH2O. About one-third of this increase in Ppa resulted from an increased Pc and the remainder resulted from an increased resistance upstream from the locus of Pc. These results are consistent with the hypothesis that the interstitial accumulation of fluid creates enough of an increase in interstitial pressure to compress extra-alveolar vessels. There was no significant correlation between the amount of edema and the measured physiologic shunt, but the hemodynamic shunt showed a highly significant correlation. The hemodynamic shunt theoretically measures the extent of obstructed airways and may be a useful index of the degree of pulmonary edema.     

Pulmonary circulation in different gaseous media

The ultrasonic method was used in acute experiments on cats with an open (under artificial lung ventilation) and closed chest to explore lung circulation in a changed gaseous medium. Moderate hypoxia (10% O2) and hypercapnia (5, 10% CO2) induce a 10-15% decrease in the lung blood flow in the inferolobular pulmonary artery in the presence of unchanged or slightly elevated minute volume of the heart. The higher hypoxia (5% O2) provokes inconclusive changes in the lung blood flow: biphasic response or increase. It is assumed that considerable elevation of blood pressure in the common pulmonary artery in all the cases points to vasoconstriction that occurs under the effect of hypoxia and hypercapnia.     

Pulmonary fluid balance following pulmocutaneous baroreceptor denervation in the toad

Pulmonary hemodynamics and net transcapillary fluid flux (NTFF) were measured in conscious toads before and following bilateral denervation of the recurrent laryngeal nerves (rLN), which contain afferents from baroreceptors located in the pulmocutaneous arteries. Denervation caused an acute doubling of the arterial-venous pressure gradient across the lung and a threefold increase in pulmonary blood flow. Calculated pulmonary vascular resistance fell and remained below control values through the period of experimentation. NTFF increased by an order of magnitude (0.74-7.77 ml X kg-1 X min-1), as filtration increased in response to the hemodynamic changes caused by rLN denervation. There was a better correlation between NTFF and pulmonary blood flow than between NTFF and pulmonary driving pressure. Our results support the view that tonic neural input from pulmocutaneous baroreceptors protects the anuran lung from edema by restraining pulmonary driving pressure and blood flow and perhaps by reflexly maintaining vascular tone in the extrinsic pulmonary artery, therefore tending to increase the pre-to-postpulmonary capillary resistance ratio and biasing the Starling relationship in the pulmonary capillaries against filtration.     

Pulmonary vascular resistance in the fluorocarbon-filled lung

Pulmonary vascular resistance was investigated in the fluorocarbon-filled lung in an in situ isolated lung preparation. Lungs were perfused at constant flow (100 ml X min-1 X kg-1) with whole blood from a donor cat. left atrial pressure was held constant at zero pressure. Measurements of pulmonary arterial pressure enabled calculation of pulmonary vascular resistance. Regional changes in pulmonary blood flow were determined by the microsphere technique. During quasi-static deflation over a range of 0-30 mmHg, dependent alveolar pressure was consistently greater for a volume of fluorocarbon than for gas, with each pressure-volume curve for the fluorocarbon-filled lung shifted to the right of the curve for the gas-filled lung. In turn, pulmonary vascular resistance was found to increase linearly as a function of increasing alveolar pressure, independent of the medium in the lung. Thus, for a given volume, pulmonary vascular resistance was consistently greater in the fluorocarbon-filled lung compared with the gas-filled lung. This increase in pulmonary vascular resistance was accompanied by a redistribution of pulmonary blood flow in which blood flow to the dependent region was decreased in the fluorocarbon-filled lung compared with the gas-filled lung. Conversely, the less-dependent regions of the lung received a relatively greater percentage of blood flow when filled with fluorocarbon compared with gas. These findings suggest that pulmonary vascular resistance is increased during liquid ventilation, largely as the result of mechanical interaction at the alveolar-vascular interface.     

Microvascular pressures measured by micropipettes in isolated edematous rabbit lungs

To study the mechanical effects of lung edema on the pulmonary circulation, we determined the longitudinal distribution of vascular resistance in the arteries, veins, and microvessels, and the distribution of blood flow in isolated blood-perfused rabbit lungs with varying degrees of edema. Active vasomotor changes were eliminated by adding papaverine to the perfusate. In three groups of lungs with either minimal [group I, mean wet-to-dry weight ratio (W/D) = 5.3 +/- 0.6 (SD), n = 7], moderate (group II, W/D = 8.5 +/- 1.2, n = 10), or severe (group III, W/D = 9.9 +/- 1.6, n = 5) edema, we measured by direct micropuncture the pressure in subpleural arterioles and venules (20-60 micron diam) and in the interstitium surrounding these vessels. We also measured pulmonary arterial and left atrial pressures and lung blood flow, and in four additional experiments we used radio-labeled microspheres to determine the distribution of blood flow during mild and severe pulmonary edema. In lungs with little or no edema (group I) we found that 33% of total vascular pressure drop was in arteries, 60% was in microvessels, and 7% was in veins. Moderate edema (group II) had no effect on total vascular resistance or on the vascular pressure profile, but severe edema (group III) did increase vascular resistance without changing the longitudinal distribution of vascular resistance in the subpleural microcirculation. Perivascular interstitial pressure relative to pleural pressure increased from 1 cmH2O in group I to 2 in group II to 4 in group III lungs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary pressure-flow relationships in the fetal lamb during in utero ventilation

Pressure-flow relationships in the ventilated lung have not been previously determined in undelivered fetal sheep. Therefore we studied 11 late-gestation chronically prepared fetal sheep during positive-pressure ventilation with different gas mixtures to determine the roles of mechanical distension and blood gas tensions on pressure-flow relationships in the lung. Ventilation with 3% O2-7% CO2 produced a substantial fall in pulmonary vascular resistance even though arterial blood gases were not changed. Increases in pulmonary arterial PO2 during ventilation were associated with falls in pulmonary vascular resistance beyond that measured during mechanical distension. Decreases in pulmonary arterial PCO2 and associated increases in pH were also associated with falls in pulmonary vascular resistance. Pulmonary blood flow ceased at a pulmonary arterial pressure that exceeded left atrial pressure, indicating that left atrial pressure does not represent the true downstream component of driving pressure through the pulmonary vascular bed. The slope of the driving pressure-flow relationship in the normal mature fetal lamb was therefore different from the ratio of pulmonary arterial pressure to pulmonary arterial flow. We conclude that mechanical ventilation, increased PO2 and decreased PCO2, and/or increased pH has an important influence on the fall in pulmonary vascular resistance elicited by positive pressure in utero ventilation of the fetal lamb and that the downstream driving pressure for pulmonary blood flow exceeds left atrial pressure.     

Influence of lung volume and left atrial pressure on reverse pulmonary venous blood flow

Infarction of the lung is uncommon even when both the pulmonary and the bronchial blood supplies are interrupted. We studied the possibility that a tidal reverse pulmonary venous flow is driven by the alternating distension and compression of alveolar and extra-alveolar vessels with the lung volume changes of breathing and also that a pulsatile reverse flow is caused by left atrial pressure transients. We infused SF6, a relatively insoluble inert gas, into the left atrium of anesthetized goats in which we had interrupted the left pulmonary artery and the bronchial circulation. SF6 was measured in the left lung exhalate as a reflection of the reverse pulmonary venous flow. No SF6 was exhaled when the pulmonary veins were occluded. SF6 was exhaled in increasing amounts as left atrial pressure, tidal volume, and ventilatory rates rose during mechanical ventilation. SF6 was not excreted when we increased left atrial pressure transients by causing mitral insufficiency in the absence of lung volume changes (continuous flow ventilation). Markers injected into the left atrial blood reached the alveolar capillaries. We conclude that reverse pulmonary venous flow is driven by tidal ventilation but not by left atrial pressure transients. It reaches the alveoli and could nourish the alveolar tissues when there is no inflow of arterial blood.     

Differential effects of prostaglandins A1 and A2 on pulmonary vascular resistance in the dog.

The effects of PGA1 and PGA2 were studied in the canine pulmonary vascular bed. Infusion of PGA1 into the lobar artery decreased lobar arterial and venous pressure but did not change left atrial pressure. In contrast, PGA2 infusion increased lobar arterial and venous pressure and the effects of this substance were similar in experiments in which the lung was perfused with dextran or with blood. These data indicate that under conditions of controlled blood flow PGA1 decreases pulmonary vascular resistance by dilating intrapulmonary veins and to a lesser extent vessels upstream to the small veins, presumably small arteries. The present data show that PGA2 increases pulmonary vascular resistance by constricting intrapulmonary veins and upstream vessels. The predominant effect of PGA2 was on upstream vessels and the pressor effect was not due to interaction with formed elements in the blood or platelet aggregation.     

Pulmonary vascular resistance after cessation of positive end-expiratory pressure

This report describes the pulmonary vascular response of infant lamb lung to abrupt cessation of positive end-expiratory pressure (PEEP) during volume-regulated continuous positive-pressure breathing (CPPB). In an intact, endobronchially ventilated preparation, the increase in left lung blood flow (QL) after abrupt cessation of 11 Torr left lung PEEP was found to be gradual, although peak airway pressure (Pmax) fell promptly from 36 to 14 Torr; 49% of the increase in QL occurred greater than 10 s after cessation of PEEP. Recruitment of zone I vasculature that had been created by balloon occlusion of the left pulmonary artery was found to occur promptly after balloon deflation. Isolated neonatal lamb lungs, perfused at constant flow rate, showed similar persistent elevation of pulmonary vascular resistance after cessation of 15 Torr PEEP, although Pmax fell abruptly from 39 to 12 Torr. This hysteresis was eliminated by calcium channel blockade with verapamil, and the magnitude of the change in pulmonary arterial pressure after either application or cessation of PEEP was reduced (25 and 26%, respectively). These observations suggest that, during CPPB, lung stretch alters neonatal pulmonary vascular tone or, by causing calcium channel-dependent lung volume hysteresis, modulates pulmonary vascular resistance. This interaction exaggerates the effect of airway pressure changes on pulmonary vascular resistance during mechanical ventilation.     

Respiratory failure after endotoxin infusion in sheep: lung mechanics and lung fluid balance

Infusion of Escherichia coli endotoxin (0.12-1.5 micrograms/kg) into unanesthetized sheep causes transient pulmonary hypertension and several hours of increased lung vascular permeability, after which sheep recover. To produce enough lung injury to result in pulmonary edema with respiratory failure, we infused larger doses of E. coli endotoxin (2.0-5.0 micrograms/kg) into 11 chronically instrumented unanesthetized sheep and continuously measured pulmonary arterial, left atrial and aortic pressures, dynamic lung compliance, lung resistance, and lung lymph flow. We intermittently measured arterial blood gas tensions and pH, made interval chest radiographs, and calculated postmortem extravascular bloodless lung water-to-dry lung weight ratio (EVLW/DLW). Of 11 sheep 8 developed respiratory failure; 7 died spontaneously 6.3 +/- 1.1 h, and one was killed 10 h after endotoxin infusion. All sheep that had a premortem room air alveolar-arterial gradient in partial pressure of O2 (PAo2-Pao2) greater than 42 Torr (58 +/- 5 (SE) Torr) died. Of eight sheep that had radiographs made, six developed radiographically evident interstitial or interstitial and alveolar edema. Pulmonary artery pressure rose from base line 22 +/- 2 to 73 +/- 3 cmH2O and remained elevated above baseline levels until death. There was an initial fourfold decrease in dynamic compliance and sixfold increase in pulmonary resistance; both variables remained abnormal until death. EVLW/DLW increased with increasing survival time after endotoxin infusion, suggesting that pulmonary edema accumulated at the same rate in all fatally injured sheep, regardless of other variables. The best predictor of death was a high PAo2-Pao2. The marked increase in pulmonary resistance and decrease in dynamic compliance occurred too early after endotoxin infusion (15-30 min) to be due to pulmonary edema. The response to high-dose endotoxin in sheep closely resembles acute respiratory failure in humans following gram-negative septicemia. Respiratory failure and death in this model were not due to pulmonary edema alone.     

Teaching the effects of gravity and intravascular and alveolar pressures on the distribution of pulmonary blood flow using a classic paper by West et al

"Distribution of blood flow in isolated lung; relation to vascular and alveolar pressures" by J. B. West, C. T. Dollery, and A. Naimark (J Appl Physiol 19: 713-724, 1964) is a classic paper, although it has not yet been included in the Essays on the American Physiological Society Classic Papers Project (http://www.the-aps.org/publications/classics/). This is the paper that originally described the "zones of the lung." The final figure in the paper, which synthesizes the results and discussion, is now seen in most textbooks of physiology or respiratory physiology. The paper is also a model of clear, concise writing. The paper and its final figure can be used to teach or review a number of physiological concepts. These include the effects of gravity on pulmonary blood flow and pulmonary vascular resistance; recruitment and distention of pulmonary vessels; the importance of the transmural pressure on the diameter of collapsible distensible vessels; the Starling resistor; the interplay of the pulmonary artery, pulmonary vein, and alveolar pressures; and the vascular waterfall. In addition, the figure can be used to generate discovery learning and discussion of several physiological or pathophysiological effects on pulmonary vascular resistance and the distribution of pulmonary blood flow.     

Hypoxia and angiotensin II infusion redistribute lung blood flow in lambs

To assess the effects of alveolar hypoxia and angiotensin II infusion on distribution of blood flow to the lung we performed perfusion lung scans on anesthetized mechanically ventilated lambs. Scans were obtained by injecting 1-2 mCi of technetium-labeled albumin macroaggregates as the lambs were ventilated with air, with 10-14% O2 in N2, or with air while receiving angiotensin II intravenously. We found that both alveolar hypoxia and infusion of angiotensin II increased pulmonary vascular resistance and redistributed blood flow from the mid and lower lung regions towards the upper posterior region of the lung. We assessed the effects of angiotensin II infusion on filtration pressure in six lambs by measuring the rate of lung lymph flow and the protein concentration of samples of lung lymph. We found that angiotensin II infusion increased pulmonary arterial pressure 50%, lung lymph flow 90%, and decreased the concentration of protein in lymph relative to plasma. These results are identical to those seen when filtration pressure increases during alveolar hypoxia. We conclude that alveolar hypoxia and angiotensin II infusion both increase fluid filtration in the lung by increasing filtration pressure. The increase in filtration pressure may be the result of a redistribution of blood flow in the lung with relative overperfusion of vessels in some areas and transmission of the elevated pulmonary arterial pressure to fluid-exchanging sites in those vessels.     

Effects of positive end-expiratory pressure on the right ventricle

Transmural cardiac pressures, stroke volume, right ventricular volume, and lung water content were measured in normal dogs and in dogs with oleic acid-induced pulmonary edema (PE) maintained on positive-pressure ventilation. Measurements were performed prior to and following application of 20 cmH2O positive end-expiratory pressure (PEEP). Colloid fluid was given during PEEP for ventricular volume expansion before and after the oleic acid administration. PEEP significantly increased pleural pressure and pulmonary vascular resistance but decreased right ventricular volume, stroke volume, and mean arterial pressure in both normal and PE dogs. Although the fluid infusion during PEEP raised right ventricular diastolic volumes to the pre-PEEP level, the stroke volumes did not significantly increase in either normal dogs or the PE dogs. The fluid infusion, however, significantly increased the lung water content in the PE dogs. Following discontinuation of PEEP, mean arterial pressure, cardiac output, and stroke volume significantly increased, and heart rate did not change. The failure of the stroke volume to increase despite significant right ventricular volume augmentation during PEEP indicates that positive-pressure ventilation with 20 cmH2O PEEP decreases right ventricular function.     

Effect of alveolar liquid on distribution of blood flow in dog lungs.

Previous studies have shown that a shift in blood flow away from edematous regions does not occur until the alveoli contain liquid. The present experiments were designed to examine the separate effect of air space liquid, air space plus interstitial liquid, and reduced lung volume on blood flow. We found that reduced lung volume was not associated with significant changes in blood flow and that no systematic change in blood flow occurred when alveoli were filled with isosmotic liquid (autologous plasma). However, when hyposmotic liquid (dilute plasma) was instilled so that both the air space and the alveolar wall interstitial space were filled, blood flow was systematically reduced. This suggested that interstitial liquid was responsible raising vascular resistance in these experiments and that it might also be important in raising local vascular resistance in pulmonary edema. This latter hypothesis was tested in isolated perfused lobes where rapid freezing and quantitative histology showed that the number of open capillaries was significantly reduced in the liquid-filled alveoli (P less than 0.001). These observations suggest that interstitial pressure rises in pulmonary edema with the result that the transmural pressure of the alveolar vessels falls and vascular resistance is increased.     

Oleic acid dose-related edema in isolated canine lung perfused at constant pressure

Fatty acid embolism of the lung results in pulmonary edema. Isolated lung lobes ventilated and blood perfused at constant pressure were treated with 1 (n = 6) or 45 microliter/kg body wt (n = 6 oleic acid or saline (n = 7). Lobe weight increase linearly over 1-3 h following oleic with regression slopes indicating a more rapid rate of weight gain at the higher oleic acid dosage. Total lobe weight gain was greater in the 45 than in the 1 microliter/kg group (0.60 +/- 0.10 vs. 0.31 +/- 0.07 g/g initial lobe wt) and greater in the acid-treated lobes than in the controls (0.13 +/- 0.05 g/g initial lobe wt). Pulmonary vascular resistance increased 79% after 45 microliter/kg oleic acid but appeared unchanged following 1 microliter/kg oleic acid or saline. The decrease in arterial O2 partial pressure was greater in the 45 microliter/kg group than in the controls, 47 vs 22 Torr. High vascular pressures and increased flow velocities in patent vessels are not essential for oleic acid-associated edema, since weight increased at constant pressure perfusion. Weight gain related to oleic acid dosage suggests that oleic acid increases permeability by affecting the vascular endothelium either directly or through biochemical intermediates endogenous to the lung or blood.