Effects of inspiratory resistance loading on lung fluid balance in awake sheep

Because pulmonary edema has been associated clinically with airway obstruction, we sought to determine whether decreased intrathoracic pressure, created by selective inspiratory obstruction, would affect lung fluid balance. We reasoned that if decreased intrathoracic pressure caused an increase in the transvascular hydrostatic pressure gradient, then lung lymph flow would increase and the lymph-to-plasma protein concentration ratio (L/P) would decrease. We performed experiments in six awake sheep with chronic lung lymph cannulas. After a base-line period, we added an inspiratory load (20 cmH2O) and allowed normal expiration at atmospheric pressure. Inspiratory loading was associated with a 12-cmH2O decrease in mean central airway pressure. Mean left atrial pressure fell 11 cmH2O, and mean pulmonary arterial pressure was unchanged; calculated microvascular pressure decreased 8 cmH2O. The changes that occurred in lung lymph were characteristic of those seen after other causes of increased transvascular hydrostatic gradient, such as increased intravascular pressure. Lung lymph flow increased twice base line, and L/P decreased. We conclude that inspiratory loading is associated with an increase in the pulmonary transvascular hydrostatic gradient, possibly by causing a greater fall in interstitial perimicrovascular pressure than in microvascular pressure.     

Ventilatory responses to increased blood flow and decreased lung volume in awake dogs

The effect of decreased lung volume on ventilatory responses to arteriovenous fistula-induced increased cardiac output was studied in four chronic awake dogs. Lung volume decreases were imposed by application of continuous negative-pressure breathing of -10 cmH2O to the trachea. The animals were surgically prepared with chronic tracheostomy, indwelling carotid artery catheter, and bilateral arteriovenous femoral shunts. Control arteriovenous blood flow was 0.5 l/min, and test flow level was 2.0 l/min. Arterial blood CO2 tension (PaCO2) was continuously monitored using an indwelling Teflon membrane mass spectrometer catheter, and inhaled CO2 was given to maintain isocapnia throughout. Increased fistula flow alone led to a mean 52% increase in cardiac output (CO), whereas mean systemic arterial blood pressure (Psa) fell 4% (P less than 0.01). Negative-pressure breathing alone raised Psa by 3% (P less than 0.005) without a significant change in CO. Expired minute ventilation (VE) increased by 27% (P less than 0.005) from control in both of these conditions separately. Combined increased flow and negative pressure led to a 50% increase in CO and 56% increase in VE (P less than 0.0025) without any significant change in Psa. Effects of decreased lung volume and increased CO appeared to be additive with respect to ventilation and to occur under conditions of constant PaCO2 and Psa. Because both decreased lung volume and increased CO occur during normal exercise, these results suggest that mechanisms other than chemical regulation may play an important role in the control of breathing and contribute new insights into the isocapnic exercise hyperpnea phenomenon.     

Inspiratory airway obstruction does not affect lung fluid balance in lambs

The purpose of this study was to examine the effects of inspiratory airway obstruction on lung fluid balance in newborn lambs. We studied seven 2- to 4-wk-old lambs that were sedated with chloral hydrate and allowed to breathe 30-40% O2 spontaneously through an endotracheal tube. We measured lung lymph flow, lymph and plasma protein concentrations, pulmonary arterial and left atrial pressures, mean and phasic pleural pressures and airway pressures, and cardiac output during a 2-h base-line period and then during a 2- to 3-h period of inspiratory airway obstruction produced by partially occluding the inspiratory limb of a nonrebreathing valve attached to the endotracheal tube. During inspiratory airway obstruction, both pleural and airway pressures decreased 5 Torr, whereas pulmonary arterial and left atrial pressures each decreased 4 Torr. As a result, calculated filtration pressure remained unchanged. Inspiratory airway obstruction had no effect on steady-state lung lymph flow or the lymph protein concentration relative to that of plasma. We conclude that in the spontaneously breathing lamb, any decrease in interstitial pressure resulting from inspiratory airway obstruction is offset by a decrease in microvascular hydrostatic pressure so that net fluid filtration remains unchanged.     

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.     

Pulmonary microcirculatory responses to leukotrienes B4, C4 and D4 in sheep

The pulmonary microvascular responses to leukotrienes B4, C4, and D4 (total dosage of 4 micrograms/kg i.v.) were examined in acutely-prepared halothane anesthetized and awake sheep prepared with lung lymph fistulas. In anesthetized as well as unanesthetized sheep, LTB4 caused a marked and transient decrease in the circulating leukocyte count. Pulmonary transvascular protein clearance (pulmonary lymph flow X lymph-to-plasma protein concentration ratio) increased transiently in awake sheep, suggesting a small increase in pulmonary vascular permeability. The mean pulmonary artery pressure (Ppa) also increased. In the acutely-prepared sheep, the LTB4-induced pulmonary hemodynamic and lymph flow responses were damped. Leukotriene C4 increased Ppa to a greater extent in awake sheep than in anesthetized sheep, but did not significantly affect the pulmonary lymph flow rate (Qlym) and lymph-to-plasma protein concentration (L/P) ratio in either group. LTD4 increased Ppa and Qlym in both acute and awake sheep; Qlym increased without a significant change in the L/P ratio. The LTD4-induced rise in Ppa occurred in association with an increase in plasma thromboxane B2 (TxB2) concentration. The relatively small increase in Qlym with LTD4 suggests that the increase in the transvascular fluid filtration rate is the result of a rise in the pulmonary capillary hydrostatic pressure. In conclusion, LTB4 induces a marked neutropenia, pulmonary hypertension, and may transiently increase lung vascular permeability. Both LTC4 and LTD4 cause a similar degree of pulmonary hypertension in awake sheep, but had different lymph flow responses which may be due to pulmonary vasoconstriction at different sites, i.e. greater precapillary constriction with LTC4 because Qlym did not change and greater postcapillary constriction with LTD4 because Qlym increased with the same rise in Ppa.     

Role of arterial hypoxemia and pulmonary mechanics in exercise limitation in adults with cystic fibrosis.

We tested the hypothesis that maximal exercise performance in adults with cystic fibrosis is limited by arterial hypoxemia. In study 1, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space. Maximal O2 consumption was significantly lower in the added dead space study vs. control (1.04 +/- 0.15 vs. 1.20 +/- 0.11 l/min; P < 0.05), with no difference in peak ventilation. There was significant O2 desaturation during exercise that was equal in both control and added dead space studies. The decrease in maximal O2 consumption with added dead space suggests that maximal exercise in cystic fibrosis is limited by respiratory factors. We subsequently examined whether pulmonary mechanics or arterial hypoxemia limits maximal exercise performance. In study 2, patients completed two maximal exercise tests, a control and a test with 400 ml of added dead space while also breathing 38% O2. Added dead space was used to overcome the suppressive effects of hyperoxia on minute ventilation. Maximal O2 consumption was significantly higher with added dead space and 38% O2 vs. control (1.62 +/- 0.16 vs. 1.43 +/- 0.14 l/min; P < 0.05). Peak ventilation and O2 saturation were significantly greater in the added dead space and 38% O2 test vs. control. The increase in maximal O2 consumption and peak ventilation with added dead space and 38% O2 suggests that maximal exercise in cystic fibrosis is limited by arterial hypoxemia.     

Transmural pressure in rat initial subpleural lymphatics during spontaneous or mechanical ventilation

The role played by the mechanical tissue stress in supporting lymph formation and propulsion in thoracic tissues was studied in deeply anesthetized rats (n = 13) during spontaneous breathing or mechanical ventilation. After arterial and venous catheterization and insertion of an intratracheal cannula, fluorescent dextrans were injected intrapleurally to serve as lymphatic markers. After 2 h, the fluorescent intercostal lymphatics were identified, and the hydraulic pressure in lymphatic vessels (P lymph) and adjacent interstitial space (P int) was measured using micropuncture. During spontaneous breathing, end-expiratory P lymph and corresponding P int were -2.5 +/- 1.1 (SE) and 3.1 +/- 0.7 mmHg (P < 0.01), which dropped to -21.1 +/- 1.3 and -12.2 +/- 1.3 mmHg, respectively, at end inspiration. During mechanical ventilation with air at zero end-expiratory alveolar pressure, P lymph and P int were essentially unchanged at end expiration, but, at variance with spontaneous breathing, they increased at end inspiration to 28.1 +/- 7.9 and 28.2 +/- 6.3 mmHg, respectively. The hydraulic transmural pressure gradient (DeltaP tm = P lymph - P int) was in favor of lymph formation throughout the whole respiratory cycle (DeltaP tm = -6.8 +/- 1.2 mmHg) during spontaneous breathing but not during mechanical ventilation (DeltaP tm = -1.1 +/- 1.8 mmHg). Therefore, data suggest that local tissue stress associated with the active contraction of respiratory muscles is required to support an efficient lymphatic drainage from the thoracic tissues.     

Human respiratory muscle blood flow measured by near-infrared spectroscopy and indocyanine green.

Measurement of respiratory muscle blood flow (RMBF) in humans has important implications for understanding patterns of blood flow distribution during exercise in healthy individuals and those with chronic disease. Previous studies examining RMBF in humans have required invasive methods on anesthetized subjects. To assess RMBF in awake subjects, we applied an indicator-dilution method using near-infrared spectroscopy (NIRS) and the light-absorbing tracer indocyanine green dye (ICG). NIRS optodes were placed on the left seventh intercostal space at the apposition of the costal diaphragm and on an inactive control muscle (vastus lateralis). The primary respiratory muscles within view of the NIRS optodes include the internal and external intercostals. Intravenous bolus injection of ICG allowed for cardiac output (by the conventional dye-dilution method with arterial sampling), RMBF, and vastus lateralis blood flow to be quantified simultaneously. Esophageal and gastric pressures were also measured to calculate the work of breathing and transdiaphragmatic pressure. Measurements were obtained in five conscious humans during both resting breathing and three separate 5-min bouts of constant isocapnic hyperpnea at 27.1 +/- 3.2, 56.0 +/- 6.1, and 75.9 +/- 5.7% of maximum minute ventilation as determined on a previous maximal exercise test. RMBF progressively increased (9.9 +/- 0.6, 14.8 +/- 2.7, 29.9 +/- 5.8, and 50.1 +/- 12.5 ml 100 ml(-1) min(-1), respectively) with increasing levels of ventilation while blood flow to the inactive control muscle remained constant (10.4 +/- 1.4, 8.7 +/- 0.7, 12.9 +/- 1.7, and 12.2 +/- 1.8 ml 100 ml(-1) min(-1), respectively). As ventilation rose, RMBF was closely and significantly correlated with 1) cardiac output (r = 0.994, P = 0.006), 2) the work of breathing (r = 0.995, P = 0.005), and 3) transdiaphragmatic pressure (r = 0.998, P = 0.002). These data suggest that the NIRS-ICG technique provides a feasible and sensitive index of RMBF at different levels of ventilation in humans.     

Increased pulmonary vascular filtration pressure does not alter lung liquid secretion in fetal sheep.

The purpose of this study was to determine whether an increase in pulmonary vascular filtration pressure affects net production of liquid within the lumen of the fetal lung. We studied 14 chronically catheterized fetal lambs [130 +/- 3 (SD) days gestation] before, during, and after a 4-h rapid (500 ml/h) intravenous infusion of isotonic saline. In seven fetuses we measured pulmonary arterial and left atrial pressures, lung lymph flow, and protein osmotic pressures in plasma and lymph. In eight lambs with a chronically implanted tracheal loop cannula, we measured the change in luminal lung liquid volume over time by progressive dilution of tracheally instilled 125I-albumin, which stays within the lung lumen. Saline infusion increased pulmonary vascular pressures by 2-3 mmHg and decreased the plasma-lymph difference in protein osmotic pressure by 1 mmHg. Lung lymph flow increased from 1.9 +/- 0.6 to 3.9 +/- 1.2 (SD) ml/h; net production of luminal lung liquid did not change (12 +/- 5 to 12 +/- 6 ml/h). Thus an increase in net fluid filtration pressure in the pulmonary circulation, which was sufficient to double lung lymph flow, had no significant effect on luminal lung liquid secretion in fetal sheep.     

Effects of hypoproteinemia on lung microvascular protein sieving and lung lymph flow

Experiments were conducted on five chronically instrumented unanesthetized sheep to determine the effects of sustained hypoproteinemia on lung fluid balance. Plasma total protein concentration was decreased from a control value of 6.17 +/- 0.019 to 3.97 +/- 0.17 g/dl (mean +/- SE) by acute plasmapheresis and maintained at this level by chronic thoracic lymph duct drainage. We measured pulmonary arterial pressure, left atrial pressure, aortic pressure, central venous pressure, cardiac output, oncotic pressures of both plasma and lung lymph, lung lymph flow rate, and lung lymph-to-plasma ratio of total proteins and six protein fractions for both control base-line conditions and hypoproteinemia base-line conditions. Moreover, we estimated the average osmotic reflection coefficient for total proteins and the solvent drag reflection coefficients for the six protein fractions during hypoproteinemia. Hypoproteinemia caused significant decreases in lung lymph total protein concentration, lung lymph-to-plasma total protein concentration ratio, and oncotic pressures of plasma and lung lymph. There were no significant alterations in the vascular pressures, lung lymph flow rate, cardiac output, or oncotic pressure gradient. The osmotic reflection coefficient for total proteins was found to be 0.900 +/- 0.004 for hypoproteinemia conditions, which is equal to that found in a previous investigation for sheep with a normal plasma protein concentration. Our results suggest that hypoproteinemia does not alter the lung filtration coefficient nor the reflection coefficients for plasma proteins. Possible explanations for the reported increase in the lung filtration coefficient during hypoproteinemia by other investigators are also made.     

Role of expiratory flow limitation in determining lung volumes and ventilation during exercise.

We determined the role of expiratory flow limitation (EFL) on the ventilatory response to heavy exercise in six trained male cyclists [maximal O2 uptake = 65 +/- 8 (range 55-74) ml. kg-1. min-1] with normal lung function. Each subject completed four progressive cycle ergometer tests to exhaustion in random order: two trials while breathing N2O2 (26% O2-balance N2), one with and one without added dead space, and two trials while breathing HeO2 (26% O2-balance He), one with and one without added dead space. EFL was defined by the proximity of the tidal to the maximal flow-volume loop. With N2O2 during heavy and maximal exercise, 1) EFL was present in all six subjects during heavy [19 +/- 2% of tidal volume (VT) intersected the maximal flow-volume loop] and maximal exercise (43 +/- 8% of VT), 2) the slopes of the ventilation (DeltaVE) and peak esophageal pressure responses to added dead space (e.g., DeltaVE/DeltaPETCO2, where PETCO2 is end-tidal PCO2) were reduced relative to submaximal exercise, 3) end-expiratory lung volume (EELV) increased and end-inspiratory lung volume reached a plateau at 88-91% of total lung capacity, and 4) VT reached a plateau and then fell as work rate increased. With HeO2 (compared with N2O2) breathing during heavy and maximal exercise, 1) HeO2 increased maximal flow rates (from 20 to 38%) throughout the range of vital capacity, which reduced EFL in all subjects during tidal breathing, 2) the gains of the ventilatory and inspiratory esophageal pressure responses to added dead space increased over those during room air breathing and were similar at all exercise intensities, 3) EELV was lower and end-inspiratory lung volume remained near 90% of total lung capacity, and 4) VT was increased relative to room air breathing. We conclude that EFL or even impending EFL during heavy and maximal exercise and with added dead space in fit subjects causes EELV to increase, reduces the VT, and constrains the increase in respiratory motor output and ventilation.     

Cardiopulmonary control during exercise in the duck

To determine the importance of nonhumoral drives to exercise hyperpnea in birds, we exercised adult White Pekin ducks on a treadmill (3 degrees incline) at 1.44 km X h-1 for 15 min during unidirectional artificial ventilation. Intrapulmonary gas concentrations and arterial blood gases could be regulated with this ventilation procedure while allowing ventilatory effort to be measured during both rest and exercise. Ducks were ventilated with gases containing either 4.0 or 5.0% CO2 in 19% O2 (balance N2) at a flow rate of 12 l X min-1. At that flow rate, arterial CO2 partial pressure (PaCO2) could be maintained within +/- 2 Torr of resting values throughout exercise. Arterial O2 partial pressure did not change significantly with exercise. Heart rate, mean arterial blood pressure, and mean right ventricular pressure increased significantly during exercise. On the average, minute ventilation (used as an indicator of the output from the central nervous system) increased approximately 400% over resting levels because of an increase in both tidal volume and respiratory frequency. CO2-sensitivity curves were obtained for each bird during rest. If the CO2 sensitivity remained unchanged during exercise, then the observed 1.5 Torr increase in PaCO2 during exercise would account for only about 6% of the total increase in ventilation over resting levels. During exercise, arterial [H+] increased approximately 4 nmol X l-1; this increase could account for about 18% of the total rise in ventilation. We conclude that only a minor component of the exercise hyperpnea in birds can be accounted for by a humoral mechanism; other factors, possibly from muscle afferents, appear responsible for most of the hyperpnea observed in the running duck.     

Effect of progressive exercise on lung fluid balance in sheep

The purpose of this study is to determine the roles of cardiac output and microvascular pressure on changes in lung fluid balance during exercise in awake sheep. We studied seven sheep during progressive treadmill exercise to exhaustion (10% grade), six sheep during prolonged constant-rate exercise for 45-60 min, and five sheep during hypoxia (fraction of inspired O2 = 0.12) and hypoxic exercise. We made continuous measurements of pulmonary arterial, left atrial, and systemic arterial pressures, lung lymph flow, and cardiac output. Exercise more than doubled cardiac output and increased pulmonary arterial pressures from 19.2 +/- 1 to 34.8 +/- 3.5 (SE) cmH2O. Lung lymph flow increased rapidly fivefold during progressive exercise and returned immediately to base-line levels when exercise was stopped. Lymph-to-plasma protein concentration ratios decreased slightly but steadily. Lymph flows correlated closely with changes in cardiac output and with calculated microvascular pressures. The drop in lymph-to-plasma protein ratio during exercise suggests that microvascular pressure rises during exercise, perhaps due to increased pulmonary venous pressure. Lymph flow and protein content were unaffected by hypoxia, and hypoxia did not alter the lymph changes seen during normoxic exercise. Lung lymph flow did not immediately return to base line after prolonged exercise, suggesting hydration of the lung interstitium.     

Effect of hypoproteinemia on lung fluid balance in awake newborn lambs

To study the influence of plasma protein concentration on fluid balance in the newborn lung, we measured pulmonary arterial and left atrial pressures, lung lymph flow, and concentrations of protein in lymph and plasma of eight lambs, 2-3 wk old, before and after we reduced their plasma protein concentration from 5.8 +/- 0.3 to 3.6 +/- 0.6 g/dl. Each lamb underwent two studies, interrupted by a 3-day period in which we drained protein-rich systemic lymph through a thoracic duct fistula and replaced fluid losses with feedings of a protein-free solution of electrolytes and glucose. Each study consisted of a 2-h control period followed by 4 h of increased lung microvascular pressure produced by inflation of a balloon in the left atrium. Body weight and vascular pressures did not differ significantly during the two studies, but lung lymph flow increased from 2.6 +/- 0.1 ml/h during normoproteinemia to 4.1 +/- 0.1 ml/h during hypoproteinemia. During development of hypoproteinemia, the average difference in protein osmotic pressure between plasma and lymph decreased by 1.6 +/- 2 Torr at normal left atrial pressure and by 4.9 +/- 2.2 Torr at elevated left atrial pressure. When applied to the Starling equation governing microvascular fluid balance, these changes in liquid driving pressure were sufficient to account for the observed increases in lung fluid filtration; reduction of plasma protein concentration did not cause a statistically significant change in calculated filtration coefficient. Protein loss did not influence net protein clearance from the lungs nor did it accentuate the increase in lymph flow associated with left atrial pressure elevation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of complement depletion on lung fluid balance after thrombin

We examined the effect of complement depletion on lung fluid and protein exchange after thrombin-induced pulmonary thromboembolization. Sheep were prepared with lung lymph fistulas to assess pulmonary transvascular fluid and protein dynamics. Studies were made in three groups: in group I (n = 5) pulmonary thromboembolization (PT) was induced by an iv infusion of thrombin (55.0 +/- 12.9 NIH U/kg); in group II (n = 6) cobra venom factor (CVF) was given ip (94.5 +/- 18.8 U/kg/day) for 2 days to deplete complement, and then thrombin (66.4 +/- 37.0 NIH U/kg) was infused to raise pulmonary vascular resistance to the same level as in group I; in group III (n = 10) left atrial pressure (Pla) was increased by 10-15 Torr in normal animals by inflation of a Foley balloon catheter. In group I, thrombin infusion caused an increase in pulmonary lymph flow (Qlym) with a gradual increase in the lymph-to-plasma protein concentration ratio (L/P). In complement-depleted sheep, thrombin caused a transient increase in Qlym, which was associated with a decrease in L/P. In group I an increase in Pla further increased Qlym but without a change in L/P, indicating an increase in lung vascular permeability to proteins; whereas in the decomplemented-thrombin sheep raising Pla increased Qlym but decreased L/P. Results in the latter group were similar to those obtained in normal animals after left atrial hypertension (group III). Therefore the complement system participates in the increase in lung vascular permeability following thrombin-induced microembolization.     

Thrombin-induced alterations in lung fluid balance in awake sheep

We examined the effect of fibrinolysis depression on thrombin-induced pulmonary microembolism in awake sheep prepared with chronic lung lymph fistulas. Fibrinolysis was depressed by an intravenous infusion (100 mg) of tranexamic acid [trans-4-(Aminomethyl)cyclohexanecarboxylic acid]. Pulmonary microembolism was induced by an intravenous infusion of alpha-thrombin (80 NIH U/kg) in normal (n = 7) and in tranexamic acid-treated (n = 6) sheep. Thrombin immediately increased pulmonary lymph flow (Qlym) in both groups. The increased Qlym was not associated with a change in the lymph-to-plasma protein concentration (L/P) ratio in the control group and with a small decrease in the tranexamic acid-treated group. The increases in Qlym and pulmonary transvascular protein clearance (Qlym X L/P ratio) in the tranexamic acid-treated group were greater and sustained at four- to fivefold above base line for 10 h after the thrombin and remained elevated at twofold above base line even at 24 h. In contrast, Qlym and protein clearance were transiently increased in the control group. The mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) increased after thrombin in tranexamic acid-treated group; the increases in Ppa and PVR in the control group were transient. Protein reflection coefficient as determined by the filtration independent method decreased after thrombin in tranexamic acid-treated sheep (n = 5), indicating an increased vascular permeability to proteins. We conclude that prolongation of microthrombi retention in the pulmonary circulation results in an increased vascular permeability to proteins. Both increased vascular permeability and vascular hydrostatic pressure are important determinants of the increases in Qlym and transvascular protein clearance after thrombin-induced pulmonary microembolism.     

Ventilatory effects of high and pulsatile blood flow in the pulmonary circulation

The mechanism of ventilatory stimulation that accompanies increases in cardiac output is unknown. Previous studies addressing this issue have been inconclusive. However, only steady pulmonary blood flow was used. The effect of flow pulsatility merits consideration, because increasing cardiac output raises not only mean pulmonary arterial pressure but also pulse pressure; mechanoreceptors with an important dynamic component to their responses may cause a response to pulsatile, but not steady, flow. Studies were done on anesthetized cats (n = 4) and dogs (n = 4). The right pulmonary artery was cannulated within the pericardium, and systemic blood was pumped from the left atrium to the right pulmonary artery. The right pulmonary circulation was perfused at different levels of flow, which was either steady or pulsatile. Steady-state flow of up to 150 ml.kg-1.min-1 (270 ml.kg-1.min-1 when corrected for the proportion of lung tissue perfused) did not affect breathing pattern. When high pulmonary flow was made pulsatile (pulse pressure approximately 23 mmHg), breath duration decreased from 3.7 +/- 0.72 to 3.4 +/- 0.81 (SD) s (P less than 0.01), representing a change in frequency of only 9%. There was no change in peak inspiratory activity. It was concluded that pulmonary vascular mechanoreceptors are not likely to contribute significantly to the increase in ventilation in association with increases in cardiac output.     

Furosemide reduces lung fluid filtration in lambs with lung microvascular injury from air emboli

To study the effects of furosemide on the neonatal pulmonary circulation in the presence of lung injury, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and concentrations of protein in lymph and plasma of nine lambs that received furosemide, 2 mg/kg iv, during a continuous 8-h intravenous infusion of air. Air embolism increased pulmonary vascular resistance by 71% and nearly tripled steady-state lung lymph flow, with no change in lymph-to-plasma protein ratio. These findings reflect an increase in lung vascular protein permeability. During sustained lung endothelial injury, diuresis from furosemide led to a rapid reduction in cardiac output (average 29%) and a 2-Torr decrease in left atrial pressure. Diuresis also led to hemoconcentration, with a 15% increase in both plasma and lymph protein concentrations. These changes were associated with a 27% reduction in lung lymph flow. In a second set of studies, we prevented the reduction in left atrial pressure after furosemide by inflating a balloon catheter in the left atrium. Nevertheless, lymph flow decreased by 25%, commensurate with the reduction in cardiac output that occurred after furosemide. In a third series of experiments, we minimized the furosemide-related decrease in cardiac output by opening an external fistula between the carotid artery and jugular vein immediately after injection of furosemide. In these studies, the reduction in lung lymph flow (average 17%) paralleled the smaller (17%) decrease in cardiac output. These results suggest that changes in lung vascular filtration pressure probably do not account for the reduction in lung lymph flow after furosemide in the presence of lung vascular injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of interstitial edema on lung lymph flow in goats in the absence of filtration.

We tested the effect of interstitial edema on lung lymph flow when no filtration occurred. In 16 anesthetized open-thorax ventilated supine goats, we set pulmonary arterial and left atrial pressures to nearly zero and measured lymph flow for 3 h from six lungs without edema and ten with edema. Lymph flow decreased exponentially in all experiments as soon as filtration ceased. In the normal lungs the mean half time of the lymph flow decrease was 12.7 +/- 4.8 (SD) min, which was significantly shorter (P less than 0.05) than the 29.1 +/- 14.8 min half time in the edematous lungs. When ventilation was stopped, lymph flow in the edematous lungs decreased as rapidly as in the normal lungs. The total quantity of lymph after filtration ceased was 2.7 +/- 0.8 ml in normal lungs and 9.5 +/- 6.3 ml in edematous lungs, even though extravascular lung water was doubled in the latter (8.4 +/- 2.4 vs. 3.3 +/- 0.4 g/g dry lung, P less than 0.01). Thus the maximum possible clearance of the interstitial edema liquid by the lymphatics was 6.3 +/- 4.8%. When we restarted pulmonary blood flow after 1-2 h in four additional goats, lymph flow recovered within 30 min to the baseline level. These findings support the hypothesis that lung lymph flow originates mainly from alveolar wall perimicrovascular interstitial liquid and that the contribution of the lung lymphatic system to the clearance of interstitial edema (bronchovascular cuffs, interlobular septa) is small.     

Spontaneous injury in isolated sheep lungs: role of perfusate leukocytes and platelets

Perfusion of isolated sheep lungs with blood causes spontaneous edema and hypertension preceded by decreases in perfusate concentrations of leukocytes (WBC) and platelets (PLT). To determine whether these decreases were caused by pulmonary sequestration, we continuously measured blood flow and collected pulmonary arterial and left atrial blood for cell concentration measurements in six lungs early in perfusion. Significant sequestration occurred in the lung, but not in the extracorporeal circuit. To determine the contribution of these cells to spontaneous injury in this model, lungs perfused in situ with a constant flow (100 ml.kg-1.min-1) of homologous leukopenic (WBC = 540 mm-3, n = 8) or thrombocytopenic blood (PLT = 10,000 mm-3, n = 6) were compared with control lungs perfused with untreated homologous blood (WBC = 5,320, PLT = 422,000, n = 8). Perfusion of control lungs caused a rapid fall in WBC and PLT followed by transient increases in pulmonary arterial pressure, lung lymph flow, and perfusate concentrations of 6-ketoprostaglandin F1 alpha and thromboxane B2. The negative value of reservoir weight (delta W) was measured as an index of fluid entry into the lung extravascular space during perfusion. delta W increased rapidly for 60 min and then more gradually to 242 g at 180 min. This was accompanied by a rise in the lymph-to-plasma oncotic pressure ratio (pi L/pi P). Relative to control, leukopenic perfusion decreased the ratio of wet weight to dry weight, the intra- plus extravascular blood weight, and the incidence of bloody lymph. Thrombocytopenic perfusion increased lung lymph flow and the rate of delta W, decreased pi L/pi P and perfusate thromboxane B2, and delayed the peak pulmonary arterial pressure. These results suggest that perfusate leukocytes sequestered in the lung and contributed to hemorrhage but were not necessary for hypertension and edema. Platelets were an important source of thromboxane but protected against edema by an unknown mechanism.