Malnutrition impairs alveolar fluid clearance in rat lungs

Inadequate nutrition complicates the clinical course of critically ill patients, and many of these patients develop pulmonary edema. However, little is known about the effect of malnutrition on the mechanisms that resolve alveolar edema. Therefore, we studied the mechanisms responsible for the decrease in alveolar fluid clearance in rats exposed to malnutrition. Rats were allowed access to water, but not to food, for 120 h. Then, the left and right lungs were isolated for the measurement of lung water volume and alveolar fluid clearance, respectively. The rate of alveolar fluid clearance was measured by the progressive increase in the concentration of Evans blue dye that was instilled into the distal air spaces with an isosmolar 5% albumin solution over 1 h. Malnutrition decreased alveolar fluid clearance by 38% compared with controls. Amiloride (10(-3) M) abolished alveolar fluid clearance in malnourished rats. Either refeeding for 120 h following nutritional deprivation for 120 h or an oral supply of sodium glutamate during nutritional deprivation for 120 h restored alveolar fluid clearance to 91 and 86% of normal, respectively. Dibutyryl-cGMP, a cyclic nucleotide-gated cation channel agonist, increased alveolar fluid clearance in malnourished rats supplied with sodium glutamate. Terbutaline, a beta(2)-adrenergic agonist, increased alveolar fluid clearance in rats under all conditions (control, malnutrition, refeeding, and glutamate-treated). These results indicate that malnutrition impairs primarily amiloride-insensitive and dibutyryl-cGMP-sensitive alveolar fluid clearance, but this effect is partially reversible by refeeding, treatment with sodium glutamate, or beta-adrenergic agonist therapy.     

Selected contribution: mechanisms that may stimulate the resolution of alveolar edema in the transplanted human lung.

Pulmonary edema is common in organ donors and lung transplant recipients. Therefore, we assessed the responsiveness of human donor lungs to pharmacological agents that stimulate clearance of alveolar edema. Organ donors whose lungs were rejected for transplantation were studied. After resection, transport (4 degrees C), and rewarming (37 degrees C) of lungs, alveolar fluid clearance was measured with (n = 8 donors) or without (n = 23 donors) beta-adrenergic stimulation. Terbutaline-stimulated clearance (10(-4) M) was higher than unstimulated clearance (7.1 +/- 1.3 vs. 4.8 +/- 2.4%/h, P < 0.01). Second, we determined whether medications given to the organ donor were associated with the extent of pulmonary edema or the rate of alveolar fluid clearance in the harvested lung. Preharvest administration of dopamine in low to moderate doses was associated with faster alveolar fluid clearance (r = 0.62, P < 0.01). Preharvest administration of diuretics was associated with lower extravascular lung water-to-dry weight ratios. This study provides the first evidence that a beta(2)-adrenergic agonist stimulates alveolar fluid clearance in the human donor lung. Aerosolized beta(2)-adrenergic agonists may have therapeutic value for hastening the resolution of alveolar edema during the management of donors before resection of lungs for transplantation or in the posttransplant setting.     

Alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema.

To characterize the rate and regulation of alveolar fluid clearance in the uninjured human lung, pulmonary edema fluid and plasma were sampled within the first 4 h after tracheal intubation in 65 mechanically ventilated patients with severe hydrostatic pulmonary edema. Alveolar fluid clearance was calculated from the change in pulmonary edema fluid protein concentration over time. Overall, 75% of patients had intact alveolar fluid clearance (>/=3%/h). Maximal alveolar fluid clearance (>/=14%/h) was present in 38% of patients, with a mean rate of 25 +/- 12%/h. Hemodynamic factors (including pulmonary arterial wedge pressure and left ventricular ejection fraction) and plasma epinephrine levels did not correlate with impaired or intact alveolar fluid clearance. Impaired alveolar fluid clearance was associated with a lower arterial pH and a higher Simplified Acute Physiology Score II. These factors may be markers of systemic hypoperfusion, which has been reported to impair alveolar fluid clearance by oxidant-mediated mechanisms. Finally, intact alveolar fluid clearance was associated with a greater improvement in oxygenation at 24 h along with a trend toward shorter duration of mechanical ventilation and an 18% lower hospital mortality. In summary, alveolar fluid clearance in humans may be rapid in the absence of alveolar epithelial injury. Catecholamine-independent factors are important in the regulation of alveolar fluid clearance in patients with severe hydrostatic pulmonary edema.     

Alveolar and lung liquid clearance in anesthetized rabbits

Alveolar and lung liquid clearance were studied over 8 h in intact anesthetized ventilated rabbits by instillation of either isosmolar Ringer lactate (2 ml/kg) or autologous plasma (2 or 3 ml/kg) into one lower lobe. The half time for lung liquid clearance of the isosmolar Ringer lactate was 3.3 h and that for plasma clearance was 6 h. In the plasma experiments, the alveolar protein concentration after 1 h was 5.2 +/- 0.8 g/dl, which was significantly greater than the initial instilled protein concentration of 4.3 +/- 0.7 g/dl (P less than 0.05). Thus alveolar protein concentration increased by 21 +/- 12% over 1 h, which matched clearance from the entire lung of 19 +/- 11% of the instilled volume. Overall the rate of alveolar and lung liquid clearance in rabbits was significantly faster than in prior studies in dogs and sheep. The fast alveolar liquid clearance rate in rabbits was not due to higher endogenous catecholamine release, because intravenous and alveolar (5 x 10(-5) M) propranolol did not slow the clearance. Also, beta-adrenergic therapy with alveolar terbutaline (10(-5) or 10(-4) M) did not increase the alveolar or lung liquid clearance rates. Phloridzin (10(-3) M) did not slow alveolar liquid clearance. However, amiloride (10(-4) M) inhibited 75% of the basal alveolar liquid clearance in rabbits, thus providing evidence that alveolar liquid clearance in rabbits depends primarily on sodium-dependent transport. This rabbit study provides further evidence for important species differences in the basal rates of alveolar liquid and solute clearance as well as the response to beta-adrenergic agonists and ion transport inhibitors.     

Keratinocyte growth factor attenuates hydrostatic pulmonary edema in an isolated, perfused rat lung model

Hydrostatic pulmonary edema is a common complication of congestive heart failure, resulting in substantial morbidity and mortality. Keratinocyte growth factor (KGF) is a mitogen for type II alveolar epithelial and microvascular cells. We utilized the isolated perfused rat lung model to produce hydrostatic pulmonary edema by varying the left atrial and pulmonary capillary pressure. Pretreatment with KGF attenuated hydrostatic edema formation. This was demonstrated by lower wet-to-dry lung weight ratios, histological evidence of less alveolar edema formation, and reduced alveolar accumulation of intravascularly administered FITC-labeled large-molecular-weight dextran in rats pretreated with KGF. Thus KGF attenuates injury in this ex vivo model of hydrostatic pulmonary edema via mechanisms that prevent increases in alveolar-capillary permeability.     

Alveolar liquid and protein clearance from normal dog lungs

To determine whether liquid and protein clearance from the air spaces and lungs of anesthetized and unanesthetized dogs is the same as in sheep, we quantified these variables at three different time periods (4, 8, and 12 h) by instilling heparinized plasma (3 ml/kg) labeled with 125I-albumin into one lower lobe. Protein clearance, measured from the residual 125I-albumin in the lung homogenate, was slow and monoexponential (approximately 1%/h), similar to our previous data for protein clearance from the lungs in sheep. Lung liquid clearance in dogs, however, was 50% less than in previous experiments in sheep. Residual lung liquid (as percent of instilled) was 88.7 +/- 7.0 at 4 h, 70.5 +/- 9.1 at 8 h, and 64.0 +/- 5.8 at 12 h. At each time period, alveolar protein concentration increased by 0.6 +/- 0.4 g/dl at 4 h, 1.3 +/- 1.2 g/dl at 8 h, and 2.1 +/- 0.8 g/dl at 12 h. This increase in alveolar protein concentration was proportional to the volume of liquid removed from the lungs. beta-Adrenergic agonist therapy with terbutaline (10(-5) M mixed with the instilled plasma) doubled the volume of liquid cleared from the lungs over 4 h, and the alveolar protein concentration increased proportionally. However, lung liquid clearance in dogs that were treated with beta-agonists was proportionally (50%) less than in sheep treated with beta-agonists. The slower liquid clearance in dogs compared with sheep cannot be explained by differences in hemodynamics, pulmonary blood flow, anesthesia, mode of ventilation, or alveolar surface area.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clearance of different-sized proteins from the alveolar space in humans and rabbits.

Investigation of the clearance of proteins from the air spaces is important for an understanding of the resolution of pulmonary edema and also because of current interest in delivery of therapeutic peptides via the distal air spaces. Few experimental studies have examined the size dependence for alveolar clearance of large macromolecules; there have been no human studies. In anesthetized rabbits, we measured clearance of cyanocobalamin and different-sized human proteins instilled into the air spaces. After 8 h, the amounts of instilled tracer recovered in the lungs were [57Co]cyanocobalamin, 19.4 +/- 3.0% (Stokes radius 0.65 nm); 125I-labeled insulin, 64.6 +/- 3.9% (1.2 nm); 131I-labeled albumin, 87.0 +/- 4.0% (3.5 nm); and 125I-labeled immunoglobulin G, 91.8 +/- 3.3% (5.5 nm) (P < 0.05). Sieving of different-sized proteins occurred across the alveolar epithelial barrier because tracer concentrations in air space lavage fluid after 8 h were decreased more for the smaller tracers than the larger ones. Size selectivity for alveolar protein clearance in humans with resolving alveolar edema was investigated by measuring the changes in albumin and total protein concentration. The fraction of total protein concentration made up of albumin was greater in the edema fluid than in the plasma initially. The albumin fraction decreased with time in 9 of 10 patients with resolving edema, from 0.62 +/- 0.2 to 0.58 +/- 0.10 (P < 0.05) after 10 +/- 5 h. Thus both rabbit studies and human studies provide evidence for size-dependent clearance of protein from the air spaces of the lung.(ABSTRACT TRUNCATED AT 250 WORDS)     

Specificity and sensitivity of noninvasive measurement of pulmonary vascular protein leak

Noninvasive techniques employing external counting of radiolabeled protein have the potential for measuring pulmonary vascular protein permeability, but their specificity and sensitivity remain unclear. We tested the specificity and sensitivity of a double-radioisotope method by injecting radiolabeled albumin (131I) and erythrocytes (99mTc) into anesthetized dogs and measuring the counts of each isotope for 150 min after injection with an external gamma probe fixed over the lung. We calculated the rate of increase of albumin counts measured by the probe (which reflects the rate at which protein leaks into the extravascular space). To assess permeability we normalized the rate of increase in albumin counts for changes in labeled erythrocyte signal to minimize influence of changes in vascular surface area and thus derived an albumin leak index. We measured the albumin leak index and gravimetric lung water during hydrostatic edema (acutely elevating left atrial pressure by left atrial balloon inflation: mean pulmonary arterial wedge pressure = 22.6 Torr) and in lung injury edema induced by high- (1.0 g/kg) and low-dose (0.25 g/kg) intravenous thiourea. To test specificity we compared hydrostatic and high-dose thiourea edema. The albumin leak index increased nearly fourfold from control after thiourea injury (27.2 +/- 2.3 X 10-4 vs. 7.6 +/- 0.9 X 10-4 min-1) but did not change from control levels after elevating left atrial pressure (8.9 +/- 1.2 X 10-4 min-1) despite comparable increases in gravimetric lung water. To test sensitivity we compared low-dose thiourea with controls. Following low-dose thiourea, the albumin leak index nearly doubled despite the absence of a measurable increase in lung water. We conclude that a noninvasive double radioisotope measurement of pulmonary vascular protein leak, employing external counting techniques and a simplified method of calculation, is specific for lung injury and is also sensitive enough to detect lung injury insufficient to produce detectable pulmonary edema.     

Lung edema clearance: 20 years of progress: invited review: alveolar edema fluid clearance in the injured lung.

Resolution of pulmonary edema involved active transepithelial sodium transport. Although several of the cellular and molecular mechanisms involved are relatively well understood, it is only recently that the regulation of these mechanisms in injured lung are being evaluated. Interestingly, in mild-to-moderate lung injury, alveolar edema fluid clearance is often preserved. This preserved or enhanced alveolar fluid clearance is mediated by catecholamine-dependent or -independent mechanisms. This stimulation of alveolar liquid clearance is related to activation or increased expression of sodium transport molecules such as the epithelial sodium channel or the Na(+)-K(+)-ATPase pump and may also involve the cystic fibrosis transmembrane conductance regulator. When severe lung injury occurs, the decrease in alveolar liquid clearance may be related to changes in alveolar permeability or to changes in activity or expression of sodium or chloride transport molecules. Multiple pharmacological tools such as beta-adrenergic agonists, vasoactive drugs, or gene therapy may prove effective in stimulating the resolution of alveolar edema in the injured lung.     

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.     

Nitric oxide-dependent inhibition of alveolar fluid clearance in hydrostatic lung edema

Formation of cardiogenic pulmonary edema in acute left heart failure is traditionally attributed to increased fluid filtration from pulmonary capillaries and subsequent alveolar flooding. Here, we demonstrate that hydrostatic edema formation at moderately elevated vascular pressures is predominantly caused by an inhibition of alveolar fluid reabsorption, which is mediated by endothelial-derived nitric oxide (NO). In isolated rat lungs, we quantified fluid fluxes into and out of the alveolar space and endothelial NO production by a two-compartmental double-indicator dilution technique and in situ fluorescence imaging, respectively. Elevation of hydrostatic pressure induced Ca(2+)-dependent endothelial NO production and caused a net fluid shift into the alveolar space, which was predominantly attributable to impaired fluid reabsorption. Inhibition of NO production or soluble guanylate cyclase reconstituted alveolar fluid reabsorption, whereas fluid clearance was blocked by exogenous NO donors or cGMP analogs. In isolated mouse lungs, hydrostatic edema formation was attenuated by NO synthase inhibition. Similarly, edema formation was decreased in isolated mouse lungs of endothelial NO synthase-deficient mice. Chronic heart failure results in endothelial dysfunction and preservation of alveolar fluid reabsorption. These findings identify impaired alveolar fluid clearance as an important mechanism in the pathogenesis of hydrostatic lung edema. This effect is mediated by endothelial-derived NO acting as an intercompartmental signaling molecule at the alveolo-capillary barrier.     

Alveolar pressure in fluid-filled occluded lung segments during permeability edema

In a model of increased hydrostatic pressure pulmonary edema Parker et al. (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44: 267-276, 1978) demonstrated that alveolar pressure in occluded fluid-filled lung segments was determined primarily by interstitial fluid pressure. Alveolar pressure was subatmospheric at base line and rose with time as hydrostatic pressure was increased and pulmonary edema developed. To further test the hypothesis that fluid-filled alveolar pressure is determined by interstitial pressure we produced permeability pulmonary edema-constant hydrostatic pressure. After intravenous injection of oleic acid in dogs (0.01 mg/kg) the alveolar pressure rose from -6.85 +/- 0.8 to +4.60 +/- 2.28 Torr (P less than 0.001) after 1 h and +6.68 +/- 2.67 Torr (P less than 0.01) after 3 h. This rise in alveolar fluid pressure coincided with the onset of pulmonary edema. Our experiments demonstrate that during permeability pulmonary edema with constant capillary hydrostatic pressures, as with hemodynamic edema, alveolar pressure of fluid-filled segments seems to be determined by interstitial pressures.     

Beta-adrenergic modulation of pulmonary transvascular fluid and protein exchange

We determined in anesthetized sheep whether isoproterenol, a beta-adrenergic agonist, prevents the increases in pulmonary fluid and protein exchange produced by thrombin-induced intravascular coagulation. Seven sheep were infused intravenously with 0.05 micrograms X kg-1 X min-1 isoproterenol before infusion of alpha-thrombin, and six sheep were infused with alpha-thrombin only and served as control subjects. The marked increases in pulmonary lymph flow and lymph protein clearance in the control thrombin group were attenuated (P less than 0.05) in the isoproterenol group in association with a higher pulmonary blood flow (P less than 0.05) and a lower pulmonary vascular resistance (P less than 0.05) in the isoproterenol group and with similar increases in pulmonary arterial and pulmonary arterial wedge pressures in both groups. The decreases in fluid and protein fluxes produced by isoproterenol are related to its beta-adrenergic properties because propranolol, a beta-adrenergic antagonist, blocked the protective effects of isoproterenol in a second group of sheep infused with propranolol, isoproterenol, and thrombin. Raising left atrial pressure to test for changes in vascular permeability increased protein flux to a much greater extent in the thrombin control group than in the isoproterenol group challenged with thrombin. The data suggest that isoproterenol attenuated the increase in fluid and protein fluxes produced by thrombin-induced intravascular coagulation by a permeability-decreasing mechanism.     

Isoproterenol improves ability of lung to clear edema in rats exposed to hyperoxia.

Exposure of adult rats to 100% O(2) results in lung injury and decreases active sodium transport and lung edema clearance. It has been reported that beta-adrenergic agonists increase lung edema clearance in normal rat lungs by upregulating alveolar epithelial Na(+)-K(+)-ATPase function. This study was designed to examine whether isoproterenol (Iso) affects lung edema clearance in rats exposed to 100% O(2) for 64 h. Active Na(+) transport and lung edema clearance decreased by approximately 44% in rats exposed to acute hyperoxia. Iso (10(-6) M) increased the ability of the lung to clear edema in room-air-breathing rats (from 0.50 +/- 0.02 to 0.99 +/- 0. 05 ml/h) and in rats exposed to 100% O(2) (from 0.28 +/- 0.03 to 0. 86 +/- 0.09 ml/h; P < 0.001). Disruption of intracellular microtubular transport of ion-transporting proteins by colchicine (0. 25 mg/100 g body wt) inhibited the stimulatory effects of Iso in hyperoxia-injured rat lungs, whereas the isomer beta-lumicolchicine, which does not affect microtubular transport, did not inhibit active Na(+) transport stimulated by Iso. Accordingly, Iso restored the lung's ability to clear edema after hyperoxic lung injury, probably by stimulation of the recruitment of ion-transporting proteins (Na(+)-K(+)-ATPase) from intracellular pools to the plasma membrane in rat alveolar epithelium.     

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.     

Lung fluid balance during acute renal failure in sheep

To determine whether uremia changes lung vascular permeability, we measured the flow of lymph and proteins from the lungs of acutely uremic sheep. Acute renal failure was induced by either bilateral nephrectomy or by reinfusing urine. Both models of renal failure increased the plasma creatinine from 0.8 +/- 0.3 to 11 +/- 1 mg/dl in 3 days but caused no significant change in the flow of lymph from the lungs. To determine whether uremia increased the protein clearance response to elevated pulmonary microvascular pressures, we inflated a balloon in the left atrium for 2 h before and 3 days after inducing acute renal failure. In seven sheep, before removing the kidneys, the 20 cmH2O elevation of left atrial pressure increased the protein clearance 3.9 +/- 3.0 ml/h (from 9.5 +/- 4.9 to 13.4 +/- 5.4 ml/h). Three days after the bilateral nephrectomy the same increase in left atrial pressure increased the protein clearance 6.4 +/- 3.6 ml/h (from 6.1 +/- 2.1 to 12.5 +/- 5.2 ml/h), which was a significantly larger increase than that measured before the nephrectomy (P less than 0.05). Sham nephrectomy in seven sheep caused the protein clearance response to the elevated left atrial pressure to fall from 4.7 +/- 1.9 ml/h before the sham nephrectomy to 2.6 +/- 1.4 ml/h 3 days later (P less than 0.05). Uremia due to reinfusion of urine in five sheep did not affect the protein clearance response to elevations in left atrial pressure. Neither model of acute uremia increased the postmortem extravascular lung water volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway level at which edema liquid enters the air space of isolated dog lungs

To identify lung units associated with liquid leakage into the air space in high-pressure pulmonary edema, we perfused air-inflated dog lung lobes with albumin solution to fill the loose peribronchovascular interstitium. Next, we perfused the lobes for 90 s with fluorescent albumin solution then froze the lobes in liquid nitrogen. This procedure confined the fluorescent perfusate to the liquid flux pathway between the circulation and the air space and eliminated the previously filled peribronchovascular cuffs as a source of the fluorescence that entered the air space. We divided each frozen lobe into three horizontal layers and prepared fluorescence-microscopic sections of each layer. In the most apical layers where alveolar flooding was minimal, 10.6 +/- 21.0% (SD) of alveolar ducts were either fluorescence filled or air filled and continuous with fluorescence-filled alveoli. In the same layers, 11.0 +/- 19.0% of respiratory bronchioles were similarly labeled. No terminal bronchioles in these layers were fluorescence labeled. This suggested that the fluorescent albumin entered the air space across the epithelium of respiratory bronchioles, alveolar ducts, or their associated alveoli. To simulate an alternative explanation, i.e., that fluorescence first entered central airways then flowed into peripheral air spaces, we prepared two additional lobes that we first partially inflated with fluorescent albumin then filled to capacity with air. This pushed the fluorescent solution along the airways into the lung periphery. In these lobes the ciliary lining of bronchi and terminal bronchioles was fluorescence coated. By comparison, cilia in fluorescence-perfused lobes were not coated. We conclude that alveolar flooding in hydrostatic pulmonary edema occurs across the epithelium of alveolar ducts, respiratory bronchioles, or their associated alveoli.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoxic pulmonary vasoconstriction does not affect hydrostatic pulmonary edema formation

We studied the effects of regional hypoxic pulmonary vasoconstriction (HPV) on lobar flow diversion in the presence of hydrostatic pulmonary edema. Ten anesthetized dogs with the left lower lobe (LLL) suspended in a net for continuous weighing were ventilated with a bronchial divider so the LLL could be ventilated with either 100% O2 or a hypoxic gas mixture (90% N2-5% CO2-5% O2). A balloon was inflated in the left atrium until hydrostatic pulmonary edema occurred, as evidenced by a continuous increase in LLL weight. Left lower lobe flow (QLLL) was measured by electromagnetic flow meter and cardiac output (QT) by thermal dilution. At a left atrial pressure of 30 +/- 5 mmHg, ventilation of the LLL with the hypoxic gas mixture caused QLLL/QT to decrease from 17 +/- 4 to 11 +/- 3% (P less than 0.05), pulmonary arterial pressure to increase from 35 +/- 5 to 37 +/- 6 mmHg (P less than 0.05), and no significant change in rate of LLL weight gain. Gravimetric confirmation of our results was provided by experiments in four animals where the LLL was ventilated with an hypoxic gas mixture for 2 h while the right lung was ventilated with 100% O2. In these animals there was no difference in bloodless lung water between the LLL and right lower lobe. We conclude that in the presence of left atrial pressures high enough to cause hydrostatic pulmonary edema, HPV causes significant flow diversion from an hypoxic lobe but the decrease in flow does not affect edema formation.     

Aerosolized Pseudomonas elastase and lung fluid balance in anesthetized sheep.

The role of the lung epithelium in lung fluid balance was studied by ventilating anesthetized sheep with an aerosol of 20 mg of elastase from Pseudomonas aeruginosa (Ps. elastase) to increase lung epithelial permeability without affecting lung endothelial permeability or lung vascular pressures. Ps. elastase had no effect on the lung vascular pressures, the alveolar-arterial PO2 gradient (A-aPO2), the flow or protein concentration of the lung lymph, or the postmortem water volume of the lungs. The morphological alveolar flooding score in these sheep was 2.5 times the control level, but this was only marginally significant. Elevation of the left atrial pressure by 20 cmH2O alone increased the postmortem lung water volume but had no effect on A-aPO2, the alveolar flooding score, or the lung epithelial permeability assessed by the clearance of 99mTc-labeled human serum albumin. Addition of aerosolized Ps. elastase to these sheep had no effect on the total lung water volume, but it caused a redistribution of water into the air spaces, as evidenced by significant increases in the alveolar flooding score and A-aPO2 (P less than 0.01). Elevation of the left atrial pressure by 40 cmH2O without elastase caused the same response as elevation of the left atrial pressure by 20 cmH2O with elastase, except the higher pressure caused a greater increase in the total lung water volume. We conclude that alteration of the integrity of the lung epithelium with aerosolized Ps. elastase causes a redistribution of lung water into the alveoli without affecting the total lung water volume.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.