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Endothelial damage is a hallmark of acute lung injury. Endothelial mediators may increase pulmonary vascular tone and induce pulmonary arterial muscularization, thereby contributing to the pulmonary hypertension seen with acute lung injury. We measured plasma levels and net pulmonary clearance of endothelin-1, a potent endothelium-derived vasoconstrictor peptide and smooth muscle mitogen, in 26 patients with early acute lung injury, the adult respiratory distress syndrome, and pulmonary hypertension. Nineteen had another data collection at clinical improvement or worsening. Control subjects (n = 25) had no pulmonary hypertension or lung injury. Initial mixed venous and systemic arterial plasma endothelin-1 levels were elevated (4.6 +/- 0.6 SEM and 4.9 +/- 0.6 pg/ml, respectively) as compared with control subjects (0.9 +/- 0.1 and 0.6 +/- 0.1 pg/ml). The systemic arterial/venous endothelin-1 ratio was 1.1 +/- 0.1 (0.7 +/- 0.1 in control subjects), indicating a reduction in normal net pulmonary endothelin-1 clearance. With clinical improvement, as compared with clinical worsening, mean plasma endothelin-1 levels, arterial/venous ratio, and pulmonary arterial pressure fell significantly towards normal. Thus, patients with acute lung injury have marked early increases in circulating plasma endothelin-1 levels, associated with abnormal pulmonary endothelin-1 metabolism. These abnormalities reverse in patients who recover. Through its actions, endothelin-1 could contribute to the pulmonary hypertension seen in acute lung injury.

Previous studies have shown that the underlying patterns of lung injury influence subsequent responses to aerosolized exogenous surfactant. The purpose of this study was to compare aerosolized versus tracheally instilled surfactant in a nonuniform lung injury. Adult sheep underwent whole lung lavage with subsequent HCl instillation into the right middle lobe (RML) and lingula (LING) to create a nonuniform injury. Animals were treated with either nebulized surfactant (Neb.Surf.), tracheally instilled surfactant (Inst.Surf.), or nebulized saline (Neb. Saline). PaO2, alveolar-arterial O2 gradient (PAO2-PaO2), PaCO2, and peak inspiratory pressure (PIP) values all significantly improved during 180 min of continuous aerosolization for Neb.Surf. animals compared with pretreatment values (p < 0.01) and with the other two treatment groups (p < 0.01). Although PaO2 and (PAO2-PaO2) values improved for the Inst.Surf. group by 180 min after treatment (p < 0.05), PaCO2 and PIP values were significantly increased 30 min after surfactant instillation (p < 0.05). Neb. Saline animals had no significant changes in physiologic parameters over 180 min. Approximately 8% of the total aerosolized surfactant deposited in lung tissue was recovered from the more severely damaged RML and LING, compared with approximately 50% of the total instilled surfactant recovered from these lobes. This resulted in significantly greater percentages of the total aerosolized surfactant deposited in each of the remaining lobes compared with the percent deposition of instilled surfactant (p < 0.05). Both the underlying pattern of lung injury and the exogenous surfactant delivery technique may influence clinical responses to surfactant therapy in patients with the adult respiratory distress syndrome (ARDS).

Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells and degraded predominantly in the pulmonary vasculature, has been implicated in the development of various organ dysfunctions. To determine the pathophysiologic role of ET-1 in adult respiratory distress syndrome (ARDS) and the impact of impaired lung function on transpulmonary peptide handling, we compared plasma levels and pulmonary ET-1 balance in 14 patients with ARDS and in seven healthy control subjects. To obtain comparable conditions in both groups, the ET-1 level was raised in the control group by exogenous infusion (0.4 pmol/kg/min) to 9.4 +/- 0.8 pmol/L. ARDS was accompanied by a hyperdynamic circulatory pattern with increased cardiac output and depressed total vascular resistance but, simultaneously, pulmonary hypertension. Venous ET-1 concentration was massively increased in ARDS (9.8 +/- 1.2 versus 2.1 +/- 0.2 pmol/L, p < 0.001). In control subjects, the lung cleared the major fraction of ET-1 (fractional extraction 43 +/- 8.8%, uptake 12.5 +/- 2.5 pmol/min). In contrast, in ARDS there was a pronounced pulmonary releases into the circulation (32.8 +/- 10.3 pmol/min). We conclude that ET-1 concentrations are elevated in ARDS as the result of both increased formation and decreased disposal. Lung failure affects not only gas exchange but also nonrespiratory, metabolic pulmonary functions.

Although shown to be safe in many other lung disorders, the safety of fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) in critically ill patients with adult respiratory distress syndrome (ARDS) remains unproven. We conducted a prospective study to evaluate the safety of BAL in patients with ARDS. There were 438 patients with ARDS at our institution during the study period. Of these, 110 underwent FOB and BAL for either research or clinical purposes. Data were collected at baseline, at 5-min intervals during the procedure, and 1 h after the procedure. We did not detect any statistically or clinically significant changes in PaO2/FlO2, mean arterial pressure, heart rate, peak inspiratory pressure, or static thoracic compliance after the procedure. A small decrease in SaO2 occurred after BAL. Although this change was statistically significant, the magnitude was not of clinical importance. Five patients (4.5%) had transient arterial oxygen desaturation to < 90% during FOB and one patient (0.9%) experienced desaturation to < 80%. There were no prolonged episodes of severe hypoxemia. No serious bleeding occurred. One pneumothorax developed during the procedure. No deaths occurred that were related to the procedure. We conclude that FOB and BAL can be performed safely and are reasonably well-tolerated in patients with ARDS.

ARDS includes a complex series of events leading to alveolar damage, high permeability pulmonary edema, and respiratory failure. The endogenous pulmonary surfactant system is crucial to maintaining normal lung function, and only recently has it been appreciated that alterations in the surfactant system significantly contributed to the pathophysiology of the lung injury of patients with ARDS. Through a combination of analyzing BAL samples from patients with ARDS and extensive animal studies, there have been significant insights into the variety of surfactant abnormalities that can occur in injured lungs. These include altered surfactant composition and pool sizes, abnormal surfactant metabolism, and inactivation of alveolar surfactant by serum proteins present within the airspace. Positive effects of exogenous surfactant administration on acute lung injury have been reported. There is now a prospective, randomized clinical trial evaluating the efficacy of aerosolized exogenous surfactant in patients with ARDS. This trial has demonstrated improvements in gas exchange and a trend toward decreased mortality in response to the surfactant. Despite these encouraging results, there are multiple factors requiring further investigation in the development of optimal surfactant treatment strategies for patients with ARDS. Such factors include the development of optimal surfactant delivery techniques, determining the ideal time for surfactant administration during the course of injury, and the development of optimal exogenous surfactant preparations that will be used to treat these patients. With further clinical trials and continued research efforts, exogenous surfactant administration should play a useful role in the future therapeutic approach to patients with ARDS.

Our purpose was to determine the effect of non-bacteria-dependent systemic inflammation on the degree and time course of lung oxidant activity and antioxidant defenses, comparing these changes with lung, physiologic, and histologic alterations. Adult male rats were given intraperitoneal zymosan (0.7 mg/g body weight) and were fluid resuscitated. Oxidant changes were measured as lung tissue oxidized glutathione (GSSG) and malondialdehyde (MDA) content, antioxidant defenses as tissue reduced glutathione (GSH), and catalase. Animals were killed at 4, 12, and 24 h, and at 5, 10, and 30 days. Lung data were compared with that found in liver. We noted a 45% mortality in the first 18 to 36 h with all remaining animals surviving. In the first 24 h, we noted a doubling of lung MDA and an 80% conversion of tissue GSH to GSSG compared with less than 5% in control animals, indicating a severe oxidant stress. These findings corresponded with marked increase in lung neutrophils. Arterial pressure (PaO2) was significantly decreased from a control of 95 +/- 4 mm Hg to 80 +/- 5 mm Hg and 75 +/- 4 mm Hg at Days 5 and 10, respectively, but returned toward control by 30 days. Lung GSSG and MDA remained significantly increased for the 30-day period, whereas amounts of the antioxidants, catalase, and GSH returned to control after 24 h. The ongoing oxidant stress corresponded with marked mononuclear cell infiltration and interstitial thickening, which persisted over the 30-day period even after peritonitis had completely resolved.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the effects of two structurally unrelated sulfidopeptide leukotriene receptor antagonists on endotoxin-induced pulmonary dysfunction in chronically instrumented unanesthetized sheep. The agents employed were L-660,711 (MK-571) (Merck-Frosst, Canada) and SK&F 104,353 (Smith Kline and French, King of Prussia, PA). The efficacy and specificity of the agents were verified in sheep by administering boluses of exogenous leukotrienes (LTB4, LTC4, LTD4, and LTE4) in doses as great as 100 micrograms while monitoring lung mechanics and vascular pressures. The antagonists blocked the changes in lung mechanics and pulmonary hemodynamics induced by the sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4) while having no effect on the animals' responses to LTB4. The endotoxin studies were performed by administering endotoxin alone (Escherichia coli endotoxin 0.75 microgram/kg) or endotoxin after pretreatment with one of the sulfidopeptide leukotriene receptor antagonists. In control studies, each animal received a continuous infusion of one of the receptor antagonists for a duration identical to that of the endotoxin studies. Neither L-660,711 nor SK&F 104,353 significantly altered the endotoxin-induced changes in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, oxygenation, or leukopenia. Peak lung lymph thromboxane B2 levels were significantly lower in sheep pretreated with L-660,711. When the antagonists were given alone, no effects were seen. We conclude that (1) sulfidopeptide leukotrienes do not measurably contribute to endotoxin-induced pulmonary dysfunction in chronically instrumented sheep; (2) sulfidopeptide leukotrienes may contribute to thromboxane release after endotoxin.

Oxygen radicals have been implicated in the pathogenesis of acute lung injury associated with clinical and experimental sepsis. With the use of endotoxin infusion as an in vivo model of sepsis we studied the effect of recombinant-human superoxide dismutase (r-hSOD; 4,200 U/mg), an enzyme that catalyzes the dismutation of superoxide anion, on both the physiologic and biochemical lung changes in awake sheep. Sheep (n = 11) were prepared for chronic measurement of pulmonary hemodynamics and lung fluid balance. Paired experiments were performed in seven of the animals in which they received either endotoxin (1 microgram/kg) alone or in combination with r-hSOD in random order. An additional four sheep received r-hSOD without the lipopolysaccharide. Intravenous infusion of r-hSOD (a loading dose of 12,600 U/kg followed by a maintenance dose of 14,700 U/kg/h for 7 h) resulted in substantial SOD activity, measured by electron spin resonance spectrometry, both in plasma and in lung lymph, and attenuated the expected changes in pulmonary arterial pressure and lung lymph flow after administration of endotoxin. When administered without endotoxin, r-hSOD produced no perceptible change in pulmonary hemodynamics and lung fluid balance. These data suggest that superoxide anion plays an important role in endotoxin-induced lung injury in sheep.

Using a simple and rapid technique, we studied the flow and volume dependence of the total resistance of the respiratory system (Rrs) in six patients with ARDS. At any given inflation volume, Rrs decreased progressively with increasing flow (V) according to the following hyperbolic function: Rrs = a/V + b, where a and b are constants. At any fixed inflation flow, Rrs increased progressively with increasing inflation volume. The observed flow and volume dependence of Rrs is probably mainly due to the viscoelastic properties of the pulmonary and chest wall tissues. The flow and volume dependence of Rrs found in the patients with ARDS is qualitatively similar to that previously observed in normal anesthetized paralyzed subjects. In ARDS, however, Rrs was considerably greater than in the normal subjects, indicating that besides a low respiratory compliance ARDS is characterized by a high flow resistance. This mainly reflects increased effective flow resistance of the pulmonary and chest wall tissues, although airway resistance is also higher than normal.

The effects of different levels of positive end-expiratory pressure (PEEP) (zero to 15 cm H2O) on the static inflation volume-pressure (V-P) curve of the respiratory system and on gas exchange were studied in eight patients with the adult respiratory distress syndrome (ARDS). Alveolar recruitment with PEEP was quantified in terms of recruited volume, i.e., as difference in lung volume between PEEP and zero end-expiratory pressure (ZEEP) for the same static inflation pressure (20 cm H2O) from the V-P curves obtained at the different PEEP levels. In addition, static compliance of the respiratory system at fixed tidal volume (0.7 L) was determined at the different PEEP levels. The results suggest that: (1) in some patients with ARDS the V-P curves determined on ZEEP exhibit an upward concavity reflecting progressive alveolar recruitment with increasing inflation volume, and PEEP results in alveolar recruitment (range of recruited volume at 15 cm H2O of PEEP: 0.11 to 0.36 L); (2) in other patients with ARDS the V-P curves on ZEEP are characterized by an upward convexity, and PEEP results in a volume displacement along this curve without alveolar recruitment and with enhanced risk of barotrauma; (3) the PEEP-induced increase in arterial oxygenation is significantly correlated to the recruited volume but not to the changes in static compliance. The shape of the static inflation V-P curves on ZEEP allows the prediction of alveolar recruitment with PEEP.

Although it has been shown in normal subjects that airway resistance changes significantly with changes in lung volume and inspiratory flow, no studies have as yet examined these phenomena in patients with adult respiratory distress syndrome (ARDS). The effect of positive end-expiratory pressure (PEEP) on airway resistance in ARDS also is unknown. We have used the technique of rapid airway occlusion during constant-flow inflation to measure the interrupter resistance (Rint,rs), which in humans is thought to correspond to airway resistance, in nine patients with ARDS under different inflation flows and volumes. This procedure was carried out at four levels of PEEP (0, 5, 10, and 15 cm H2O). We found that (1) at constant inflation volume, Rint,rs did not change significantly with increasing flow; (2) at constant inflation flow, Rint,rs showed an initial decrease followed by a distinct rise with increasing lung volume; (3) on average, PEEP did not significantly change Rint,rs measured during baseline ventilation; and (4) this latter finding occurred because patients behaved differently with application of PEEP, depending on their degree of lung inflation: Rint,rs measured close to full inflation almost invariably exhibited a rise, but values obtained at lower volumes exhibited the characteristic decrease of Rint,rs with increasing inflation volume.

We hypothesized that the ventilatory capacity needed to wean from mechanical ventilation (mv) depends on two variables: ventilatory endurance and the efficiency of gas exchange. We also hypothesized that these variables could be assessed from data readily available at the bedside, including tidal volume (VT) on mv and during spontaneous breathing (sb), ventilator peak inspiratory pressure (Ppk), and patient negative inspiratory pressure (NIP). Ventilatory endurance was evaluated using a modified pressure-time index: PTI = TI/Ttot x Pbreath/NIP, where Pbreath = Ppk x VTsb/VTmv. Defining VE40 as the minute ventilation needed to bring PaCO2 to 40 mm Hg, the efficiency of gas exchange was evaluated by calculating VE40/VTsb = (VE x PaCO2)mv/VTsb x 40. Because high levels of inspiratory effort might cause patients to reduce VTsb and thereby compromise CO2 elimination, we devised a weaning index (WI) that combines ventilatory endurance and the efficiency of gas exchange: WI = PTI x (VE40/VTsb). The study population comprised 38 patients with chronic obstructive pulmonary disease, adult respiratory distress syndrome, pneumonia, neuromuscular disease, and miscellaneous other conditions. They had been mechanically ventilated more than 3 days and were considered by clinical criteria to be ready for weaning. Of 46 weaning trials, 19 were successful, 2 were partially successful, and 25 failed. PTI and VE40/VTsb were higher in patients who failed (p less than 0.05), but neither variable alone had sufficient sensitivity or specificity to predict the outcome of weaning trials accurately.(ABSTRACT TRUNCATED AT 250 WORDS)

The time course of leukotriene generation in the adult respiratory distress syndrome (ARDS) was investigated by measurement of urinary leukotriene E4 (LTE4) excretion, the major urinary LT metabolite in humans. Sequential measurements were made in nine subjects entered into the study within 48 h of the onset of ARDS, defined by an arterial/alveolar PO2 ratio of less than 0.3 and radiographic evidence of diffuse bilateral pulmonary edema. Initial urinary LTE4 excretion was significantly elevated (1.250 +/- 0.050 ng/mg creatinine sulphate; n = 7) compared with a non-ARDS postoperative group (0.254 +/- 0.114 ng/mg; n = 5) and normal control subjects (0.035 +/- 0.010 ng/mg; n = 12). LTE4 excretion in the first 24 h was estimated to be 6.9 micrograms, representing a release of 0.1 micrograms/kg/h of peptido leukotrienes into the bloodstream. These values were physiologically important based on a comparison with the increased urinary LTE4 excretion observed after antigen-induced bronchoconstriction in allergic asthmatics (baseline LTE4, 0.06 +/- 0.04 ng/mg; postantigen, 0.56 +/- 0.14 ng/mg; 0.17 micrograms LTE4/24 h; n = 8). In subjects with ARDS, this pathologic LTE4 excretion persisted during a subsequent 5-day study period. Leukotriene E4 excretion was associated with persistent abnormalities in gas exchange, pulmonary edema, and lung compliance, suggesting an important role for peptido leukotrienes in the pathophysiology of ARDS.

We investigated the effects of positive end-expiratory pressure (PEEP) upon respiratory resistance during mechanical ventilation in 21 subjects anesthetized for surgery (normal subjects) and in 11 patients with the adult respiratory distress syndrome (ARDS). We measured tracheal pressure (Ptr) near the end of the endotracheal tube through a 1.5-mm ID catheter and airflow (V) at 0, 5, and 10 cm H2O PEEP (normal subjects) and at 0, 5, 10, 15, and 20 cm H2O PEEP (patients with ARDS). We computed respiratory system static elastance (Estrs), maximal (Rrsmax) and minimal (Rrsmin) inspiratory resistance by the end-inspiratory occlusion method during constant-flow inflation. Rrsmin represents the ohmic respiratory resistance, whereas Rrsmax is Rrsmin plus the additional respiratory impedance caused by the stress adaptation phenomena of the respiratory system tissues and to time constant inhomogeneities between lung units (pendelluft). The difference (Rrsmax - Rrsmin) has been termed DRrs. We also computed expiratory resistance (Rrsexp) at preselected volume (50% of expiration; Rrsexp50) and flow (0.3 L/s; Rrsexp0.3) using the equation: Rrsexp = (Pelrs(t) - Ptr(t]/Flow(t), where elastic recoil pressure (Pelrs) at time t was computed as:Estrs . V(t) + PEEP, in which V(t) is the volume above end-expiratory volume at time t. We found that (1) at PEEP 0, expiratory resistances (Rrsexp50: 7.38 +/- 1.92 versus 5.35 +/- 1.97 cm H2O.L-1.s) and DRrs (3.08 +/- 1.9 versus 1.66 +/- 0.77 cm H2O.L-1.s) were significantly higher in the ARDS group than in the normal group.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor alpha (TNF alpha) is a monokine released in response to endotoxin and has been suggested as a primary mediator of endotoxic shock. We have recently demonstrated that infusion of recombinant human tumor necrosis factor alpha (rTNF alpha) into sheep elicits a physiologic response in the lung that closely resembles endotoxemia. The present study examines the morphologic changes that accompany these alterations in pulmonary physiology. Five anesthetized, open-chest sheep received 0.01 mg/kg of protein (2.24 x 10(7) U rTNF alpha/mg) intravenously over 30 min. Lung biopsy tissue for light and electron microscopy was obtained from random lobes 7.5, 15, 30, 60, 120, 180, and 240 min after beginning the infusion. Pulmonary (Ppa) and systemic arterial pressures, cardiac output, and peripheral blood leukocyte number and differential counts were monitored throughout the study. Three control animals were treated in a similar manner but received either saline (n = 1) or rTNF alpha denatured by boiling for 30 min (n = 2). rTNF alpha caused an early increase in Ppa and peripheral blood leukopenia. Light microscopy revealed a threefold increase in the number of granulocytes per 100 alveolar profiles by 30 min and a fivefold increase by 2 h. From 60 min, increased alveolar wall thickness, red cell congestion, and peribronchovascular edema were apparent; from 2 h, there was increased cellularity of the alveolar walls and mononuclear cell infiltration of perivascular connective tissue. Electron microscopy revealed damage to alveolar Type I and II pneumonocytes and progressive endothelial injury from 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)

We measured extravascular density (EVD) and the pulmonary transcapillary escape rate (PTCER) for 68Ga-transferrin using positron emission tomography in 14 normal volunteers and 29 patients with radiographic infiltrates, including six patients with congestive heart failure (CHF), eight patients with the adult respiratory distress syndrome (ARDS), and 15 patients with focal pneumonia. Contralateral, radiographically normal regions were also evaluated in the patients with focal pneumonia. Mean EVD was elevated in the patients with CHF, ARDS, and pneumonia in regions of radiographic infiltrate compared with values from normal subjects (p less than 0.05), but it was not significantly different among the three patient groups. PTCER in normal subjects and in patients with CHF was not significantly different (21 +/- 11 versus 44 +/- 16 x 10(-4) min-1, respectively, p = NS). PTCER was elevated in regions of infiltrate because of either pneumonia (173 +/- 99) or ARDS (170 +/- 79). PTCER was also elevated in regions contralateral to those with focal infiltrate during pneumonia, even though these regions were radiographically normal and had normal EVD values. These results suggest that PTCER is a sensitive but nonspecific index of abnormal pulmonary vascular permeability, which may be useful for classifying patients in clinical studies of pulmonary edema.

Current knowledge of alveolar pathophysiology during early sepsis-induced acute lung injury (ALI) and the role of resident alveolar macrophages (AM) in mediating alveolar inflammatory events during sepsis is limited. Further, the effects of ibuprofen pretreatment upon alveolar pathophysiology and AM function during early sepsis-induced ALI is unclear. Utilizing repetitive bronchoalveolar lavage (BAL) in a porcine model of sepsis-induced ALI, we studied changes in alveolar cellular constituents, BAL protein content and molecular composition, and AM superoxide anion (O2-.) generation during early sepsis. The neutrophil percentage of recovered alveolar cells (17 +/- 8%, t = 300 min versus 2 +/- 1%, t = 0; p = 0.06) and the bronchoalveolar lavage total protein content (493 +/- 110 micrograms/ml, t = 300 min versus 109 +/- 18 micrograms/ml, t = 0; p less than 0.05) increased in septic animals. Increases in BAL fluid total protein were primarily due to low-molecular-weight plasma protein, indicating relative preservation of alveolar-capillary membrane size selectivity. Alveolar macrophages harvested following 300 min of sepsis generated significantly less O2-. following phorbol myristate acetate (PMA) stimulation compared to AM harvested at baseline. Ibuprofen pretreatment of septic animals completely blocked leakage of plasma proteins into the alveoli and attenuated neutrophil migration but did not prevent downregulation of AM O2-. generation. Increased alveolar-capillary membrane permeability, neutrophil migration into the alveoli, and downregulation of AM oxidant generation occur within hours of the onset of sepsis. Ibuprofen pretreatment significantly attenuates early sepsis-induced ALI without altering sepsis-induced AM dysfunction.

To test the hypothesis that PAF partially mediates endotoxin-induced lung dysfunction, we studied the effects of two structurally dissimilar PAF receptor antagonists (SRI 63-441 and WEB 2086) on endotoxin-induced lung dysfunction in chronically instrumented awake sheep. Each animal was studied three times in varied order: infusion of endotoxin alone (Escherichia coli endotoxin 0.5 micrograms/kg over 20 min [E]), infusion of the competitive platelet-activating factor (PAF) receptor antagonist alone, or with endotoxin given 1 h after beginning the 6-h drug infusion (E + SRI, E + WEB). Neither drug alone had significant effects on any of the measured variables, but both were able to abolish the pulmonary pressor effect of a 0.25-micrograms/kg bolus of PAF. SRI 63-441 (10 to 20 mg/kg/h) attenuated the endotoxin-induced pulmonary hypertension (peak pulmonary arterial pressure, 53 +/- 12 versus 65 +/- 7 cm H2O; p greater than 0.05) and fall in dynamic compliance of the lungs (to 65.1 +/- 9.8% baseline versus 32.6 +/- 5.1% baseline). Lung lymph flow increased 6.1- and 5.8-fold at 2 and 5 h for (E) versus 1.9- and 2.5-fold at identical time points for (E + SRI). SRI 63-441 attenuated the acute leukopenia noted after endotoxemia. WEB 2086 (20 mg/kg/h) similarly attenuated the late alterations in lung mechanics and lymph flow caused by endotoxin, but it had little effect on the early pulmonary hypertension and lung mechanic changes. Both agents significantly attenuated the rise in lymph thromboxane B2 levels after endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the effect of pentoxifylline (PTX) on the development of pulmonary edema in a model of adult respiratory distress syndrome in rabbits. Lung injury was induced by repeated saline lavages in adult rabbits weighing 2.5 to 3.5 kg. Rabbits pretreated with PTX (20 mg/kg bolus followed by 20 mg/kg/h infusion) developed significantly lower amounts of lung edema 4 h after saline lavage (extravascular lung water to dry weight ratio [W/D], 6.9 +/- 0.6 SD versus 8.9 +/- 0.5 in control animals). PTX produced a 25% increase in cardiac output, but there were no differences between treated and untreated groups in calculated pulmonary vascular resistance or microvascular pressure. To determine whether PTX could have lowered pulmonary venous resistance and thus lowered effective microvascular pressure for fluid filtration, we directly measured pulmonary artery and left atrial pressures, and measured by micropuncture the pressure in 20 to 40 microns subpleural venules in four open-chested rabbits 3 to 4 h after lavage. Venous resistance was low (venous pressure drop 0.9 +/- 0.1 mm Hg) and was unchanged by PTX infusion. To determine if PTX decreased lung water by accelerating active alveolar fluid reabsorption, a single 60-ml aliquot of saline was instilled into the lungs of normal rabbits treated with saline or PTX. Both groups had a similar decrease in lung water content 1 and 4 h later. Our data indicate that PTX reduces edema formation in rabbits after saline lavage, not by lowering microvascular pressures for fluid filtration or by acceleration alveolar fluid reabsorption, but possibly by its anti-inflammatory effect on neutrophil function.

The present study explored the possibility of using a short-term dobutamine infusion to disclose oxygen uptake/supply dependency. The effects of a standard dose of 5 micrograms/kg/min of dobutamine on oxygen-derived variables were studied in 73 acutely ill patients with heart failure (n = 24) or sepsis (n = 49). In each group, patients were separated according to their blood lactate concentrations (either above or below 2 mEq/L). In all patient groups, dobutamine resulted in significant increases in cardiac output and oxygen transport. However, oxygen consumption increased significantly only in patients with elevated blood lactate levels (cardiac failure: from 108 +/- 26 to 131 +/- 25 ml/min/M2, n = 8, p less than 0.01; sepsis: from 139 +/- 44 to 167 +/- 68 ml/min/M2, n = 16, p less than 0.01) and not in the other patients (heart failure: from 121 +/- 29 to 115 +/- 31 ml/min/M2, n = 28, NS; sepsis: from 158 +/- 39 to 166 +/- 45 ml/min/M2, n = 21, NS). These data, therefore, indicate that dobutamine at the dose used does not increase oxygen consumption in critically ill patients unless there is coexistent tissue hypoxia reflected by increased blood lactate levels. A short-term dobutamine infusion can be used to disclose an oxygen uptake/supply dependency phenomenon.

In patients with adult respiratory distress syndrome (ARDS), oxygen consumption (VO2) is pathologically dependent on oxygen delivery (DO2). Because of alterations in ventricular function, DO2 may be inadequate to satisfy oxygen demand and may contribute to multiple-system organ failure (MSOF). To determine whether there are differences in DO2, VO2, ventricular function, and MSOF, between survivors and nonsurvivors of ARDS, we studied 29 patients without cardiac disease early in the course of ARDS (hypoxemia, diffuse bilateral pulmonary infiltrates, and pulmonary artery occlusion pressure less than 18 mm Hg). Simultaneous hemodynamic, radionuclide cineangiographic, and oxygen transport measurements were made within 24 h of onset of ARDS. Thirteen survivors had greater DO2 and VO2 than did 16 nonsurvivors (p = 0.004 and 0.001, respectively). MSOF developed in no survivors and in 63% of nonsurvivors. In four survivors and in six nonsurvivors in whom DO2 was changed acutely, VO2 was dependent on DO2 (p = 0.014). Survivors had greater stroke volume index and right and left ventricular end-diastolic volume indices than did nonsurvivors despite similar right atrial and pulmonary artery occlusion pressures. There were no differences between survivors and nonsurvivors in biventricular ejection fractions. We conclude that survivors of ARDS have greater DO2 and VO2 than do nonsurvivors. Survival may be explained by the strong inverse relation between DO2 and development of MSOF.(ABSTRACT TRUNCATED AT 250 WORDS)

We conducted indicator dilution studies on the lungs of patients in the early phases of adult respiratory distress syndrome (ARDS) to test the hypothesis that capillary permeability was increased in patients with respiratory failure. Indicator dilution studies were performed using 51Cr-erythrocytes, 125I-albumin, 14C-urea, and 3H-water as tracers. The injectate was infused as a bolus into a central venous line. Peripheral arterial blood was collected and counted for radioactivity. Mathematical analysis of the indicator curves yielded cardiac output, measures of the product of capillary permeability and surface area for urea (PS and D1/2S), the intravascular lung volume (Vv), and the extravascular lung water volume (Ve). Permeability was separated from surface area by normalizing PS and D1/2S to Vv. Patients could be divided into 16 in whom blood gas determinations and radiologic criteria for ARDS were reversed and 23 in whom they were not. We examined indicator dilution and other measures of lung function in the two groups to determine whether significant differences in microvascular function existed. PS and PS/Vv were significantly higher in the nonreversal patients. Ve was above normal, but not different between groups. Linear regression analysis showed significant correlations for all of the following in the nonreversal group: Ve and all measures of permeability, pulmonary vascular resistance (PVR), and the inverse of permeability-surface area measures and AaDO2 and PVR. Only measures of Ve and PS correlated in the reversal group. These results support the hypothesis that capillary permeability is increased in patients with early ARDS and continuing respiratory failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Although it has been proposed that the circulating granulocyte (PMN) is an effector cell that causes pulmonary vascular injury in the adult respiratory distress syndrome (ARDS), the functional status of PMNs from patients with this disorder has not been previously defined. In the present study we found that PMNs in samples of pulmonary artery blood from patients with ARDS are in a functionally and metabolically activated state. The mean chemotactic index of PMNs from ARDS patients was 172 +/- 22 SEM compared with a mean chemotactic index of 79 +/- 8 of PMNs from normal subjects (p = 0.0001), a 227 +/- 24% increase over the control value. Respiratory burst activity of PMNs, as assessed by the chemiluminescence response (CL), was 151 +/- 12% of control (mean peak CL of PMNs from patients with ARDS, 166 +/- 31 cpm X 10(3); mean peak CL of normal PMNs, 105 +/- 16 cpm X 10(3); p = 0.04), suggesting that granulocytes from patients with ARDS are likely to generate increased quantities of active oxygen metabolites when stimulated. The chemotactic and chemiluminescence responses of PMNs from patients with ARDS were much greater than those of critically ill patients without ARDS, were enhanced in the absence of concurrent bacterial infection, and did not appear to be blunted by recent administration of glucocorticoids. The PMNs from patients with ARDS had increased ratios of intracellular cyclic GMP to cyclic AMP (165 +/- 5% of control, p = 0.0002), which may be related to the enhanced metabolic activity. Release of superoxide anion, a potential mediator of endothelial injury, was increased over that of control by PMNs from 4 of 8 patients with ARDS (mean, 205 +/- 71% of normal). The results suggest that the circulating PMN is in an activated state in patients with ARDS and may be more likely to release active oxygen species and other inflammatory mediators when perturbed, potentially contributing to pulmonary vascular injury and alveolitis.

Hemodynamics, blood gases, lung mechanics, and the distributions of ventilation-perfusion ratios (VA/Q) were studied before and after iv diltiazem, 0.5 mg/kg over 30 min, in 6 patients with pulmonary hypertension secondary to the adult respiratory distress syndrome (ARDS) ventilated with 7 to 20 cm H2O positive end-expiratory pressure (PEEP). Diltiazem decreased systemic and pulmonary arterial pressures without changes in cardiac output and in filling pressures of the heart, and with a slowing of heart rate. Pulmonary vascular resistances decreased from 401 +/- 59 to 329 +/- 58 dyne.s.cm-5.m2 (mean +/- SEM), p less than 0.01. Arterial Po2 decreased from 87 +/- 10 to 80 +/- 11 mm Hg (p less than 0.02) without changes in arterial PCO2, mixed venous PO2, and O2 consumption. Lung compliance and airway resistances did not change. Diltiazem increased true shunt from 23 +/- 5 to 30 +/- 7% of total blood flow (p less than 0.02) without other modification in the pattern of VA/Q distribution as measured by the multiple inert gas elimination technique. These results suggest that pulmonary vascular tone contributes to the maintenance of VA/Q matching in patients with ARDS.

Recent studies have shown that an influx of polymorphonuclear neutrophils into distal air spaces occurs early in the adult respiratory distress syndrome (ARDS). To study the mechanism of cell accumulation in this syndrome, we have evaluated the chemotactic activity in bronchoalveolar lavage fluid from patients with ARDS. Lavage fluid was obtained from 16 patients with ARDS within 24 h of endotracheal intubation and from 5 normal nonsmoking subjects. Lavage fluid from patients with ARDS had an average of 85% neutrophils on differential counts of cytologic preparations compared to less than 3% neutrophils for the control subjects. After removal of cells and lipids, lavage fractions of molecular weight greater than 10,000 daltons were chemotactic for human neutrophils in 14 of 16 patients, but no activity was seen with the normal lavages. Preliminary studies to identify the chemotactic factor were performed.

To establish whether a general dysfunction, i.e., an increase in permeability, had occurred in 16 trauma patients (6 with adult respiratory distress syndrome [ARDS]), we measured beta 2-microglobulin (beta 2MG), myoglobin (MG), immunoglobulin G (IgG), and transferrin (TF) concentrations in bronchoalveolar lavage fluid (BAL), serum, and urine as well as extravascular lung water content (EVLW) over a period of 14 days. Our results show a positive correlation (p = 0.03) between increases of EVLW, reflecting lung edema, and beta 2MG concentrations in urine of all patients with ARDS, indicating systemically increased permeability. Generalized increase of permeability can also explain the elevation of MG urine concentrations (p = 0.03) together with an EVLW increase, and an increase of BAL protein concentrations (IgG, TF, p less than 0.01) in the early post-trauma phase during the first 48 h after admission. In contrast, commonly used kidney function tests remained unchanged over the time course of 14 days.

To test the hypothesis that impairment after the adult respiratory distress syndrome (ARDS) is uncommon, we evaluated 41 ARDS survivors using ATS standards for determination of impairment. A total of 101 trials of pulmonary function tests were obtained between 1 and 388 wk after the onset of ARDS. It was possible to evaluate impairment at 1 yr or more after ARDS in 27 subjects. Eighteen of the 27 were impaired. The percentage of ARDS survivors who were impaired on the basis of FVC, FEV1, FEV1/FVC, and DLCOsb was 50.0, 61.1, 33.3, and 82.4%, respectively. Impairment was mild in 13 (72.2%), moderate in four (22.2%), and severe in one (5.6%). Smoking status had no predictive value in determining impairment. Physiologic indices of ARDS severity (maximal pulmonary artery pressure, lowest static thoracic compliance, and maximal level of PEEP) were found to be significantly different when those impaired 1 yr or more after ARDS were compared with those not impaired. Symptoms were found to have no association with impairment. We conclude that, using ATS criteria, impairment 1 yr or more after ARDS onset is common. Patient characteristics and symptoms after ARDS have no association with impairment 1 yr or more after ARDS onset, whereas physiologic indices of severity during ARDS do.

Although reduced lung compliance is a hallmark of the adult respiratory distress syndrome (ARDS), the role of increased airflow resistance in this disorder has not been well studied. Because animal models of ARDS show marked increases in airflow resistance and because mediators known to participate in lung parenchymal injury have also been implicated in models of increased airway reactivity, we hypothesized that increased airflow resistance is a major contributor to altered lung mechanics in human ARDS. We studied 10 mechanically ventilated patients with ARDS (criteria: PaO2 less than or equal to 70 mm Hg breathing FIO2 greater than or equal to 0.4; bilateral pulmonary roentgenographic infiltrates; Ppaw less than or equal to 18 mm Hg) measuring dynamic (Cdyn) and static (Cstat) compliance, airflow resistance across the lungs (RL), shunt fraction (QS/QT breathing FIO2 = 1.0), minute ventilation (VE), (a/A)PO2, dead space to tidal volume ratio (VD/VT), airflow (pneumotachograph), transpulmonary pressure (intratracheal pressure minus esophageal pressure) and volume (integrated from flow) at 50 L/min peak flow rate. Airflow resistance was uniformly elevated and averaged six times normal (5.32 +/- 0.92 cm H2O/L/s versus 0.88 +/- 0.08) (p less than 0.05). Cdyn correlated directly with (a/A)PO2. RL correlated with peak pressure, but did not correlate with VE, shunt, (a/A)PO2, or VD/VT. We conclude that increased pulmonary airflow resistance contributes significantly to the altered lung mechanics in ARDS. These data are consistent with studies of animal models of ARDS and long-term survivors of ARDS and may be secondary to tissue factors, airway hyperreactivity, or airway inflammation.

The predominant mechanism of the cardiac output reduction associated with positive end-expiratory pressure (PEEP) is unclear. Reported possibilities include decreased systemic venous return, increased pulmonary vascular resistance, or change in ventricular contractility. We investigated this question by studying 9 patients with the adult respiratory distress syndrome (ARDS) during PEEP application. We used an equilibrium radionuclide angiography method modified for improved right ventricular imaging to evaluate changes in left and right ventricular volume and contractility. Thermodilution cardiac output and stroke volume progressively declined (27 and 33% mean decrease, respectively) with increasing increments of PEEP. Right and left ventricular end diastolic counts, reflecting volume, also progressively diminished as PEEP increased (38 and 27% mean decrease in RV and LV counts, respectively; p less than 0.001 for both ventricles). A slight upward trend in ejection fraction was found for both ventricles. These findings support the concept that during PEEP application the reduction in cardiac output is due to biventricular reduction in blood volume. This biventricular volume reduction is compatible with either preload reduction to both ventricles because of impeded venous return or to change in ventricular configuration caused by external compression of both ventricles.

The mechanics of gas flow in endotracheal (ET) tubes have been evaluated extensively in vitro under static and dynamic conditions. Previous bedside determinations of respiratory system mechanics in patients with acute respiratory failure have been based on assumptions derived from in vitro measurements without direct measurement of in vivo ET tube resistance (RET). We hypothesized that the RET measured in vivo would be greater than those values obtained in vitro when peak flow rates and ET tube size were held constant. We measured airflow, volume (pneumotachograph), esophageal pressure (nasogastric-esophageal balloon), and airway pressure (airway catheter) in 10 patients intubated with no. 8.0 orotracheal tubes. We also studied the static and dynamic flow-pressure relationships for five different sizes of ET tubes in vitro (artificial lung) (6.0, 7.0, 7.5, 8.0, and 8.5). The static and dynamic values of RET and the Rohrer coefficients of linear and nonlinear resistance (K1 and K2) were similar to values previously reported in the literature. Although there was considerable individual variation, values of RET measured in vivo were generally higher than those derived from in vitro measurements at both peak flow rates tested, perhaps because of secretions, head or neck position, tube deformation, or increased turbulence. We conclude that ET tubes contribute significantly to total airflow resistance and that RET is often significantly greater than indicated by in vitro studies. Estimates of work of breathing in critically ill patients must take into consideration the contribution of in vivo RET on total pulmonary system resistance.

To test the hypothesis that regulation of tissue oxygen (O2) extraction is disturbed in adult respiratory distress syndrome (ARDS), the relationship between O2 availability and O2 extraction ratio (O2ER) was studied in 36 patients with pulmonary edema who met the criteria for either ARDS (n = 21) or acute congestive heart failure (CHF) (n = 15). We found that in response to changes in the levels of O2 availability there was a significantly (p = 0.01) greater negative correlation of change in O2ER for the CHF (r = -0.67) than for the ARDS group (r = -0.41). Whereas patients with CHF eventually died of pump failure and low O2 delivery, the ARDS group developed multiorgan failure, especially renal failure, despite significantly higher ratios of O2 availability to O2 consumption. These findings suggest that patients with ARDS have lost their ability to regulate their tissue O2 extraction to compensate for changes in the availability of O2 in order to meet demand. Pulmonary capillary endothelial injury, through its role on whole-body metabolism, may be responsible for this observation.

Pulmonary function studies were performed on 13 survivors of adult respiratory distress syndrome (ARDS). Six of these 13 patients had a forced vital capacity (FVC) and total lung capacity (TLC) less than 80% of predicted within 2 months of the onset of ARDS. Seven patients followed 6 months or more showed no significant difference between measured and predicted FVC (p = 0.26) or TLC (p = 0.12). The diffusing capacity of carbon monoxide was significantly lower than predicted normal values (p less than 0.001). Although the alveolar arterial oxygen tension gradient (delta AaPO2) was within the predicted normal range for 11 nonsmokers at rest, for 7 patients who exercised (1.0 less than VO2 less than 1.5 L/min), delta AaPO2 increased. The ratio of dead space to tidal volume decreased to less than 0.25 when VCO2 exceeded 1.0 L/min. We concluded that lung mechanics return to predicted normal values within 4 to 6 months after ARDS, but abnormalities of pulmonary gas exchange persist. Pulmonary vascular obstruction does not appear to explain persistent abnormalities of gas exchange.

This study was designed to determine whether acute alterations in oxygen delivery (DO2) induced by the institution of positive end-expiratory pressure (PEEP) would affect oxygen uptake (VO2) in patients with adult respiratory distress syndrome (ARDS). In 8 patients with ARDS who exhibited normal blood lactate concentrations, we evaluated the relationship between DO2 and VO2 during 3 consecutive periods: intermittent positive pressure ventilation (IPPV), continuous positive pressure ventilation (CPPV) with a 10 cm H2O PEEP, and finally CPPV with volume loading. Oxygen uptake was measured directly with a mass spectrometer system. Oxygen delivery was calculated as the product of cardiac output (thermodilution) and arterial blood oxygen content (Lex-O2-Con analyzer). By comparison with the IPPV period, application of PEEP led to a decrease of DO2, which returned to baseline values when volume loading was added to PEEP. In none of the patients did VO2 parallel the changes of DO2. They demonstrated, therefore, a properly enhanced oxygen extraction during the PEEP-induced decrease of DO2. We conclude that, when measured independently, DO2 and VO2 are not correlated in patients with ARDS with normal blood lactate who are mechanically ventilated with PEEP.

This study examined the effect of fluid balance on survival in ARDS. Of the 213 patients entered into a prospective data collection study, we evaluated 113 patients who met strict criteria for ARDS. Multiple variables were analyzed for as long as 14 days after intubation including cardiac output, pulmonary capillary wedge pressure, mean blood pressure, intake minus output (I-O), cumulative intake minus output (cum I-O), and change in weight (delta wt). We found significant differences in cum I-O and delta wt between survivors and nonsurvivors on almost every day. Survivors lost weight and had a significantly lower cum I-O compared with nonsurvivors. Logistic regression was used to determine if delta wt and cum I-O could predict survival. Patients who lost 3 kg or more weight had a much higher survival than did those who gained 3 kg or more weight (67 and 0%, respectively, on Day 14). Similar results were obtained using comparably low and high values for cum I-O. The logistic regression equations demonstrated that weight loss and low cumulative I-O correlated with improved survival. Although cause and effect relationships are difficult to determine from these types of analyses, they can be used to formulate prospective studies and predict survival in patients.

Humans with bacterial sepsis are predisposed to acute lung injury with respiratory failure and have an increased risk of pulmonary infection. Because the alveolar macrophage is the resident phagocyte in the lung and a defect in antimicrobial activity could predispose to infection, we assessed the functional integrity of these cells in vitro in a canine model of Escherichia coli endotoxin-induced lung injury with respiratory failure. Dogs were given 2 or 20 mg/kg of E. coli endotoxin 055:B5, and alveolar macrophages from pulmonary lavage were compared with those from control dogs. The physiologic criteria for the adult respiratory distress syndrome and pathologic confirmation of acute lung injury were produced in all endotoxin-treated animals. The production of acute lung injury with respiratory failure by E. coli endotoxin was associated with several alterations in alveolar macrophage function. Adherence was significantly reduced for cells from the endotoxin groups. The alveolar macrophages from endotoxin-treated animals differed from those from control animals, with significantly greater production of hydrogen peroxide, significantly greater peaks in chemiluminescence, significantly reduced phagocytosis of Staphylococcus aureus and E. coli at all times, and a diminished ability to kill cell-associated S. aureus and E. coli over time. These derangements could play a role in the therapeutic failures of pneumonia, an increased risk for nosocomial pneumonias, or the propagation of acute lung injury with respiratory failure.

We investigated the early changes of respiratory mechanics in mechanically ventilated patients with acute respiratory failure (ARF): 8 patients after acute exacerbation of chronic airway obstruction (CAO), 8 patients with cardiogenic pulmonary edema (CPE), and 8 patients with adult respiratory distress syndrome (ARDS). The patients were studied within the first day from the onset of mechanical ventilation. Flow, changes in lung volume, and airway pressure were measured using the 900C Servo Ventilator. End-inspiratory and end-expiratory occlusions of the airway were performed to obtain respiratory compliance and resistance. We found that: (1) acute exacerbation of CAO was characterized by high respiratory resistance (reflecting in part time-constant inequalities within the lung) and severe pulmonary hyperinflation, with "intrinsic" PEEP (PEEPi) up to 22 cm H2O (mean [SD], 13.5 [6.7] cm H2O); (2) PEEPi, even if not high, was present in almost all patients with pulmonary edema, averaging 3.8 and 3.0 cm H2O in ARDS and CPE, respectively; (3) respiratory resistance was increased in patients with CPE and ARDS who had no history of airway disease; (4) patients with ARDS were characterized also by low compliance (mean [SD], 0.035 [0.005] L/cm H2O) and high resistance, the latter also reflecting a substantial component caused by time-constant inequalities; (5) in all 24 patients, static respiratory compliance (and its reciprocal, elastance) was significantly correlated with the pulmonary oxygenation index, i.e., the PaO2/PAO2 ratio. We conclude that early assessment of respiratory mechanics in mechanically ventilated patients with ARF can provide better understanding of the patients' conditions as well as guidelines for therapeutic approach and weaning attempts.

There is considerable evidence suggesting that substrate (e.g., oxygen) distribution and utilization are abnormal in the setting of acute respiratory failure from the adult respiratory distress syndrome (ARDS). The mechanisms that may explain this anomalous relationship include: redistribution of cardiac output resulting in the nonuniform delivery of substrate to regional vascular beds; increases in flow through anatomic precapillary arteriovenous channels; increased organ metabolic demand; and direct injury to the regional microvasculature. To test these hypotheses, we used radiolabeled 15-mu microspheres to measure cardiac output, regional blood flow, total systemic shunt flow, oxygen uptake (VO2), and oxygen delivery (QO2) in dogs after phorbol myristate acetate (PMA: 30 micrograms/kg; n = 5)-induced neutrophil activation and acute lung injury. These studies demonstrated that neutrophil activation and acute lung injury was accompanied by an increase in the level of QO2 (e.g., 19.1 ml/min.kg) necessary to maintain a constant level of VO2. Although PMA-induced acute lung injury did not result in an increase in the fraction of cardiac output comprising total systemic shunt flow or in an increase in whole body metabolic demand compared to control animals (e.g., PMA = 0 micrograms/kg; n = 10), it did result in a significant decrease in cardiac output. In addition, there were significant reductions in blood flow to most organs after PMA-induced acute lung injury that were not reversible with intravascular volume expansion (80 ml isotonic saline/kg; n = 5). The exclusion of reversible volume depletion, anatomic shunts, and increased metabolic demand suggest a role for microvascular injury in the development of the regional blood flow abnormalities and the supply dependence of oxygen uptake observed in this study. In the context of the mechanisms of lung injury known to be operative in this model, these microcirculatory abnormalities may be mediated through the intravascular activation of circulating neutrophils.

The low rate of survival in patients with the adult respiratory distress syndrome (ARDS) may in part reflect a failure to consider that the lung's response to applied therapies may not be constant throughout the course of illness. To test this notion, we used hyperoxia to produce progressive lung damage in rats and administered dexamethasone at different times during O2 exposures of various lengths. Dexamethasone improved survival and decreased lung damage if given when exposure to hyperoxia was to be soon terminated; pulmonary inflammation was marked at the time at which the administration of dexamethasone led to increased survival. Dexamethasone worsened lung damage and diminished survival when given early during exposure to hyperoxia; inflammation was minimal early in the course of exposure to hyperoxia. These findings point to the need for a more analytical approach to research on therapy of ARDS; agents that are harmful at one time may be beneficial at another time.

Fibrin is often seen occluding the lung vessels of patients dying from ARDS and is surrounded by regions of lung necrosis. To learn if we could observe increased or focal fibrin deposition and assess the kinetics of plasma fibrinogen turnover during severe acute respiratory failure, we injected technetium 99m-labeled human purified fibrinogen (Tc-HF) and used gamma camera scanning for as long as 12 h in 13 sequential patients as soon as possible after ICU admission. The fibrinogen uptake rates were determined by calculating the lung:heart radioactivity ratios at each time point. Slopes of the lung:heart ratio versus time were compared between ARDS and mild acute respiratory failure (ARF). The slope of the lung:heart Tc-HF ratio of the 9 patients with ARDS (2.9 +/- 0.4 units) was markedly higher (p less than 0.02) than the slope of the 4 patients with mild ARF (1.1 +/- 0.4) and the 3 patients studied 5 to 9 months after recovery from respiratory failure (0.7 +/- 0.07). In the 1 patient with ARDS and the 2 patients with mild ARF studied both during acute lung injury and after recovery, the lung:heart Tc-HF ratio had decreased at recovery. To compare the pulmonary uptake of Tc-HF to 99mTc-labeled human serum albumin (Tc-HSA), 5 patients were injected with 10 mCi of Tc-HSA, and scanning of the thorax was performed with a similar sequential imaging protocol 24 h after conclusion of the Tc-HF study.(ABSTRACT TRUNCATED AT 250 WORDS)

The natural history of change in pulmonary vascular permeability (PVP) during the adult respiratory distress syndrome (ARDS) is unknown. Therefore, we evaluated PVP by measuring the pulmonary transcapillary escape rate (PTCER) for transferrin with positron emission tomography (PET) in 15 ARDS patients, including 5 patients studied within 4 days of onset and 13 patients studied at least 7 days after onset. In 3 patients, studies were performed at both early and late stages. These results were compared to 12 non-smoking adult volunteers. Regional PTCER and extravascular lung density (EVD) were determined from a 1-h PET scan after intravenous injection of gallium-68 citrate, which binds rapidly to native transferrin. Oxygenation, radiologic score, as well as outcome were recorded for each patient. Mean PTCER was highest during the early phase of ARDS (560 +/- 275 x 10(-4) min-1) although PTCER in the late ARDS patients was also significantly higher than in normals (319 +/- 187 vs 58 +/- 33 x 10(-4) min-1; p less than .01). EVD was similar in both early and late ARDS groups (.39 +/- .08 and .37 +/- .13 g/ml lung, respectively) and markedly higher than in normals (.22 +/- .05 g/ml lung, p less than 0.01). PTCER decreased in each of the 3 serial studies. The correlation between PTCER and EVD was poor, as were correlations for either PTCER or EVD versus changes in oxygenation, radiologic score, survival, or duration of ventilator dependency. In the late ARDS patients, PTCER was usually elevated even if EVD had returned to normal.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess its usefulness as an index of lung injury in critically ill patients with respiratory failure, the lung microvascular permeability surface area product for urea (14C-PSu) was measured using a multiple radioisotopic indicator dilution technique in 10 patients with the adult respiratory distress syndrome (ARDS) and in a control population of 5 patients without ARDS. The mean values for 14C-PSu and for extravascular lung water (EVLW) were both significantly elevated in patients with ARDS compared with those in control patients (14C-PSu: 18.7 +/- 4.4 versus 7.6 +/- 0.7, p less than 0.05; EVLW: 676 +/- 55 versus 269 +/- 53, p less than 0.001); 14C-PSu and EVLW were significantly correlated (R = 0.52, p less than 0.001). In the patients with ARDS, 14C-PSu and oxygenation, assessed as the alveolar-arterial oxygen difference, did not appear to be correlated. Repeated measurements of 14C-PSu were variable in the 3 control patients in whom 4 or more measurements were obtained (SD = 50, 57, and 54% of the mean values, respectively); 14C-PSu did not predict clinical outcome assessed by survival of individual patients with ARDS. These data suggest that measurement of 14C-PSu in critically ill patients is a clinically applicable parameter that reflects the degree of microvascular injury in groups of patients. However, our study did not indicate a clear advantage of 14C-PSu over EVLW in assessing lung injury in this patient population. The variability in 14C-PSu control patients also suggests that directional changes in 14C-PSu, as a measure of changes in the degree of lung microvascular dysfunction, should be interpreted with caution.