Noninvasive measurement of pulmonary transvascular protein flux in normal man.

Onset of lung edema is usually associated with increase in the pulmonary transvascular flux of water and proteins. Clinical measurement of these parameters may aid in early diagnosis of pulmonary edema, and allow differentiation between "cardiogenic" and "noncardiogenic" types base on the magnitude of the detected changes. We have previously described a noninvasive method for estimating transvascular protein flux in lung (Gorin, A. B., W. J. Weidner, R. H. Demling, and N. C. Staub, 1978. Noninvasive measurement of pulmonary transvascular protein flux in sheep. J. Appl. Physiol. 45: 225-233). Using this method we measured the net transvascular flux of [113mIn]transferrin (mol wt, 76,000 in lungs of nine normal human volunteers. Plasma clearance of [113In]transferrin occurred with a T1/2 = 7.0 +/- 2.6 h (mean +/- SD). The pulmonary transvascular flux coefficient, alpha, was 2.9 +/- 1.4 X 10(-3) ml/s (mean +/- SD) in man, slightly greater than that previously measured in sheep (2.7 +/- 0.7 X 10(-3) ml/s; mean +/- SD). The pulmonary transcapillary escape rate is twofold greater than the transcapillary escape rate for the vascular bed as a whole, indicating a greater "porosity" of exchanging vessels in the lung than exists for the "average" microvessel in the body. Time taken to reach half-equilibrium concentration of tracer protein in the lung interstitium was quite short, 52 +/- 13 min (mean +/- SD). We have shown that measurement of pulmonary transvascular protein flux in man is practical. The coefficient of variation of measurements of alpha (between subjects) was 0.48, and of measurements of pulmonary transcapillary escape rates was 0.39. In animals, endothelial injury commonly results in a two- to threefold increase in transvascular protein flux. Thus, external radioflux detection should be a suitable means of quantitating lung vascular injury in human disease states.

Continuous negative external chest pressure decreases transvascular lung water transport in sheep after Pseudomonas bacteremia.

We studied the effects of continuous negative external chest pressure (CNECP) produced by a cuirass appliance on lung water and protein transport in sheep with chronic lung lymphatic fistulas. We compared data obtained during periods of mechanical ventilation (base line) to period of CNECP, using identical ventilatory support. Three groups were studied: six sheep were studied before and after application of CNECP for 1 h (control) and again after induction of a pulmonary vascular permeability defect (PVPD) by infusing live Pseudomonas bacteria (group I); another six sheep were studied under control conditions before and after prolonged application of CNECP for over 4 h (group II); 10 sheep were studied 24 h after a Pseudomonas infusion (PVPD), before and after 4 h of CNECP (group III). Compared to base-line data, CNECP produced significant increases in functional residual capacity and decreases in pulmonary blood volume, pulmonary artery pressure, and left atrial pressure in all groups. Lung lymph flow (Q(L)) was unchanged during the 1st h of CNECP and therefore was not significantly different from base line in group I, but after prolonged CNECP a steady-state decrease in Q(L) as well as a decrease in lung albumin transport was found in groups II and III (P < 0.05 by paired t test). We postulate that decreased pleural pressure during CNECP produces decreased hydrostatic filtration pressures, thereby decreasing Q(L). Reduction of both convective forces as well as microvascular surface area available for solute exchange account for decreases in lung albumin transport. Histologic examination and gravimetric studies on four sheep failed to demonstrate increase in lung water accumulation after 4 h of CNECP. We conclude that CNECP mechanically reversed the PVPD in our group III sheep. These physiologic effects of CNECP may be of benefit in the management of patients with adult respiratory distress syndrome.

Release of angiotensin converting enzyme by the lung after Pseudomonas bacteremia in sheep.

We studied release of angiotensin-converting enzyme (ACE) by the lung after acute injury associated with an increase in pulmonary vascular permeability. In eight adult sheep with chronic lung lymph fistulas, we measured lymph flow (QL), and both ACE activity and total protein content in lymph and plasma under base-line conditions and during 24 h after an infusion of live pseudomonas organism. Under base-line conditions, ACE activity in plasma was 4.93 +/- 0.43 U/ml (mean +/- SEM). The [lymph]/[plasma] ([L]/[P]) ratio for ACE was 0.93 +/- 0.18, compared with a ratio of 0.79 +/- 0.08 for albumin (mean +/- SD). We estimated the molecular weight of ovine ACE to be 145,000 by gel chromatography. Predicted [L]/[P] ratio for a molecule this size is 0.51. Thus, a substantial fraction of ACE activity detected lung lymph under base-line conditions (11.1 +/- 6.2 U/h; mean +/- SD) originated in the lung, and did not diffuse passively from plasma. After pseudomonas infusion, endothelial injury was demonstrated by a rise in pulmonary vascular clearance for total protein (Crp = QL X [L]/[P]). Crp = 3.1 +/- 0.6 ml/h before pseudomonas bacteremia, and rose to 6.7 +/- 1.2 ml/h by 2 h after onset of the infusion (means +/- SEM, p less than 0.05). Crp remained significantly elevated for at least 10 h after the infusion. Release of ACE into lung lymph doubled after acute lung injury and equaled 22.3 +/- 13.8 U/h at 4 h after onset of the infusion. ACE secretion into lung lymph had returned to baseline levels by 24 h after bacteremia. We did not observe a significant rise in plasma ACE activity after acute lung injury. Pseudomonas bacteremia in sheep results in acute, reversible lung injury associated with increased pulmonary vascular permeability, and increased release of ACE by the lung. Failure to detect a rise in plasma ACE content might result from dilution in the large vascular pool or rapid catabolism of the enzyme at some site distant from the lung.

Diagnostic yield of fiberoptic bronchoscopy in evaluating solitary pulmonary nodules.

STUDY OBJECTIVES: To evaluate factors affecting the diagnostic yield of flexible fiberoptic bronchoscopy in evaluating solitary pulmonary nodules (SPNs). DESIGN: Retrospective analysis of bronchoscopies performed over a 4-year period. SETTING: A tertiary teaching hospital. PATIENTS: One hundred seventy-seven patients with pulmonary nodules without endobronchial lesions who underwent bronchoscopy with brushing, washing, and transbronchial biopsy. RESULTS: There were 151 malignant and 26 benign lesions. The diagnostic accuracy of bronchoscopy in malignant and benign lesions were 64% (97 of 151) and 35% (9 of 26), respectively. The yield of bronchoscopy was directly related to lesion size (p < 0.001, chi(2)). When lesions were grouped according to distance from the hilum, yields of bronchoscopy in central, intermediate, and peripherally located lesions were 82, 61, and 53%, respectively (p = 0.05, chi(2)). When we stratified distance from the hilum by lesion size, the difference in yield was not significant. However, lesions

Chronic cavitary histoplasmosis. Failure of oral treatment with ketoconazole.

Ketoconazole appears to be a safe drug in the treatment of chronic cavitary histoplasmosis. Primary failure and relapse have been described, requiring amphotericin B, even after long therapy with ketoconazole. Four typical cases are presented. We caution about such potential failures and stress the importance of close observation of patients begun on therapy with ketoconazole for chronic cavitary histoplasmosis.

Noninvasive measurement of regional interstitial lung volume in sheep.

The noninvasive external radioflux detection method (ERD) measures net transvascular flux of tracer protein into and out of the lung extravascular compartment (EV) and time to zero flux between compartments. With this information we can now estimate regional interstitial volume in the field of the external probe (VIs). Dividing the mass of EV tracer by VIs, we obtain interstitial concentration ([Is]). Directly sampling plasma concentration of the tracer, we can construct plasma-interstitium equilibration curves that are analogous to plasma-lymph equilibration curves without invasive surgery. We completed 46 ERD studies in 21 sheep with chronic lung lymph fistulas. Sheep were studied under baseline conditions (n = 30) and after elevating left atrial pressure by mitral obstruction (n = 7), or intravascular volume infusion (n = 8), and increasing lung vascular permeability (n = 1). In each study we compared the slope of the regression through plasma-lymph concentration of tracer protein over time ([P]-[L], measured directly) with that through values of plasma-interstitial concentration ([P]-[Is], assessed noninvasively), an index of vascular permeability. For this correlation, r = 0.94, and the regression line approximates identity. Mean [Is] appears to approximate [L] in sheep.

Permeability of barriers to albumin flux in lungs of sheep resuscitated from hemorrhagic shock.

We assessed pulmonary endothelial and epithelial permeability and lung lymph flow in nine adult sheep under base-line conditions and after resuscitation from profound hemorrhagic shock. Animals were mechanically ventilated and maintained on 1% halothane anesthesia while aortic pressure was held at 40 Torr for 3 h. Systemic heparin was not used. After reinfusion of shed blood, sheep recovered from anesthesia and we measured lung lymph flow (QL), lymph-to-plasma concentration ratio for proteins, and time taken to reach half-equilibrium concentration of intravenous tracer albumin in lymph (t1/2). Twenty-four hours after bolus injection of radio-albumin we lavaged subsegments of the right upper lobe and determined fractional equilibration of the tracer in the alveolar luminal-lining layer. In each sheep we had measured these parameters 7 days earlier under base-line conditions. Animals were killed, and the lungs were used for gravimetric determination of extravascular lung water (gravimetric extravascular lung water-to-dry weight ratio) 24 h after resuscitation from shock. Pulmonary endothelial injury after resuscitation was evidenced by marked increase in QL, without fall in lymph-to-plasma ratio. Time taken to reach half-equilibrium concentration fell from 169 +/- 47 (SD) min in base-line studies to 53 +/- 33 min after shock. There was no evidence of lung epithelial injury. Gravimetric extravascular lung water-to-dry weight ratio was significantly increased in these animals killed 24 h after resuscitation (4.94 +/- 0.29) compared with values in our laboratory controls (4.13 +/- 0.09, mean +/- SD). These data demonstrate a loss of lung endothelial integrity in sheep after resuscitation from profound hemorrhagic shock.

Concentrations of immunoglobulin classes in subcompartments of the sheep lung.

The concentrations of IgA, IgG and IgM were measured in plasma, lung lymph and lung lavage fluid from adult sheep. Immunoglobulin concentrations in lymph and lavage fluid should fall sequentially during diffusive flux from the vascular compartment as a result of molecular sieving at the capillary endothelium and the alveolar epithelium. This was seen only for the IgG class. High concentrations of IgA and IgM in the interstitial (lymph) and luminal (lavage) compartments of the lung (relative to plasma levels) suggest either local synthesis of these classes or the existence of class specific active transport.

Differential permeability of endothelial and epithelial barriers to albumin flux.

We measured the flux of albumin between the vascular space and the pulmonary interstitial and luminal lining fluids in 20 adult sheep with chronic lung lymph fistulas. We sampled the bronchoalveolar lining layer by episodic fiberbronchoscopic lavage. A total of 62 alveolar lavages were performed at times ranging between 30 min and 60 h after intra-arterial injection of 100 microCi of 125I-labeled albumin. Samples of lymph and plasma were obtained simultaneously with lavage fluid, and the radioactivity and albumin content of all samples were measured and expressed as specific activity (counts/min . g albumin). We found that alveolar lavage fluid collected by our technique is not significantly contaminated by plasma or interstitial fluid proteins. Proteins present in alveolar lavage fluid and also present in plasma reach the alveolar space by a normal diffusive process, and not as a result of epithelial membrane damage occurring at the time of lavage. Lung epithelial permeability to albumin in small, but finite (4.3--5.8 x 10(-10) cm/s). Virtually all (greater than 92%) of resistance to albumin flux across the alveolocapillary membrane lies in the epithelial barrier. Increases in permeability of the respiratory epithelium, even minor, would have a marked effect on water and solute balance in the lung. Epithelial injury will potentiate pulmonary edema formation even in the presence of normal pulmonary microvascular pressure, plasma oncotic pressure, and endothelial permeability.

Changes in serum angiotensin-converting enzyme during cardiopulmonary bypass in humans.

In 15 male patients 45 to 74 yr of age, we measured angiotensin-converting enzyme (ACE) activity during and after cardiopulmonary bypass (all values were corrected for hemodilution occurring during surgery). Baseline ACE measurements (prior to onset of bypass) were 17.6 +/- 6.7 nmol of hippuric acid formed/min/ml (mean +/- SD). After the lung was isolated, serum ACE activity fell rapidly (half-clearance time, 39.5 min) and after 20 min during bypass reached a new steady state 33% below baseline values. Within 10 min of lung reperfusion, serum ACE rose to 90% of baseline values. ACE activity fell (half-clearance time, 198.3 min) and was again significantly below baseline for the period from 60 to 300 min after the end of cardiopulmonary bypass. Serum ACE activity had again returned to baseline when assessed 24 h after surgery; ACE activity in serum fluctuates rapidly, and it is rapidly cleared from serum at a site distant from the lung, probably the liver. Secretion of ACE into the vascular compartment by the lung is impaired in the period immediately after cardiopulmonary bypass.

Effect of prolonged recombency on pulmonary blood volume in normal humans.

We have observed a progressive decrease in pulmonary blood volume during sustained recumbency measured using two independent methods. Pulmonary capillary blood volume (Vc) was estimated by the method of Roughton and Forster (J. Appl. Physiol. 11: 290, 1957). We measured regional pulmonary blood volume (PBVR) using 99mTc-labeled erythrocytes (Gorin et al., J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 45: 225, 1978). In 21 studies in 19 normal subjects, we measured pulmonary CO diffusing capacity by the single-breath technique and calculated Vc with the subjects seated and at fixed times after lying down. After 5 min in the recumbent position, there was a mean 49% increase in Vc over the value in the seated position. With sustained recumbency Vc decreased 18.3%/h over 90 min. In 12 studies in 8 normal subjects, PBVR declined 16.7%/h with prolonged recumbency in studies lasting 60-90 min. The initial increase in Vc after subjects assumed a supine position has been well described. The subsequent fall in pulmonary blood volume to levels equal to or below that measured with the subject seated has not previously been reported.

Undiagnosed sleep apnea in patients with essential hypertension.

The prevalence of sleep apnea was studied in 46 middle- and older-aged men with "essential hypertension." Thirty-four age- and weight-similar normotensive men were also studied. Fourteen hypertensive men and three controls had sleep apnea syndrome, as defined as greater than ten apneas per hour of sleep. Hypertensive men with apnea tended to be more overweight and slightly older than the hypertensive men without apnea, but differences were not statistically significant. Individual men with apnea could not be distinguished by their answers on a questionnaire that elicited symptoms related to apnea. Seven hypertensive men with apnea were treated with protriptyline and one with uvulopalatopharyngoplasty, and apnea index (apneas per hour) decreased by 77% from pretreatment levels while mean blood pressure decreased from 149/95 mm Hg to 139/90 mm Hg. Undiagnosed sleep apnea syndrome may be associated with systemic hypertension in many middle- and older-aged men. In some, sleep apnea syndrome could be the cause of hypertension, and in others it may contribute to hypertension of another cause.

Arteriovenous acid-base disparity in circulatory failure: studies on mechanism.

The normal relationship between arterial and venous acid-base composition is altered in hemodynamic compromise. Because the mechanism of this phenomenon remains conjectural, we have studied the acid-base profile and the end-tidal PCO2 of dogs with normal or depressed hemodynamic status in association with either normal ventilation or respiratory arrest. Reductions in cardiac output widened the arteriovenous difference in PCO2 and pH, largely due to arterial hypocapnia but also to venous hypercapnia, and decreased end-tidal PCO2. The arteriovenous gradients for PCO2 and pH of -5.1 +/- 0.4 mmHg and 0.02 +/- 0.01, respectively, during normal hemodynamics widened progressively with graded circulatory compromise reaching values of -30 +/- 5 mmHg for PCO2 (P less than 0.01) and 0.35 +/- 0.05 for pH (P less than 0.01) during cardiac arrest. Development of this disparity, however, required the presence of substantial pulmonary ventilation, since respiratory arrest obliterated the arteriovenous gradients. We propose that arterial hypocapnia, which occurs in association with reduced CO2 excretion, is secondary to an increased ventilation-to-perfusion ratio that reflects a disproportionate decrement in cardiac output. Venous hypercapnia, on the other hand, results from a greater than normal addition of CO2 per unit of blood traversing the capillaries of the hypoperfused peripheral tissues and a diminished CO2 excretion because of pulmonary hypoperfusion. Titration of bicarbonate stores by ongoing production of organic acids might also contribute to venous hypercapnia.

Assessing acid-base status in circulatory failure. Differences between arterial and central venous blood.

To assess arteriovenous differences in acid-base status, we measured the pH and partial pressure of carbon dioxide (PCO2) in blood drawn simultaneously from the arterial and central venous circulations in 26 patients with normal cardiac output, 36 patients with moderate and 5 patients with severe circulatory failure, and 38 patients with cardiac or cardiorespiratory arrest. The patients with normal cardiac output had the expected arteriovenous differences: venous pH was lower by 0.03 unit, and venous PCO2 was higher by 0.8 kPa (5.7 mm Hg). These differences widened only slightly in those with moderate cardiac failure. Additional simultaneous determinations in mixed venous blood from pulmonary arterial catheters were nearly identical to those in central venous blood. In the five hypotensive patients with severe circulatory failure there were substantial differences between the mean arterial and central venous pH (7.31 vs. 7.21) and PCO2 (5.8 vs. 9.0 kPa [44 vs. 68 mm Hg]). Large arteriovenous differences were present during cardiac arrest in patients whose ventilation was mechanically sustained, whether sodium bicarbonate had been administered (pH, 7.27 vs. 7.07; PCO2, 5.8 vs. 8.6 kPa [44 vs. 65 mm Hg]) or not (pH, 7.36 vs. 7.01; PCO2, 3.7 vs. 10.2 kPa [28 vs. 76 mm Hg]). By contrast, in patients with cardiorespiratory arrest, large arteriovenous differences were noted only when sodium bicarbonate had been given (pH, 7.24 vs. 7.01; PCO2, 9.5 vs. 16.9 kPa [71 vs. 127 mm Hg]). We conclude that both arterial and central venous blood samples are needed to assess acid-base status in patients with critical hemodynamic compromise. Although information about arterial blood gases is needed to assess pulmonary gas exchange, in the presence of severe hypoperfusion, the hypercapnia and acidemia at the level of the tissues are detected better in central venous blood.

Removal of endobronchial foreign body by fiberoptic bronchoscopy.

A relatively large foreign body (ham bone) was seen in the left upper lobe bronchus of a 25-year-old woman and was successfully extracted with the use of a standard fiberoptic bronchoscope. Although the removal of foreign bodies by the fiberoptic bronchoscope has serious technical limitations, the use of this instrument should be considered when the foreign body is not within range of the rigid bronchoscope.

Effect of paraquat on serum angiotensin converting enzyme.

Intraperitoneal administration of paraquat to mice produced a linear dose-response increase (20 to 50 mg/kg of body weight) in serum angiotensin converting enzyme (ACE). The peak increase (31%) in ACE occurred after 50 mg/kg of paraquat and began at approximately 4 h. ACE was still significantly elevated 8 h after the administration of paraquat, but it began to return to normal 24 h later. Although serum ACE increased during the first 5 h after the administration of paraquat, lung ACE decreased. The enzyme that we measured in mouse serum was inhibited 100% by 10(-7) M of SQ 20881, a known ACE inhibitor.