Role of cyclooxygenase inhibition and hyperoxia in regulating pulmonary perfusion in dogs.

To assess the roles of cyclooxygenase inhibition and hyperoxia in regulating pulmonary perfusion, we studied 13 dogs with diffuse granulomatous lung disease (DGLD) and 13 normal dogs. Baseline observations were obtained at fractional inspired O2 (FIO2) 0.21 and 1.0 and repeated after infusion of meclofenamate (Mec; n = 8) or saline (n = 5). Resistance to flow was evaluated from the pulmonary end-diastolic gradient (PDG) and by ohmic pulmonary vascular resistance (PVR). Distribution of blood flow was evaluated with sulfur hexafluoride in DGLD and with multiple inert gas alveolar ventilation-perfusion (VA/Q) plots in normal dogs. Before infusion, there were no differences between the saline and Mec groups at either FIO2. Saline induced no significant changes at either FIO2. After Mec in DGLD, PDG at FIO2 0.21 rose from 4 +/- 2 to 6 +/- 4 mmHg (P < 0.04), PVR increased from 297 +/- 98 to 484 +/- 181 dyn.s.cm-5.m-2 (P < 0.01), whereas shunt flow (Qs/Qt) fell form 13.6 +/- 12.0 to 6.2 +/- 5.3% (P < 0.03). At FIO2 1.0 PDG rose from 3 +/- 2 to 4 +/- 3 mmHg (P < 0.02), PVR increased from 262 +/- 78 to 374 +/- 139 dyn.s.cm-5.m-2 (P < 0.01), whereas Qs/Qt fell from 14.5 +/- 13.3 to 6.4 +/- 5.2% (P < 0.02). After Mec in normal dogs, PDG at FIO2 0.21 rose from 3 +/- 1 to 4 +/- 1 mmHg (P < 0.015) and PVR increased from 256 +/- 92 to 340 +/- 101 dyn.s.cm-5.m-2 (P < 0.05); at FIO2 1.0 PDG and PVR were unchanged from preinfusion levels. In normal dogs, no parameters of VA/Q changed significantly with hyperoxia or Mec. These data suggest that perivascular inflammation enhances perfusion in DGLD by elaboration of vasodilator prostaglandins (PG). By inhibiting PG synthesis, Mec selectively increases resistance in diseased lung at FIO2 0.21 and lowers Qs/Qt. In contrast, there was vasoconstriction without flow redistribution in normal dogs, suggesting that vasodilator PGs contribute to the low tone in the normal pulmonary bed. The vasodilation without flow redistribution in both models during hyperoxia after Mec suggests an effect of O2 that is related neither to PG synthesis nor to hypoxic vasoconstriction.

Pulmonary vascular resistance in emphysema.

To assess the hemodynamic effects of pulmonary microvasculature disruption in emphysema, we examined resting pulmonary hemodynamics and lung function in 12 carefully identified patients with type A chronic obstructive pulmonary disease. Individuals with respiratory muscle weakness and intercurrent infection were excluded. Standard spirometry, helium dilution lung volumes, and single-breath carbon monoxide diffusing capacity (DCOSB) were obtained within 24 h of right heart catheterization. Resistance to pulmonary blood flow was assessed using the difference between pulmonary arterial (PA) diastolic and mean wedge pressures, and expressed as the pulmonary diastolic gradient (PDG). Mean FEV1/FVC was 51 +/- 8 percent, RV/TLC was 48 +/- 11 percent, DCOSB percent predicted was 62 +/- 29 percent, PaO2 was 72 +/- 11 mm Hg (FIO2, 0.21), and PaCO2 was 39 +/- 5 mm Hg. Mean PDG was 5 +/- 3 mm Hg (normal < or = 3 mm Hg) with normal PA pressures, indicating mildly elevated resistance to pulmonary blood flow. The PDG correlated most closely with DCOSB, rising in curvilinear fashion as DCOSB fell (r = -0.869, p < 0.001). These observations were compared with our previous report of analogous findings in patients with chronic, diffuse interstitial lung disease (ILD). In that group, PDG also increased curvilinearly as DCOSB fell (r = -0.839, p < 0.001). Subjects with FVC greater than 50 percent predicted had elevated PDG with normal pressures, while those with FVC less than 50 percent had pulmonary hypertension. The regression of PDG on DCOSB was strikingly similar to emphysema, although the slope in emphysema was less than that in ILD (p < 0.001). These observations suggest that elevated pulmonary vascular resistance in emphysema stems from disruption of the microcirculation in a fashion similar to that encountered in mild-moderate ILD. However, the magnitude of increase is not sufficient to generate resting pulmonary hypertension in the absence of disturbed gas exchange.

Control of shunt pathway perfusion in diffuse granulomatous lung disease.

To assess the roles of cyclooxygenase inhibition and alveolar hypoxia in controlling the distribution of pulmonary perfusion in granulomatous lung injury, we studied 15 dogs (anesthetized and ventilated) 4 wk after intravenous injection of complete Freund's adjuvant (0.5-0.75 ml/kg). Base-line hemodynamic and blood gas observations were obtained at fractional O2 concentration (FIO2) 0.21 and 0.10. Observations at each FIO2 were repeated 30 min after infusion of meclofenemate (2 mg/kg; n = 10) or saline (n = 5). Resistance to pulmonary blood flow was assessed using the difference between pulmonary arterial diastolic and left atrial pressures (PDG). Distribution of blood flow between normal and diseased regions of the lung was evaluated with measurement of inert gas shunt flow. Before infusion, there were no significant differences between the two groups at either FIO2. At FIO2 0.10 PDG rose from 3 +/- 1 to 7 +/- 3 mmHg in the saline group and from 3 +/- 1 to 8 +/- 3 mmHg in the meclofenemate group, although the shunt flow increased from 8.7 +/- 7.7 to 12.2 +/- 9.2% and from 10.7 +/- 11.0 to 17.6 +/- 18.3 in the two groups, respectively. Saline induced no significant changes at either FIO2. After meclofenemate, PDG at FIO2 0.21 rose to 7 +/- 4 mmHg (P less than 0.015) while shunt flow fell to 5.2 +/- 6.2% (P less than 0.0125), whereas at FIO2 0.10 PDG rose to 15 +/- 5 mmHg (P less than 0.001) while shunt flow rose only to 14.3 +/- 16.4% (P = NS). We propose that perivascular inflammation enhanced perfusion of abnormal lung by elaborating vasodilator prostanoids. By inhibiting prostanoid biosynthesis, meclofenemate selectively increased resistance in diseased lung at FIO2 0.21 and lowered shunt flow. The persistent rise in shunt during hypoxia after meclofenemate suggests that factors other than prostanoids may account for the apparent attenuation of hypoxic vasoconstriction in diseased lung.

Respiratory complications of cardiac transplantation.

The authors evaluated all respiratory complications of cardiac transplantation in a 10-year study of 94 consecutive recipients. Mean follow-up time was 20 +/- 17 months. The initial 20 patients were treated with azathioprine and prednisone, while the subsequent 74 patients received cyclosporine and prednisone. In the azathioprine group, respiratory infections accounted for 24 of 60 (40%) infections. Two-thirds of the respiratory infections occurred in the first 3 postoperative months and were generally localized processes (focal pneumonitis, nodule(s), abscess, or empyema). Gram-positive and gram-negative bacteria (8/30) and aspergillus (8/30) were the predominant pathogens. Respiratory failure occurred in 29% of infectious episodes. In the cyclosporine group, there were significantly fewer respiratory infections. There was also a reduction in the number of nonrespiratory infections; hence, the percentage of total infections due to respiratory causes, 26 of 50 (52%), was not significantly different. In contrast, however, nearly two-thirds of the respiratory infections in cyclosporine-treated patients occurred after the first 3 postoperative months, and were usually diffuse processes. Despite diffuse disease, respiratory failure was observed with similar frequency (19%). Pneumocystis carinii (9/31) and cytomegalovirus (CMV) (7/31) were the predominant pathogens. CMV pneumonitis tended to occur earlier than that due to P. carinii (2.9 +/- 1.9 mo vs. 9.8 +/- 11.2 mo, respectively), but there was considerable overlap. In comparison with infectious processes, there were 50% fewer noninfectious respiratory complications in both groups. These were primarily pleural (46%) or thromboembolic (18%) disorders. Four of five pulmonary emboli occurred in patients with intercurrent cardiorespiratory illness, and were detected only at autopsy. The authors conclude that respiratory infections account for one-half of all infections observed in cardiac transplant recipients, despite the reduced infection rate associated with the use of cyclosporine. Furthermore, respiratory infections in cyclosporine-treated patients exhibit different clinical and etiologic features than those seen in azathioprine-treated patients. Finally, occult thromboemboli may be difficult to recognize in cardiac transplant recipients because of the high incidence of coexisting cardiorespiratory disease.

Utility of airway endoscopy in the diagnosis of respiratory complications of cardiac transplantation.

We evaluated 39 episodes (in 32 patients) of pulmonary parenchymal infiltrates following cardiac transplantation with fiberoptic bronchoscopy (FOB) in a prospective study of 94 consecutive recipients. Initial FOB established the diagnosis in 24/39 (62 percent) instances. Subsequent examinations included repeat FOB (five), open lung biopsy (five), needle aspiration (two), and autopsy (nine), establishing 49 diagnoses. Specific pathogens were identified in 45 instances, neoplasm in two, and idiopathic interstitial pneumonitis in two. Bronchoalveolar lavage alone yielded diagnoses in 63 percent and transbronchial biopsy and bronchial washings/brushings in 46 and 43 percent, respectively. Transbronchial biopsy suggested idiopathic interstitial pneumonitis in 17 instances, but four had spontaneous clearing, and open lung biopsy or autopsy showed alternative diagnoses (particularly CMV and Aspergillus) in 11. The main complication of FOB was moderate (25 to 100 ml) hemorrhage after transbronchial biopsy (10 percent); no severe episodes occurred despite elevated pulmonary vascular pressures. In this population of immunocompromised hosts: (1) bronchoalveolar lavage is the most sensitive bronchoscopic technique for detecting infection; (2) transbronchial biopsy is not useful in detecting CMV or Aspergillus infection; (3) pulmonary hypertension is associated with some risk of moderate but not severe hemorrhage after transbronchial biopsy.

Meclofenamate enhances blood oxygenation in acute oleic acid lung injury.

To assess the role of vasoactive prostanoids in acute lung injury, we studied 16 dogs after intravenous injection of oleic acid (OA; 0.08 ml/kg). Animals were ventilated with 100% O2 and zero end-expiratory pressure. Base-line hemodynamic and blood gas observations were obtained 90-120 min following OA. Observations were repeated 30 min after infusion of meclofenamate (2 mg/kg; n = 10), or after saline (n = 6). Resistance to pulmonary blood flow was assessed using the difference between pulmonary arterial diastolic and left atrial pressures (PDG). Ventilation-perfusion (VA/Q) distributions were derived with the multiple inert gas technique. Prior to infusion, there were no significant differences between the two groups. PDG was elevated mildly above normal levels, and shunt flow was the principal gas exchange disturbance. Saline induced no significant changes in hemodynamics or gas exchange. Meclofenamate enhanced PDG to a small, significant degree and effected a 32% reduction in shunt flow (P less than 0.01). Perfusion was redistributed to normal VA/Q units with little change in low VA/Q perfusion or in overall flow. Arterial PO2 rose from 75 +/- 36 to 184 +/- 143 Torr (P less than 0.05). At autopsy, there were no significant differences in wet to dry lung weights. Prostaglandin inhibition redistributes perfusion from shunt to normal VA/Q units, thereby improving arterial PO2, without altering lung water acutely.

Patent foramen ovale complicating heart transplantation. A window on posttransplantation hemodynamics.

A patient developed refractory hypoxemia and right-to-left shunt across a patent foramen ovale after orthotopic cardiac transplantation. The right-to-left shunt was produced by volume overload of the donor right ventricle during the period of early postoperative myocardial depression and resolved with preload reduction and diuresis. Increased preload of the right heart needs to be considered in the early postoperative management after cardiac transplantation. The foramen ovale of the donor and recipient should be evaluated at operation by visual and probe examination and securely closed if either is patent, since this pattern of hemodynamic changes is common following cardiac transplantation.

Nocardia pneumonitis and the adult respiratory distress syndrome.

This report describes the progression of an acute regional Nocardia pneumonitis to diffuse pulmonary parenchymal disease in a previously healthy man. The pathophysiologic manifestations of disease evolved from that of a severe bacterial pneumonia to the adult respiratory distress syndrome. This progression may be representative of pyogenic bacterial pneumonias, which are associated with the syndrome even when the infections are adequately treated.

Effect of chronic airways obstruction on measurement of the single-breath carbon-monoxide-diffusing capacity.

We have examined the effect of chronic airways obstruction on the measurement of the single-breath carbon-monoxide-diffusing capacity (DLCLSB). We reviewed the results of 136 consecutive pulmonary function tests (comprising standard spirometry, helium dilution lung volumes and DLCOSB) obtained in patients who had an FEV1/FVC less than 70%. We calculated DLCOSB using two different values for alveolar volume (VA). In the first method (HeDL), VA was measured by single-breath dilution of helium during the test. In the second method (RbDL), VA was measured as the sum of the inspiratory vital capacity, performed during the test, and the residual volume, determined separately by helium rebreathing. The mean HeDL/RbDL, reflecting disparity between computations of DLCOSB in individual subjects was 0.85 +/- 0.13 in patients with moderate obstruction (40 less than or equal to FEV1/FVC% less than 60) and was 0.80 +/- 0.14 in those with severe obstruction (FEV1/FVC% less than 40). The mean HeDL/RbDL was lowest (0.73 +/- 0.12) in those with severe elevation of RV/TLC (RV/TLC% greater than 60). HeDL/RbDL correlated best with RV/TLC (r = -0.71, p less than 0.001). Unexplained variance in HeDL/RbDL was not significantly reduced by including the relationship between HeDL/RbDL and pulmonary function indices commonly used to measure airways resistance. These data suggest (1) the difference between HeDL and RbDL in patients with moderate and severe chronic airways obstruction is greater than previously reported; (2) the disparity between HeDL and RbDL stems from slow space ventilation rather than from increased resistance to air flow, and (3) HeDL underestimates gas transfer in poorly ventilated lung compartments.

Redistribution of pulmonary blood flow in interstitial lung diseases: the chest radiograph as a physiologic tool.

Posteroanterior radiographs of the chest showed enlargement of vessels in the upper lung fields in 18 of 29 patients with interstitial lung diseases, despite normal pulmonary wedge pressures and normal or reduced pulmonary blood volumes. The degree of such redistribution ("diversion") did not correlate either with the severity of pulmonary hypertension observed at cardiac catheterization or with radiologic assessment of predominance of disease at the lung bases. Diversion did correlate with several indices of disease severity: reduction in vital capacity, reduction in diffusing capacity, reduction in pulmonary blood volume and radiographic severity of parenchymal abnormalities. Furthermore, diversion correlated with lung height, a variable which was not statistically related to the other indices of disease severity. Distension of upper lung vessels occurs in interstitial lung diseases as the result of a decreased hydrostatic gradient over which the lung is perfused (decreased lung height), partial obliteration of the vascular bed (decreased pulmonary volume), and, more speculatively, decreased extravascular pressure (increased lung recoil).

Oxygen transport and oxygen consumption in shock.

A review of data from patients in shock, or with very low cardiac output, shows that oxygen consumption is maintained above 90 ml . min-1 . m-2, even at the lowest values of arterial oxygen transport. CAIN [3] has found a limiting value of oxygen delivery in anesthetized, hypoxic dogs of about 10 ml . kg-1 . min-1, below which oxygen consumption falls dramatically. No comparable value has been established for man in shock.

Radiologic assessment of pulmonary arterial pressure and blood volume in chronic, diffuse, interstitial pulmonary diseases.

Chronic, diffuse, interstitial pulmonary diseases may cause an increase in mean pulmonary arterial pressure (PAP) and a decrease in pulmonary blood volume (PBV). We compared 12 cardiovascular and three parenchymal assessments on plain chest radiographs with values of PAP and PBV obtained during cardiac catheterization in 29 patients with such diseases (progressive systemic sclerosis 20, sarcoidosis six, miscellaneous three) and normal pulmonary venous pressures. PAP ranged from 10 to 40 torr (mean 19, SD +/- 7), PBV from 6.4 to 10.8% of total blood volume (mean 8.4, SD +/- 1.2). PBV was significantly related to eight radiologic variables. PAP was significantly related to the severity of parenchymal disease and size of the central pulmonary arteries, both of which were assessed radiologically. Diversion of blood flow to upper zones was significantly related to restriction of the pulmonary vascular bed, but was not necessarily a sign of increased PAP. In general, pulmonary hemodynamic abnormalities appeared proportional to the radiologic severity of parenchymal disease.

The influence of heart rate on pulmonary arterial-left ventricular pressure relationships at end-diastole.

Increased resistance to blood flow stemming from structural and functional abnormalities of the lungs may cause pressure in the pulmonary artery to exceed that in the left ventricle at the end of ventricular diastole. This study explores the possible contribution of heart rate to the diastolic pressure gradient observed in the presence of acutely induced hypoxia. Pulmonary hemodynamics were examined in mongrel dogs with chronic atrioventricular dissociation with and without hypoxia at two different heart rates and during sequential increments in heart rate while the animals breathed room air. Studies during sequential pacing indicate that heart rate was of greater importance than blood flow in determining the magnitude of the gradient. Heart rate has to be considered when the causes of pulmonary hypertension and the effects of drugs or other agents on the pulmonary circulation are being investigated.

Prediction of the normal blood volume. Relation of blood volume to body habitus.

Predictions of blood volume (BV) assume the existence of a constant ratio between BV and body weight or surface area (SA). We examined the validity of this assumption by calculating BV from plasma volume and body hematocrit in 160 normal volunteers whose weights ranged from -38.7 to 210.8% of desirable weight (assessed by a modification of the Metropolitan Life Insurance Company Desirable Weight tables). BV is not a constant fraction of body weight or SA in this population. Its prediction from such constant ratios results in a large error of estimate which is systematically biased with respect to height and weight. BV prediction from the observed regressions of the parameter on weight and SA reduces the error substantially but remains biased with respect to height. BV prediction from the subject's degree of deviation from desirable weight affords a smaller error of estimate which is apparently free from systematic bias.