Lung structure and function with age in normal rats and rats with papain emphysema.

Intrapulmonary deposition of the proteolytic enzyme papain produces a lesion resembling emphysema in experimental animals. The natural history of this lesion has not been well defined. The present study was performed to evaluate changes in lung structure and function with aging in normal rats and rats exposed to an aerosol of papain at 2 mo of age. Groups of control and papain-exposed animals were studied at 4, 8, and 18 mo of age. The parameters of lung function studied were specific airways' conductance (G(aw)/TGV), diffusing capacity per unit of alveolar volume (D(Lco)/V(A)), diffusing capacity (D(Lco)), and functional residual capacity (FRC). Morphometric parameters were the postfixation lung volume (V(L)) and mean chord length (L(M)); internal surface area (ISA) and ISA extrapolated to both the mean V(L) of the corresponding papain group and a V(L) of 10 ml (ISA(10)) were calculated. At 4 mo of age L(M) and FRC were significantly increased and ISA, D(Lco)/V(A), and D(Lco) were significantly reduced in the papain group. At 8 mo of age L(M) was significantly increased and ISA was significantly decreased in the papain group: physiologic studies were not performed in this group. At 18 mo of age L(M) was significantly increased and D(Lco)/V(A), D(Lco), and ISA were significantly decreased. Neither progression nor healing of the lesion was observed despite similar lung growth in both groups. This study demonstrates that a single proteolytic lung injury produces a fixed deficit of lung parenchyma. Progressive lung destruction may require repeated or continuous lung injury.

Effects of elastase, collagenase, and papain on structure and function of rat lungs in vitro.

Present concepts of the roles of collagen and elastin in lung elastic behavior and maintenance of lung structure have been largely inferred from anatomical observations or from studies of isolated fibers in vitro. Based on the intimate association of elastin and collagen it has been postulated that elastin contributes little to elastic behavior and that collagen is the major determinant of lung structure. Using clostridial collagenase, pancreatic elastase, and papain we have selectively degraded these fibers and studied the resulting changes in elastic behavior and structure of rat lungs in vitro.Pressure-volume curves were recorded during continuous slow air inflation and deflation (10.5 ml/min) before and after the intratracheal instillation of 0.5 ml of control or enzyme solution. Surface tension-lowering activity of lavaged material was studied. All lungs were fixed inflated at 25 cm H(2)O pressure and whole lung sections were stained for elastin, collagen, and reticulin. Collagenase produced a marked susceptibility to pleural rupture but did not alter elastic behavior or lung structure. Elastase and papain produced segments of lung with increased compliance; this change was not due to alteration in surface forces but was associated with decreased tissue elastic recoil. Histologically, altered tissue recoil correlated well with evidence of damaged elastin fibers. In contrast to previous concepts these results suggest that elastin is the major connective tissue determinant of lung structure and elastic behavior.

Early bacterial clearance from murine lungs. Species-dependent phagocyte response.

Two sets of phagocytic cells are available to defend the lung against inhaled bacteria. Both resident alveolar macrophages and granulocytes from the circulation have been observed in pulmonary air spaces after the deposition of bacteria; their functional roles, however, have been defined. We rendered mice selectively granulocytopenic with heterologous antiserum in order to ascertain the relative contributions of these two groups of cells in intrapulmonary bacterial killing. The clearance of Staphylococcus aureus was unimpaired in granulocytopenic animals, confirming the primary role of the alveolar macrophages in the killing of these organisms. In contrast, granulocytopenic animals cleared only 10.0+/-7.0% of an inoculum of Klebsiella pneumoniae compared with 33.0+/-4.0% clearance in normal animals (P < 0.02), and Pseudomonas aeruginosa proliferated to 513% of baseline levels in granulocytopenic animals, whereas normal mice cleared 26.8+/-10.6% of the inoculum. These findings indicate that circulating granulocytes play a major role in the clearance of the latter two organisms. This variation in cellular response to different bacterial species suggests that the defense of the lung against pathogenic bacteria is more complex than has been previously assumed.

Bacterial growth in vivo. An important determinant of the pulmonary clearance of Diplococcus pneumoniae in rats.

Lung clearance of Diplococcus pneumoniae was markedly reduced in rats with acute hemorrhagic pulmonary edema produced by instillation of hydrochloric acid. Bacterial clearance was enhanced in both control and acid-instilled animals by pretreatment with a bacteriostatic antibiotic, tetracycline, 30 mg/kg. From these data the contributions of bacterial multiplication and bacterial elimination to net lung bacterial clearance were estimated. In control animals the constant for exponential bacterial elimination was -1.4283 (fractional clearance = 76% per h), and the doubling time for the pneumococcus was 170 min. In acid-instilled rats the elimination constant was -0.5336 (fractional clearance = 41% per h), and the doubling time of the pneumococcus was 47 min, approximating the doubling time of 42 min observed with pneumococci grown in broth. These results indicate that, in the case of pneumococci, both bacterial elimination and bacterial growth contribute to lung bacterial clearance in normal animals as well as animals with damaged lungs. In the present study changes in both parameters were required to explain the observed results in acid-instilled animals. The pulmonary pathogenicity of some bacterial species may be determined by their capacity for growth in the lung, since infection of the lung occurs when bacterial multiplication exceeds the rate of elimination of viable organisms.

The effect of complement depletion on lung clearance of bacteria.

We have investigated the effect of hypocomplementemia on early pulmonary clearance of four species of bacteria. The experiments were performed in an inbred animal model to minimize immunologic variability. Complement was depleted by cobra venom factor, and activity in serum was monitored with a phagocytic assay. Bacterial specific antibodies were examined by an indirect radioimmunoassay, and animals with high levels of activity were excluded from anaysis. 4 h after aerosolization with Streptococcus pneumoniae, complement-depleted animals had cleared only 75% of the initial number of organisms, whereas saline-treated controls cleared 91% (P less than 0.01). Aerosolization with Pseudomonas aeruginosa was followed at 4 h by a twofold greater growth of organisms in the complement-depleted animals (446% of original deposition) as compared to the saline-treated controls (211% of original deposition) (P less than 0.02). Clearance of Klebsiella pneumoniae and Staphylococcus aureus were similar in complement-depleted animals and saline-treated controls. These experiments suggest that hypocomplementemia predisposes to bacterial pneumonia and may explain the high incidence of pulmonary infections in patients having impaired complement activity. Our results further indicate that varying defense mechanisms may be involved with clearing the lung of differing bacterial species.

Determinants of lung bacterial clearance in normal mice.

The determinants of the lung clearance of Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus were studied in normal mice after exposure to an aerosol of viable bacteria and 99mTc-labeled dead bacteria. The fraction of bacteria in lungs that remained viable 4 h after exposure were: S. pneumoniae, 7.3%; K. pneumoniae, 121%; E. coli, 88.5%; S. aureus, 27.6%. The rate of physical removal of bacterial particles (Kmc) was determined from the change in lung 99mTc counts with time: Kmc ranged between 7 and 12%/h and and was similar in all species. The rate of mucociliary clearance and of intrapulmonary bacterial killing (Kk + Kmc) was calculated from the change in bacterial counts with time in animals that had received tetracycline to inhibit bacterial multiplication. Kk, the rate of intrapulmonary killing, was obtained by subtraction of Kmc from (Kk + Kmc). The calculated values for Kk were: S. pneumoniae, - 87%/h; K. pneumoniae, - 17%/h; E. coli, - 18%/h; S. aureus, - 22%/h. The rate of intrapulmonary bacterial multiplication (Kg) was estimated from the relationship of bacterial counts in tetracycline and nontetracycline-treated animals, assuming that tetracycline altered only Kg. Kg, expressed as the doubling time, was: S. pneumoniae, 310 min; K. pneumoniae, 217 min; E.coli, 212 min; S. aureus, infinity (no multiplication). The data indicate that the marked differences in the clearance of these species from the normal mouse lung result from the interaction of differing rates of in vivo bacterial multiplication and killing.

Spontaneous fibrinolysis in pulmonary embolism.

This study correlated levels of activated fibrinolysis with the presence, extent, and rate of resolution of angiographically documented pulmonary emboli. Pulmonary emboli demonstrable by angiography were associated with detectable fibrin split products in the serum of 24 of 25 patients. In the absence of increased fibrin split products, pulmonary emboli large enough to be demonstrated by angiography were found in only 2 of 25 positive pulmonary angiograms. Spontaneous resolution of pulmonary emboli could not be correlated with the the concentration or persistence of fibrin split products but did correlate well with the presence of a reversible precipitating cause. Thrombophlebitis in the absence of clinical evidence of pulmonary embolism was not associated with increased concentrations of fibrin split products in eight of nine patients. The one patient with increased fibrin split product concentration had evidence on lung scan of silent pulmonary embolism.

Hypoxemia in pulmonary embolism, a clinical study.

The cause of hypoxemia was studied in 21 patients with no previous heart or lung disease shortly after an episode of acute pulmonary embolism. The diagnosis was based on pulmonary angiography demonstrating distinct vascular filling defects or "cutoffs." It was found that virtually all of the hypoxemia in patients with previously normal heart and lungs could be accounted for on the basis of shunt-like effect. The magnitude of the shunting did not correlate with the percent of the pulmonary vascular bed occluded nor with the mean pulmonary artery pressure. The shunts tended to gradually recede over about a month after embolism. Patients without pulmonary infarction were able to inspire 80-111% of their predicted inspiratory capacities, and this maneuver temporarily diminished the observed shunt. Patients with pulmonary infarcts were able to inhale only to 60-69% of predicted inspiratory capacity, and this did not reverse shunting. These data suggest that the cause of right-to-left shunting in patients with pulmonary emboli is predominantly atelectasis. When the elevation of mean pulmonary artery pressure was compared to cardiac index per unit of unoccluded lung, it fell within the range of pulmonary hypertension predicted from published data obtained in patients with exercise in all except one case. This observation suggests that pulmonary vasoconstriction following embolism is not important in humans, although these data are applicable only during the time interval in which our patients were studied and in patients receiving heparin.

Intravascular coagulation associated with the adult respiratory distress syndrome.

In seven of 30 consecutive patients with the adult respiratory distress syndrome, disseminated intravascular coagulation (DIC) developed. Increasing respiratory dysfunction characterized by decreased effective static compliance and increased hypoxemia coincided with the development of DIC. Patients in whom DIC developed were characterized by a high incidence of bleeding, gangrene of the extremities, renal dysfunction, mortality and autopsy evidence of fibrin microthrombi in the lungs, kidney and skin. In 12 of 23 patients who did not meet the criteria for DIC, the platelet count decreased by at least 50 per cent of the initial values at some time during their illness. Fibrin microthrombi were found in the lungs in the majority of the patients subjected to autopsy. These data support the concept that depostion of platelet on damaged pulmonary capillary endothelium may be more common in the adult respiratory distress syndrome than the DIC syndrome.

Pharyngeal aspiration in normal adults and patients with depressed consciousness.

A sensitive technic using indium111 chloride was devised to investigate the occurrence of pharyngeal aspiration. Twenty normal subjects and 10 patients with depressed consciousness were studied. Forty-five per cent of the normal subjects aspirated during deep sleep. Normal subjects who did not aspirate were noted to sleep poorly. Seventy per cent of the patients with depressed consciousness aspirated. Aspiration of pharyngeal secretions occurs frequently in patients with depressed sensorium and also in normal adults during deep sleep. Bacterial pneumonia may result when aspirated bacteria are not effectively cleared. This may result when clearance mechanisms are impaired or when they are overwhelmed by large volumes of aspirated secretions.

Controlled oxygen administration in acute respiratory failure in chronic obstructive pulmonary disease: a reappraisal.

Controlled oxygen therapy may aggravate carbon dioxide retention during acute exacerbations of chronic obstructive pulmonary disease (COPD). Of 50 consecutive patients with COPD and acute respiratory failure, 13 required intubation because of carbon dioxide narcosis. With discriminant analysis of their arterial oxygen tension (PaO2) and pH on admission, a diagram separated patients into those at high risk and those at low risk for carbon dioxide narcosis. This diagram was then used to predict carbon dioxide narcosis in 73 patients with COPD and acute respiratory failure who were treated with controlled oxygen. In 16 of these patients carbon dioxide narcosis developed. Thirteen (81 per cent) were predicted by the diagram to be at high risk for this complication. Only two (4 per cent) patients judged by the diagram to be at low risk for carbon dioxide narcosis required mechanical ventilation. Utilizing an oxygen tension (PO2), carbon dioxide tension (PCO2) diagram a patient's ventilatory response was compared to that of ambulatory patients with COPD. These data suggest that hypoxemia and acidosis are more discriminatory for "carbon dioxide narcosis" than hypercapnia.

Treatment of pneumonia in patients at risk of infection with gram-negative bacilli.

Patients with a history of chronic debilitating disease due to a variety of causes are known to be at risk for infection with coliform gram-negative bacilli when they present with community-acquired pneumonia. Empiric treatment with broad-spectrum parenteral antibiotics is often begun in such patients pending the result of blood and other cultures. The optimal duration of broad-spectrum empiric therapy in such patients when cultures fail to reveal a specific pathogen is unknown. Review was made of the charts of 131 patients with community-acquired pneumonia admitted to the hospital and treated with broad-spectrum parenteral antibiotics in whom a specific pathogen was never isolated. Overall, 89 percent of these patients were cured without complication or relapse. Patients receiving broad-spectrum therapy for four days or less due to rapid clinical improvement had a successful outcome in 95 percent of cases. It is concluded that broad-spectrum parenteral antibiotic therapy can safely be abbreviated provided response to therapy is prompt.

Use of probenecid in ticarcillin-induced hypokalemia.

Probenecid has been suggested as a prophylactic treatment of penicillin-induced hypokalemia, the proposed mechanism being that penicillin will be prevented from acting as a nonreabsorbable anion binding potassium and resulting in increased urinary losses. A rapidly occurring hypokalemia, unresponsive to intravenous replacement of potassium, can be explained by redistribution rather than urinary wastage. We report a case where probenecid was administered for ticarcillin-induced hypokalemia without any significant benefits.

A new method of perineal reconstruction following vulvectomy.

We propose a method in which vulvar reconstruction could be accomplished at the time of vluvectomy. A full-thickness pedicle flap is rotated from the vaginal vault to the area of excision, providing excellent coverage without subsequent contracture, and obviating the need for clitorectomy. This technique may also aid in palliating the psychological trauma induced by genital disfigurement.

Pneumoconiosis among the activated-carbon workers.

The prevalence of respiratory symptoms and chest radiographic and spirometric abnormalities was assessed among 397 employees of an activated carbon plant. Definite radiographic findings of pneumoconiosis, consisting of p-type, rounded opacities in the lower lung fields without firbosis or coalescence, were present in 9.6% of men and were related to cumulative dust exposure. Lesser degrees of radiographic abnormality suggesting pneumoconiosis were present in 11% of men and 2% of women. Spirometric values were substantially lower in blacks than in whites. However, cumulative dust exposure was not an important determinant of pulmonary function in either race. Review of lung biopsy speciments that had been obtained previously in two employees revealed extensive carbon depositiion but minimal associated fibrosis. Prolonged inhalation of activated carbon dust leads to pulmonary deposition of carbon and raciographic signs of pneumoconiosis; such deposition has little, if any, effect on respiratory symptoms or pulmonary function.