Transdermal clonidine reduced some withdrawal symptoms but did not increase smoking cessation.

BACKGROUND: Clonidine may be useful in controlling tobacco withdrawal and in facilitating smoking cessation. This study was developed to test the efficacy of transdermal clonidine in promoting smoking cessation. METHODS: We conducted a five-center, double-blind, placebo-controlled, randomized controlled trial of transdermal clonidine in conjunction with a minimal behavioral intervention for smoking cessation. The intervention was based on the American Lung Association's Freedom From Smoking program. Self report of not smoking was validated with exhaled air carbon monoxide of less than 8 ppm and salivary cotinine of less than 20 ng/mL. Transdermal clonidine therapy began 1 week before the target quit date: 0.1 mg/24 h for the first 4 days increasing to 0.2 mg/24 h for the next 3 days, if the lower dose was tolerated. The highest tolerated dose was then continued for 6 weeks after target quit day. Withdrawal symptoms were measured daily for the first 7 days after target quit day. RESULTS: A total of 213 patients were enrolled (106 active drug and 107 placebo). During the study, 15.5% of patients had drug therapy discontinued due to adverse effects, 24.5% (26/106) taking active drug vs 8.4% (9/107) receiving placebo. There was a significant reduction in anxiety score from 3.0 to 2.4 (placebo vs active) and irritability score from 2.2 to 1.7 (placebo vs active) during the first week after cessation. There was no reduction in other withdrawal symptoms. The overall 12-week abstinence rate was 33.0% (35/106) in the active drug group vs 34.5% (37/107) in the placebo group (not significant). CONCLUSION: This study demonstrated some reduction in early withdrawal symptoms with the use of a clonidine transdermal patch, but no increase in cessation rate, 6 weeks after medication had been discontinued.

Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study.

We performed a dose-response study of ipratropium bromide as a nebulized solution in patients with stable chronic obstructive pulmonary disease (COPD) using a double-blind crossover format. Five doses from 0.05 to 0.6 mg of ipratropium bromide as a nebulized solution, the standard dose of ipratropium bromide by metered-dose inhaler, 40 micrograms, and placebo were given in random order on separate days. End points were the maximal increase in FEV1 and FVC, and the area under the FEV1 and FVC curves in the 8 h after administration of each of the seven treatments. Forty-two patients completed all seven study days. By each of the above end points for FEV1, 0.4 and 0.6 mg of nebulized ipratropium bromide achieved significantly more bronchodilatation than did each of the other treatments. These two doses were not significantly different from each other, suggesting that the optimal dose in this patient population is 0.4 mg. After this dosage, the FEV1 increased by 440 +/- 194 (mean +/- 1 SD) ml at peak effect between 1 and 2 h, and significant bronchodilatation persisted for 6.5 h. Ipratropium bromide by metered-dose inhaler (40 micrograms) was equivalent to approximately 0.1 mg by nebulized solution and achieved only 63 to 73% of the bronchodilatation achieved by optimal doses of the nebulized solution. In terms of FVC, all treatments with ipratropium were significantly better than with placebo. The area under the FVC curve was significantly greater after 0.4 and 0.6 mg of nebulized solution than after other treatments. No significant adverse experiences occurred with any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Mild emphysema is associated with reduced elastic recoil and increased lung size but not with air-flow limitation.

Thirty-nine excised human lungs were examined to identify early changes in the small airways, their size distribution, and their elastic recoil in relation to mild degrees of emphysema. Elastic recoil measurement, single-breath nitrogen (SBN2) tests, and FEV1 were obtained from 18 lungs with no emphysema and 21 emphysematous lungs with no greater than Grade 5 emphysema score. The mean number of alveolar attachments per brochiole was determined from all the bronchioles cut in cross section. When the 2 groups of lungs were compared, the percentage of predicted elastic recoil of the nonemphysematous lungs was significantly greater at 50, 70, 80, and 90% of TLC than in the mildly emphysematous lungs. The TLC of the emphysematous lungs (% of predicted) was also significantly greater than in the nonemphysematous lungs. Pigment of the small airways was the only pathologic feature that was significantly greater in the emphysematous lungs than in the nonemphysematous lungs. Size distribution in the small airways was similar except for the airways zero to 0.2 mm, which were more frequent in the emphysematous lungs. When data from both groups were combined, elastic recoil was shown to be related to both the number of alveolar attachments (p less than 0.03) and the mean diameter of the small airways (p less than 0.01). We conclude that structural and functional changes in lungs with mild emphysema include reduced elastic recoil, increased lung size, and some size distribution changes in the small airways. Mild emphysema is not associated with air-flow limitation.

Radial traction and small airways disease in excised human lungs.

We studied 47 excised human lungs in order to examine the relationship between the number of alveolar attachments surrounding bronchioles 2 mm or less in diameter and the presence of small airways disease and overall lung function. Expiratory pressure-volume curves, the FEV1, and the single-breath nitrogen washout were obtained from 11 lungs without emphysema and 36 lungs with various degrees of emphysema. The lungs were subsequently inflation-fixed at 20 cm H2O. Gough sections were used to measure emphysema. Six to 10 blocks of tissue were cut at random from a midsagittal slice of lung tissue for the small airways and alveolar attachment study. We measured the inside diameters of all nonrespiratory bronchioles (2 mm or less in diameter) and made corrections for shrinkage during processing. The number of alveolar attachments on the outside wall of the bronchioles cut in cross section were obtained from all the sections observed. The mean number of alveolar attachments per bronchiole was determined for each lung. The histopathologic features of the bronchioles were evaluated by the method of Cosio and coworkers (2). We found a positive correlation between the number of alveolar attachments and the percentage of predicted FEV1 (r = 0.328, p less than 0.03) and the percentage of predicted closing capacity (r = 0.553, p less than 0.01). There was a negative correlation of the mean number of alveolar attachments and the small airways fibrosis score (r = -0.344, p less than 0.02). A correlation also existed between the number of alveolar attachments and the mean internal bronchiolar diameter (r = 0.561, p less than 0.001). We conclude that the alveolar attachments and elastic recoil are related to the size and function of the small airways.

The lungs and causes of death in the nocturnal oxygen therapy trial.

Autopsy findings and a morphometric study of the lungs were compared in 18 subjects receiving nocturnal oxygen and 15 receiving continuous oxygen in the National Heart, Lung, and Blood Institute Nocturnal Oxygen Therapy Trial (about half of those who died). The emphysema score, average interalveolar wall distance, central airway lesions, peripheral airway lesions, and the ratio of weights of left ventricle plus septum to right ventricle were similar in the two groups. The causes of death in the two groups were also similar. This evidence supports the hypothesis that the improved prognosis observed with continuous oxygen therapy nocturnal oxygen therapy in patients with severe chronic airflow obstruction and hypoxemia was due to treatment. There was a trend for there to be more interstitial fibrosis and type 2 alveolar epithelial cell hyperplasia in those treated with nocturnal oxygen; in the hands of one observer, the type 2 cell hyperplasia was significant.

Small airway disease is associated with elastic recoil changes in excised human lungs.

We studied 54 excised human lungs, 15 with no emphysema and 39 with varying degrees of emphysema, to examine the relationship of small airway disease and elastic recoil. We found a negative correlation between the total small airway pathology score and the mean internal bronchiolar diameter (r = -0.309, p = less than 0.03), as well as with other measurements of small airway size. The internal bronchiolar diameter correlated well with both the elastic recoil expressed as a percentage of predicted values at 70% of total lung capacity (r = 0.533, p less than 0.001) and elastic recoil expressed as an exponential constant k (r = -0.370, p less than 0.01). Fibrosis of the small airways was associated with a reduced internal bronchiolar diameter (r = 0.460, p less than 0.001), as well as the percentage of predicted elastic recoil at 70% of total lung capacity (r = -0.382, p less than 0.01) and elastic recoil expressed as an exponential constant k (r = 0.348, p less than 0.02). We have concluded that changes in elastic recoil seen in these lungs and fibrosis of small airways may be related by a common inflammatory process.

Sonographic identification of lung maturation in the fetal lamb.

Ultrasound evaluation of fetal lung development in utero could be a noninvasive method for frequent monitoring of the state of pulmonary maturity and predicting when parturition could occur with minimum or no risk of respiratory distress syndrome of the newborn. In cases of high-risk obstetric management in premature labor, this ability may be a particularly useful tool. To pursue this possibility, the lungs and livers of 13 living fetal lambs were successfully imaged with a modified clinical B-scanner under carefully controlled conditions; physiologic function tests on the excised lungs determined the state of pulmonary maturity. In eight cases, maturity or immaturity was correctly identified by sonographic criteria. The results wer ambiguous in four cases. One case of immature lung was incorrectly identified as mature. The trends established in these animal studies appear promising and with refinement may form the basis for sonographic assessment of fetal lung maturity in a clinical setting.

The morphology and morphometry of small airways disease (relevance to chronic obstructive pulmonary disease).

The morphologic and morphometric characteristics of the small airways of the lung and their relationship to airflow as measured by forced expiratory volume in one second (FEV1) were determined in 37 excised human lungs. After fixation the lungs were graded as to the degree of emphysema and the degree of small airway pathology. The internal diameters of the small airways were measured and corrected for shrinkage during processing. The mean bronchiolar diameter was positively correlated with the % predicted FEV1 (p less than 0.001) and negatively correlated with the small airway fibrosis (p less than 0.01). We conclude that fibrosis of the small airways of the lung is associated with a decrease in airway dimension which is in turn correlated with decreased FEV1 in excised human lungs.

Small airway dimension and size distribution in human lungs with an increased closing capacity.

Pulmonary function tests were obtained in 7 emphysema-free and 27 emphysematous lungs with minimal small airway disease. The lungs were divided into 2 groups on the basis of whether they had a small or large, i.e., increased closing capacity. The lungs were subsequently fixed and the small airways (less than or equal to 2.00 mm) from 6 to 10 blocks of tissue were counted and inside diameters were measured. There was a significant increase in the number of airways measuring 0.40 mm or less (p less than 0.03) and a decrease of airways measuring 0.81 to 1.0 mm (p less than 0.03) in the lungs that had larger closing capacities. When the data of both groups were combined there was a negative correlation between the mean bronchiole inside diameter as a function of the percentage of predicted closing capacity (r = -0.381, p less than 0.03) and a positive correlation between small airway inside diameter and the forced expiratory volume in one second (r = 0.595, p less than 0.001) and the maximal mid-expiratory flow rate (r = 0.527, p less than 0.01). We conclude that in lungs that are normal or involved with minimal lung disease, function can be related to the caliber of the small airways.

Functional correlations with mild and moderate emphysema in excised human lungs.

The relation between mold to moderate emphysema and lung function tests, including tests reported to identify "early" or mild disease, were examined using 24 excised human lungs, 5 with no emphysema, 11 with grade 5 or less emphysema, and 8 with as much as grade 50 emphysema. Static pressure volume curves, single breath nitrogen (SBN2) tests, maximal exemphysema. Static pressure volume curves, single breath nitrogen (SBN2) tests, maximal expiratory flow volume (MEFV) curves with air and a mixture of 80% He and 20% O22, and forced expiratory volume in one second (FEV1) were measured in all lungs. Negative correlations were found (r - -0.489, p less than 0.02) between the emphysema grade and the per cent predicted static lung recoil at 50% of total lung capacity and the emphysema grade and the per cent predicted FEV1 (r = 0.428, p less than 0.05). There was no significant correlation between the grade of emphysema and the SBN2, or MEFV test. Negative correlations were found between the elastic recoil, expressed as per cent predicted slope of Phase III (r = 0.482 p less than 0.02), and the per cent predicted FEV1 (r = -0.619, p less than 0.01). We concluded that mild to moderate degrees of emphysema are not correlated with single breath nitrogen test or flow volume curves using air or helium, but are better related to loss of elastic recoil in excised human lungs.

Diagnosis of adult respiratory distress syndrome associated with underlying severe emphysema.

Adult respiratory distress syndrome (ARDS) notably produces bilateral homogeneous alveolar infiltrates and decreased lung compliance. We encountered a patient whose severe underlying emphysema altered these distinctive clinical features. The chest roentgenogram showed bilateral infiltrates containing multiple radiolucencies that simulated a cavitary process. Also, lung-chest wall compliances measured during mechanical ventilation were higher than usually observed in patients with ARDS. We suggest that the pathologic features of the emphysematous lung with multiple blebs and decreased elastic recoil properties impart these unique findings. When ARDS develops in a patient with severe underlying emphysema, an atypical presentation may produce a confusing clinical picture.

Elastic recoil changes in early emphysema.

An attempt was made to determine if emphysema and static lung recoil were related in a group of 65 excised human lungs. We studied 23 normal lungs, 24 lungs with an emphysema score of 5 or less, and 18 lungs with an emphysema score greater than 5. A comparison of the percentage of predicted elastic recoil revealed that both emphysema groups were significantly different from normal lungs. In addition, the total lung capacities were significantly different between the three groups. In the group with an emphysema score greater than 5 we found a linear negative correlation between the extent of emphysema and percent of predicted elastic recoil at 90% total lung capacity (r = -0.696, p < 0.01). We found a negative correlation between the percentage of predicted elastic recoil and the lung volume (r = -0.612, p < 0.01). We conclude that a significant loss of elastic recoil and a significant increase in total lung capacity occurs in the early stages of emphysema.

The elastic properties of lobes of excised human lungs.

Static pressure-volume curves were obtained from the upper and lower lobes of 5 excised human lungs. Comparison of the upper and lower lobe pressure-volume curves showed a small but significant difference. The upper lobes contained a greater percentage of total lobar capacity above approximately 80 per cent of the lung volume. It would thus appear that the difference in lobar elastic properties could influence ventilation distribution in normal humans.

Abnormalities in lung elastic properties and surfactant function in adult respiratory distress syndrome.

We have examined the lungs from five patients who died with the adult respiratory distress syndrome (ARDS). Pressure volume curves were obtained and bronchoalveolar lavage fluid was studied on a surface balance. The pressure volume curves revealed reduced compliance compared to normal or near normal lungs. A significant loss of volume was also found. The data obtained from the surface balance studies show a normal range of minimum surface tension when compared to "normals," but the ARDS lung lavage fluid revealed an increase in surface film compressibility relative to "normal." The increased compressibility may be an important factor contributing to the stiff lungs of patients with the adult respiratory distress syndrome.

Effect of increased static lung recoil on ventilation distribution in excised human lungs.

The contour of a modified Fowler single-breath nitrogen washout was determined in 15 postmortem human lungs before and after static lung recoil had been increased by ventilation. Before ventilation, expiratory nitrogen versus volume curves exhibited the 4 phases similar to those seen in intact human lungs. The tests were repeated after ventilation with humidified air at room temperature for 3 hours at pleural pressures between -20 and +10 cm H2O at 15 breaths per min. After ventilation, the slope of the alveolar plateau (Phase III) decreased (P less than 0.01); the volume of Phase IV increased (P less than 0.01); and the closing capacity (Phase IV plus minimal volume) decreased (P less than 0.01). The data suggest that in the human lung the onset of Phase IV is not solely dependent on a pleural pressure gradient and that after ventilation, when static lung recoil is increased, the distribution of inspired gas in the excised human lung is more uniform, and at least some lung units empty more completely before zero transpulmonary pressure is reached.

Characteristics of pulmonary surfactant in adult respiratory distress syndrome associated with trauma and shock.

Broncho-alveolar lavage fluid was obtained from a 24-year-old man who developed the adult respiratory distress syndrome one day after massive trauma and hemorrhagic shock. The lungs were available 3 days later when organ transplantation was performed. When the various fractions of the lavage material obtained by centrifugation, including the purified surface-active lipid-protein aggregates, were examined on the film balance, they revealed the usual minimal surface tension of 16 to 18 dyne per cm at 37 degrees C, but the compressibility of the films from the lungs with adult respiratory distress syndrome was 5 to 10 times higher than the normal range. This suggests that surfactant films in the adult respiratory distress syndrome are less responsive to stress, and that as a result, a loss of film elasticity may contribute to the abnormal pressure-volume relationships observed with the intact lung. Changes in the lipid-to-protein ratios of the purified lipid-protein aggregates were also found, as indicated by the recovery of 3 lipid-protein aggregates with different isopycnic densities from the lung with adult respiratory distress syndrome; only one major aggregate could be recovered from the lavages of normal lungs.

The right ventricle in chronic airway obstruction: a clinicopathologic study.

In men 40 or more years of age at death, the upper limits of normal (means plus 2 SD) cardiac ventricular weights were 69 g for the right ventricle and 203 g for the left ventricle plus septum. Right ventricular thickness, as usually determined at autopsy, was a relatively poor index of hypertrophy. When one ventricle hypertrophies as a result of stress, the other tends to enlarge simultaneously, even if no stress on it has been evident. Right ventricular weight correlated positively, although not strongly, with severity of emphysema and with the severity of clinical chronic airway obstruction. Correlations between right ventricular weight and pathologic changes in the airways were weak or absent, except that subjects with abnormal large airways, but normal small airways, showed improved correlation between severity of emphysema and right ventricular hypertrophy, compared with the entire series. There was no correlation between left ventricular weight and severity of emphysema. The electrocardiogram was very reliable in the diagnosis of right ventricular hypertrophy (corpulmonale) due to chronic airway obstruction; the chest roentgenogram was somewhat less sensitive in this regard.

The morphologic features of the bronchi, bronchioles, and alveoli in chronic airway obstruction: a clinicopathologic study.

A 6-year semiquantitative clinicopathologic study revealed that among 196 men and 46 women 40 or more years of age at death, the severity of destructive emphysema was overwhelmingly the most important morphologic correlate of the clinical state of chronic airway obstruction. The pathogenic mechanisms whereby emphysema may lead to airway obstruction are probably multifactorial, but our data are consistent with a growing consensus that loss of small airway support by surrounding lung tissue in emphysema may cause kinking, tortuosity, and collapse of the airways, with subsequent increased airflow resistance and clinical obstruction. Pathologic changes (inflammation, fibrosis, increased goblet cells, and mucous gland enlargement) in large or small airways in the absence of much emphysema were very seldom associated with significant chronic airway obstruction, and correlated rather poorly with chronic airway obstruction, regardless of severity of emphysema. A subjective method of evaluating mucous gland enlargement in the large airways was consistently better than the Reid Index in correlations with clinical and anatomic abnormalities, presumably because it took all glands into consideration. The clinical features of subjects with severe centrilobular versus severe panlobular emphysema were essentially the same. "Blue bloater" and "pink puffer" clinical types of chronic airway obstruction continued to reveal differences in airway pathologic features, but no longer revealed a major difference in the severity of emphysema at the time of death. Presumably this was due, at least partially, to improved treatment, longer survival, and fusion into a similar end-stage. The total exposure to cigarette smoke was quantitatively related to clinical chronic airway obstruction and to both alveolar and airway pathologic features.

Bronchoconstriction and pulmonary hypertension during abortion induced by 15-methyl-prostaglandin F2alpha.

Patients have experienced severe breathlessness during second trimester abortion initiated by the intramuscular injection of 15-methyl-prostaglandin F2alpha (15-me-PGF2alpha). In four healthy women given 400 mug of 15-me-PGF2alpha to induce abortion, pulmonary function tests showed reductions in arterial oxygen tension, maximum expired air flow and vital capacity. Residual lung volume and the slope of phase III of the closing volume curves increased.