Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease.

Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV(1) and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV(1) and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 microg delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 microg, and advantages suggested by the safety profile at doses below 36 microg in this study, a dose of 18 microg once daily was selected for use in long-term studies of the safety and efficacy of tiotropium.

Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group.

STUDY OBJECTIVE: To study the safety and efficacy of aerosolized recombinant human DNase I in the treatment of idiopathic bronchiectasis. DESIGN: Double-blind, randomized, placebo-controlled, multicenter study. POPULATIONS: Three hundred forty-nine adult outpatients in stable condition with idiopathic bronchiectasis from 23 centers in North America, Great Britain, and Ireland. INTERVENTIONS AND MEASUREMENTS: Study patients received aerosolized rhDNase or placebo twice daily for 24 weeks. Primary end points were incidence of pulmonary exacerbations and mean percent change in FEV1 from baseline over the treatment period. RESULTS: Pulmonary exacerbations were more frequent and FEV1 decline was greater in patients who received rhDNase compared with placebo during this 24-week trial. CONCLUSIONS: rhDNase was ineffective and potentially harmful in this group of adult outpatients in stable condition with idiopathic bronchiectasis. This contrasts with previously published results that demonstrated efficacy of rhDNase in patients with cystic fibrosis bronchiectasis.

Clostridium difficile infection as a cause of severe sepsis.

Although colitis is often seen in critically all patients who have received multiple broad-spectrum antibiotics, there are no reports describing severe sepsis as a result of Clostridium difficile infection. We describe three cases of severe sepsis with local intestinal Clostridium difficile infection as the only identifiable etiology. The mechanism of severe sepsis may be a derangement of the gastrointestinal barrier function. This could result in absorption of microbes or endotoxin or activation of inflammatory cascades in the submucosa of the intestine or liver.

Pulmonary rehabilitation in the elderly patient.

Pulmonary rehabilitation in the elderly can be a rewarding experience for the patient and the health care provider. Rehabilitation programs are well established as a means of enhancing standard medical therapy, optimizing functional capacity, and restoring a patient to the highest possible level of independent function. The demonstrated benefits of pulmonary rehabilitation include an improved quality of life, increased exercise endurance, improved ability to perform daily tasks, reduced hospitalization, and improved psychosocial adjustment. Participation in a group program helps reduce social isolation, whereas postprogram patient-support groups help to keep patients motivated and positive in their outlook. Through pulmonary rehabilitation the elderly patient learns to accept and overcome the reality of his or her disease rather than dwell on its limitations. An individually tailored comprehensive rehabilitation program can make the difference between a fulfilling life and a life of pulmonary disability.

Delivery of topical antibiotics: pharmacokinetics and clinical problems.

Despite major advances in new therapeutic agents to treat pneumonia, pneumonia remains a major cause of morbidity and mortality in hospitalized patients. Topical antibiotics offer many potential advantages in the treatment and prevention of nosocomial pneumonia. These include a high delivery of the drug to the site of infection and the potential for little systemic absorption and, as a result, reduced side effects. The potential disadvantages include failure of topical therapy to reach all diseased areas of the lung and the emergence of resistant organisms. Failure of many of the previous clinical studies has been ascribed to these potential disadvantages. However, little attention has been paid in previous clinical studies to actual dosage and regional distribution of aerosolized antibiotics in the lung and the pharmacokinetics of the aerosol after deposition. One major exception to this has been the use of aerosolized pentamidine, in which careful attention has been paid to nebulizer design, dosage to the lung, regional distribution, and pharmacokinetics. It should serve as the model for the testing of topical antibiotics therapy in the future.

Delivered dose and regional distribution of aerosolized pentamidine using different delivery systems.

Aerosolized pentamidine has gained acceptance as a form of treatment for the prevention of Pneumocystis carinii pneumonia. However, different studies have used different delivery systems, making comparison of results difficult. This study was designed to determine the dose to the lung, regional distribution, extrapulmonary deposition, and side effects using four different delivery systems: the Respirgard II, the Aero Tech II, the Portasonic, and the Fisoneb. Ten homosexual subjects who were infected with HIV virus were studied. Particle size, as determined by cascade impaction, varied among nebulizers. Mass median aerodynamic diameter was 0.90 mu for the Respirgard II, 1.30 mu for the Aero Tech II, 1.40 mu for the Portasonic, and 3.90 mu for the Fisoneb. Subjects inhaled a solution containing 60 mg pentamidine in 3 ml of sterile water, and 1 ml of 99mTc bound to human serum albumin for each nebulizer system. Regional distribution was determined by comparing each deposition scan obtained by a posteriorly positioned gamma camera to the subjects' equilibrium xeon scan. The deposition scan was used to quantitate lung dose and extrapulmonary deposition. Marked differences were seen among delivery systems. Dose to the lung varied fivefold. The deposition in the lung, expressed as a percentage of the amount placed in the nebulizer, was 5.3 percent in the Respirgard II, 15.7 percent in the Aero Tech II, 17.30 percent in the Portasonic, and 26.4 percent in the Fisoneb (p less than 0.0001 by ANOVA). Wide differences in extrapulmonary deposition and side effects were noted among nebulizers (Fisoneb greater than Portasonic, Aero Tech II greater than Respirgard II). Regional distribution in the lung as measured by the AI, also showed differences, with the Respirgard having the most homogeneous distribution of aerosol (Respirgard greater than Portasonic, Aero Tech greater than Fisoneb). Regional distribution and extrapulmonary deposition varied in a manner consistent with the particle size of the nebulizers. These data should provide a framework for the comparison and design of future clinical studies using these delivery systems.

Benefits of a multidisciplinary pulmonary rehabilitation program. Improvements are independent of lung function.

We evaluated the conditions of 33 patients who completed an outpatient pulmonary rehabilitation program to determine what types of improvements occurred, and whether these changes were related to the baseline degree of ventilatory impairment, to determine whether rehabilitation was beneficial to patients, regardless of the degree of underlying lung dysfunction. Endurance measurements, including sustained submaximal performance on a cycle ergometer and the 12-minute walk distance (1,349 +/- 625 feet to 1,700 +/- 670 feet) increased significantly (p less than 0.01), as did multiple educational and subjective parameters. Maximal exercise performance on a graded cycle test improved very little, with a decline in the ventilatory equivalent for oxygen consumption (VE/VO2) being the only significant change (48.2 +/- 28.3 L/ml to 36.6 +/- 8.7 L/ml). Of the observed changes, only one endurance measurement, the sustained submaximal exercise performance, correlated with FEV1 (r = 0.5, p less than 0.01), but only if it was expressed as an absolute number (liters) and not as percent predicted. Lung function did not correlate with changes in the 12-minute walk distance, in maximal exercise performance on the cycle ergometer or with changes in educational and subjective parameters. We conclude that because the magnitude of change in both physiologic and psychologic parameters was not directly related to lung function, the benefits of rehabilitation can extend to all patients with chronic lung disease, regardless of the severity of preexisting pulmonary dysfunction.

Regional deposition of aerosolized pentamidine. Effects of body position and breathing pattern.

OBJECTIVE: To evaluate the effects of varying body position and breathing pattern on overall lung distribution of aerosolized pentamidine. DESIGN: Nonrandomized control trial with four weekly inhalational treatments. SETTING: The nuclear medicine department of a voluntary hospital. PATIENTS: Sixteen men with the acquired immunodeficiency syndrome (AIDS) or positive serology for the human immunodeficiency virus (HIV). Thirteen patients (81%) completed the study. INTERVENTIONS: Patients inhaled a solution of either saline and technetium-99m bound to diethylenetriamine penta-acetic acid or sterile water, pentamidine (60 mg), and technetium-99m bound to human serum albumin. On weekly visits, the patients inhaled the aerosol solution using four methods: sitting, supine, sitting with an abdominal binder, and sitting and breathing from residual volume with a shallow inspiration. MEASUREMENTS AND MAIN RESULTS: Deposition scans, obtained after each aerosol inhalation, were superimposed on each patient's equilibrium xenon scan, and a frequency distribution histogram was constructed. An asymmetry index was determined from this histogram. The lower the asymmetry index, the more homogeneous the aerosol distribution. Only use of the supine position showed a significant decrease in the asymmetry index (mean, 0.34 +/- 0.02 in the supine position, 0.48 +/- 0.03 in the sitting position; P less than 0.001). CONCLUSIONS: Aerosol distribution in the lungs was more uniform when administered to patients in the supine position. Patients receiving aerosolized pentamidine may benefit from inhalation in the supine position; these results should be verified by clinical study.

Relationship between tracheobronchial particle clearance rates and sites of initial deposition in man.

Mucociliary clearance was compared in three groups of normal subjects; each group inhaled a different type of aerosol (sebecate, iron oxide, and aqueous) labelled with 99Tc, to determine the relationship between deposition pattern and the subsequent total lung clearance. Standardization for deposition was accomplished by measuring a central to peripheral ratio (C/P) of deposited radioactivity in the thorax. Lung particle retention at 30, 60, 90, 120 min, and 24 h was measured, and compared at each time period to the C/P ratio. A linear relationship between the retention of aerosol at each time period and the C/P ratio was seen among all aerosols, e.g., aerosol with high C/P ratios had less retention of aerosol at a given time period than aerosols with more diffuse deposition patterns and lower C/P ratios. Furthermore, the relationship was similar to that of the more traditional measurement of regional deposition, the 24-h percentage retention. Lung particle retention was compared among aerosols, using analysis of covariance to standardize for C/P ratio. The intersubject variability was similar among all three aerosol groups. Thus, mucociliary clearance can be standardized in healthy subjects by using an initial deposition index, the C/P ratio, with similar accuracy to the 24-h percentage retention, as an index of aerosol deposition. The use of the C/P ratio, however, has distinct advantages over the 24-h retention, in that studies can be conveniently shortened, used with short lived isotopes, and be adapted to techniques investigating lung permeability instead of tracheobronchial clearance. An unexpected finding was the more rapid clearance of sebecate particles, compared with iron oxide or aqueous particles.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual pathway clearance of 99mTc-DTPA from the bronchial mucosa.

Many studies have reported clearance rates of 99mTc-DTPA from the alveolar epithelial surface, but few have measured clearance of this solute from the bronchial mucosa. Those that have attempted such measurements have discounted the possibility that 99mTc-DTPA may be removed from the bronchial airways by mucocilliary transport as well as by absorption through the epithelium. This study was designed to better approximate the rate of 99mTc-DTPA absorption across the bronchial epithelium by correcting the measurements of total 99mTc-DTPA clearance for mucus transport. On two separate study days, each normal, nonsmoking subject (n = 8) breathed an aqueous aerosol (2.0 microns MMAD, sigma g = 2.0) containing 99mTc bound to DTPA or human serum ablumin (HSA) (a relatively nonpermeable solute that is cleared only by mucus transport over the period of measured clearance) while seated in front of a gamma camera. Breathing pattern was standardized to produce a similar central deposition of particles on both study days. From measurements of retention versus time over a 1-h period, exponential rate constants (Ktot and Km) were determined for the clearance of 99mTc-DTPA and 99mTc-HSA, respectively. By modeling the airways as a single compartment with two possible routes of clearance, we determined the permeability rate constant, Kp, as Ktot minus Km. Results showed that mucus clearance (Km) accounted for two thirds of the total rate of 99mTc-DTPA clearance (Ktot) (mean Ktot = 0.00985, Km = 0.00698, and Kp = 0.00287/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Permeability of the bronchial mucosa to 99mTc-DTPA in asthma.

Previous investigators, using 99mTc-DTPA aerosol as a marker to assess epithelial permeability in asthma, did not find an increased permeability in this group. However, they either failed to deliver the aerosol to the optimal site (bronchial mucosa, not alveoli) or failed to account for mucociliary clearance in analyzing their results. We studied 10 asthmatics and eight age-matched control subjects using a dosimeter (Spira-Elektra 2) and a carefully controlled breathing pattern to deliver aerosol to the subjects' airways. Two aerosols were delivered on separate days in each patient; 99mTc-DTPA aerosol, and 99mTc-HSA (human serum albumin), using similar breathing patterns to ensure reproducibility of the deposition pattern with the two aerosols. From measurements of retention versus time over a 1-h period, rate constants Ktot and Km were determined for the clearance of 99mTc-DTPA and 99mTc-HSA, respectively. By modelling the airways as a single compartment with two possible routes of clearance, we determined the permeability rate constant, Kp, as Ktot minus Km. There was no significant difference between Ktot in normal subjects and asthmatics; however, because of the slower mucociliary clearance in the asthmatic group, and the relative importance of mucociliary clearance in determining the washout of 99mTc-DTPA aerosol, there was a significant difference in airway permeability between the normal subjects and the asthmatics (t1/2 = 296 min +/- 141 SD and 126 min +/- 58, p less than 0.01, in normal subjects and asthmatics, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Bilateral upper lobe Pneumocystis carinii pneumonia in a patient receiving inhaled pentamidine prophylaxis.

A 46-year-old man with AIDS, receiving inhaled pentamidine for Pneumocystis carinii pneumonia (PCP) prophylaxis, developed bilateral upper lobe infiltrates. Bronchoalveolar lavage confirmed the diagnosis of PCP. Therapy with intravenous trimethoprim-sulfamethoxazole (TMP-SMX) was begun, with gradual resolution of these infiltrates noted. An explanation for the development of upper lobe PCP, despite aerosol chemoprophylaxis, is presented and emphasizes the importance of aerosol particle size (and therefore of nebulizer type) on the distribution of inhaled pentamidine.

Quantitative deposition of aerosolized gentamicin in cystic fibrosis.

In cystic fibrosis (CF), the clinical effectiveness of aerosolized antibiotics is controversial. Previous investigators have not considered the type of nebulizer, droplet size, and dose to the lung in assessing the results of aerosol therapy. The present study tests the importance of these factors by standardizing an aerosol system for delivery of antibiotics and other agents to patients with CF. Particle size, distribution, and output from a commercially available nebulizer were measured. Thirteen patients with CF inhaled aerosol (MMAD = 1.1 micron) containing gentamicin (160 mg in nebulizer) and 99mTc-labeled human serum albumin. Patients' sputum and serum were analyzed for gentamicin levels by immunoenzymatic assay (Emit; Syva Corp., Palo Alto, CA). Using a gamma camera and suitable filters, central versus peripheral deposition (C/P ratio) and whole lung deposition were measured and related to sputum gentamicin levels. Gentamicin deposit averaged 12.3 mg +/- 5.9 (SD) or 7.69% of the original amount placed in the nebulizer. Peak sputum levels averaged 376.6 micrograms/ml +/- 275, whereas serum levels were undetectable in all patients. When peak sputum levels were normalized for the amount deposited, a close correlation with C/P ratio was obtained (r = 0.88, p less than 0.05). Furthermore, an inverse relationship was found between the C/P ratio and the %FEV1 (r = 0.76, p less than 0.05). Finally, a bell-shaped relationship between deposited dose and minute ventilation was seen in the patients (r = 0.88, p less than 0.05), i.e., an optimal minute ventilation was shown. These relationships may be important when designing future clinical studies.