The effect of inhaled histamine on human tracheal mucus velocity and bronchial mucociliary clearance

The effect of inhaled histamine on human tracheal mucus velocity (TMV) and bronchial mucociliary clearance (CB) was investigated in six healthy subjects using radioaerosol techniques in a randomized double-blind crossover study. Subjects inhaled repeated doses of either phosphate-buffered saline (PBS) or histamine, immediately after the inhalation of a radioaerosol and during the subsequent 2.5-h clearance measurements. Histamine was administered in concentrations previously demonstrated to induce a 20% fall in FEV1 at intervals permitting 90% recovery (mean recovery time = 25 min). Both TMV and CB were significantly increased by inhaled histamine (p less than 0.001). Average TMV throughout the 2.5-h studies increased from 4.9 +/- 1.3 to 8.4 +/- 1.6 mm/min. The increase in TMV above control values became apparent from 5 to 20 min after the first histamine administration. The percentage of aerosol clearance in 60 min increased 33%. The enhancement of CB became statistically significant at 21 min and persisted throughout the 2.5-h measurements (p less than 0.05). The increase in CB could not be attributed to differences in aerosol deposition because measurements of aerosol penetration were not significantly different between PBS and histamine studies. These data indicate that the bronchoconstriction caused by histamine is accompanied by an increase in tracheal and bronchial mucus transport. Release of histamine, as part of an inflammatory response, may alter mucociliary clearance in humans.     

The effect of bronchial obstruction on central airway deposition of a saline aerosol in patients with asthma

We studied the effect of bronchial obstruction on central airway deposition of a 0.9% saline aerosol (MMAD = 1.12 micron; sigma g = 2.04) labeled with 99mTc sulfur colloid. Radioaerosol was inhaled on 2 occasions by 8 patients with asthma. The degree of bronchial obstruction at the time of radioaerosol inhalation was measured by the FEV1. Mucociliary clearance of the radioaerosol was used as an index of regional aerosol distribution, because clearance from the densely ciliated central airways occurs more rapidly than from the peripheral, nonciliated regions of the lung. Using the Weibel lung model and an average mucociliary clearance rate of 1 mm/min, we determined that clearance of the radioaerosol from lung generations 1 to 5 (central airways) would be complete within approximately 90 min. Central airway deposition was therefore quantified as radioaerosol clearance in 97 min using a gamma camera. On Days 1 and 2, clearance ranged from 0 to 45% and from 0 to 17%, respectively; FEV1 as a percent of predicted FEV1 ranged from 36 to 88 on Day 1, and on Day 2 from 54 to 92. Radioaerosol clearance was inversely correlated with the baseline FEV1, with r = -0.7673 (linear regression analysis; p less than 0.05). These data suggest that the magnitude of bronchial obstruction is a determinant of aerosol distribution within the lung of patients with asthma and that increased bronchial obstruction enhances central airway deposition of inhaled particles.     

The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.

It has been postulated that hypertonic saline (HS) might impair the antimicrobial effects of defensins within the airways. Alternative non-ionic osmotic agents such as mannitol may thus be preferable to HS in promoting bronchial mucus clearance (BMC) in patients with cystic fibrosis (CF). This study reports the effect of inhalation of another osmotic agent, dry powder Mannitol (300 mg), compared with its control (empty capsules plus matched voluntary cough) and a 6% solution of HS on BMC in 12 patients with cystic fibrosis (CF). Mucus clearance was measured using a radioaerosol/gamma camera technique. Post-intervention clearance was measured for 60 min, followed by cough clearance for 30 min. Neither mannitol nor HS improved BMC during the actual intervention period compared with their respective controls. However during the post-intervention measurement there was a significant improvement in BMC for both the mannitol (8.7+/-3.3% versus 2.8+/-0.7%) and HS (10.0+/-2.3% versus 3.5+/-0.8%). There was also a significant improvement in cough clearance with the Mannitol (9.7+/-2.4%) compared with its control (2.5+/-0.8%). Despite premedication with a bronchodilator, a small fall in forced expiratory volume in one second (FEV1) was seen immediately after administration of both the mannitol (7.3+/-2.5%) and HS (5.8+/-1.2%). Values of FEV1 returned to baseline by the end of the study. Inhaled mannitol is a potential mucoactive agent in cystic fibrosis patients. Further studies are required to establish the optimal dose and the long-term effectiveness of mannitol.     

Influence of inhaled steroids on pulmonary epithelial permeability to Tc99m-dTPA in atopic asthmatic children.

The lung permeability of asthmatic children has been reported to be similar, lower, or higher than that of healthy subjects. The aim of this study was to clarify these discrepancies and also assess the effect of inhaled steroids on lung permeability. Tc99m-diethylenetriaminepentaaceticacid (Tc99m-DTPA) clearance in children with mild unstable asthma (n = 13; mean age 9.3 +/- 0.7 years) was compared with that of a group of healthy subjects (n = 11; mean age 8.9 +/- 0.8 years). Symptom scores, forced-expiratory volume in the first second (FEV1), and peak expiratory flow rate variability (PEFR-v) of asthmatics were recorded and an inhaled steroid (budesonid) was recommended after first scintigraphic evaluation for 8 weeks. Two consecutive scintigraphic studies were performed before and after treatment. Symptoms, FEV1, and PEFR-v significantly improved throughout the study. Baseline DTPA clearance rate in the asthmatics was significantly higher from that of control group (1.3 +/- 0.2 and 0.7 +/- 0.1%/min, respectively) (p < 0.05). DTPA clearance rate of asthmatics significantly increased to 1.7 +/- 0.3%/min at end of inhaled therapy (p < 0.05). Our data show that DTPA clearance in unstable asthmatic children is significantly higher than that found in healthy subjects, and that a higher rate was obtained following inhaled steroid therapy. Thus, the clinical significance of these observations needs further studies to test whether DTPA clearance index is a valid tool for monitoring asthmatic children and to explore the mechanisms involved in radioaerosol clearance rates in pediatric asthma.     

Effects of terbutaline in combination with mannitol on mucociliary clearance.

Beta2-agonists and osmotic agents stimulate mucociliary clearance (MCC) via different mechanisms which could potentially interact. The effects of inhaling terbutaline in combination with mannitol on MCC were investigated in nine healthy (aged 19+/-1 yrs) and 11 mild (aged 21+/-4 yrs) asthmatic subjects. Using 99mTc-sulphur colloid radioaerosol and a gamma camera, MCC was studied on four separate days with each of the following interventions: 1) terbutaline or its placebo inhaled 10 min before mannitol (in random, double blind); 2) terbutaline inhaled 5 min after mannitol; and 3) terbutaline inhaled 10 min before the control for mannitol. Lung images were collected over a period of 120 min postintervention and over 150 min in total. The mannitol-induced increase in clearance was transiently inhibited by terbutaline pretreatment and transiently enhanced when terbutaline was administered after mannitol both in asthmatic and healthy subjects. The order of administration of mannitol and terbutaline did not affect the total clearance of radioactive mucus over 140 min from the start of intervention in both groups. The pathways through which terbutaline and mannitol increase mucociliary clearance may transiently interact in an inhibitory or synergistic way, depending on the order of administration. However, this did not affect the overall increase in mucociliary clearance over 140 min.     

The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD

STUDY OBJECTIVE: To assess the effects of tiotropium on lung mucociliary clearance in COPD. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Outpatients of an urban-area university teaching hospital. PATIENTS: Thirty-four patients with COPD aged 40 to 75 years classified equally into two groups. INTERVENTION: Single (18 microg) daily dose of tiotropium inhalation capsules or of placebo for 21 days. METHODS: Six-hour tracheobronchial clearance of inhaled 99mTc-labeled polystyrene particles using a 48-h retention measurement to determine the "nontracheobronchial" deposition fraction. RESULTS: Test radioaerosol penetration into the lungs increased significantly (p < 0.003) as did FEV1 (p < 0.006) in the tiotropium-treated patients, but measured mucociliary clearance was not significantly changed despite the increased pathway length for clearance (mean +/- SE area under the tracheobronchial retention curve changed from 442 +/- 22 to 453 +/- 20%/h). Smaller (nonsignificant) decreases of radioaerosol penetration and FEV1 occurred in the placebo group together with a small (nonsignificant) decrease in the area under the retention curve. CONCLUSION: Twenty-one days of inhaled tiotropium, 18 microg/d, as a dry powder does not retard mucus clearance from the lungs.     

Effect of aerosolized uridine-5'-triphosphate on airway clearance with cough in patients with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormal ciliary structure and function and impaired mucociliary clearance. Because patients with PCD use cough clearance as an airway defense mechanism, we tested the hypothesis that aerosolized uridine-5'-triphosphate (UTP) would improve clearance during cough by its actions to stimulate Cl- secretion and mucin release by goblet cells. We measured clearance during cough in 12 patients with PCD (ages 14 to 71 yr, FEV1 43% to 89% predicted) in a double blind, randomized, crossover study after aerosolization of a single dose of UTP (5 mg/ml, 3.5 ml) or vehicle (0.12% saline, 3.5 ml). Clearance during cough (whole lung) was quantified during and after a series of controlled coughs by measuring the clearance of [99mTc]Fe2O3 particles via gamma camera scanning over 120 min. Safety parameters were recorded during and after drug delivery. Aerosolized UTP improved whole-lung clearance during cough as compared with vehicle (from 0 to 60 min: 0.40 +/- 0.07%/min [UTP] versus 0.26 +/- 0. 04%/min [vehicle] [mean +/- SEM], p = 0.01), and from 0 to 120 min: 0.38 +/- 0.05%/min [UTP] versus 0.25 +/- 0.04%/ min [vehicle], p = 0. 02). Aerosolized UTP is safe, with no serious adverse effects. Whole-lung clearance during cough in patients with defective ciliary function is enhanced after inhalation of UTP.     

The 24-h effect of mannitol on the clearance of mucus in patients with bronchiectasis

Study objective: To investigate the acute effect of mannitol on the clearance of mucus, and (1) the 24-h mucus retention, and (2) the mucus clearance rate and lung function 24 h after inhalation of a single dose of mannitol. DESIGN: Clearance of mucus was measured on 3 consecutive days using (99m)Tc-sulfur colloid radioaerosol and a gamma camera. INTERVENTIONS: Mannitol, 330 +/- 68 mg (mean+/- SD), was inhaled using a dry powder inhaler only on day 2. PATIENTS: Eight patients with bronchiectasis (age range, 29 to 70 years). Measurements and results: On each day, lung images were collected over 2 h and at 24 h. Key findings of the study are as follows: (1) the 24-h retention of mucus was reduced the day after mannitol had been inhaled, compared to the day without mannitol (day 1) in the whole right lung (57.6 +/- 6.2% vs 68.1 +/- 5.9%), central (47.5 +/- 6.7% vs 56.9 +/- 6.5%), intermediate (61.7 +/- 5.6% vs 73.8 +/- 5.5%), and peripheral regions (70.9 +/- 4.3% vs 86.6 +/- 4.6%)(p < 0.02); and (2) mannitol helped patients clear mucus within 2 h that might otherwise take up to 24 h, from the whole right lung and defined regions. However, clearance over 60 min measured 24 h after mannitol inhalation was not significantly different to baseline clearance without mannitol (8.7 +/- 1.9% on day 1 vs 9.7 +/- 3.7% 24 h after mannitol; p > 0.8). The patients maintained the same lung function the day before and after mannitol had been inhaled: FEV(1) (percent predicted), 79 +/- 5 on day 1 vs 80 +/- 5 on day 3; and forced expiratory flow, midexpiratory phase (percent predicted), 50 +/- 6 on day 1 vs 51 +/- 6 on day 3; p > 0.6). CONCLUSIONS: Mannitol inhalation acutely increases clearance of mucus, and this effect extends beyond the acute study period, resulting in decreased mucus retention at 24 h.     

Effect of a short course of rhDNase on cough and mucociliary clearance in patients with cystic fibrosis

The aim of the study was to measure the effect of a short course of recombinant human deoxyribonuclease I (rhDNase) on ciliary and cough clearance in a group of cystic fibrosis patients, using a radioaerosol and gamma camera technique. Patients were initially randomized to receive either rhDNase (2.5 mg qd) or placebo. Following the measurement of baseline clearance, patients were given a 7-day course of either rhDNase or placebo. The patient then returned on the seventh day for follow-up clearance measurements. This was followed by a 2-week washout period before the whole process was repeated with the alternative inhalation solution. On each of the study days, mucociliary clearance was initially measured for a period of 60 min (IC). This was followed by cough clearance (CC) measurements for 30 min, during which patients were requested to cough a total of 120 times. Post-cough clearance (PCC) was then measured for a further 60 min. Thirteen patients completed the study. Patients' age ranged between 18-38 years, and they had baseline values of FEV(1) of 27-103% of predicted values. Following completion of the course of rhDNase, there was a mean percent increase from baseline of 7.5% for FEV(1) and 5.4% for FVC% (P = 0. 03). There was a small, nonsignificant increase in IC (6.2 +/- 3.6%) on the rhDNase arm compared with the placebo arm (-2.3 +/- 2.9%), P = 0.1. No changes were seen in either CC (1.0 +/- 3.2% [rhDNase] vs. 1.9 +/- 2.4% [placebo], P = 0.9) or PCC (-0.7 +/- 1.5% [rhDNase] vs. 0.9 +/- 1.7% [placebo], P = 0.3). Patients who achieved a 10% or greater improvement in FEV(1) (n = 5) in response to rhDNase did not show any greater change in clearance than nonresponders. In conclusion, we were unable to demonstrate any improvements in either ciliary or cough clearance in response to a short course of rhDNase. The mechanism of action of this drug in vivo remains uncertain.     

Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis.

Bronchiectasis is a disease characterized by hypersecretion and retention of mucus requiring physical and pharmacologic treatment. Recently we reported that inhalation of dry powder mannitol markedly increases mucociliary clearance (MCC) in asthmatic and in healthy subjects (Daviskas, E., S. D. Anderson, J. D. Brannan, H. K. Chan, S. Eberl, and G. Bautovich. 1997. Inhalation of dry-powder mannitol increases mucociliary clearance. Eur. Respir. J. 10:2449-2454). In this study we investigated the effect of mannitol on MCC in patients with bronchiectasis. Eleven patients 40 to 62 yr of age inhaled mannitol (approximately 300 mg) from a Dinkihaler. MCC was measured over 90 min, in the supine position, on three occasions involving: mannitol or control or baseline, using a radioaerosol technique. On the control day patients reproduced the breathing maneuvers and the number of coughs induced by the mannitol. Mannitol significantly increased MCC over the 75 min from the start of the intervention compared with control and baseline in the whole right lung, central, and intermediate region. Mean (+/- SEM) clearance with mannitol was 34.0 +/- 5.0% versus 17.4 +/- 3.8% with control and 11.7 +/- 4.4% with baseline in the whole right lung (p < 0.0001). The mean number of coughs induced by mannitol was 49 +/- 11. In conclusion, inhalation of dry powder mannitol increased clearance of mucus and thus has the potential to benefit patients with bronchiectasis.     

Acute and long-term amiloride inhalation in cystic fibrosis lung disease. A rational approach to cystic fibrosis therapy

Cystic fibrosis (CF) is the most common inherited fatal disorder among Caucasians. Bronchial mucus in CF contains more potassium and less sodium, which may be due to increased sodium absorption, resulting in a reduced airway water content. We studied 23 patients with CF after inhalation of normal saline or amiloride (10(-3) M), a sodium transport blocker. Mucociliary clearance (MC) and cough clearance (CC) were determined with a gamma camera that traced the movement of 99mTc-labeled, hardened erythrocytes over a 1-h period after the patients inhaled these particles as an aerosol. Before and after each investigation pulmonary function tests (PFT) and blood pressure (BP) were measured. Sputum thread formation was measured by means of a filancemeter. Six of the patients also completed a 3-wk trial of amiloride inhalation therapy. MC increased significantly (p less than 0.001) after acute amiloride inhalation (bronchial deposition, 0.07 mg amiloride) compared with that in the saline control. CC also increased, but not as much as MC. After 3 wk of amiloride inhalation (2 times a day) clearance values (both MC and CC) were markedly enhanced (p less than 0.01); after a similar period of saline inhalation, clearance values were not different from baseline. Sputum filance values also decreased significantly after amiloride inhalation. There were no adverse effects of the amiloride inhalation compared with saline. We conclude that amiloride inhalation administered as a single dose or as long-term therapy is able to increase MC and CC in CF airways and that the effect of 10(-3) M amiloride inhalation on MC lasts at least 40 min. (ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of aerosolized uridine 5'-triphosphate on mucociliary clearance in mild chronic bronchitis.

Previous studies show that uridine 5'-triphosphate (UTP), a P2Y(2) receptor agonist, is effective at acutely enhancing mucociliary clearance in healthy, nonsmoking adults. UTP solution for inhalation is being developed by Inspire Pharmaceuticals under the compound number INS316. In a double-blind, randomized, crossover, placebo-controlled study we tested the single-dose effect of UTP in chronic smokers with mild chronic bronchitis (n = 15) by measuring the clearance of (99m)Tc-Fe(2)O(3) particles (4.0 microm mass median aerodynamic diameter [MMAD]) after inhalation of nebulized placebo (0.9% saline) and two doses of UTP (20 and 100 mg in the nebulizer). On each study day, gamma camera scanning was performed over a 2-h period. After an initial deposition scan, subjects inhaled placebo or UTP during the first 20 min of scanning. Analysis of whole lung clearance showed that the retention-time curves for each day were biphasic and that the earliest break point in the average curves occurred at 50 min. Mean particle clearance rate (Clr in %/min) through 50 min for placebo treatment was Clr = 0.65 +/- 0.27 whereas treatment with UTP showed Clr significantly increased to 0.95 +/- 0.48 and 0.93 +/- 0.44 for the 20-mg and 100-mg dose respectively, p < 0.005 for both as compared with placebo. These data show that mucociliary clearance associated with mild chronic bronchitis is acutely improved with minimal doses of aerosolized UTP, presumably because of its stimulation of ciliary beating and hydration of airway secretions.     

Domiciliary humidification improves lung mucociliary clearance in patients with bronchiectasis

Inspired air humidification has been reported to show some benefit in bronchiectatic patients. We have investigated the possibility that one effect might be to enhance mucociliary clearance. Such enhancement might, if it occurs, help to lessen the risks of recurrent infective episodes. Using a radioaerosol technique, we measured lung mucociliary clearance before and after 7 days of domiciliary humidification. Patients inhaled high flow saturated air at 37 degrees C via a patient-operated humidification nasal inhalation system for 3 h per day. We assessed tracheobronchial mucociliary clearance from the retention of (99m)Tc-labelled polystyrene tracer particles monitored for 6 h, with a follow-up 24-h reading. Ten out of 14 initially recruited patients (age 37-75 years; seven females) completed the study (two withdrew after their initial screening and two prior to the initial clearance test). Seven patients studied were non-smokers; three were ex-smokers (1-9 pack-years). Initial tracer radioaerosol distribution was closely similar between pre- and post-treatment. Following humidification, lung mucociliary clearance significantly improved, the area under the tracheobronchial retention curve decreased from 319 +/- 50 to 271 +/- 46%h (p < 0.07). Warm air humidification treatment improved lung mucociliary clearance in our bronchiectatic patients. Given this finding plus increasing laboratory and clinical interest in humidification mechanisms and effects, we believe further clinical trials of humidification therapy are desirable, coupled with analysis of humidification effects on mucus properties and transport.     

Value of technetium-99m diethyltriamine pentaaceticacid radioaerosol inhalation lung scintigraphy for the stage of amiodarone-induced pulmonary toxicity

BACKGROUND: Amiodarone is a potent antiarrhythmic agent that is limited in clinical use by its adverse effects, including potentially life threatening amiodarone-induced pulmonary toxicity (AIPT). The alteration of technetium-99m diethyltriaminepentaaceticacid (Tc-99m DTPA) radioaerosol lung clearance in AIPT was experimentally investigated. METHODS: Eighteen white New Zealand rabbits (initial weight 4.1+/-0.2 kg) were divided into two groups. AIPT group (n=13) was administered amiodarone (20 mg/kg BW) ip as a 5% aqueous solution for 6 week. The controls (n=5) were administered the same amount of 0.9% saline ip. Four rabbits of AIPT group died due to AIPT. The reminders of AIPT group (n=9) and controls underwent Tc-99m DTPA radioaerosol lung scintigraphy at the end of the treatment period. AIPT group was divided into two subgroups according to histopathologic evaluation. AIPT-I had interstitial pneumonitis (n=4) and AIPT-II had interstitial pneumonitis with fibrosis (n=5). RESULTS: The mean T(1/2) values of in control, AIPT-I, and AIPT-II groups were found 54+/-4.4, 39.2+/-11.7 and 114.6+/-16.7 min, respectively. The mean T(1/2) values of Tc-99m DTPA significantly differ than other groups (X(2)=11.78, P=0.02). The significantly increased T(1/2) values was noted in AIPT-II group when compared with control (P=0.001). In contrast, AIPT-I group has significantly lower T(1/2) values than control group (P=0.03). CONCLUSION: We suggested that Tc-99m DTPA radioaerosol inhalation lung scintigraphy provides an accurate evaluation about stage of lung toxicity and therefore may be a useful tool for the monitoring of AIPT.     

The effect of airway deposition on the assessment of lung injury by 99mTc-DTPA clearance--lung injury in interstitial lung diseases assessed by using the duplicated 99mTc-DTPA aerosol inhalation method

The 99mTc-DTPA aerosol inhalation method permits detection of pulmonary epithelial damage. We investigated one of several problems, airway deposition of inhaled aerosol, on the assessment of pulmonary epithelial permeability in healthy nonsmokers and patients with interstitial lung diseases. We used the rate constant of pulmonary 99mTc-DTPA clearance curve, k, as a parameter of the epithelial permeability. The alveolar-peripheral airway deposition of aerosol was estimated by the duplicated inhalation method, which we newly developed. The mean k in patients with interstitial lung diseases (2.52 +/- 0.72%/min, n = 8; p less than 0.01) was significantly greater than that in healthy nonsmokers (0.92 +/- 0.20%/min, n = 4). The alveolar-peripheral airway deposition was similar in both healthy nonsmokers and interstitial lung diseases (73.5 +/- 7.8% and 75.5 +/- 9.2%, respectively). The mean k corrected for alveolar-peripheral airway deposition (corrected k; kc) was higher in patients with interstitial lung diseases (4.08 +/- 1.63%/min; p less than 0.01) as compared with healthy nonsmokers (1.36 +/- 0.47%/min). The mean k was significantly greater than the mean kc in both groups (p less than 0.01, p less than 0.01). However, there was a significant correlation between the k and kc obtained among the subjects (r = 0.951; p less than 0.01). We, therefore, conclude that correction for alveolar-peripheral airway deposition was not necessary to distinguish the patients with interstitial lung diseases from the healthy nonsmokers using 99mTc-DTPA aerosol inhalation method although the correction was significant in the individual subjects.     

Targeting aerosol deposition in patients with cystic fibrosis: effects of alterations in particle size and inspiratory flow rate

STUDY OBJECTIVE: To determine if aerosolized medications can be targeted to deposit in the smaller, peripheral airways or the larger, central airways of adult cystic fibrosis (CF) patients by varying particle size and inspiratory flow rate. DESIGN: Randomized clinical trial. SETTING: Outpatient research laboratory. PATIENTS: Nine adult patients with CF. INTERVENTIONS: Patients inhaled an aerosol comprised of 3.68+/-0.04 microm saline solution droplets (two visits) or 1.01+/- 0.2 microm saline solution droplets (two visits) for 30 s, starting from functional residual capacity and breathing at a slow or faster inspiratory flow rate. On all visits, the saline solution was admixed with the radioisotope (99m)Tc. Immediately after inhalation, a gamma camera recorded the deposition pattern of the radioaerosol in the lungs. Deposition images were analyzed in terms of the inner:outer zone (I:O) ratio, a measure of deposition in an inner zone (large, central airways) vs. an outer zone (small airways and alveoli). MEASUREMENTS AND RESULTS: For the 3.68-microm aerosol, I:O ratios averaged 2.29+/-1.45 and 2.54+/-1.48 (p>0.05), indicating that aerosol distribution within the lungs was unchanged while breathing at 12+/-2 L/min vs. 31+/-5 L/min, respectively. For the 1.01-microm aerosol, I:O ratios averaged 2.09+/-0.96 and 3.19+/-1.95 (p<0.05), indicating that deposition was predominantly in the smaller airways while breathing at 18+/-5 L/min and in the larger airways while breathing at 38+/-8 L/min, respectively. CONCLUSIONS: These results suggest that the targeted delivery of an aerosol to the smaller, peripheral airways or the larger, central airways of adult CF patients may be achieved by generating an aerosol comprised of approximately 1.0-microm particles and inspiring from functional residual capacity at approximately 18 L/min and approximately 38 L/min, respectively.     

Effect of terbutaline administered from metered dose inhaler (2 mg) and subcutaneously (0.25 mg) on tracheobronchial clearance in mild asthma

Tracheobronchial mucus clearance was measured in nine mild asthmatics, using an objective radioaerosol technique, on 3 separate days at intervals of 1 week. Immediately after radioaerosol inhalation, drug or placebo was administered via subcutaneous injection (SC) plus metered dose inhaler (MDI)--2 puffs. Three randomized treatments were used: saline placebo SC plus 2 mg terbutaline by MDI (1 mg per puff); 0.25 mg terbutaline SC plus placebo (propellants and surfactant only) by MDI; and double placebo. Changes in lung mucociliary clearance showed an inverse relationship to baseline clearance of both proximal and distal ciliated airways following inhaled terbutaline, whereas terbutaline SC related inversely only to baseline clearance of the distal ciliated airways. This may reflect the surface concentrations of drug, established by each route.     

Acute sustained hypoxia suppresses the cough reflex in healthy subjects

RATIONALE: An intact cough reflex is important to protect the lung from injurious substances and to clear excess secretions. A blunted cough reflex may be harmful or even fatal in respiratory disease. Hypoxia is common in respiratory disorders and has been shown to have depressant effects on respiratory sensation and ventilation. We hypothesized that it might also suppress the cough reflex. OBJECTIVES: To determine if acute hypoxia increases cough threshold and cough tachyphylaxis to inhaled capsaicin. METHODS: On two occasions, 16 healthy subjects inhaled a saline control followed by doubling doses of capsaicin aerosol (range, 0.49-500 microM) every minute for 15 s during controlled ventilation (approximately 190% baseline) with isocapnic hypoxia (SpO2, approximately 80%) or isocapnic normoxia, in random order. When a subject responded to a dose with five or more coughs, the next doubling dose of capsaicin was administered continuously for 60 s to assess acute tachyphylaxis. MAIN RESULTS: The capsaicin concentration required to elicit five coughs was significantly higher during isocapnic hypoxia compared with normoxia (29.6 +/- 16.0 vs. 23.4 +/- 15.6 microM, p = 0.01). During continuous capsaicin inhalation, significantly more coughs were evoked in the first 10 s compared with the last (2.3 +/- 0.3 vs. 1.3 +/- 0.3, p < 0.01), indicating cough tachyphylaxis. However, the decrease was the same during hypoxia and normoxia (-1.3 +/- 0.4 vs. -0.9 +/- 0.6, p = 0.54). CONCLUSIONS: Acute isocapnic hypoxia suppresses cough reflex sensitivity to inhaled capsaicin. This finding raises the possibility that the cough reflex may be impaired during acute exacerbations of hypoxic-respiratory disorders.     

Impaired efficacy of cough in patients with Parkinson disease

STUDY OBJECTIVES: Aspiration pneumonia, a leading cause of death in patients with Parkinson disease (PD), usually occurs at the advanced stages of the disease. We investigated both motor and sensory components of cough and induced-sputum substance P (SP) concentrations in patients with early and advanced stages of PD to assess whether cough efficacy is impaired in PD. SUBJECTS: Fifteen female patients with early stages of PD (Hoehn and Yahr stage II-III), 10 patients with advanced stages of PD (Hoehn and Yahr stage IV), and 15 age-matched female control subjects were investigated. MEASUREMENTS: The motor component of cough efficacy was assessed by monitoring voluntary maximal cough peak flow. The sensory component of cough efficacy was assessed by measuring cough reflex sensitivity to citric acid inhalation. Sputum SP concentrations were measured in sputum induced by hypertonic saline solution inhalation. RESULTS: The mean (+/- SD) cough peak flow rates in patients with both early PD (230 +/- 74 L/min; p < 0.005) and advanced PD (186 +/- 60 L/min; p < 0.0001) were significantly weaker than that in control subjects (316 +/- 70 L/min). Cough reflex sensitivity in patients with advanced PD (46.7 +/- 49.3 g/L) was significantly lower compared to control subjects (14.5 +/- 16.6 g/L; p < 0.01) and patients with early PD (11.2 +/- 14.8 g/L; p < 0.005). The sputum SP concentration was significantly lower in patients with advanced PD (11.2 +/- 8.4 pg/mL) compared to that in control subjects (35.6 +/- 15.4 pg/mL) and patients with early PD (28.5 +/- 16.4 pg/mL). CONCLUSION: In the early stages of the disease, mainly the motor component of cough was impaired. In advanced stages of the disease, both the motor and sensory components of cough were impaired. Sputum SP concentration significantly declined in patients with advanced PD. The results suggest that the combination of impaired motor and sensory components of cough may play an important role in the development of aspiration pneumonia in PD.     

Pilot study of safety and tolerability of inhaled hypertonic saline in infants with cystic fibrosis

Inhaled hypertonic saline (HS) positively affects both lung function and pulmonary exacerbations in children and adults with cystic fibrosis (CF). Early initiation of treatment may potentially reduce lung function decline and improve outcome of CF patients. However, the safety and tolerability of HS have not been established in infants and young children. We conducted a prospective trial of inhaled HS in infants with CF. Raised volume rapid thoracoabdominal compression (RVRTC) maneuvers were performed at baseline, 10 min after salbutamol inhalation and 15 min after inhalation of a 7% HS solution. Oxygen saturation, respiratory rate, heart rate, and cough frequency were recorded during each inhalation. A clinically important change in lung function was defined a priori as a change in FEV 0.5 of > or =20%. Thirteen infants (5 female) aged 25-140 weeks were enrolled in the study. Overall, there was no difference between FEV(0.5) or FEF(25-75) at baseline, after bronchodilator or after HS. Respiratory and heart rate as well as oxygen saturation remained stable during inhalation of the HS. Three infants had cough during inhalation; one of the infants woke up due to cough but recovered within 5 min. No other side effects were observed during or immediately after inhalation. There was no difference in microbiologic yield between pre- and post-HS throat swabs. In this pilot study, inhalation of HS was well tolerated in CF infants. These results support a study of the efficacy of HS in this age group.