Clickhaler (a novel dry powder inhaler) provides similar bronchodilation to pressurized metered-dose inhaler, even at low flow rates

STUDY OBJECTIVE: Comparison of the bronchodilator response to an albuterol novel dry powder inhaler (DPI) (Clickhaler [CH]; ML Laboratories PLC; St. Albans, UK) activated at various inspiratory flow rates and to an albuterol pressurized metered-dose inhaler (pMDI) by patients with moderate to moderately severe stable asthma. DESIGN: Randomized, double-blind, placebo-controlled comparison of the bronchodilator response to albuterol DPI (200 microg) at inspiratory flow rates of approximately 15, 30, and 60 L/min in patients with stable asthma with demonstrated reversibility to albuterol. Active (albuterol via pMDI inhaled at 30 L/min) and placebo controls were included. SETTING: Single center study at the chest/allergy unit of a teaching hospital in Canada. PATIENTS: Sixteen patients with moderate to moderately severe stable asthma. MEASUREMENTS AND RESULTS: Efficacy end points were FEV1, FVC, FEV1/FVC, maximum expiratory flow, and forced expiratory flow between 25% and 75% of vital capacity. Safety end points included heart rate, BP, and tremor. There was no significant difference between the bronchodilator response to albuterol via the CH at 15, 30, and 60 L/min inspiratory flow rate and, at all flow rates, no significant difference was found comparing albuterol CH with the pMDI. All of the techniques for delivering albuterol provided significantly better bronchodilatation than placebo. Adverse events were minimal and did not differ between CH and pMDI or between the various flow rates inhaled through the CH. CONCLUSION: A novel passive albuterol DPI (CH) provides a similar bronchodilator response at 15, 30, and 60 L/min inspiratory flow rates compared with a pMDI used optimally.     

Comparison of the effects of single oral doses of nebivolol and celiprolol on airways in patients with mild asthma

OBJECTIVE: The respiratory effects of nebivolol, a new selective ss(1)-adrenergic blocking agent, and celiprolol, a ss-blocker possessing strong ss(1)-adrenoceptor antagonist and mild ss(2)-agonist properties, were investigated in 12 patients with mild asthma. DESIGN: Changes in several spirometric indexes (FVC, FEV(1), and forced expiratory flow rate at 50% of FVC) were measured. The interaction with the bronchodilator effect of the ss(2)-adrenoceptor-selective agonist albuterol also was investigated. RESULTS: The effect of both nebivolol and celiprolol on FEV(1) was considered to be significant (p < 0.05). The administration of nebivolol and celiprolol, but not of placebo, elicited a decrease in FEV(1): mean maximum difference for nebivolol, -0.272 L (95% confidence interval [CI], -0.402 to -0.142); mean maximum difference for celiprolol, -0.193 L (95% CI, -0.316 to -0.071); mean maximum difference for placebo, -0.0001 L (95% CI, -0.087 to 0.085). The inhalation of albuterol, up to a dose of 800 microg, significantly (p < 0.05) improved FEV(1), but the values after nebivolol and celiprolol administration were lower than the initial values. Both ss-blockers caused equal changes in heart rate, systolic BP, and diastolic BP. CONCLUSIONS: There were no significant differences between the respiratory actions of the two active drugs.     

An evaluation of nebulized levalbuterol in stable COPD

BACKGROUND: Levalbuterol, the R-isomer of albuterol, has advantages over racemic albuterol in asthma; however, the effectiveness of this beta-agonist in COPD has received little attention. OBJECTIVES: To evaluate the effectiveness of a single dose of nebulized levalbuterol in COPD. DESIGN: A randomized, double-blind, placebo-controlled trial comparing nebulized levalbuterol to racemic albuterol, combined racemic albuterol and ipratropium, and placebo. PATIENTS: Thirty patients with stable COPD (FEV(1) between 45% and 70% of predicted) were studied. METHODS: After withholding usual bronchodilator medications for appropriate washout periods, patients were randomized on separate visits to receive single doses of each the following nebulized bronchodilator medications: (1) levalbuterol, 1.25 mg; (2) racemic albuterol, 2.5 mg; (3) combined racemic albuterol, 2.5 mg, and ipratropium, 0.5 mg; or (4) placebo. FEV(1), FVC, pulse rate, and oxygen saturation were measured at baseline, 0.5 h following nebulization, and hourly for 6 h. Hand tremor, using a 7-point scale, was measured at baseline, 0.5 h, 1 h, and 2 h. Treatment-placebo differences were analyzed using repeated-measures analysis of variance and least-squares means. RESULTS: The mean age (+/- SD) of patients was 69 +/- 15 years. Mean FEV(1) was 1.15 +/- 0.49 L. By 0.5 h following study drug administration, all three nebulized bronchodilator treatments led to similar, significant improvements in FEV(1) compared to placebo. These effects persisted at 1 h and 2 h for all three treatments; however, by 3 h, only the combined albuterol/ipratropium group had a mean change in FEV(1) significantly greater than placebo. There were no significant differences between bronchodilator groups at any time period. A mild increase in pulse rate was observed in all treatment groups. There were no significant treatment-placebo differences in oxygen saturation or hand tremor. CONCLUSION: For single-dose, as-needed use in COPD, there appears to be no advantage in using levalbuterol over conventional nebulized bronchodilators.     

Use of a mucus clearance device enhances the bronchodilator response in patients with stable COPD

STUDY OBJECTIVE: To determine whether the use of a mucus clearance device (MCD) [Flutter; Axcan Scandipharm; Birmingham, AL] could improve the bronchodilator response to inhaled ipratropium and salbutamol delivered by a metered-dose inhaler in patients with stable, severe COPD. PATIENTS: Twenty-three patients with severe COPD were studied. Mean +/- SD age was 71.7 +/- 6.3 years. Mean FEV(1) was 0.74 +/- 0.28 L or 34.5 +/- 12.7% predicted. METHODS: Patients were tested in random order on 2 subsequent days after using an MCD or a sham MCD. A bronchodilator (four puffs; each puff delivering 20 microg of ipratropium bromide and 120 microg of salbutamol sulfate) was administered by metered-dose inhaler with a holding chamber after use of the MCD or sham MCD. Spirometry was performed before and after use of the MCD or sham MCD, and at 30 min, 60 min, and 120 min after the bronchodilator. Six-minute walk distance was tested between 30 min and 60 min; oxygen saturation, pulse, and a dyspnea score were recorded before and after walking. RESULTS: Immediately after use of the MCD, but not the sham MCD, there was a statistically significant (p < 0.05) improvement in FEV(1) and FVC (11 +/- 24% vs 1 +/- 7% and 18 +/- 33% vs 6 +/- 18%, respectively). Whether patients were pretreated with the MCD or sham MCD, there was a significant improvement in FEV(1) and FVC compared to baseline with combined bronchodilator therapy. At 120 min, the change in FEV(1) after treatment with the MCD was greater than with the sham MCD (186 +/- 110 mL vs 130 +/- 120 mL; p < 0.05). When comparing the MCD to the sham MCD, 6-min walk distance was greater (174 +/- 92 m vs 162 +/- 86 m; p < 0.05), with less dyspnea before and at the end of walking. CONCLUSION: Patients with severe COPD may demonstrate a significant bronchodilator response to combined ipratropium and salbutamol delivered by metered-dose inhaler. This response may be enhanced and additional functional improvement obtained with the prior use of a bronchial MCD.     

Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration

BACKGROUND: There is controversy about the development of bronchodilator subsensitivity after regular administration of long-acting beta(2)-agonists. OBJECTIVES: The purpose of the study was to evaluate whether regular treatment with formoterol affects the bronchodilator response to repeated puffs of albuterol, and also to assess the effects of acute administration of a bolus dose of IV or inhaled corticosteroid. MATERIALS AND METHODS: Twelve patients (mean [SD] age, 43 [15] years; FEV(1), 57 [17] % predicted) with stable, moderate to severe persistent asthma who were all taking inhaled corticosteroids were evaluated in a randomized, placebo-controlled, double-blind, double-dummy, crossover study. Patients received treatments each for 2 weeks followed by a bolus (IV/inhaled) of corticosteroid or placebo: (1) placebo inhaler bid + bolus placebo; (2) formoterol Turbuhaler 24 microg metered dosage bid (delivered dosage 18 microg bid) + placebo; (3) formoterol 24 microg bid + bolus IV hydrocortisone, 200 mg; or (4) formoterol 24 microg bid + bolus inhaled budesonide, 1,600 microg. Bronchodilator response to repeated puffs of albuterol (200 to 1,600 microg) for > 80 min was measured at 2 h after bolus administration of placebo or corticosteroid. The study was powered at the 80% level to detect a 20% difference in area under curve between 20 and 80 min (AUC) for FEV(1) response to albuterol as change from baseline (primary end point). RESULTS: There was significant subsensitivity (p = 0.01) of the mean albuterol FEV(1) response (as AUC, L x s) after formoterol alone (737) as compared to placebo (1,453) along with partial reversal by steroid administration: formoterol + hydrocortisone (1, 050), and formoterol + budesonide (942). There was a similar pattern of subsensitivity (p = 0.03) for the mean albuterol forced expiratory flow between 25% and 75% of vital capacity response (as AUC, L): placebo (2,149), formoterol alone (1,002), formoterol + hydrocortisone (1,402), and formoterol + budesonide (1,271). CONCLUSION: Regular treatment with formoterol produced significant bronchodilator subsensitivity to repeated puffs of albuterol, which was partially reversed by a bolus dose of systemic or inhaled corticosteroid.     

Bronchodilator response to formoterol after regular tiotropium or to tiotropium after regular formoterol in COPD patients

We conducted a randomized, crossover trial with tiotropium 18 microg once daily (group A), and formoterol 12 microg twice daily (group B) over a 5-day period for each drug, with a 10-day washout, in 20 COPD patients. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence (group A: tiotropium 18 microg+formoterol 12 microg; group B: formoterol 12 microg+tiotropium 18 microg). FEV1 and FVC were measured at baseline and after 30, 60, 120, 180, 210, 240, 300 and 360 min. FEV1 and FVC further improved after crossover with both sequences. The mean maximal change in FEV1 over baseline was 0.226 L (0.154-0.298) after tiotropium+formoterol and 0.228 L (0.165-0.291) after formoterol+tiotropium; the mean maximal change in FEV1 over pre-inhalation the second drug value was 0.081 L (0.029-0.133) after tiotropium+formoterol and 0.054 L (0.016-0.092) after formoterol+tiotropium. The mean maximal change in FVC over baseline was 0.519 L (0.361-0.676) after tiotropium+formoterol and 0.495 L (0.307-0.683) after formoterol+tiotropium; the mean maximal change in FVC over pre-inhalation of the second drug value was 0.159 L (0.048-0.270) after tiotropium+formoterol and 0.175 L (0.083-0.266) after formoterol+tiotropium. The FEV1 AUCs(0-360 min) were 62.70 (45.67-79.74) after tiotropium+formoterol and 69.20 (50.84-87.57) after formoterol+tiotropium, the FEV1 AUCs(0-180 min) were 24.70 (18.19-31.21) after tiotropium+formoterol and 29.74 (21.02-38.46) after formoterol+tiotropium, whereas the FEV1 AUCs(180-360 min) were 15.70 (10.88-20.52) after tiotropium+formoterol and 11.71 (7.21-16.21) after formoterol+tiotropium. Differences between the two treatments were not statistically significant (P>0.05). The addition of second different long-acting bronchodilator to a regularly administered long-acting bronchodilator seems to be to patient's advantage.     

Effect of an inhaled glucocorticosteroid on airway mucosal blood flow in mild asthma

We determined airway mucosal blood flow (Qaw) and FEV (1) before and after inhaled albuterol in 19 glucocorticosteroid (GS)-naive patients with mild intermittent asthma, and assessed the effects of a 2-wk course of fluticasone propionate (FP; 440 microg daily) on these parameters. Twelve healthy nonsmokers served as controls. Baseline Qaw was 55.5 +/- 0.7 microl/min/ml (mean +/- SE) in the asthmatic subjects and 44.2 +/- 0.7 microl/min/ml in the controls; the respective FEV(1) values were 2.8 +/- 0.2 L and 3.4 +/- 0.2 L (p < 0.01 for both parameters). Albuterol increased Qaw by 27 +/- 3% in the control subjects (p < 0.01) but had no effect on Qaw in the asthmatic subjects; it increased FEV (1) by 7 +/- 1% and 6 +/- 1% in the two groups, respectively. Qaw decreased to 49.2 +/- 0.8 microl/min/ml (p < 0.05 versus baseline), and the Qaw responsiveness to albuterol was restored ( +21 +/- 2%; p < 0.05) in the asthmatic subjects after FP. Eleven asthmatic subjects stopped using FP at this time; 2 wk later, their Qaw returned to baseline (55.2 +/- 0.9 microl/min/ml) and they lost the Qaw responsiveness to albuterol. Mean ( +/- SE) FEV(1) and FEV(1) responsiveness to albuterol were not affected by FP. The GS-sensitive increase in Qaw and its hyporesponsiveness to albuterol in asthmatic subjects may be consequences of airway inflammation.     

Subcutaneous administration of the cardiac hormone BNP in symptomatic human heart failure

BACKGROUND: Brain natriuretic peptide (BNP) is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin-aldosterone-inhibiting and lusitropic properties. We have demonstrated that acute subcutaneous (SQ) administration of BNP in experimental congestive heart failure results in elevation of plasma BNP and its second messenger 3',5'-cyclic guanosine monophosphate (cGMP) with natriuresis and reduction in cardiac filling pressures. Furthermore, chronic subcutaneous BNP in experimental congestive heart failure also resulted in increases in cardiac output and decreases in pulmonary capillary wedge pressure and systemic vascular resistance. METHODS: The objective of the current study was to assess the safety and efficacy of repeated doses of subcutaneous human BNP, nesiritide, a recombinant form of human BNP (Scios Inc, Fremont, CA) in human subjects with New York Heart Association class II-III congestive heart failure. We defined the cardiorenal and humoral responses to subcutaneous BNP (nesiritide) administered every 12 hours with a total of 5 doses over 72 hours in a single-blind placebo-controlled design (n=8). The mean dose of nesiritide was 10 microg/kg every 12 hours. RESULTS: Initial saline placebo resulted in no change in any measured parameters (P<.05 versus baseline). With the first dose of BNP (nesiritide), cardiac output increased (4.8+/-0.4 to 6.4+/-0.5 L/min) and systolic blood pressure decreased (125+/-5 to 104+/-3 mm Hg) without a change in heart rate. Plasma BNP (167+/-115 to 830+/-470 pg/mL), cGMP (4+/-2 to 14+/-4 pmol/mL), and urinary cGMP excretion (3900+/-930 to 10,600+/-5000 pmol/min) increased with natriuresis and diuresis. Both plasma renin activity and plasma aldosterone decreased. These favorable biologic responses were observed with the fifth dose 72 hours after the initial dose. All the subjects tolerated the study well without any adverse events except for 1 subject who had a vasovagal episode during micturition after receiving the fifth dose on day 3. CONCLUSION: We conclude that subcutaneous administration of BNP (nesiritide) represents a novel and efficacious therapeutic strategy in human congestive heart failure to deliver BNP, a cardiac hormone which possesses unique cardiorenal and neurohumoral properties.     

Unsupervised self-testing of airway obstruction by forced oscillation at the patient's home.

As active patient cooperation is not required, the forced oscillation technique (FOT) could be suitable for measuring airway obstruction in routine home applications. Nevertheless, FOT has never been used at the patient's home to date. The aim of this study was to assess the feasibility of FOT and the reproducibility of measured respiratory resistance (Rrs) in routine patient self-testing at home. Altogether, nine asthmatic patients self-measured their Rrs with a portable FOT device and spirometry for 10-14 days, in the morning and evening, and before and after bronchodilator inhalation. During each measurement session, the patients carried out four consecutive FOT measurements. Grubbs' discordancy test for detecting outliers was used to evaluate intermeasure reliability. Only 4.9% of Rrs data reported by patients were rejected as artefacts. The coefficient of variation of Rrs was 7.9 +/- 6.3% (mean +/- SD). When compared with spirometry, the per cent change in Rrs for detecting a positive bronchodilator response showed an 83% sensitivity and 72% specificity. Unsupervised self-measurement of respiratory resistance at the patient's home provided results similar to those obtained by a technician in a lung function lab. Forced oscillation technique could be a useful tool for the routine follow-up of asthmatic patients at home.     

Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD

BACKGROUND: A 6-week, multicenter, randomized, double-blind, parallel-group study was conducted in patients with COPD to compare lung function improvements of tiotropium, 18 microg qd, plus formoterol, 12 microg bid, to salmeterol, 50 microg bid, plus fluticasone, 500 microg bid. METHODS: Following a screening visit, subjects entered a run-in period in which they received regular ipratropium. At randomization, patients were assigned to either tiotropium plus formoterol or salmeterol plus fluticasone. After 6 weeks of treatment, a 12-h lung function profile was obtained. The coprimary end points were FEV(1) area under the curve for the time period 0 to 12 h (AUC(0-12)) and peak FEV(1). RESULTS: A total of 729 patients were screened, and 605 patients were randomized and treated. A total of 592 patients (baseline FEV(1), 1.32 +/- 0.43 L/min [+/-SD]) were included in the analysis. After 6 weeks, the 12-h lung function profiles in the group receiving tiotropium plus formoterol were superior to those in the group receiving salmeterol plus fluticasone (mean difference in FEV(1) AUC(0-12), 78 mL [p = 0.0006]; mean difference in FVC AUC(0-12), 173 mL, p < 0.0001). Also, peak responses were in favor of tiotropium plus formoterol (difference in peak FEV(1), 103 mL [p < 0.0001]; difference in peak FVC, 214 mL [p < 0.0001]), as were FEV(1) and FVC at each individual time point after dose (p < 0.05). Predose FVC was significantly higher with the bronchodilator combination, while predose FEV(1) and rescue medication use did not differ significantly between groups. Both treatments were well tolerated. CONCLUSIONS: Tiotropium plus formoterol was superior in lung function over the day compared to salmeterol plus fluticasone in patients with moderate COPD. Long-term studies in patients with severe COPD are warranted to assess the relative efficacy of different treatment combinations. Trial registration: Clinicaltrials.gov Identifier: NCT00239421.     

Oscillatory resistance measured during noninvasive proportional assist ventilation.

Setting proportional assist ventilation (PAV) requires the measurement of patient resistance and elastance. To avoid patient sedation/paralysis or the use of an esophageal balloon, noninvasive PAV is indirectly set by the "runaway" method or in accordance with patient comfort. The aim of this study was to ascertain whether the forced oscillation technique (FOT) applied by the ventilator during noninvasive PAV is useful in assessing patient respiratory resistance. Nasal PAV was applied to 14 patients with severe chronic obstructive pulmonary disease. During PAV a modified ventilator applied a 5-Hz pressure oscillation to noninvasively assess FOT resistance (Rrs). Lung resistance (RL) was measured in seven of the patients by using an esophageal balloon. Moreover, measurements were also performed in five of the patients when PAV was applied through the mouth. Rrs was close to RL both during nasal (Rrs = 8.9 +/- 3.1, RL = 9.0 +/- 2.6; cm H(2)O x s/L; n = 7, p > 0.05) and mouth (Rrs = 5.6 +/- 2.1, RL = 5.8 +/- 1.4; cm H(2)O x s/L; n = 5, p > 0.05) breathing. Rrs was slightly greater than the maximum value of flow assistance applied during the setting of PAV (FAmax): 11.1 +/- 5.4 and 9.5 +/- 2.9 cm H(2)O x s/L, respectively (n = 14, p > 0.05), both variables being significantly correlated (r = 0.72, p < 0.05). FOT applied by the PAV ventilator allowed the assessment of patient resistance. These results suggest that FOT could be useful in setting PAV flow assistance and in automatically and continuously updating this setting in accordance with patient resistance.     

The effect of heliox-driven bronchodilator aerosol therapy on pulmonary function tests in patients with asthma.

To compare the effects of heliox-driven (He 80:O2 20) to air-driven (N 79:O2 21) beta2-agonist aerosol therapy on pulmonary function tests (PFTs) in patients with asthma, a prospective randomized crossover study was undertaken in the asthma clinic of the university-affiliated county hospital in Houston, TX. Thirty-one patients (22 female, age range 18-44) with clinically stable asthma consented. All patients were studied on two different days with both heliox and air as driving gas, therefore serving as their own controls. The PFTs including forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), maximal mid-expiratory flow rate (FEF(25-75)), and maximal expiratory flow rate (FEFmax) were obtained while breathing ambient air at baseline and 30 min after the bronchodilator treatment. Albuterol sulfate 2.5 mg was nebulized with either heliox or compressed air at 8 L/min for 8 min. When heliox was used as driving agent, additional heliox was delivered via a closed system and no entrainment of external air was allowed. Primary outcome measure was absolute change in FEV1 (deltaFEV1). There were no statistically significant differences in baseline PFTs on the two days of the study. All patients had good bronchodilator response (> or = 12% improvement in FEV1) with either driving gas. The deltaFEV1 after heliox-driven bronchodilator (HDBD) and air-driven bronchodilator (ADBD) were 0.68+/-0.38 L/sec (CI: 0.54-0.82) vs. 0.51+/-0.26 L/sec (CI: 0.42-0.60), respectively (p=0.004). The deltaFEV1 with HDBD was 49+/-90% (range -36% to 433%) more than ADBD. A subgroup analysis showed this was largely due to better response rates in patients with moderate to severe obstruction. There was more improvement in both FVC and FEFmax with HDBD than ADBD (p<0.05). The changes in FEF(25-75) were similar. We conclude that HDBD therapy improves FEV1, FVC, and FEFmax significantly more than ADBD in patients with asthma. Further large randomized studies are needed to better characterize responders and the impact on clinical outcomes.     

Comparison of the effects of salmeterol and formoterol in patients with severe asthma

STUDY OBJECTIVE: Several studies have demonstrated the superiority of salmeterol and formoterol to either regular treatment with albuterol or placebo. However, to date there have been no trials comparing the efficacy of salmeterol and formoterol in patients with severe asthma. DESIGN: We undertook a randomized, placebo-controlled, crossover study to compare 4 weeks of treatment with inhaled formoterol (12 microg twice daily) or salmeterol (50 microg twice daily) in patients with severe asthma whose conditions were not being adequately controlled by therapy with high doses of inhaled corticosteroids (i.e., > or = 1,500 microg daily) or with regular oral corticosteroid treatment. Morning pretreatment peak expiratory flow (PEF) during the last 14 days of the treatment period was the primary outcome variable. Patients recorded morning and evening pretreatment PEF, daytime and nighttime symptom scores, and any use of rescue medication. Spirometry and bronchial reversibility were performed after each treatment. RESULTS: Forty-two nonsmoking patients (29 women; mean age, 45 +/- 2 years; mean [+/- SEM] FEV(1), 61.8 +/- 3.4% of predicted) took part in the trial, and 27 patients completed the trial. The mean morning PEF was greater in patients receiving formoterol (mean increase, 14.4 L/min; 95% confidence interval [CI]. 0.2 to 28.6) or salmeterol (mean increase, 14.8 L/min; 95% CI, 0.5 to 29.1) compared with those receiving placebo, but there was no difference between these treatments. There were no significant treatment effects for any of the secondary outcome variables (i.e., FEV(1,) FVC, mean evening PEF, mean daytime symptom score, or nighttime symptom score). CONCLUSION: We conclude that the long-acting beta(2)-agonists salmeterol and formoterol improve morning PEF in patients with severe asthma, but that there is no difference in efficacy between the two drugs.     

Forced oscillometry is applicable to epidemiological settings to detect asthmatic children.

Forced oscillometry (FOT) has been reported as a simple method to detect respiratory resistance (Rrs) changes. The aim of this study was to evaluate FOT capacity to detect children with clinical characteristics of asthma in a school setting. One thousand thirty children, 6-7 years old, were investigated by questionnaire. Children with wheezing symptoms in the last 12 months but without previous diagnosis of asthma were selected and underwent evaluations. FOT measurements were performed pre- and post-salbutamol administration, with a level of significant reduction of Rrs of >29%. Patients were further investigated for atopy by skin-prick tests (SPTs) and for bronchial hyperreactivity (BHR) by exercise free-running test. Of 1030 children participating in the study, 120 were selected by questionnaire responses for respiratory symptoms. Twenty-two children had a significant reduction of Rrs of 6 Hz (p < 0.001; group 1); 98 children presented no variation of Rrs to bronchodilator (group 2). Prick test positivity and significant bronchoconstriction after exercise tests were significantly more frequent in group 1 than in group 2 (77% and 64% versus 8% and 12%, respectively; p < 0.001). In a school setting FOT changes after bronchodilator are able to detect airway obstruction in children with wheezing symptoms. Children with significant FOT variability present more significantly atopy and BHR and therefore more probable asthma.     

Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation

OBJECTIVES: Current criteria use FEV(1) to assess bronchodilator responsiveness, despite its insensitivity and inability to predict improvement in symptoms or exercise tolerance. Response in lung volumes remains largely unexplored even though volume parameters, such as inspiratory capacity (IC), closely correlate with functional improvements. Therefore, we assessed the response of lung volumes (i.e., by IC, total lung capacity [TLC], functional residual capacity [FRC], residual volume [RV], and FVC) to salbutamol and the relationship of these changes to improvements in the spirometry in these patients. DESIGN: A retrospective review of data extracted from a large database of patients who were undergoing spirometry and static lung volume measurements before and after the administration of 200 microg salbutamol. PATIENTS: Patients with an FEV(1)/FVC ratio of < 85% of predicted values were defined as being severely hyperinflated (SH) if TLC was > 133% of predicted and as being moderately hyperinflated (MH) if TLC was 115 to 133% of predicted. RESULTS: Two hundred eighty-one SH patients and 676 MH patients were identified. Salbutamol significantly reduced the mean (+/- SEM) TLC (SH patients, 222 +/- 23 mL; MH patients, 150 +/- 10 mL; p < 0.001), FRC (SH patients, 442 +/- 26 mL; MH patients, 260 +/- 39 mL; p < 0.001), and RV (SH patients, 510 +/- 28 mL; MH patients, 300 +/- 14 mL; p < 0.001) and increased both the IC (SH patients, 220 +/- 15 mL; MH patients, 110 +/- 11 mL; p < 0.001) and FVC (SH patients, 336 +/- 21 mL; MH patients, 204 +/- 13 mL; p < 0.001). FEV(1) improved in a minority of patients (SH patients, 33%; MH patients, 26%), but if lung volume measurements are also considered, the overall bronchodilator response may improve to up to 76% of the SH group and up to 62% of the MH group. Changes in volumes correlated poorly with changes in maximal airflows. CONCLUSIONS: Bronchodilators reduce hyperinflation. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness.     

Bronchodilating effect of oxitropium bromide in heart disease patients with exacerbations of COPD: double-blind, randomized, controlled study

Anti-cholinergic agents are considered the bronchodilator therapy of first-choice in the treatment of patients with stable chronic obstructive pulmonary disease (COPD) associated with heart disease since they may be as effective or more effective than inhaled beta2-agonists and, moreover, they do not interact with cardiac beta-adrenoceptors. The aim of our study was to evaluate the bronchodilator activity of oxitropium bromide in outpatients suffering from exacerbations of COPD associated with heart diseases (ischaemic heart disease and/or arrhythmias). We recruited 50 consecutive outpatients (33 males and 17 females, mean age 68.6 years, 15 current smokers and 35 ex-smokers). Each patient performed body plethismography in basal condition and 30 min after inhalation of 200 microg metered dose inhaler (MDI) oxitropium bromide administered by a device (Fluspacer). FEV1, FVC, MMEF25-75, sRaw and tRaw were evaluated. Thirty minutes after 200 microg oxitropium bromide administration, we observed a significant improvement in FEV1 11.6% +/- 1 (mean +/- SEM) (P<0.01); FVC, MMEF25-75 sRaw variation was respectively: 9.2% +/- 0.6, 31.4 +/- 2.9, -19.9 +/- 1.1. Placebo did not significantly change pulmonary function. Our data suggest that oxitropium bromide bronchodilator activity is effective in exacerbations of COPD.     

Effects of ipratropium bromide nebulizer solution with and without preservatives in the treatment of acute and stable asthma.

In a recent study, it was suggested that the preservatives in ipratropium bromide nebulizer solution may cause a paradoxic bronchoconstrictor response in 20 percent or more of patients with stable asthma. The frequency of this response in patients with acute asthma is unknown. The aim of this study was to examine the acute effects of the usual dose of nebulized ipratropium bromide (0.25 mg) in patients with either stable or acute asthma using formulations with and without added preservatives. Twenty-five patients with stable asthma and 25 patients with acute asthma were studied. Each subject was given preservative-containing ipratropium bromide, preservative-free ipratropium bromide, pH 7 preservative-free ipratropium bromide, and saline solution in random order using a double-blind crossover technique with at least 4 h between drug administrations. Very frequent measurements of FEV1 were made for 30 min after each drug administration and then 5 mg of albuterol was nebulized and the FEV1 was measured again after another 30 min. Changes in FEV1 were expressed as a percentage of the predicted FEV1. Paradoxic bronchoconstriction to ipratropium was detected in only one patient with acute asthma (12 percent fall in FEV1) but in none of the patients with stable asthma. A 6 percent fall in FEV1 change occurred with the saline solution in this subject suggesting that the response may have been a nonspecific one due to increased bronchial responsiveness. The mean response (+/- 1 SD) to albuterol plus either preservative-containing ipratropium, preservative-free ipratropium, or pH7 preservative-free ipratropium was significantly greater (p less than 0.05) than the response to albuterol alone both in the patients with acute asthma (25 +/- 12 percent, 27 +/- 15 percent, 26 +/- 15 percent, and 20 +/- 15 percent, respectively) and stable asthma (26 +/- 7 percent, 25 +/- 8 percent, 24 +/- 6 percent, and 22 +/- 9 percent) supporting the use of ipratropium bromide as an additional bronchodilator in patients with asthma who do not show a satisfactory response to nebulized beta-adrenergic agonist.     

Normal bronchial blood flow in COPD is unaffected by inhaled corticosteroids and correlates with exhaled nitric oxide

BACKGROUND: In COPD patients, there is reduced vascularity and inflammation of the bronchi, which may have opposite effects on bronchial blood flow (QAW). We studied the relationship of QAW with the fraction of exhaled nitric oxide (FENO), which is a potent vasodilator. We also investigated the vascular response to budesonide and a beta(2)-agonist. METHODS: We measured QAW in 17 patients with COPD (mean [+/- SEM] age, 67 +/- 3 years; 10 male patients; mean FEV(1), 57 +/- 3% predicted; mean FEV(1)/FVC ratio, 54 +/- 4%), all of whom were ex-smokers, and in 16 age-matched nonsmoking volunteers (mean age, 64 +/- 4 years) and compared this to FENO. QAW was measured using the acetylene dilution method. RESULTS: Mean QAW was similar in patients with COPD (34.29 +/- 1.09 microL/mL/min) compared to healthy subjects (35.50 +/- 1.74 microL/mL/min; p > 0.05) and was not affected by long-term treatment (35.89 +/- 1.63 microL/mL/min) or short-term treatment (32.50 +/- 1.24 microL/mL/min; p < 0.05) with inhaled budesonide. QAW positively correlated with the diffusion of carbon monoxide (ie, carbon monoxide transfer coefficient: r = 0.74; p < 0.05). FENO levels were mildly elevated in steroid-treated patients (10.89 +/- 0.87 parts per billion [ppb]) and untreated patients (9.40 +/- 0.86 ppb) compared to the control group (8.22 +/- 0.57 ppb; p < 0.05) and were correlated with QAW (r = 0.6; p < 0.05). Ten minutes after the inhalation of 200 microg of albuterol, QAW was more elevated in healthy control subjects (59.33 +/- 2.40 microL/mL/min) compared to COPD patients (38.00 +/- 0.58 microL/mL/min; p < 0.05), indicating that COPD patients may have a reduced bronchial vascular reactivity. CONCLUSIONS: QAW is normal in COPD patients and is not affected by therapy with inhaled corticosteroids or beta(2)-agonists. In addition, QAW correlates with levels of FENO, which may have a regulatory role.