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We evaluated pathophysiological characteristics of the lower urinary tract dysfunction in a streptozotocin (STZ)-induced diabetic rat model. STZ (60 mg/kg) was injected intraperitoneally into male Wistar rats. In vitro bladder muscle strip experiments, in vivo cystometry, and simultaneous recordings of bladder pressure + urethral perfusion pressure (BP + UPP) with or without intravenous administration of L-arginine (300 mg/kg) or tadalafil (0.03 mg/kg) were performed at several time points. In vitro muscle strip experiments demonstrated that diabetic rats had significantly higher contractile responses to carbachol at 4-16 weeks, and a tendency for higher contractile responses to electrical field stimulation at 4-12 weeks, but this was reversed at 16 weeks. Diabetic rats had significant increases in voided volume, residual volume, bladder capacity, maximal voiding pressure, and amplitude and frequency of non-voiding contractions at 16 weeks. Tadalafil decreased the residual volume in diabetic rats. Diabetic rats had significantly higher UPP nadir and mean UPP during high-frequency oscillation at 16 weeks, which were reversed by tadalafil or L-arginine administration. The present results suggest that urethral relaxation failure, probably related to impairment of the NO/cGMP signalling pathway, rather than bladder contractile dysfunction may be a prominent cause for voiding dysfunction in STZ-induced chronic diabetic rats.

Background: Inflammation in small airways is particularly clinically active in severe asthma but they still continue to be ignored as considered silent. Recently, the Atlantis study reports small airways involvement in 91% of the asthma population. Therefore in the era of phenotype driven therapy, the aim of this study was to verify if high-strength extrafine ICS/LABA in fixed dose increases clinical efficacy in moderate asthmatic patients with small airways dysfunction and it could be proposed as phenotype driven therapy., Methods: In this prospective, non-interventional, real-life pilot study we enrolled 37 consecutive patients with moderate asthma who were uncontrolled despite GINA step 3 treatment. All subjects at enrollment were divided in two groups according to the presence of small airways dysfunction:1) small airways phenotype (SAP) group: smokers (≥10 packs/die), ex-smokers (>20 packs/year) with air trapping (FVC <80% - VR >100% - FEF 25-75% <60%); 2) non-small airways phenotype (NSAP) group: non-smokers, without air trapping (FVC ≥80% - VR ≤ 100% - FEF 25-75% ≥60%). We later proceeded in both groups with a step up in therapy with high-strength extrafine pMDI beclomethasone dipropionate/formoterol fumarate (BDP/FF) (200/6 μg) in fixed dose to achieve a better control and followed patients for 6 months., Results: Treatment with extrafine BDP/FF(200/6 μg) in SAP group showed a more significant improvement of FEF25-75%, FVC, RV, and a reduction of alveolar inflammatory markers such as FENO350 and alveolar exhaled pH compared with NSAP patients., Conclusions: Our preliminary results support the use of high-strength extrafine pMDI BDP/FF (200/6 μg) as phenotype driven treatment directed to small airways dysfunction demonstrating an increase of clinical efficacy in moderate asthmatics with SAP., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hyperinflation has been associated with negative cardiocirculatory consequences in patients with chronic obstructive pulmonary disease (COPD). These abnormalities are likely to worsen when the demands for O 2 increase, e.g., under the stress of exercise. Thus, pharmacologically-induced lung deflation may improve cardiopulmonary interactions and exertional cardiac output leading to higher limb muscle blood flow and oxygenation in hyperinflated patients with COPD., Methods: 20 patients (residual volume = 201.6 ± 63.6% predicted) performed endurance cardiopulmonary exercise tests (75% peak) 1 h after placebo or tiotropium/olodaterol 5/5 μg via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Cardiac output was assessed by signal-morphology impedance cardiography. Near-infrared spectroscopy determined quadriceps blood flow (indocyanine green dye) and intra-muscular oxygenation., Results: Tiotropium/olodaterol was associated with marked lung deflation (p < 0.01): residual volume decreased by at least 0.4 L in 14/20 patients (70%). The downward shift in the resting static lung volumes was associated with less exertional inspiratory constraints and dyspnoea thereby increasing exercise endurance by ~50%. Contrary to our premises, however, neither central and peripheral hemodynamics nor muscle oxygenation improved after active intervention compared to placebo. These results were consistent with those found in a subgroup of patients showing the largest decrements in residual volume (p < 0.05)., Conclusions: The beneficial effects of tiotropium/olodaterol on resting and operating lung volumes are not translated into enhanced cardiocirculatory responses to exertion in hyperinflated patients with COPD. Improvement in exercise tolerance after dual bronchodilation is unlikely to be mechanistically linked to higher muscle blood flow and/or O 2 delivery., (Copyright © 2019. Published by Elsevier Ltd.)

Hyperinflation, gas trapping and their responses to long-acting bronchodilator are clinically important in COPD. The forced oscillation technique (FOT) measures of respiratory system resistance and reactance are sensitive markers of bronchodilator response in COPD. The relationships between changes in resistance and reactance, and changes in hyperinflation and gas trapping, following long-acting bronchodilator (LA-BD) have not been studied. 15 subjects with mild-moderate COPD underwent FOT, spirometry then body plethysmography, before and 2 hours after a single 150 microg dose of the LA-BD indacaterol. Hyperinflation was quantified as the inspiratory capacity to total lung capacity ratio (IC/TLC), and gas trapping as residual volume to TLC ratio (RV/TLC). At baseline, FOT parameters were moderately correlated with IC/TLC (|r| 0.53-0.73, p < 0.05). At 2 hours post-LA-BD, there were moderate correlations between change in FOT and change in RV/TLC (|r| 0.60-0.82, p < 0.05). Baseline FOT parameters also correlated with the subsequent post-LA-BD change in both IC/TLC (|r| 0.54-0.62, p < 0.05) and RV/TLC (|r| 0.57-0.76, p < 0.05). FOT impedance reflects hyperinflation and gas trapping in COPD, and the potential for long-acting bronchodilator responsiveness. These results provide us with further insight into the physiological mechanisms of action of long-acting bronchodilator treatment, and may be clinically useful for predicting treatment responses.

Background: Studies on pulmonary function tests (PFTs) in Growth Hormone Deficiency (GHD) children are lacking. The aims of this study were: (i) to investigate PFTs in GHD pre-pubertal children with respect to Controls, before starting Growth Hormone Therapy (GHT) (T0); (ii) to evaluate changes of PFTs in GHD vs Controls, after 1-year GHT (T1). For both aims the mediation analysis (MA) was applied to evaluate the extent to which the relationship between GHD and PFTs could be ascribed to a height-mediated (indirect) or a GH direct effect., Methods: 47 pre-pubertal GHD children (aged 5-14 years) underwent PFTs at T0 and T1. At T0, 47 healthy children matched for age and sex were enrolled as Controls. A MA was performed to assess the relationship between GHD and PFTs and height. Statistical analyses were performed using the statistical software R (https://cran.r-project.org/mirrors.html). A p-value <0.05 was considered significant., Measurements and Main Results: At T0, PFTs indices were significantly lower in GHD than in Controls. From T0 to T1 a significant improvement was found in PFTs. The percentages of the mediated effect on FVC, FEV 1 , FEF 25-75% and TLC were <50% at T0, suggesting that the direct effect was prevalent. At T1, the percentages of the mediated effect for spirometry indices were ≥50%, indicating that the indirect (height-mediated) effect was the most relevant., Conclusions: The study shows that pre-pubertal children with GHD have an impairment of lung function not exclusively attributable to the indirect (height-mediated) effect, but also to the direct GH action which is mitigated after 1-year of GHT., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The aim of this study was to compare gastric residual volume (GRV) in patients given a split-dose versus a conventional single-dose of polyethylene glycol (PEG) preparation before undergoing anesthetic colonoscopy. Methods. In a prospective observational study, we assessed GRV in outpatients undergoing same-day anesthetic gastroscopy and colonoscopy between October 8 and December 30 of 2016. Outpatients were assigned to the split-dose (1 L PEG in the prior evening and 1 L PEG 2-4 h before endoscopy) or single-dose (ingestion of 2 L PEG ≥ 6 h before endoscopy) regimen randomly. Bowel cleansing quality was assessed with the Boston Bowel Preparation Scale (BBPS). Results. The median GRV in the split-dose group (17 ml, with a range of 0-50 ml; N = 65) was significantly lower than that in the single-dose group (22 ml, with a range of 0-62 ml; N = 64; p = 0.005), with a better bowel cleansing quality (BBPS score 8.05 ± 0.82 versus 7.64 ± 1.21; p = 0.028). GRV was not associated with diabetes or the use of medications. Conclusions. GRV after a split-dose preparation and fasting for 2-4 hours is not larger than that after a conventional single-dose preparation and fasting for 6-8 hours. The data indicates that the split-dose bowel preparation might not increase the risk of aspiration.

Background: Reversibility of obstructive lung disease is traditionally defined by changes in FEV 1 or FVC in response to bronchodilators. These may not fully reflect changes due to a reduction in hyperinflation or air-trapping, which have important clinical implications. To date, only a handful of studies have examined bronchodilators' effect on lung volumes. The authors sought to better characterize the response of residual volume and total lung capacity to bronchodilators., Methods: Responsiveness of residual volume and total lung capacity to bronchodilators was assessed with a retrospective analysis of pulmonary function tests of 965 subjects with obstructive lung disease as defined by the lower limit of normal based on National Health and Nutritional Examination Survey III prediction equations., Results: A statistically significant number of subjects demonstrated response to bronchodilators in their residual volume independent of response defined by FEV 1 or FVC, the American Thoracic Society and European Respiratory Society criteria. Reduced residual volume weakly correlated with response to FEV 1 and to FVC. No statistically significant correlation was found between total lung capacity and either FEV 1 or FVC., Conclusions: A significant number of subjects classified as being nonresponsive based on spirometry have reversible residual volumes. Subjects whose residual volumes improve in response to bronchodilators represent an important subgroup of those with obstructive lung disease. The identification of this subgroup better characterizes the heterogeneity of obstructive lung disease. The clinical importance of these findings is unclear but warrants further study., (Copyright © 2016 by Daedalus Enterprises.)

Background: Intolerance to enteral nutrition is common in critically ill adults, and may result in significant morbidity including ileus, abdominal distension, vomiting and potential aspiration events. Prokinetic agents are prescribed to improve gastric emptying. However, the efficacy and safety of these agents in critically ill patients is not well-defined. Therefore, we conducted a systematic review and meta-analysis to determine the efficacy and safety of prokinetic agents in critically ill patients., Methods: We searched MEDLINE, EMBASE, and Cochrane Library from inception up to January 2016. Eligible studies included randomized controlled trials (RCTs) of critically ill adults assigned to receive a prokinetic agent or placebo, and that reported relevant clinical outcomes. Two independent reviewers screened potentially eligible articles, selected eligible studies, and abstracted pertinent data. We calculated pooled relative risk (RR) for dichotomous outcomes and mean difference for continuous outcomes, with the corresponding 95 % confidence interval (CI). We assessed risk of bias using Cochrane risk of bias tool, and the quality of evidence using grading of recommendations assessment, development, and evaluation (GRADE) methodology., Results: Thirteen RCTs (enrolling 1341 patients) met our inclusion criteria. Prokinetic agents significantly reduced feeding intolerance (RR 0.73, 95 % CI 0.55, 0.97; P = 0.03; moderate certainty), which translated to 17.3 % (95 % CI 5, 26.8 %) absolute reduction in feeding intolerance. Prokinetics also reduced the risk of developing high gastric residual volumes (RR 0.69; 95 % CI 0.52, 0.91; P = 0.009; moderate quality) and increased the success of post-pyloric feeding tube placement (RR 1.60, 95 % CI 1.17, 2.21; P = 0.004; moderate quality). There was no significant improvement in the risk of vomiting, diarrhea, intensive care unit (ICU) length of stay or mortality. Prokinetic agents also did not significantly increase the rate of diarrhea., Conclusion: There is moderate-quality evidence that prokinetic agents reduce feeding intolerance in critically ill patients compared to placebo or no intervention. However, the impact on other clinical outcomes such as pneumonia, mortality, and ICU length of stay is unclear.

Study Design: This is a retrospective study., Objectives: The objective of this study was to determine outcome predictors for urethral injection of botulinum toxin to treat detrusor sphincter dyssynergia (DSD) in patients with spinal cord injury., Methods: Botulinum toxin type A (100 Units Botox, Allergan) was injected into the external urethral sphincter using a transperineal approach under EMG guidance. Treatment was indicated if DSD was found on urodynamic testing with a post-void residual volume (PVR) above 100 ml. Urodynamic tests and cystourethrograms were performed at baseline. Dysuria (scale of 1-5) and PVR (48- h bladder diary) were evaluated at baseline and 1 month. The outcome was deemed excellent when PVR was equal to or <100 ml and 20%, and dysuria rated <3., Results: Seventy-two men with tetraplegia and 27 with paraplegia were included. There were significant reductions in PVR (from 227 to 97 ml and 63% to 27%) and dysuria (from 4.3 to 2.3). Excellent outcomes were found in 48 patients (48%), and the duration of effectiveness was 6.5 months. The need for catheterisation was decreased or eliminated in 18 patients. Vesicoureteral reflux disappeared in some patients. Poor outcome was significantly related to the presence of bladder neck dyssynergia and the absence of detrusor contraction in standard cystometry. Outcome was also related to the severity of DSD, with a strong correlation between PVR before and after injection (r=0.58). Injections were repeated in 36 patients and yielded similar outcomes in most cases (89%)., Conclusions: Detrusor contractions (odds ratio=8.6) and normal bladder neck activity (odds ratio=7.1) are strong predictors of excellent outcome.

Rationale and Objectives: (3)He magnetic resonance imaging (MRI) can be used to quantify functional responses to asthma therapy and provocation. Ventilation imaging offers quantitative information beyond ventilation defects that have not yet been exploited. Therefore, our objective was to evaluate hyperpolarized (3)He MRI ventilation defect percent (VDP) and compare this and pulmonary function measurements to ventilation image texture features and their changes post-bronchodilator administration in patients with asthma., Materials and Methods: Volunteers with a diagnosis of asthma provided written informed consent to an ethics board-approved protocol and underwent pulmonary function tests and MRI before and after salbutamol inhalation. MR images were analyzed using VDP, and their texture was evaluated via gray-level run-length matrices. These texture classifiers were compared to VDP in responders to bronchodilation based on VDP (VDP responders) and forced expiratory volume in 1 s (FEV1) (FEV1 responders)., Results: In total, 47 patients with asthma (18 males 39 ± 13 years, FEV1 = 79 ± 21%) reported significantly improved FEV1, FEV1/forced vital capacity (FVC), residual volume (RV)/total lung capacity (TLC) (all P = .0001) and VDP (P = .01) post-salbutamol. Post-salbutamol, VDP responders and nonresponders to salbutamol were significantly different for coarse-texture features including long-run emphasis (LRE) and long-run, low gray-level emphasis (LRLGE, both P < .05) and for FEV1 responders to salbutamol, there was significantly different long-run, high gray-level emphasis (LRHGE, P = .04). There were significant relationships for VDP with LRE (R = .50, P = .0003), LRLGE (R = .34, P = .02), and LRHGE (R = .56, P = .0001). Receiver operating characteristic curves showed VDP with the strongest performance (AUC = .92), followed by coarse-texture classifier LRHGE (AUC = .83), FEV1 (AUC = .80), LRE (AUC = .66), FVC (AUC = .58), and LRLGE (AUC = .42)., Conclusions: In patients with asthma, differences in ventilation patchiness post-salbutamol can be quantified using coarse-texture classifiers that are significantly different in bronchodilator responders., (Copyright © 2015 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Inhaled long-acting β2-agonists (LABA) are often poorly adhered to by elderly patients with chronic obstructive pulmonary disease (COPD). We hypothesized that older age and compromised cognitive function might contribute to poor adherence to inhaled medications among COPD patients, and that transdermally delivered medications could improve adherence, exercise tolerance and quality of life (QOL)., Objective: To compare adherence and effects on health outcomes between transdermal and inhaled LABA., Methods: A total of 44 treatment-naïve, elderly Japanese patients with moderate-to-severe COPD were treated with a transdermal tulobuterol patch (TP; 2 mg, once a day) or inhaled salmeterol (50 µg, twice a day) in a randomized crossover manner. The primary outcomes were adherence to the LABA medications and changes in QOL measured by the St George's Respiratory Questionnaire. Secondary outcomes were changes in 6-min walk distance (6MWD) and spirometric values., Results: The overall adherence rate was 90.3 ± 1.6% for TP and 75.5 ± 2.9% for salmeterol (P < 0.001). Adherence to salmeterol was correlated with age and Mini-Mental State Examination (MMSE) score (P < 0.05 and P < 0.01, respectively), although that to TP was relatively constant regardless of age and MMSE score. 6MWD and QOL were significantly improved from baseline after TP, but not after salmeterol treatment (P < 0.05). Similar degrees of increase in spirometric values occurred after treatment with TP and salmeterol., Conclusions: Adherence levels were higher overall with TP than with inhaled salmeterol, and more stable across age groups and MMSE levels. TP might be a favorable treatment option for COPD patients with poor adherence to an inhaled LABA., (© 2012 Japan Geriatrics Society.)

Background: Spirometry is regarded as the gold standard for the diagnosis of COPD, yet the condition is widely underdiagnosed. Therefore, additional screening methods that are easy to perform and to interpret are needed. Recently, we demonstrated that low frequency ultrasound (LFU) may be helpful for monitoring lung diseases. The objective of this study was to evaluate whether LFU can be used to detect air trapping in COPD. In addition, we evaluated the ability of LFU to detect the effects of short-acting bronchodilator medication., Methods: Seventeen patients with COPD and 9 healthy subjects were examined by body plethysmography and LFU. Ultrasound frequencies ranging from 1 to 40 kHz were transmitted to the sternum and received at the back during inspiration and expiration. The high pass frequency was determined from the inspiratory and the expiratory signals and their difference termed ΔF. Measurements were repeated after inhalation of salbutamol., Results: We found significant differences in ΔF between COPD subjects and healthy subjects. These differences were already significant at GOLD stage 1 and increased with the severity of COPD. Sensitivity for detection of GOLD stage 1 was 83% and for GOLD stages worse than 1 it was 91%. Bronchodilator effects could not be detected reliably., Conclusions: We conclude that low frequency ultrasound is cost-effective, easy to perform and suitable for detecting air trapping. It might be useful in screening for COPD., Trial Registration: ClinicalTrials.gov: NCT01080924.

Patients with traumatic brain injury (TBI) have delayed gastric emptying and often require prokinetic drug therapy to improve enteral feeding tolerance. The authors hypothesized that metoclopramide was less efficacious for improving gastric feeding tolerance for trauma patients with TBI compared to trauma patients without TBI. A retrospective analysis was conducted of patients admitted to the trauma or neurosurgical intensive care unit who received gastric feeding from January 2006 to April 2008. Gastric feeding intolerance was defined by a gastric residual volume >200 mL or emesis with abdominal distension or discomfort. Patients with gastric feeding intolerance were given metoclopramide 10 mg intravenously every 6 hours, followed by a dose escalation to 20 mg, and then combination therapy with metoclopramide and erythromycin 250 mg intravenously every 6 hours if intolerance persisted. In total, 882 trauma patients (49% with TBI) were evaluated. TBI patients had a higher incidence of gastric feeding intolerance than those without TBI (18.6% vs 10.4%, P < or = .001). Efficacy rates for metoclopramide 10 mg, metoclopramide 20 mg, and metoclopramide-erythromycin were 55%, 62%, and 79%, respectively (P < or = .03). Metoclopramide failure occurred in 54% of patients with TBI compared to 35% of patients without TBI, respectively (P < or = .02), due to a greater prevalence of tachyphylaxis. Single-drug therapy with metoclopramide was less effective for TBI trauma patients compared to trauma patients without TBI. Combination therapy with erythromycin as first-line therapy for TBI trauma patients with gastric feeding intolerance is indicated if there are no contraindications or significant drug interactions.

Background: The non-specific bronchial hyper-responsiveness reported in mild to moderate COPD is usually attributed to reduced airway calibre accentuating the effect of airway smooth muscle shortening. We hypothesized that in more severe COPD the fall in forced expiratory volume in 1 second (FEV(1)) seen during methacholine challenge would result from an increase in residual volume and decrease in vital capacity rather than an increase in airways resistance., Methods: Twenty-five subjects with moderate to severe COPD and 10 asthmatic subjects had spirometry and oscillatory mechanics measured before methacholine challenge and at a 20% fall from baseline post challenge (PC(20)FEV(1))., Results: In the COPD subjects median PC(20) was 0.35mg/mL. Comparing baseline to PC(20) there were significant falls in forced vital capacity (FVC) (2.91 vs. 2.2L; p<0.001), slow vital capacity (3.22 vs. 2.58L; p<0.001) and IC (2.21 vs. 1.75L; p<0.001) without change in FEV(1)/FVC ratio (0.52 vs. 0.52; not significant) or in total lung capacity where this was measured. Total respiratory system resistance (R(5)) was unchanged (0.66 vs. 0.68; not significant) but total respiratory system reactance decreased significantly (-0.33 vs. -0.44; p<0.001). In contrast, the asthmatics became more obstructed and showed a proportionally smaller fall in lung volume with increase in R(5) (0.43 vs. 0.64; p<0.01)., Conclusions: In moderate to severe COPD the fall in FEV(1) with methacholine is mainly due to increases in residual volume, which may represent airway closure and new-onset expiratory flow limitation.

Background: Although airway obstruction, as defined by improvement of forced expiratory volume in one second (FEV1) and/or forced vital capacity (FVC), is irreversible in patients with COPD, they clearly seem to benefit from treatment with inhaled bronchodilators., Aims: To assess the response pattern of residual volume (RV) compared to FEV1 after bronchodilation in patients with reversible and irreversible airway obstruction., Methods: Changes in static lung volumes were compared with improvement in dynamic lung volumes in 396 consecutive patients undergoing reversibility testing with repeat bodyplethysmography. Reversibility was defined as improvement of FEV1 >200 ml and >12% after inhalation of fenoterol hydrobromide., Results: Irreversibility was found in 297 out of 396 patients with airway obstruction. Except for total lung capacity (TLC), all parameters (residual volume [RV], vital capacity [VC], forced inspiratory vital capacity [IVC], forced vital capacity [FVC], forced expiratory volume in one second [FEV1] and the FEV1/VC ratio) showed statistically significant changes after bronchodilation in 396 patients. The multiple linear regression model adjusted for age, sex and BMI showed a non-linear relationship between DeltaFEV1 or DeltaVC compared to DeltaRV after bronchodilation. If the increase in DeltaFEV1 is lower than 0.1 L, DeltaRV remains constant. However, if the increase in DeltaFEV1 is more than 0.1 L, DeltaRV decreases too. The same is found at an increase in VC of 0.3 L., Conclusion: In summary, in patients with irreversible airway obstruction DeltaRV cannot be predicted by DeltaFEV1 or DeltaVC after bronchodilation. Therefore, spirometric assessment should be complemented by bodyplethysmography.

Background: High fractions of inspired oxygen (Fio2) result in resorption atelectasis shortly after their application. However, the impact of different levels of Fio2 and their interaction with positive end-expiratory pressure (PEEP) on functional residual capacity (FRC) and ventilation distribution is unknown in anesthetized children. We hypothesized that the use of a Fio2 of 1.0 results in a decrease of FRC and ventilation homogeneity compared with that of a Fio2 of 0.3, and that this decrease is prevented by PEEP of 6-cm H2O compared to a PEEP of 3-cm H2O., Methods: Forty-six children (3-6 yr) without cardiopulmonary disease were randomly allocated to receive PEEP of 6-cm H2O (PEEP 6 group) during the entire study period or PEEP of 3-cm H2O (PEEP 3 group). The order of the Fio2 (0.3 or 1.0) was also randomized. A defined recruitment maneuver was performed after tracheal intubation and 5 min later the first measurement. This procedure was then repeated with the second Fio2 level. FRC and lung clearance index (LCI) were calculated by a blinded observer., Results: While FRC (mean +/- sd) was similar at both levels of Fio2 (0.3: 25.6 +/- 2.9 mL/kg vs 1.0: 25.6 +/- 2.8 mL/kg, P = 0.189) in the PEEP 6 group, FRC decreased in the PEEP 3 group (0.3: 24.9 +/- 3.8 vs 1.0: 21.7 +/- 4.1, P < 0.0001). Furthermore, with continuous PEEP of 6-cm H2O a similar LCI was observed at both levels of Fio2 (0.3: 6.45 +/- 0.4 vs 6.43 +/- 0.4, P = 0.668) while LCI increased at the higher Fio2 in the PEEP 3 group (0.3: 6.5 +/- 0.5 vs 1.0: 7.7 +/- 1.2, P < 0.0001)., Conclusions: During the application of a very low PEEP of 3-cm H2O, FRC and ventilation distribution decreased significantly at an Fio2 of 1.0 compared with that at an Fio2 of 0.3. This decrease could be counterbalanced by the administration of PEEP of 6-cm H2O, indicating that a low level of PEEP is sufficient to maintain FRC and ventilation distribution regardless of the oxygen concentration.

Background: Estimated ambient concentrations of acrolein, a hazardous air pollutant, are greater than the U.S. Environmental Protection Agency (EPA) reference concentration throughout the United States, making it a concern for human health. However, there is no method for assessing the extent of risk under the U.S. EPA noncancer risk assessment framework., Objectives: We estimated excess risks from ambient concentrations of acrolein based on dose-response modeling of a study in rats with a relationship between acrolein and residual volume/total lung capacity ratio (RV/TLC) and specific compliance (sC(L)), markers for altered lung function., Methods: Based on existing literature, we defined values above the 90th percentile for controls as "adverse." We estimated the increase over baseline response that would occur in the human population from estimated ambient concentrations of acrolein, taken from the U.S. EPA's National-Scale Air Toxics Assessment for 1999, after standard animal-to-human conversions and extrapolating to doses below the experimental data., Results: The estimated median additional number of adverse sC(L) outcomes across the United States was approximately 2.5 cases per 1,000 people. The estimated range of additional outcomes from the 5th to the 95th percentile of acrolein concentration levels across census tracts was 0.28-14 cases per 1,000. For RV/TLC, the median additional outcome was 0.002 per 1,000, and the additional outcome at the 95th percentile was 0.13 per 1,000., Conclusions: Although there are uncertainties in estimating human risks from animal data, this analysis demonstrates a method for estimating health risks for noncancer effects and suggests that acrolein could be associated with decreased respiratory function in the United States.

Study Objective: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium., Methods: IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH., Results: At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003)., Conclusion: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.

Study Objectives: The distal airways are likely to contribute to asthma pathobiology and symptoms but have rarely been specifically evaluated in relation to systemic oral therapy. We hypothesized that treatment with montelukast, an oral cysteinyl-leukotriene receptor antagonist, would improve both proximal and distal lung physiology in patients with mild asthma., Design: Randomized, double-blind, crossover design., Setting: Academic referral center., Patients: Subjects with mild asthma limited to using short-acting inhaled beta(2)-agonists., Interventions: Nineteen subjects with mild asthma underwent a baseline assessment of lung function, lung mechanics, and symptoms, followed by randomization to therapy with montelukast, 10 mg taken in the evening, or placebo in a crossover, double-blind fashion. Each treatment phase lasted 4 weeks, with a 2-week washout period. A repeat evaluation was performed during the last week of each treatment phase., Measurements and Results: Montelukast resulted in improvement in (mean +/- SD) proximal and distal lung function parameters (change in FEV(1): montelukast, 0.16 +/- 0.06 L; placebo, -0.05 +/- 0.05 L; p = 0.008); change in specific conductance: montelukast, 7.2 +/- 2.9% predicted; placebo, -17 +/- 8% predicted; p = 0.007; change in % predicted residual volume [RV]: montelukast, 18.4 +/- 8.3% predicted; placebo, 3.0 +/- 2.9% predicted; p = 0.05). Improvement in symptoms (ie, wheeze and chest tightness) correlated with improvements in RV while receiving montelukast, but not while receiving placebo (Pearson coefficients: 0.55 and 0.66, respectively; p < 0.008 and 0.04, respectively)., Conclusions: The systemically acting oral agent montelukast improves proximal and distal lung physiology. Improvements in distal lung function correlate with improvements in asthma symptoms.

We examined the effects of chest wall strapping (CWS) on the response to inhaled methacholine (MCh) and the effects of deep inspiration (DI). Eight subjects were studied on 1 day with MCh inhaled without CWS (CTRL), 1 day with MCh inhaled during CWS (CWSon/on), and 1 day with MCh inhaled during temporary removal of CWS (CWSoff/on). On the CWSon/on day, MCh caused greater increases in pulmonary resistance, upstream resistance, dynamic elastance, residual volume, and greater decreases in maximal expiratory flow than on the CTRL day. On the CWSoff/on day, the changes in these parameters with MCh were not different from the CTRL day. Six of the subjects were again studied using the same protocol on CTRL and CWSon/on days, except that, on a third day, MCh was given after applying the CWS, but the measurements before and after the inhalation were made without CWS (CWSon/off). The latter sequence was associated with more severe airflow obstruction than during CTRL, but less than with CWSon/on. The bronchodilator effects of a DI were blunted when CWS was applied during measurements (CWSon/on and CWSoff/on) but not after it was removed (CWSon/off). We conclude that CWS is capable of increasing airway responsiveness only when it is applied during the inhalation of the constrictor agent. We speculate that breathing at low lung volumes induced by CWS enhances airway narrowing because the airway smooth muscle is adapted at a length at which the contractile apparatus is able to generate a force greater than normal.

We hypothesized that structural airway remodeling contributes to airways hyperresponsiveness (AHR) in asthma. Small, medium, and large airways were analyzed by computed tomography in 21 asthmatic volunteers under baseline conditions (FEV1 = 64% predicted) and after maximum response to albuterol (FEV1 = 76% predicted). The difference in pulmonary function between baseline and albuterol was an estimate of AHR to the baseline smooth muscle tone (BSMT). BSMT caused an increase in residual volume (RV) that was threefold greater than the decrease in forced vital capacity (FVC) because of a simultaneous increase in total lung capacity (TLC). The decrease in FVC with BSMT was the major determinant of the baseline FEV1 (P < 0.0001). The increase in RV correlated inversely with the relaxed luminal diameter of the medium airways (P = 0.009) and directly with the wall thickness of the large airways (P = 0.001). The effect of BSMT on functional residual capacity (FRC) controlled the change in TLC relative to the change in RV. When the FRC increased with RV, TLC increased and FVC was preserved. When the relaxed large airways were critically narrowed, FRC and TLC did not increase and FVC fell. With critical large airways narrowing, the FRC was already elevated from dynamic hyperinflation before BSMT and did not increase further with BSMT. FEV1/FVC in the absence of BSMT correlated directly with large airway luminal diameter and inversely with the fall in FVC with BSMT. These findings suggest that dynamic hyperinflation caused by narrowing of large airways is a major determinant of AHR in asthma.

Aims: Spirometry, plethysmography and impulse oscillometry (IOS) measure different aspects of lung function. These methods have not been compared for their ability to assess long- and short-acting anticholinergic agents. We therefore performed a double-blind, placebo-controlled, four-way cross-over study in 30 healthy subjects., Methods: Single doses of tiotropium bromide (Tio) 54 and 18 mcg, ipratropium bromide (IB) 40 mcg and placebo were administered. Specific conductance (sGaw), total lung capacity (TLC), inspiratory capacity (IC) and residual volume (RV) were measured using plethysmography, while IOS measured resistance (R5-25) and reactance (RF and X5). Pulmonary function was measured for 26 h post dose., Results: Tio caused significant improvements in sGaw, forced expiratory voume in 1 s (FEV(1)), maximum mid-expiratory flow (MMEF) and R5-R25 at time points up to 26 h, with no clear differences between doses. IB improved the same parameters, but only up to 8 h. The weighted mean change (0-24 h) caused by Tio 54 mcg compared with placebo for FEV(1) was 240 ml (95% confidence interval 180, 300), while for sGaw the ratio of geometric means (Tio compared with placebo) was 1.35 (1.28, 1.41). Neither drug caused consistent statistically significant changes in RF, forced vital capacity, TLC or IC over 26 h. RV was significantly improved from 8 to 24 h by Tio 54 mcg only., Conclusions: In addition to spirometry, IOS resistance measurements and sGaw can distinguish between the effects of long- and shortacting anticholinergic effects in healthy subjects.

Chronic obstructive pulmonary disease (COPD) causes disabling, slowly progressive breathlessness on exertion, chronic cough and sputum production. Its natural history is punctuated by increasingly frequent exacerbations which in turn accelerate disease progression and reduce a patient's quality of life. COPD has previously been ignored in the mistaken belief that nothing could be done. There are now a number of therapies that can be used to reduce symptoms and prevent exacerbations. In turn this reduces disability, improves the patient's health-related quality of life and has the potential to reduce costs to the health service and to society.

Objective: In children with chronic persistent asthma, we evaluated whether the presence of increased residual volume (RV) after anti-inflammatory treatment correlates with the detection of low-density areas on high-resolution computed tomography (HRCT), similar to those in emphysema., Methods: Children with a confirmed diagnosis of asthma (n = 32) were enrolled in a prospective study. All patients had reduction of airflow in the peripheral airways, increased RV, and increased serum eosinophil cationic protein (ECP) values indicating airway inflammation. All the children were treated with salmeterol (50 microg twice daily) and fluticasone (250 microg twice daily) for a 3-month period., Results: At the end of treatment, peripheral eosinophil counts, serum ECP, forced expiratory volume in 1 second (FEV(1)), mean forced expiratory flow during the middle half of forced vital capacity (FEF(25-75)), RV, and total lung capacity values improved in all the patients. HRCT was normal in 22 children (68.8%); in the remaining 10 subjects, low-density areas were found despite normalization of FEV(1), FEF(25-75), and significant reduction in ECP. A significant correlation was found between persistence of RV values >150% predicted and the presence of low-density areas on HRCT (r = 0.84, P <.0001)., Conclusions: Structural changes similar to emphysema are also present in asthmatic children. Our findings suggest that the persistence of increased RV may be used to identify subjects with low-density areas on HRCT.

The difficulty of assessing nebulizer responses in chronic obstructive pulmonary disease (COPD) has been demonstrated before. This study aims to re-examine both the role of domiciliary nebulizers in COPD and also bronchodilator (BD) assessment in individuals. In a double-blind, randomized, cross-over trial, 19 stable patients with severe COPD were given the following medication 6-hourly for 2-week periods: (1) nebulized salbutamol 2.5 mg with ipratropium 0.5 mg and placebo inhalers (MDI) with spacer; (2) placebo nebules and inhaled salbutamol 400 microg with ipratropium 80 microg via MDI with spacer; (3) inhaled salbutamol 400 microg with ipratropium 80 microg via MDI with spacer (but no placebo nebulized drugs). Both nebulized and MDI drugs produced highly significant improvements in forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), specific airways conductance, 6-min walking distance (6MWD) and residual volume. There were no significant differences between BD responses obtained after active nebulized and active MDI BDs. From the diary cards, 2 weeks of active nebulized BDs produced a slightly higher median peak expiratory flow (PEF) than active MDI BDs (236 and 219 l m(-1), respectively, P=0.01) and slightly less extra inhaler use (0.8 and 1.1 puffs, respectively, P<0.05) but no significant difference in dyspnoea or quality of life (QOL) scores. There were significant correlations between domiciliary PEF and acute BD-induced changes in FVC and 6MWD, and also between domiciliary dyspnoea scores and acute changes in both total lung capacity and 6MWD. In conclusion, nebulized medication conferred little clinical advantage over the regular use of inhalers with spacers in this group of patients with severe COPD. However, acute changes in total lung capacity, FVC and 6MWD may be useful predictors of the longer-term effects of nebulized BDs in individual patients.

SUMMARY. In this prospective open study of 14 children with cystic fibrosis (CF), we evaluated the effect of 1 year adjuvant therapy with lansoprazole, a proton pump inhibitor (PPI), on growth, fecal fat loss, body composition and lung function. Only stable patients with pancreatic insufficiency were included, and their data were compared to those of a large Dutch pediatric normal reference population. During the use of the PPI, mean weight and height did not change significantly, while body mass index improved (P < 0.05). An immediate significant and persistent reduction of fecal acid steatocrit (P < 0.05) was demonstrated. Compared to normal Dutch children, the CF patients showed significantly decreased standard deviation scores (SDS) for total body fat (TBF, -0.966) and fat-free mass (FFM, -1.826). Under lansoprazole, TBF improved significantly (P < 0.05), while mean FFM remained unchanged. A significant improvement in total lung capacity (P < 0.05), residual volume (P = 0.055), and maximal inspiratory mouth pressure (P = 0.002) was also demonstrated. Hyperinflation tended to decrease during the use of a PPI. Daily recordings of peak expiratory flow (PEF) showed a maximal diurnal variability of 28% of recent best PEF and minimal morning PEF of 72% of recent best PEF, confirming that bronchial hyperresponsiveness is increased in CF. We conclude that adjuvant therapy with lansoprazole in young CF patients with persistent fat malabsorption, decreased fat losses and improved total body fat. Lung hyperinflation decreased, which may partly explain the improvement in inspiratory muscle performance. The simultaneous improvements in body composition and lung hyperinflation suggest a relationship between these two parameters. Further research is necessary to confirm such a relationship and to elucidate the mechanisms involved., (Copyright 2001 Wiley-Liss, Inc.)

Background: A number of employees at an aircraft factory were accidentally exposed to hydrogen sulfide. Because of concern that this may have resulted in lung injury, forty-seven workers were referred for clinical and physiological evaluation., Methods: Comprehensive pulmonary function tests were performed including spirometry, flow volume curves, static lung volumes, and diffusion capacity for carbon monoxide., Results: The results obtained indicated that ten people (23%) had an isolated reduction in residual volume. This was an unexpected finding as other physiological indices of lung function were within normal limits. Clinical examination was also normal, therefore, radiological investigations were considered inappropriate., Conclusions: It is suggested that the decrement in residual volume, in the presence of other normal indices of lung function, could represent a sub-acute manifestation of hydrogen sulfide intoxication., (Copyright 2000 Wiley-Liss, Inc.)

Pirfenidone is an antifibrotic drug that we have shown attenuates the increase in collagen buildup in hamsters exposed to bleomycin, in turn reducing pulmonary function and blood gas decrements seen in this model of interstitial pulmonary fibrosis. The systemic effects of pirfenidone ingestion, however, are unknown. We examined the effect of diet-ingested pirfenidone on pulmonary function, systemic and pulmonary cardiovasculature and blood gas measurements, breathing pattern and lung hydroxyproline content in rats fed either a control diet or a diet containing 0.5% pirfenidone. Residual volume was higher and expiratory reserve volume lower in the pirfenidone group, with no change in functional residual capacity. Tidal volume was also lower in the pirfenidone group, with no change in the overall level of ventilation. There was a trend toward a reduced hydroxyproline content and an increased lung compliance in the pirfenidone group. There were no differences in systemic or pulmonary pressures, cardiac output, stroke volume, heart rate, pH or blood gases between the two groups. These data indicate that pirfenidone has few systemic side-effects but may have a mild effect on the basal level of lung collagen content with resulting clinical changes in some pulmonary function measurements and changes in breathing pattern.

In bronchial asthma, measurement of absolute lung volumes may reveal lung dysfunction more readily than forced expiratory spirometry. Sixty-one children (aged 4-16 years) with mild to moderate bronchial asthma and 35 children (aged 7-16 years) with other symptoms of the lower airways (OSLA) were studied, and the plethysmographic results were compared with data obtained from 36 healthy volunteers aged 6-16 years. In the first test session, repeatability of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), residual volume (RV), functional residual capacity (FRC) and total lung capacity (TLC) were good. Control subjects were also tested the next day, and intra-subject variability of repeat pulmonary function testing was in the normal range. The FEV1/FVC ratio was significantly higher in control subjects than in patients with asthma or OSLA, but only the decrease in RV after bronchodilator challenge separated patients with asthma from patients with OSLA. Changes in FEV1 and RV after bronchodilator challenge had a significant, although low, inverse correlation. An increase of > or = 5% in FEV1 had a positive predictive value of 44% and a negative predictive value of 68% for the clinical diagnosis of bronchial asthma; for a decrease of > or = 24% in RV, the figures were 86% and 71% respectively. The support of baseline absolute lung volumes on clinical decision-making is not necessarily great. Bronchodilator response, particularly in RV, is more pertinent and may enhance the detection of reversible lung dysfunction.

Both rheumatoid arthritis (RA) and methotrexate (MTX) are reported to be associated with the development of pulmonary disease. To determine whether MTX enhanced the risk of developing abnormalities in pulmonary function in patients with RA, we prospectively studied 31 subjects (12 male, 19 female) with the diagnosis of classic RA for an average period of 4.4 yr (range, 1 to 5 yr). Each subject was placed on low-dose weekly MTX (mean 17 mg, range 2.5 to 40) for control of RA symptoms. Other medications included non-steroidal anti-inflammatory agents and prednisone if required for control of arthritis symptoms. No other immunosuppressive therapy was used. Each subject was evaluated by pulmonary function tests (PFT) and chest X-ray initially, and at 1, 2, 3.5, and 5 yr. Chest X-rays obtained initially and at the end of the study period were found to be normal. The percent predicted values for initial PFTs in the study group were within the normal range. From the beginning to the end of the observation period, the following mean changes in lung function were observed: 1.9% increase in TLC, 5.1% increase in residual volume (RV), 1.8% increase in FVC, 0.71% decrease in FEV1, 14.7% improvement in alveolar-arterial oxygen (A-aO2) difference, and a 12.7% increase in single-breath diffusing capacity (DLCO). To determine whether MTX (average dose, weekly dose, or cumulative dose) was significantly related to changes in pulmonary function, we used multivariate techniques to control for the initial measure of lung function while assessing the relationship between MTX and the subsequent measures of lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

In cystic fibrosis (CF), it has been suggested that increases in FEV1 postbronchodilator (BD) can be accompanied by paradoxical decreases in isovolume maximal flow at 25% of vital capacity (V25iso) measured from maximum expiratory flow-volume curves (MEFVC), raising concerns about determining the benefits of BD in CF. MEFVC measured using expired volume has been shown to be subject to errors due to gas compression. In the present study, BD response was assessed in 91 patients with asthma and 78 with CF using the percentage of change in FEV1 and V25iso determined using MEFVC from both mouth (m) and plethysmograph (p) volumes. From the two curves, volume of compression (Vcomp) was measured. Baseline measurements were similar for both groups, except that the residual volume to total lung capacity ratio (RV/TLC) was higher and Vmax25 and FVC were lower in CF. Both groups showed significant (p < 0.05) increases in FVC, FEV1, and V25iso after BD. The percentage of change in FEV1 correlated with the percentage of change in V25iso (r = 0.53 for CF and 0.66 for asthma, p < 0.001). Baseline Vcomp25 was higher in asthma than in CF. The percentage of change in V25iso was not related to the change in Vcomp25iso for either group. Only four patients with CF showed a paradoxical decrease in V25iso, and the differences in flow were small. Two had an increase in Vcomp and two had a decrease. We conclude that paradoxical decreases in V25iso are rare, are associated with small changes in flow, and are not related to changes in Vcomp.(ABSTRACT TRUNCATED AT 250 WORDS)

Perfluorochemicals are fluorine-saturated carbon-based molecules which demonstrate utility in the areas of imaging and oxygen delivery. In general, these molecules are biologically inert and, therefore, do not pose toxicologic risk from metabolic degradation. Intravenous (i.v.) perfluorocarbon (PFC) emulsions are cleared from the blood through a process involving phagocytosis of emulsion particles by reticuloendothelial macrophages (RES) and ultimate elimination through the lung in expired air. RES phagocytosis of PFC emulsion particles leads to characteristic, predictable, and reversible biological effects that are a consequence of a normal host-defense mechanism. This mechanism is characterized by dose-related stimulation of macrophages and subsequent release of intracellular products (particularly metabolites of the arachidonic acid cascade and cytokines) which are responsible for most of the biological effects associated with i.v. PFC emulsions (i.e., cutaneous flushing and fever at lower doses, and macrophage hypertrophy and recruitment at higher doses). These biological effects are reversible, and do not result in any permanent tissue alteration, even with prolonged exposure at relatively high doses. The rate of PFC elimination from the RES is proportional to the vapor pressure of the PFC, inversely proportional to molecular weight and positively influenced by lipophilicity. This dose-dependent respiratory excretion occurs with no evidence of metabolic products. Repeated administration of high doses of PFC emulsion may lead to a saturation of the RES-mediated clearance capacity, resulting in a redistribution of PFC to non-RES tissues and ingestion by resident or mobile macrophages. This condition is benign with respect to the integrity of the surrounding parenchyma, as well as to the macrophages themselves. Increased pulmonary residual volume (IPRV) due to pulmonary gas (air) trapping, a reversible side effect, has been observed with i.v. doses of PFC emulsion in some animal species. The gross morphological change associated with IPRV is not accompanied by any histological alteration other than the appearance of vacuolated macrophages (characteristic of the normal clearance mechanism) and some minor, increased interalveolar cellularity. Animal lungs affected by IPRV have a normal, pale pink appearance with no visible lesions or signs of edema. The degree of IPRV is dependent on species, PFC dose, and type of PFC administered; PFCs with higher vapor pressures produce the most severe cases of IPRV in sensitive species. Species sensitivity depends upon physiological and morphological characteristics. There is no evidence indicating that IPRV occurs in humans. Although i.v. PFC emulsions may elicit minor untoward effects, these effects are reversible and, at clinically relevant doses, do not pose a toxicologic risk.

The effect of large doses of salbutamol (S) and ipratropium bromide (IB) were tested in a double-blind, randomized, crossover study. Nine patients with cystic fibrosis (CF), aged 12.8 +/- 2 years (mean +/- SE), were studied for 8 h on 2 separate days. Pulmonary function tests (PFTs) included spirometry (FEV1), lung volumes (FRC), and airway resistance (Raw) measured by body plethysmography. Heart rate (HR) and oxygen saturation (SaO2) were measured before each test. On 1 day patients received S 200 micrograms, S 400 micrograms, and IB 80 micrograms, by inhalation at 45-min interval (sequence A). On the other day, the sequence was IB 80 micrograms, S 200 micrograms, and S 400 micrograms (sequence B). The PFTs were obtained at baseline, 45 min after each inhalation, and 4 and 8 h after baseline measurements. Baseline PFTs (mean +/- SE) were not significantly different on the 2 study days (FEV1, 1.48 +/- 0.1 vs 1.42 +/- 0.1 L; FRC, 2.77 +/- 0.6 vs 2.87 +/- 0.6 L; Raw, 4.04 +/- 0.2 vs 4.00 +/- 0.3 cm H2O/L/s). The FEV1 and Raw improved from baseline after each inhalation, and at 4 and 8 h during both days (p < 0.05). Forty-five minutes after S 200 micrograms, plus S 400 micrograms, FEV1, FRC, and Raw were not significantly different compared with the values 45 min after IB 80 micrograms, plus S 200 micrograms (1.67 +/- 0.1 vs 1.63 +/- 0.1 L; 2.81 +/- 0.6 vs 2.65 +/- 0.5 L; and 2.98 +/- 0.2 vs 2.66 +/- 0.1 cm H2O/L/s, respectively). The PFTs were not significantly different after maximal doses of IB (80 micrograms) compared with S (600 micrograms). The HR and SaO2 were not significantly different from baseline throughout the study period. These results indicate that both single and sequential therapy have a similar acute bronchodilator effect provided that large doses are used. We speculate that adrenergic and muscarinic pathways are equally important in airflow obstruction in patients with CF.

237 out-patients suffering from chronic obstructive lung disease (COLD) were selected from 7 Italian clinical centers. They were randomly allocated to either placebo or bromhexine 30 mg b.i.d. p.o., in a double-blind fashion. Sputum volume and quality, facility of expectoration, cough, dyspnea, auscultatory thoracic symptoms, forced expiratory volume, peak expiratory flow rate and residual volume were evaluated. Bromhexine showed a statistically significant therapeutic activity in comparison to placebo. This action was rapid, marked and effective in determining a modulation of bronchial secretions.