Treatment response according to small airways disease status: The effects of high-strength extrafine pMDI beclomethasone dipropionate/formoterol fumarate in fixed dose combination in moderate uncontrolled asthmatic patients.

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.

Bronchodilator Responses in Respiratory Impedance, Hyperinflation and Gas Trapping in COPD.

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.

The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials.

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.

Predictors of outcome for urethral injection of botulinum toxin to treat detrusor sphincter dyssynergia in men with spinal cord injury.

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.

Detection of air trapping in chronic obstructive pulmonary disease by low frequency ultrasound.

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.

Pathophysiological changes of the lower urinary tract behind voiding dysfunction in streptozotocin-induced long-term diabetic rats.

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.

Effects of lung deflation induced by tiotropium/olodaterol on the cardiocirculatory responses to exertion in COPD.

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 O2 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 ±â€¯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 O2 delivery.

Bronchodilator response in residual volume in irreversible airway obstruction.

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.

Direct and indirect effects of Growth Hormone Deficiency (GHD) on lung function in children: A mediation analysis.

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, FEV1, FEF25-75% 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.

Estimating risk from ambient concentrations of acrolein across the United States.

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.

Tiotropium and simplified detection of dynamic hyperinflation.

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.

The impact of positive end-expiratory pressure on functional residual capacity and ventilation homogeneity impairment in anesthetized children exposed to high levels of inspired oxygen.

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.

Gastric Residual Volume after Split-Dose Bowel Preparation versus Conventional Single-Dose Regimen before Anesthetic Colonoscopy.

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.

Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast.

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.

Effects of chest wall strapping on mechanical response to methacholine in humans.

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.

The structural basis of airways hyperresponsiveness in asthma.

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.

Residual Volume and Total Lung Capacity to Assess Reversibility in Obstructive Lung Disease.

BACKGROUND: Reversibility of obstructive lung disease is traditionally defined by changes in FEV1 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 FEV1 or FVC, the American Thoracic Society and European Respiratory Society criteria. Reduced residual volume weakly correlated with response to FEV1 and to FVC. No statistically significant correlation was found between total lung capacity and either FEV1 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.

Second-order Texture Measurements of (3)He Ventilation MRI: Proof-of-concept Evaluation of Asthma Bronchodilator Response.

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.

The effect of high doses of inhaled salbutamol and ipratropium bromide in patients with stable cystic fibrosis.

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.

Changes in pulmonary hyperinflation and bronchial hyperresponsiveness following treatment with lansoprazole in children with cystic fibrosis.

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.