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Chest Feb 2020The respiratory duty cycle (T/T) can influence bronchoprovocation test results and nebulized drug delivery. The T/T has not yet been examined in individuals with airway...
BACKGROUND
The respiratory duty cycle (T/T) can influence bronchoprovocation test results and nebulized drug delivery. The T/T has not yet been examined in individuals with airway hyperresponsiveness (AHR) in typical bronchoprovocation test conditions. This study investigated the mean T/T in participants with and without AHR and whether the T/T changes with increasing bronchoconstriction.
METHODS
Fifteen participants with AHR and fifteen participants without AHR completed this randomized crossover study. An ultrasonic spirometer was used for continuous measurement of the T/T as participants inhaled room air or aerosolized solution. Each participant completed two methacholine challenges, one using a continuous-output vibrating mesh nebulizer/ultrasonic spirometer and one with the nebulizer only. Prior to each methacholine challenge, participants inhaled room air and aerosolized saline through the nebulizer/spirometer setup to record baseline T/T data.
RESULTS
The mean T/T findings [95% CIs] during room air inhalation were 0.392 [0.378-0.406] and 0.447 [0.426-0.468] in participants with and without AHR, respectively (P < .001). The mean T/T during saline inhalation were 0.389 [0.373-0.405] and 0.424 [0.398-0.450] in participants with and without AHR (P = .040). The T/T showed a nonsignificant downward trend with progressive methacholine-induced bronchoconstriction.
CONCLUSIONS
The mean T/T in participants with AHR closely resembles the assumed T/T of 0.40 recommended for standard use when calculating methacholine challenge results. Since the T/T did not change significantly over the course of a methacholine challenge, the same T/T can be used to calculate the dose of methacholine inhaled, regardless of the level of bronchoconstriction.
TRIAL REGISTRY
ClinicalTrials.gov; No.: NCT03505489; URL: www.clinicaltrials.gov.
Topics: Adolescent; Adult; Bronchial Provocation Tests; Bronchoconstrictor Agents; Case-Control Studies; Cross-Over Studies; Female; Forced Expiratory Volume; Humans; Inhalation; Male; Methacholine Chloride; Middle Aged; Random Allocation; Respiratory Hypersensitivity; Spirometry; Time Factors; Young Adult
PubMed: 31542451
DOI: 10.1016/j.chest.2019.09.005 -
Respiratory Physiology & Neurobiology Mar 2020Nocturnal worsening of asthma may be due to reduced lung volumes and fewer sigh breaths, which have been shown to increase airway resistance and bronchoreactivity. We... (Clinical Trial)
Clinical Trial
Nocturnal worsening of asthma may be due to reduced lung volumes and fewer sigh breaths, which have been shown to increase airway resistance and bronchoreactivity. We hypothesized that mimicking deep inspiration using nocturnal mechanical support would improve symptoms in patients with asthma. Subjects with asthma underwent usual care and bilevel positive airway pressure (PAP) therapy for 4 weeks, separated by 4 weeks, and methacholine challenge (PC) and subjective assessments. 13 patients with asthma alone and 8 with asthma + OSA completed the protocol. Change in bronchoreactivity (ratio of Post/Pre PC) was not significantly different during usual care and bilevel PAP [0.86 (IQR 0.19, 1.82) vs 0.94 (IQR 0.56, 2.5), p = 0.88], nor was the change in Asthma Control Test different: 0.1 ± 2.2 vs. -0.2 ± 2.9, p = 0.79, respectively. Bilevel PAP therapy for four weeks did not improve subjective or objective measures of asthma severity in patients with asthma or those with asthma and OSA, although there was heterogeneity in response.
Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchoconstrictor Agents; Continuous Positive Airway Pressure; Cross-Over Studies; Female; Humans; Lung Volume Measurements; Male; Methacholine Chloride; Middle Aged; Outcome Assessment, Health Care; Sleep Apnea, Obstructive
PubMed: 31805396
DOI: 10.1016/j.resp.2019.103355 -
Pulmonary Pharmacology & Therapeutics Feb 2020Methacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a... (Clinical Trial)
Clinical Trial
BACKGROUND
Methacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a sensitive population, such as in subjects with asthma. Here, we evaluate the variability of the methacholine challenge recovery model, and compare the results obtained for both incremental and bolus challenge methods.
METHODS
The extent, time course and variability of change in forced expiratory volume in 1 s (FEV) following repeated methacholine challenges in subjects with mild asthma were investigated in an open-label, four-period, fixed-sequence, two-method, replicate crossover study. At Visits 1 and 2, subjects underwent an incremental challenge using doubling doses of methacholine until a ≥20% decrease in FEV was observed; at Visits 3 and 4, subjects underwent a bolus challenge, inhaling a single dose of methacholine calculated from the cumulative dose established during Visit 1.
RESULTS
A total of 19 subjects were included in the study. Both the mean FEV area under the curve (FEV AUC) and mean maximum reductions in FEV (absolute and relative) 120 min post-challenge values were higher for the incremental challenges than the bolus challenges, with no reported difference between repetitions of the same methodology. FEV AUC decrease 120 min post challenge demonstrated an intra-subject coefficient of variation (CV) of 47.2% (incremental) and 78.3% (bolus), suggesting considerable between-visit variability. The mean absolute, and similarly relative, maximum reductions in FEV compared with post-diluent baseline values demonstrated lower intra-subject variability (incremental 21.16%, bolus 40.67%) than the FEV AUC-based endpoint. There was a trend towards faster recovery following the bolus challenge than with the incremental challenge. The provocative dose of methacholine inducing a ≥20% decrease in FEV resulted in a between-group mean difference of 27.20% in the incremental challenge periods, with a high intra-subject CV of 80.64%, demonstrating considerable variability.
CONCLUSION
Maximum reduction in FEV had the lowest variability. There was little difference between repetitions of the same methodology, as indicated by overlapping confidence intervals. There was a trend towards faster recovery following bolus challenge than with the incremental challenge. The results of this trial could be of value when designing future clinical trials using the methacholine challenge methodology.
Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Anti-Asthmatic Agents; Asthma; Cross-Over Studies; Drug Delivery Systems; Female; Forced Expiratory Volume; Humans; Lung; Male; Methacholine Chloride; Middle Aged
PubMed: 31843704
DOI: 10.1016/j.pupt.2019.101876 -
Pulmonary Pharmacology & Therapeutics Dec 2014This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by...
BACKGROUND
This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by airway narrowing following exposure to a wide variety of non-immunological stimuli. Undescended testis (UDT) is one of the most common male congenital anomalies. The orl rat is a Long Evans substrain with inherited UDT. Since boys born with congenital UDT are more likely to manifest asthma symptoms, the main aim of this study was to investigate the alternative hypothesis that orl rats have greater AHR to a methacholine aerosol challenge than wild type rats.
METHODS
Long Evans wild type (n = 9) and orl (n = 13) rats were anesthetized, tracheostomized, and mechanically ventilated at 4 weeks of age. Escalating concentrations of inhaled methacholine were delivered. The methacholine potency and efficacy in the strains were measured. Respiratory resistance was the primary endpoint. After the final methacholine aerosol challenge, the short-acting β2-adrenoceptor agonist albuterol was administered as an aerosol and lung/diaphragm tissues were assayed for interleukin (IL)-4, IL-6, and tumor necrosis factor (TNF)-α. Histological and histomorphometrical analyses were performed.
RESULTS
The methacholine concentration-response curve in the orl group indicated increased sensitivity, hyperreactivity, and exaggerated maximal response in comparison with the wild type group, indicating that orl rats had abnormally greater AHR responses to methacholine. Histological findings in orl rats showed the presence of eosinophils, unlike wild type rats. β2-Adrenoceptor agonist intervention resulted in up-regulation of IL-4 diaphragmatic levels and down-regulation of IL-4 and IL-6 in the lungs of orl rats.
CONCLUSION
orl rats had greater AHR than wild type rats during methacholine challenge, with higher IL-4 levels in diaphragmatic tissue homogenates. Positive immunostaining for IL-4 was detected in lung and diaphragmatic tissue in both strains. This model offers advantages over other pre-clinical murine models for studying potential mechanistic links between cryptorchidism and asthma. This animal model may be useful for further testing of compounds/therapeutics options for treating AHR.
Topics: Administration, Inhalation; Albuterol; Animals; Anti-Asthmatic Agents; Asthma; Bronchoconstrictor Agents; Cryptorchidism; Disease Models, Animal; Dose-Response Relationship, Drug; Interleukin-4; Interleukin-6; Lung; Male; Methacholine Chloride; Rats, Long-Evans; Tumor Necrosis Factor-alpha
PubMed: 25218882
DOI: 10.1016/j.pupt.2014.09.001 -
Respiratory Physiology & Neurobiology Jan 2019To clarify the potential of dopamine to alter airway tone in the presence of different bronchoconstrictor stimuli, changes in airway function following dopamine...
To clarify the potential of dopamine to alter airway tone in the presence of different bronchoconstrictor stimuli, changes in airway function following dopamine administrations were characterized when the bronchial tone was elevated by stimulating the histaminic or cholinergic pathway. Airway resistance, tissue damping and tissue elastance were measured in anesthetized mechanically ventilated rabbits under baseline conditions, during steady-state bronchoconstriction induced by methacholine or histamine, and following intravenous dopamine (5 and 15 μg/kg/min). Bronchoconstriction induced by methacholine and histamine was significantly ameliorated by dopamine (14.8 ± 2.9% and 14.9 ± 2.9%; p < 0.05 for both), with no difference between the mode of stimuli. Dopamine had no effect on the tissue mechanics. These findings indicate that dopamine relaxes the elevated airway smooth muscle tone without affecting the lung periphery, and this effect is independent of the mode of constrictor stimuli. This profile of dopamine suggests its ability to treat effectively cholinergic and histaminergic bronchoconstriction, besides its positive inotropic effects on the myocardial contractility.
Topics: Airway Resistance; Animals; Blood Pressure; Bronchoconstriction; Dopamine; Heart Rate; Histamine; Methacholine Chloride; Muscarinic Agonists; Muscle, Smooth; Rabbits; Respiratory Mechanics
PubMed: 30367990
DOI: 10.1016/j.resp.2018.10.006 -
Respirology (Carlton, Vic.) Aug 2014Airway hyperresponsiveness is a common feature of asthma. Methacholine and mannitol are two representative agonists for bronchial challenge. They have theoretically... (Comparative Study)
Comparative Study
BACKGROUND AND OBJECTIVE
Airway hyperresponsiveness is a common feature of asthma. Methacholine and mannitol are two representative agonists for bronchial challenge. They have theoretically different mechanisms of action, and may have different diagnostic properties. However, their difference has not been directly evaluated among Korean adults. In this study, we compare the diagnostic properties of methacholine and mannitol bronchial provocation tests.
METHODS
Asthmatic patients and non-asthmatic controls were recruited prospectively from four referral hospitals in Korea. Participants were challenged with each of methacholine and mannitol inhalation on different days. Their diagnostic utility was evaluated by calculating their sensitivity and specificity for asthma diagnosis. Response-dose ratio was also compared.
RESULTS
A total of 50 asthmatic adults and 54 controls were enrolled (mean age 43.8 years). The sensitivity and specificity of mannitol challenge (defined by a PD15 of <635 mg) were 48.0% and 92.6%, respectively, whereas those of methacholine (defined by a PC20 of <16 mg/mL) were 42.0% and 98.1%, respectively. Twenty asthmatic participants (24%) showed positive response to a single agonist only. In the receiver operating curve analyses using response-dose ratio values, area under the curve was 0.77 (95% confidence interval (CI): 0.68-0.86) for mannitol, and 0.89 (95% CI: 0.83-0.95) for methacholine. The correlations between log- transformed mannitol and methacholine response-dose ratios were significant but moderate (r = 0.683, P < 0.001).
CONCLUSIONS
The present study demonstrated overall similar diagnostic properties of two diagnostic tests, but also suggested their intercomplementary roles for asthma. The clinical trial registration number at ClinicalTrial.gov is NCT02104284.
Topics: Adult; Asthma; Bronchial Provocation Tests; Case-Control Studies; Dose-Response Relationship, Drug; Female; Humans; Lung; Male; Mannitol; Methacholine Chloride; Middle Aged; Prospective Studies; ROC Curve; Republic of Korea; Sensitivity and Specificity
PubMed: 24975800
DOI: 10.1111/resp.12334 -
American Journal of Physiology. Lung... Jun 2017Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing lysosomal glycogen....
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing lysosomal glycogen. Deficiency of GAA leads to systemic glycogen accumulation in the lysosomes of skeletal muscle, motor neurons, and smooth muscle. Skeletal muscle and motor neuron pathology are known to contribute to respiratory insufficiency in Pompe disease, but the role of airway pathology has not been evaluated. Here we propose that GAA enzyme deficiency disrupts the function of the trachea and bronchi and this lower airway pathology contributes to respiratory insufficiency in Pompe disease. Using an established mouse model of Pompe disease, the mouse, we compared histology, pulmonary mechanics, airway smooth muscle (ASM) function, and calcium signaling between and age-matched wild-type (WT) mice. Lysosomal glycogen accumulation was observed in the smooth muscle of both the bronchi and the trachea in but not WT mice. Furthermore, mice had hyporesponsive airway resistance and bronchial ring contraction to the bronchoconstrictive agents methacholine (MCh) and potassium chloride (KCl) and to a bronchodilator (albuterol). Finally, calcium signaling during bronchiolar smooth muscle contraction was impaired in mice indicating impaired extracellular calcium influx. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the trachea and bronchi and impairs the ability of lower ASM to regulate calcium and respond appropriately to bronchodilator or constrictors. Accordingly, ASM dysfunction may contribute to respiratory impairments in Pompe disease.
Topics: Albuterol; Animals; Bronchi; Calcium Signaling; Extracellular Space; Glycogen; Glycogen Storage Disease Type II; Lung; Methacholine Chloride; Mice; Muscle Contraction; Muscle, Skeletal; Potassium Chloride; Trachea; alpha-Glucosidases
PubMed: 28336814
DOI: 10.1152/ajplung.00568.2016 -
The Clinical Respiratory Journal Aug 2021The American Thoracic Society (ATS) guideline for methacholine challenge testing (MCT) recommended using the English Wright (EW) nebuliser. However, other brands of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The American Thoracic Society (ATS) guideline for methacholine challenge testing (MCT) recommended using the English Wright (EW) nebuliser. However, other brands of nebulisers are also indicated to be acceptable for this technique, but further validation of nebuliser performance is recommended.
OBJECTIVE
To compare the methacholine provocation concentration causing a 20% fall in forced expiratory volume in 1 second (PC -FEV ) measured by using EW nebuliser and DV 646 nebuliser.
METHODS
Subjects were randomly assigned to undergo 2-min tidal breathing methacholine challenge with either EW or DV 646 nebuliser on two separate days, which were at least 24 hours but not more than 7 days apart. The above procedure was repeated for each subject in 1 month, but the nebulisers were selected in a reverse order.
RESULTS
The study includes 15 mild and stable asthmatic patients. The geometric means (SD) of methacholine PC measured with using EW and DV 646 nebulisers were 1.82 (6.38) mg/mL versus 0.83 (1.82) mg/mL, respectively in the initial two visits and 2.56 (6.29) mg/mL versus 0.78 (1.40) mg/mL in the following two visits (both P < 0.05). There are well correlations between PC20-EW1 and PC20-EW2 (r = 0.99, P < 0.01), PC20-DV1 and PC20-DV2 (r = 0.88, P < 0.01), and between PC20-EW1 and PC20-DV1 (r = 0.91, P < 0.01), PC20-EW2 and PC20-DV2 (r = 0.78, P < 0.01).
CONCLUSIONS
PC -FEV measured by using the two conventional jet nebulisers was both repeatable and the results were highly correlated.
Topics: Asthma; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Methacholine Chloride; Nebulizers and Vaporizers
PubMed: 33840150
DOI: 10.1111/crj.13374 -
Journal of Aerosol Medicine and... Apr 2018The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in clinics and research. Such investigations are necessary for accurately determining the provocative dose of methacholine causing a 20% fall in FEV (PD) delivered by a given device. The standard English Wright (Wright) jet nebulizer recommended in the 1999 guidelines by the American Thoracic Society has become difficult to obtain and possesses some characteristics that complicate the calculation of dose delivery from this device (e.g. evaporation). Our objective was to determine if the Aerogen Solo (Solo) vibrating mesh nebulizer provides similar methacholine challenge test results compared to the currently used Wright jet nebulizer.
METHODS
Sixty mild-to-moderate asthmatics were studied across three research sites in a randomized crossover study. Both methacholine challenges were completed at least 24 hours apart within a 2-week period. Testing with the Wright device was performed as per the 2-minute tidal breathing protocol. The Solo study arm followed the same procedure except for a shorter inhalation time of 1 minute. The provocative concentration of methacholine causing a 20% fall in FEV (PC) and the methacholine PD were calculated following each methacholine challenge.
RESULTS
The geometric mean methacholine PC values for the Solo and the Wright differed statistically (0.65 mg/mL vs. 2.58 mg/mL, respectively, p < 0.00001) and clinically. Between-nebulizer geometric mean methacholine PD results are comparable by clinical standards [81.7 μg (Solo) vs. 64.7 μg (Wright)], although the slight difference in dose was statistically significant (p = 0.018).
CONCLUSIONS
The comparability of PD values between the Solo and the Wright validates the importance of reporting airway responsiveness to methacholine in terms of dose and not concentration, as stressed in the latest testing guidelines. This finding along with several benefits associated with the Solo make it a promising nebulizer for performing MCT.
Topics: Administration, Inhalation; Adult; Asthma; Bronchial Provocation Tests; Bronchoconstrictor Agents; Cross-Over Studies; Female; Forced Expiratory Volume; Humans; Male; Methacholine Chloride; Nebulizers and Vaporizers; Vibration; Young Adult
PubMed: 28813613
DOI: 10.1089/jamp.2017.1392 -
Journal of Applied Physiology... Jun 2018It is suggested that the frequent strain the airways undergo in asthma because of repeated airway smooth muscle (ASM)-mediated constrictions contributes to airway wall...
It is suggested that the frequent strain the airways undergo in asthma because of repeated airway smooth muscle (ASM)-mediated constrictions contributes to airway wall remodeling. However, the effects of repeated constrictions on airway remodeling, as well as the ensuing impact of this presumptive remodeling on respiratory mechanics, have never been investigated in subjects without asthma. In this study, we set out to determine whether repeated constrictions lead to features that are reminiscent of asthma in mice without asthma. BALB/c mice were subjected to a 30-min constriction elicited by aerosolized methacholine every other day over 6 wk. Forty-eight hours after the last constriction, the mechanics of the respiratory system was evaluated at baseline and in response to incremental doses of nebulized methacholine with the flexiVent. The whole-lung lavages, the tracheas, and the lungs were also collected to evaluate inflammation, the contractile capacity of ASM, and the structural components of the airway wall, respectively. The resistance and the compliance of the respiratory system, as well as the Newtonian resistance and the resistive and elastic properties of the lung tissue, were not affected by repeated constrictions, both at baseline and in response to methacholine. All the other examined features also remained unaltered, except the number of goblet cells in the epithelium and the number of macrophages in the whole-lung lavages, which both increased with repeated constrictions. This study demonstrates that, despite causing goblet cell hyperplasia and a mild macrophagic inflammation, repeated constrictions with methacholine do not lead to structural changes that adversely impact the physiology. NEW & NOTEWORTHY Repeated airway constrictions led to signs of remodeling that are typically observed in asthma, which neither altered respiratory mechanics nor the contractile capacity of airway smooth muscle. These findings shed light on a debate between those claiming that constrictions induce remodeling and those convinced that methacholine challenges are harmless. Insofar as our results with mice relate to humans, the findings indicate that repeated challenges with methacholine can be performed safely.
Topics: Airway Remodeling; Animals; Bronchoconstriction; Female; Inflammation; Methacholine Chloride; Mice, Inbred BALB C; Muscle, Smooth
PubMed: 29470147
DOI: 10.1152/japplphysiol.01073.2017