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Respirology (Carlton, Vic.) May 2023
Topics: Humans; Respiratory Function Tests; Asthma; Bronchi; Bronchial Provocation Tests; Methacholine Chloride; Bronchial Hyperreactivity; Forced Expiratory Volume
PubMed: 36722470
DOI: 10.1111/resp.14463 -
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 -
Respiratory Research Jul 2023Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested...
INTRODUCTION
Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested effects of Chronic Intermittent Hypoxia (CIH) - a hallmark of OSA - on airway hyperresponsiveness (AHR), in a rat model of chronic allergen-induced inflammation.
METHODS
Brown Norway rats were exposed to six weeks of CIH or normoxia (NORM) concurrent with weekly house dust mites (HDM) or saline (SAL) challenges. At endpoint, we assessed responses to seven Methacholine (Mch) doses (0, 4, 8, 16, 32, 64, 128 mg/mL) on a FlexiVent system (Scireq). Maximal (or plateau) responses (reactivity) for total respiratory system Resistance (R) and Elastance (E), Newtonian airway resistance (R a measure of central airways function) and tissue damping (G, a measure of distal airways function) were plotted.
RESULTS
HDM/CIH-treated animals demonstrated the highest reactivity to Mch in R and E compared to all other groups (HDM/NORM, SAL/CIH and SAL/NORM p < 0.05 for all comparisons, for doses 5-7 for R, and for doses 4-7 for E). The enhanced R response was due to an increase in G (doses 4-7, p < 0.05 for comparisons to all other groups), whereas R was not affected by CIH.
CONCLUSIONS
In rats chronically challenged with HDM, concurrent CIH exposure induces AHR primarily in the distal airways, which affects the respiratory system frequency-dependent elastic properties.
Topics: Rats; Animals; Pyroglyphidae; Allergens; Respiratory Hypersensitivity; Lung; Hypoxia; Methacholine Chloride; Inflammation; Sleep Apnea, Obstructive; Disease Models, Animal
PubMed: 37468919
DOI: 10.1186/s12931-023-02493-4 -
Respiratory Care Mar 2021A 20% reduction in the FEV is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV is effort dependent, and some patients are not...
BACKGROUND
A 20% reduction in the FEV is routinely used as an end point for methacholine challenge testing (MCT). Measurement of FEV is effort dependent, and some patients are not able to perform acceptable and repeatable forced expiration maneuvers. The goal of the present study was to investigate the diagnostic value of airway resistance measurement by forced oscillation technique (FOT), body plethysmography, and interrupter technique compared with the traditionally accepted standard FEV measurement in evaluating the responsiveness to methacholine during MCT.
METHODS
We included in the study adult subjects referred for MCT because of asthma-like symptoms and with normal baseline spirometry. We modified routine MCT protocol by adding the assessment of airway resistance to the measurement of FEV at each step of MCT.
RESULTS
We observed, in the subjects with airway hyper-responsiveness versus those with normal airway responsiveness, a significantly greater percentage change in median (interquartile range) FOT resistance at 10 Hz (25.9% [13.7%-35.4%] vs 16% [15.7%-27.2%]), plethysmographic resistance (70.2% [39.5%-116.3%] vs 37.1% [23.9%-81.9%]), and mean ± SD conductance (-41.3 ± 15.4% vs -29.6 ± 15.9%); and a significantly greater change in mean ± SD FOT reactance at 10 Hz (-0.41 ± 0.48 cm HO/L/s vs -0.09 ± 0.32 cm HO/L/s) and at 15 Hz (-0.29 ± 0.2 cm HO/L/s vs -0.1 ± 0.19 cm HO/L/s). We also recorded significant differences in airway resistance parameters (FOT resistance at 10 Hz, FOT reactance at 15 Hz, plethysmographic airway resistance, and conductance indices as well as interrupter resistance) in FEV non-responders at the onset of respiratory symptoms during MCT compared with baseline.
CONCLUSIONS
Measurements of airway resistance could possibly be used as an alternative method to spirometry in airway challenge. Significant changes in airway mechanics during MCT are detectable by airway resistance measurement in FEV non-responders with methacholine-induced asthma-like symptoms. (ClinicalTrials.gov registration NCT02343419.).
Topics: Adult; Airway Resistance; Bronchial Provocation Tests; Forced Expiratory Volume; Humans; Methacholine Chloride; Spirometry
PubMed: 33203723
DOI: 10.4187/respcare.08331 -
American Journal of Physiology. Lung... Feb 2022There are renewed interests in using the parameter K of Salazar-Knowles' equation to assess lung tissue compliance. K either decreases or increases when the lung's...
There are renewed interests in using the parameter K of Salazar-Knowles' equation to assess lung tissue compliance. K either decreases or increases when the lung's parenchyma stiffens or loosens, respectively. However, whether K is affected by other common features of respiratory diseases, such as inflammation and airway smooth muscle (ASM) contraction, is unknown. Herein, male C57BL/6 mice were treated intranasally with either saline or lipopolysaccharide (LPS) at 1 mg/kg to induce pulmonary inflammation. They were then subjected to either a multiple or a single-dose challenge with methacholine to activate ASM to different degrees. A quasi-static pressure-driven partial pressure-volume (P-V) maneuver was performed before and after methacholine. The Salazar-Knowles' equation was then fitted to the deflation limb of the P-V loop to obtain K, as well as the parameter A, an estimate of lung volume (inspiratory capacity). The fitted curve was also used to derive the quasi-static elastance (E) at 5 cmHO. The results demonstrate that LPS and both methacholine challenges increased E. LPS also decreased A, but did not affect K. In contradistinction, methacholine decreased both A and K in the multiple-dose challenge, whereas it decreased K but not A in the single-dose challenge. These results suggest that LPS increases E by reducing the open lung volume (A) and without affecting tissue compliance (K), whereas methacholine increases E by decreasing tissue compliance with or without affecting lung volume. We conclude that lung tissue compliance, assessed using the parameter K of Salazar-Knowles' equation, is insensitive to inflammation but sensitive to ASM contraction.
Topics: Airway Resistance; Animals; Inflammation; Lipopolysaccharides; Lung; Lung Compliance; Male; Methacholine Chloride; Mice; Mice, Inbred C57BL; Muscle Contraction; Respiratory Mechanics
PubMed: 34936511
DOI: 10.1152/ajplung.00384.2021 -
The European Respiratory Journal Jan 2011Vocal cord dysfunction (VCD) is a disorder caused by episodic unintentional paradoxical adduction of the vocal cords, which may induce acute severe dyspnoea attacks not... (Review)
Review
Vocal cord dysfunction (VCD) is a disorder caused by episodic unintentional paradoxical adduction of the vocal cords, which may induce acute severe dyspnoea attacks not responsive to conventional asthma therapy. The aetiology of VCD is complex and often multifactorial. The essential pathophysiology is that of a hyperfunctional laryngeal reflex to protect the lower airway as a result of any combination of post-nasal drip, gastro-oesophageal reflux, laryngopharyngeal reflux and/or psychological conditions. Laryngoscopic demonstration of the paradoxical motion while wheezing or stridorous is considered the diagnostic gold standard. Speech therapy, including the use of special relaxed-throat breathing patterns is effective for VCD that is purely of the functional nature. Knowledge of the clinical features of VCD and identifying factors that may be contributing to the development of VCD can provide adequate clues to the correct diagnosis and management.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Infant; Infant, Newborn; Laryngeal Diseases; Laryngoscopy; Male; Methacholine Chloride; Middle Aged; Plethysmography; Pulmonary Medicine; Vocal Cords
PubMed: 21205712
DOI: 10.1183/09031936.00192809 -
Respirology (Carlton, Vic.) Mar 2023
Topics: Humans; Methacholine Chloride; Asthma; Bronchial Provocation Tests
PubMed: 36411237
DOI: 10.1111/resp.14416 -
Respirology (Carlton, Vic.) Jul 2019
Topics: Aged; Asthma; Humans; Methacholine Chloride; Obesity; Phenotype; Respiratory System
PubMed: 30901134
DOI: 10.1111/resp.13533 -
Pulmonary Pharmacology & Therapeutics Feb 2015Mice with Plp1 gene duplication model the most common form of Pelizaeus-Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications....
Mice with Plp1 gene duplication model the most common form of Pelizaeus-Merzbacher disease (PMD), a CNS disease in which patients may suffer respiratory complications. We hypothesized that affected mice would lack airway responsiveness compared to wild-type and carrier mice during methacholine challenge. Wild-type (n = 10), carrier female (n = 6) and affected male (n = 8) mice were anesthetized-paralyzed, tracheostomized and ventilated. Respiratory mechanics were recorded at baseline and during escalating doses of nebulized methacholine followed by albuterol. Lung resistance (RL) was the primary endpoint. Lung tissues were assayed for inflammatory and histological differences. At baseline, phase angles were higher in carrier and affected mice than wild-type. Dose-response RL curves in affected and carrier mice indicated a lack of methacholine response. Albuterol reduced RL in wild-type and carrier, but not affected mice. Affected mice exhibited lower interleukin (IL)-6 tissue levels and alveolar inflammatory infiltrates. Affected and carrier mice, compared to wild-type, lacked airway reactivity during methacholine challenge, but only affected mice exhibited decreased lung tissue levels of IL-6 and inflammation.
Topics: Albuterol; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Duplication; Interleukin-6; Male; Methacholine Chloride; Mice; Myelin Proteolipid Protein; Pelizaeus-Merzbacher Disease; Pneumonia; Respiratory Mechanics
PubMed: 25445931
DOI: 10.1016/j.pupt.2014.10.004 -
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