Bronchodilating and Bronchoprotective Effects of Deep Inspirations

Bronchodilating and Bronchoprotective Effects of Deep Inspirations in Asthma, Cough Variant Asthma and Chronic Cough With Normal Airway Sensitivity and Sensory-Mechanical Responses to High-Dose Methacholine in Healthy Normal Subjects

The objectives of this research are to compare (i) the bronchodilating and (ii) the bronchoprotective effects of deep inspirations (DIs) in individuals with: (a) asthma, (b) CVA, (c) methacholine-induced cough but normal airway sensitivity and .

(d) in healthy individuals (without asthma, chronic cough or asymptomatic airway hyperresponsiveness).

Hypotheses:

i. The bronchodilating effect of a DI will be: (a) absent or impaired in individuals with classic asthma; (b) impaired in individuals with CVA; (c) preserved in individuals with methacholine-induced cough but normal airway sensitivity; and (d) preserved in healthy individuals (without asthma, chronic cough or asymptomatic airway hyperresponsiveness).

ii. The bronchoprotective effect of a DI will be: (a) absent in individuals with classic asthma; (b) impaired in individuals with CVA; (c) preserved in those with methacholine-induced cough but normal airway sensitivity; and (d) preserved in healthy individuals (without asthma, chronic cough or asymptomatic airway hyperresponsiveness).

iii. Healthy individuals without asthma, chronic cough, or asymptomatic airway hyperresponsiveness, will not cough, or develop significant dyspnea, small airways obstruction or dynamic hyperinflation during high-dose methacholine bronchoprovocation.

Study Overview

• Status: Completed
• Conditions: Cough; Asthma
• Intervention / Treatment: Other: Methacholine(MCh) Challenge Testing; Other: Methacholine(MCh) Challenge Testing

Detailed Description

Asthma is a chronic respiratory condition characterized by eosinophilic airway inflammation. Individuals with classic asthma experience paroxysmal symptoms including cough, wheeze, shortness of breath and chest tightness. Cough variant asthma (CVA) is asthma in which chronic cough (cough lasting eight weeks or more) is the sole or predominant symptom of asthma. The pathophysiologic mechanisms which differentiate asthma, CVA, and eosinophilic bronchitis without asthma are not fully understood. We have recently identified individuals with chronic cough who cough during methacholine but have normal airway sensitivity (ie. do not have asthma or CVA) and may or may not have eosinophilic bronchitis. The purpose of this research is to examine the pathophysiologic differences between three causes of chronic cough: asthma, cough variant asthma and methacholine-induced cough with normal airway sensitivity. The responses in healthy normal subjects are crucial to understand the clinical relevance of methacholine-induced cough with normal airway sensitivity.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital at Queen's University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Individuals aged 18-65 years of age with asthma, CVA and individuals with methacholine-induced cough but normal airway sensitivity. The following definitions will be used:

  1. asthma: episodic respiratory symptoms occurring in association with variable airflow obstruction (Canadian Asthma Consensus Report definition);
  2. CVA: chronic cough (≥8 weeks) is the sole or predominant symptom and positive methacholine challenge (PC20 ≤ 16 mg/mL) and history of cough responding to specific asthma treatment (such as inhaled steroid or 1 week trial of bronchodilator);
  3. Methacholine-induced cough but normal airway sensitivity: chronic cough (≥8 weeks) is the sole or predominant symptom and negative methacholine challenges (PC20 > 16 mg/mL).
• Individuals aged 18-65 years of age with no history of asthma or chronic cough.

Exclusion Criteria:

• an exacerbation necessitating a change in medication, emergency department visit or hospitalizations within the previous 4 weeks
• inability to perform acceptable spirometry

• medical contraindications to methacholine challenge testing

  1. Severe airflow limitation (FEV1 <50% predicted or <1.0 L);
  2. Heart attack or stroke in last 3 months;
  3. Uncontrolled hypertension, systolic BP > 200 or diastolic BP > 100;
  4. Known aortic aneurysm;
  5. Moderate airflow limitation <60% predicted or 1.5) is a relative contraindication;
  6. Inability to perform acceptable quality spirometry;
  7. Current use of cholinesterase inhibitor medication (for myasthenia gravis); and
  8. Pregnant or nursing mothers.
• smoking history in excess of 10 pack years

Note: Previous treatment with inhaled or systemic corticosteroids is not an exclusion criterion; medication use will be recorded and examined in the analysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Asthma; Individuals diagnosed with asthma.	Other: Methacholine(MCh) Challenge Testing; Visit 1: High-dose methacholine challenge test Visit 2 or 3: Will be conducted in random order and subjects will perform one of two modified single-dose methacholine challenge tests at either visit. During these modified challenges, subjects will (a) perform five DIs from functional residual capacity (FRC) to total lung capacity (TLC) back to FRC, or (b) refrain from taking DIs prior to inhaling the previously measured single PC20 dose of methacholine.; Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine; Other: Methacholine(MCh) Challenge Testing; Visit 1: Baseline tests, and subjects will be randomized to complete either a high-dose methacholine using maximal expiratory flow-volume loop (MEFV), or a high-dose methacholine challenge with impulse oscillometry (IOS) and partial expiratory flow-volume loop (PEFV) and MEFV at each dose step. Visit 2: Subjects will perform the opposite protocol, based on their first visit: Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine
Experimental: Cough Variant Asthma; Individuals diagnosed with cough variant asthma.	Other: Methacholine(MCh) Challenge Testing; Visit 1: High-dose methacholine challenge test Visit 2 or 3: Will be conducted in random order and subjects will perform one of two modified single-dose methacholine challenge tests at either visit. During these modified challenges, subjects will (a) perform five DIs from functional residual capacity (FRC) to total lung capacity (TLC) back to FRC, or (b) refrain from taking DIs prior to inhaling the previously measured single PC20 dose of methacholine.; Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine; Other: Methacholine(MCh) Challenge Testing; Visit 1: Baseline tests, and subjects will be randomized to complete either a high-dose methacholine using maximal expiratory flow-volume loop (MEFV), or a high-dose methacholine challenge with impulse oscillometry (IOS) and partial expiratory flow-volume loop (PEFV) and MEFV at each dose step. Visit 2: Subjects will perform the opposite protocol, based on their first visit: Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine
Experimental: Mch-induced cough w/normal airway sensitivity; Individuals with chronic cough normal PC20 MCh(>16 mg/mL) & who cough during Mch challenge testing.	Other: Methacholine(MCh) Challenge Testing; Visit 1: High-dose methacholine challenge test Visit 2 or 3: Will be conducted in random order and subjects will perform one of two modified single-dose methacholine challenge tests at either visit. During these modified challenges, subjects will (a) perform five DIs from functional residual capacity (FRC) to total lung capacity (TLC) back to FRC, or (b) refrain from taking DIs prior to inhaling the previously measured single PC20 dose of methacholine.; Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine; Other: Methacholine(MCh) Challenge Testing; Visit 1: Baseline tests, and subjects will be randomized to complete either a high-dose methacholine using maximal expiratory flow-volume loop (MEFV), or a high-dose methacholine challenge with impulse oscillometry (IOS) and partial expiratory flow-volume loop (PEFV) and MEFV at each dose step. Visit 2: Subjects will perform the opposite protocol, based on their first visit: Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine
Experimental: Normal; Individuals with no history of asthma or chronic cough	Other: Methacholine(MCh) Challenge Testing; Visit 1: High-dose methacholine challenge test Visit 2 or 3: Will be conducted in random order and subjects will perform one of two modified single-dose methacholine challenge tests at either visit. During these modified challenges, subjects will (a) perform five DIs from functional residual capacity (FRC) to total lung capacity (TLC) back to FRC, or (b) refrain from taking DIs prior to inhaling the previously measured single PC20 dose of methacholine.; Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine; Other: Methacholine(MCh) Challenge Testing; Visit 1: Baseline tests, and subjects will be randomized to complete either a high-dose methacholine using maximal expiratory flow-volume loop (MEFV), or a high-dose methacholine challenge with impulse oscillometry (IOS) and partial expiratory flow-volume loop (PEFV) and MEFV at each dose step. Visit 2: Subjects will perform the opposite protocol, based on their first visit: Other Names: Drug:MCh[inhalation of sequential doubling doses of MCh(0.0625-256 mg/mL)]; Other names: Provocholine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mid expiratory flows	The bronchodilating effect of a DI will be examined using responses to high-dose methacholine challenge testing (Visit 1) in these subgroups by comparing the mid-expiratory flow difference between the partial (PEF) and full maximal flow-volume (MEF) loops at 40% above Residual Volume (RV) from the forced vital capacity (FVC) (PEF40 and MEF40 respectively) at PC20 and PC50 with that recorded at baseline.	Time frame of the methacholine challenge varies between individuals. At provocative concentration of methacholine causing a 20% and 50% decline in FEV1 (PC20 and PC50 respectively). On average, these occur about 15-25 minutes into the challenge test.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percent fall in FEV1	The bronchoprotective effect of a deep inspiration will be measured by the difference between the percent fall in FEV1 following administration of methacholine using modified single-dose methacholine challenge tests on Visits 2 and 3 (with or without preceding deep inspirations)	After methacholine administration; will occur 2-5 minutes after 1 dose of methacholine.
respiratory system reactance (X5)	The bronchoprotective effect of a DI will be also examined by comparing mechanical responses to methacholine using impulse oscillometry (IOS). Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing.	After methacholine administration; will occur 2-5 minutes after 1 dose of methacholine.
peripheral resistance (R5-R20)	The bronchoprotective effect of a DI will be also examined by comparing mechanical responses to methacholine using impulse oscillometry (IOS). Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing.	After methacholine administration; will occur 2-5 minutes after 1 dose of methacholine.
Central airway resistance	The bronchoprotective effect of a DI will be also examined by comparing mechanical responses to methacholine using impulse oscillometry (IOS). Single IOS will measure peripheral airway function using respiratory system reactance (X5) and peripheral resistance (R5-R20) and central resistance (R20) will be used as an index of airway narrowing.	After methacholine administration; will occur 2-5 minutes after 1 dose of methacholine.
Forced vital capacity (FVC)	As an index of airway closure.	After methacholine administration; will occur 2-5 minutes after 1 dose of methacholine.
FEV1/FVC	As an index of airway narrowing (obstruction)	After methacholine administration; will occur 2-5 minutes after 1 dose of methacholine.

Collaborators and Investigators

• Sponsor: Queen's University
• Investigators: Principal Investigator: M. Diane Lougheed, MD MSc, Queen's University

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: July 30, 2012
• First Submitted That Met QC Criteria: August 4, 2012
• First Posted (Estimate): August 7, 2012

Study Record Updates

• Last Update Posted (Actual): April 6, 2018
• Last Update Submitted That Met QC Criteria: April 4, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: methacholine; deep inspiration; bronchoprotective effect; bronchodilating effect
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Immune System Diseases; Respiration Disorders; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Signs and Symptoms, Respiratory; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Respiratory Aspiration; Asthma; Cough; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Cholinergic Agonists; Respiratory System Agents; Miotics; Parasympathomimetics; Bronchoconstrictor Agents; Muscarinic Agonists; Methacholine Chloride
• Other Study ID Numbers: 2012-01 (AP HM)