Reversal of Acute β-Blocker Induced Bronchoconstriction

Study Overview
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Brief Summary
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Current therapies for the management of asthma include inhalers. Types of these medications (beta agonists), improve asthma symptoms by stimulating areas (receptors) within the human airway resulting in dilation of the human airway. Whilst these drugs are highly effectively in the immediate setting their longterm use, constantly stimulation of receptors within the airway has been associated with increased asthma exacerbations and rare cases of death. Conversely medications that block receptors within the human airway (betablockers)have been avoided in asthma. The main reason for this is because of the possible acute airway narrowing that can occur after soon after administration. However chronic use of betablockers in asthma has recently been shown to be of benefit in reducing airway inflammation which is of great importance in improving asthma control and reducing symptoms. Despite this early evidence supporting chronic use of beta blockers in asthma, there is concern in 2 major regards:their potential to cause acute airway narrowing (irrespective of longterm benefit) and the possibility that they could block the reliever action of beta agonists. The objective of this study is to establish how best to reverse the short term effects of a single dose of beta blocker. This study is designed as a single centre study, with participants attending the department on approximately 3 separate visits (including a screening visit) at approximately 1 weekly intervals.

Detailed Description
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Asthma was originally thought to be associated with an intrinsic defect of β2- adrenoceptor function tipping the balance towards parasympathetic bronchoconstriction. While β2-agonists are highly effective for the acute relief of bronchoconstriction, their chronic use is accompanied by an adaptive reduction in β2ADR numbers and associated desensitisation of response, resulting in increased exacerbations and rare cases of death. Conversely the chronic use of β blockers have been shown in murine models to reduce airway inflammation and mucous metaplasia. Recent work in humans has further demonstrated a potential benefit of β blockers in asthmatics by demonstrating a significant improvement in airway hyperresponsiveness to bronchial challenge1. Despite this early evidence supporting chronic use of β blockers in asthma, there is concern in 2 major regards: their potential to cause acute bronchoconstriction (irrespective of long-term benefit) and the possibility that they could block the reliever action of β-agonists. Sub-sensitivity of β-adrenoceptors occurs following treatment with long-acting β-agonists. Previous work in our department has shown that high dose steroids can re-establish the β-adrenoceptor function following such down-regulation2. It therefore seems plausible that a similar response may occur following β-blockade (reversing β-blockade and re-establishing β-agonist sensitivity). The investigators wish to gather evidence for the best methods to treat β-blocked patients in the short term. The investigators therefore wish to examine the effects of acute-β blockade with low dose propranolol on mild-to-moderate asthmatics. The investigators wish to simulate airway stress and rescue in acutely β-blocked patients. For safety purposes the investigators have chosen propranolol due to its short half-life of 3 to 5 hours. Importantly the ability to achieve airway reversibility and recovery following acute β-blockade will influence the long term viability of chronic β blockers use in the management of asthma.

Official Title
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Reversal of Acute β-Blocker Induced Bronchoconstriction

Conditions
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Asthma

Intervention / Treatment
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* Drug: Hydrocortisone/ Placebo and Propranolol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to obtain Informed consent. Mild to Moderate Asthmatics taking ≤1000μg BDP per day or equivalent. Histamine PC10 Ability to perform spirometry, IOS, bronchial challenge and all domiciliary measurements. Withhold LABAs, montelukast and theophyllines for 1 week prior to study. FEV1 >80% predicted with diurnal FEV1 variation <20% post wash out. Exclusion Criteria: Uncontrolled symptoms of asthma. Resting BP<110 systolic or HR<60. Pregnancy or lactation. Known or suspected sensitivity to IMP. Inability to comply with protocol. Any degree of heart block. Rate limiting medication including β blockers, rate limiting Calcium Channel Blockers and Amiodarone. Any other clinically significant medical condition that may either endanger the health or safety of the participant, or jeopardise the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydrocortisone and Propranolol<br>Participant administered 10 or 20mg propranolol orally. Participants meeting the parameters are randomised to receive 400mg Hydrocortisone intravenously. Participant then receives Histamine PC10 challenge, Administered 5mg Salbutamol via nebuliser, administered 500mcg Ipratropium Bromide via nebuliser; visit end | Drug: Hydrocortisone/ Placebo and Propranolol<br>* Hydrocortisone 400mcg Propranolol 10mg or 20 mg<br>|
| Placebo Comparator: Placebo and propranolol<br>identical to other arm but participant receive placebo injection as opposed to hydrocortisone | Drug: Hydrocortisone/ Placebo and Propranolol<br>* Hydrocortisone 400mcg Propranolol 10mg or 20 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To establish whether acute β-blockade influences the ability to achieve airway reversibility and recovery with systemic corticosteroids and nebulised bronchodilators following histamine challenge in mild to moderate asthmatics. |  | 3 weeks |