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Bronchospasm -- a sudden constriction of smooth muscles of the bronchi walls that narrows the airways and obstructs breathing -- is termed paradoxical when it occurs in the presence of a bronchodilatory medication. This report describes one such .¹ Although paradoxical bronchospasm is potentially life threatening, it is often not recognized by clinicians, despite warnings on beta2-agonist package inserts. About 8% of patients using a beta2-agonist are affected by paradoxical bronchospasm,² which often occurs with the first use of a new vial of inhalation solution.³

The Case

A 25-year-old, non-smoking African-American male with a history of moderate asthma and allergic rhinitis is referred for investigation regarding shortness of breath that he has been experiencing for the last 4 weeks. He reports that symptoms occur immediately after using his albuterol inhaler.

His prescribed treatment regimen includes a combination inhaled corticosteroid / long-acting beta-agonist (ICS/LABA), a short-acting beta-agonist (SABA), and a leukotriene receptor antagonist (LTRA) medication, as listed respectively:

• fluticasone propionate 250 mcg/salmeterol 50 mcg (Advair diskus) two puffs twice daily,
• albuterol 90 mcg (ProAir hydrofluoroalkane (HFA) two puffs every 20 minutes as needed for shortness of breath
• montelukast 10 mg (Singulair) daily

The patient notes that up to 8 months previously his asthma had been well controlled. In keeping with the National Asthma Education and Prevention Program's ⁴ step-down approach to asthma treatment, his dosage of the Advair diskus was reduced from 250/50 mcg to 100/50 mcg two puffs twice daily. This caused an almost immediate recurrence of chest constriction and breathing difficulty.

In order to control the symptoms and maintain performance at a physically demanding job, the patient doubled use of his Advair diskus 100/50 mcg from two to four puffs twice daily, and managed his exacerbations with more frequent use (four to five times/day) of his ProAir inhaler.

Case Challenge 1

Proton pump inhibitors (PPIs) are acid-suppressive medications used to treat gastroesophageal reflux disease , which often coexists with asthma and may have a role in asthma exacerbations through both direct aspiration and neurogenic mechanisms. Current guidelines suggest that patients with asthma and symptomatic GERD should be treated.⁶

Pulmonary Function Assessments

The physician's initial assessment noted a pre-bronchodilator forced vital capacity (FVC) of 4.17 litres (L) (76% predicted). Administration of four puffs of levalbuterol 90 mcg (Xopenex HFA) was associated with a decline in lung function.

The patient is then referred for further investigation. He is not experiencing symptoms and is found to be hemodynamically stable – his blood pressure is 119/60 mmHg, heart rate is 78 beats per minute, respiratory rate is 16 breaths per minute, and oxygen saturation is 97% on room air.

Follow-up assessments of the patient's pre-bronchodilator lung volumes are notable for end reserve volume (ERV) of 2.00 L (183% predicted), residual volume of 1.85 L (121% predicted), and total lung capacity of 6.27 L (91% predicted).

At the second encounter, four puffs of albuterol 90 mcg administered via spacer result in a further asymptomatic decrease in lung function, as indicated by declines in both forced vital capacity (FVC) (-12%) and forced expiratory volume in 1 second (FEV1) (-11%).

Clinicians decide on a change in dose and formulation of the patient's fluticasone/salmeterol, which is increased to 230 mcg HFA delivery, and schedule repeat pulmonary function tests (PFTs) with alternative bronchodilators.

Further tests to exclude other diseases note no abnormalities, including high-resolution chest computed tomography, which showed no subpleural reticulation, honeycombing, bronchiectasis, or significant airtrapping. However, a regional allergen skin test reveals an elevated IgE to 1,618 IU/ml (reference range 0–100 IU/ml) and multiple regional allergens including but not limited to cat dander, dog dander, cockroach, cedar, and grass.

The patient is asked to refrain from using his Advair and ProAir inhalers on the evening prior to and the morning of testing. However, due to the patient's intolerable shortness of breath, his PFTs are performed just 2-3 hours after his last use of Advair.

At the patient's third encounter, use of nebulized albuterol sulfate 2.5 mg resulted in a 9% improvement in FEV1 outcomes to 77%, with no change in FVC.

At the patient's next encounter, designed to assess the efficacy of ipratropium bromide (Atrovent HFA), he is able to avoid pre-test medication use. Again, his FVC remains unchanged at 4.85 L (104% predicted) before and after bronchodilator administration, while four puffs of ipratropium bromide improve his FEV1 by 7%.

Case Challenge 2

Treatment and Outcome

The patient's albuterol HFA prescription is discontinued, and he is asked to use an ipratropium HFA as rescue for exacerbations and to continue his increased daily dose of fluticasone/salmeterol HFA. This treatment change appears to bring his asthma under control, and he reports no further symptoms.

Discussion

Clinic physicians tested several theories to explain the paradoxical bronchospasm affecting this non-smoking asthmatic patient. The decline in lung function with various inhaled formulations of B2-agonists formulations and contrasting improvement with a nebulized formulation raised suspicion that excipients in the inhalers may have caused the problem.

Inactive ingredients, including oleic acid (found in Xopenex HFA)^7,8 and ethanol (found in ProAir HFA),^9,10 are reported to cause bronchial reactivity leading to a decline in lung function.

Furthermore, the patient's improved pulmonary function with a nebulized formulation of albuterol supports this theory that these inactive ingredients may have caused the reaction. As well, he demonstrated no clinically significant response to Advair HFA, which contains only a suspension fluticasone propionate and salmeterol xinafoate in propellant HFA-134a and no other excipients.¹¹

Therapy with B2-agonists in the absence of inhaled corticosteroids has been associated with a decline in lung function and an increase in exacerbations and in response to methacholine. This is thought to result from a heightened sensitivity to allergens without a change in bronchodilation produced by the treatment.¹² Indeed, this rapid decrease in response to treatment following repeated use of beta-agonists was linked with duration of bronchodilation but not with peak bronchodilatory effects.

Chronic use of inhaled beta2-agonists is also known to have a negative effect in long-term control of asthma.¹³ Albuterol has been associated with cases of unexpected bronchoconstriction in allergically inflamed airways.

Given this patient's tendency to allergic rhinitis, documented elevated IgE level, and significant evidence of regional allergies, physicians were expecting a decrease in lung function with inhalation of ipratropium bromide (Atrovent HFA) – which contains dehydrated alcohol and a similar propellant as the other inhalers. The suggestion is that the expected sensitivity to the excipients may have been suppressed by the medication's anticholinergic and anti-inflammatory properties.

The patient's physicians dismissed the possibility that the bronchospasm was related to the medication's use of HFA propellant – given that it is a noted smooth muscle relaxant – and the patient's positive response to treatment with the other inhalers containing HFA-134a propellant.

While the exact mechanism underlying the bronchospasm remains unknown, it is believed that the patient's symptoms were due to a reaction to the excipients in his inhalers.

Limitations

Limitations to the approach include the inability – for safety reasons – to discontinue the patient's fluticasone/salmeterol HFA in order to assess treatment effects on PFTs, and lack of access to placebo metered-dose inhalers (MDIs) with excipients only.

Conclusion

Beta2-agonists are commonly used to treat asthma, which affects 7.8% of the U.S. population and accounts for more than 3,600 deaths per year.¹⁴

As noted in the black box warnings for albuterol sulfate and other beta2-agonists, excessive use of inhaled sympathomimetic drugs (and home use of nebulizers) can have a clinically significant cardiac effect, and has been linked with fatalities.¹⁵

It is crucial that prescribing physicians educate their patients about the importance of their asthma control -- e.g., using The Asthma Control Test^TM (ACT) () -- and to seek evaluation if symptoms worsen. If paradoxical bronchospasm or other acute symptoms develop, use of the inhaled beta-adrenergic agonist should be discontinued immediately and alternative therapy initiated.

References

1. Magee JS, et al. Paradoxical Bronchoconstriction with Short-Acting Beta Agonist. Am J Case Rep 2018;19:1204-1207.

2. Albuterol Sulfate Inhalation Solution, 0.083% 2.5 mg*/3 ml. Orlando, Fla., USA: Nephron Pharmaceuticals Corporation; November 2009. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=574824f3-51cc-4b94-9c10-e3204d8b19f8.

3. LEVALBUTEROL INHALATION- levalbuterol inhalation 0.31mg/3ml solution Dr. Reddy's Laboratories , Inc. June 2014. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=163dfa7c-aad3-4290-9fe9-d9592b0ba317.

4. Asthma Care Quick Reference. Guidelines from the National Asthma Education and Prevention Program. National Institutes of Health. National Heart, Lung and Blood Institute. Revised September 2012 https://www.nhlbi.nih.gov/files/docs/guidelines/asthma_qrg.pdf.

5. Huizen J. What is a bronchospasm and what causes it? Medical News Today. Last reviewed Mon 27 November 2017. https://www.medicalnewstoday.com/articles/320162.php.

6. Ates F, Vaezi MF. Insight Into the Relationship Between Gastroesophageal Reflux Disease and Asthma. Gastroenterol Hepatol (N Y). 2014;10(11):729-736. http://www.gastroenterologyandhepatology.net/archives/november-2014/insight-into-the-relationship-between-gastroesophageal-reflux-disease-and-asthma/

7. Gonçalves-de-Albuquerque CF, et al. Acute respiratory distress syndrome: Role of oleic acid-triggered lung injury and inflammation. Mediators of Inflammation. 2015;2015:260465.

8. Shim CS, Williams MH Jr. Cough and wheezing from beclomethasone aerosol. Chest 1987; 91: 207-209.

9. Antonicelli L, et al. Bronchospasm induced by inhalant corticosteroids: The role of ethanol. Allergy 2006; 61(1): 146-147.

10. Trevisani M, et al. Ethanol causes inflammation in the airways by a neurogenic and TRPV1-dependent mechanism. J Pharmacol Exp Ther 2004; 309(3): 1167-1173.

11. Advair HFA (fluticasone propionate and salmeterol). Research Triangle Park, NC, USA: GlaxoSmithKline; February 2017. Available from https://www.accessdata.

12. Riesenfeld EP, et al. Inhaled salmeterol and/or fluticasone alters structure/function in a murine model of allergic airways disease. Respir Res 2010; 11: 22.

13. Taylor DR, et al. Regular inhaled beta agonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48: 134-138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC464288/

14. Center for Disease Control and Prevention. Asthma: Data, statistics, and surveillance. Available from https://www.cdc.gov/asthma/most_recent_data.

15. Schisslet AJ, Cellib BR. Prevalence of paradoxical bronchoconstriction after inhaled albuterol. Respiratory Medicine 2018; 141:100-102.

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