DTI © 2020 The Authors. This article is published by AboutScience and licensed under Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Any commercial use is not permitted and is subject to Publisher’s permissions. Full information is available at www.aboutscience.eu ISSN 1177-3928 Drug Target Insights 2020; 14: 12-15 SHORT COMMUNICATION DOI: 10.33393/dti.2020.2188 Paradoxical bronchoconstriction caused by β 2 -adrenoceptor agonists Khadija Ayed, Islam Latifa Hadj Khalifa, Salma Mokaddem, Saloua Ben Khamsa Jameleddine Department of Physiology, Faculty of Medicine of Tunis, University of Tunis el Manar, Tunis - Tunisia ABSTRACT Introduction: Salbutamol and terbutaline are short-acting β 2 adrenergic agonists that produce bronchial smooth muscle relaxation and are widely used in obstructive pulmonary diseases. Nevertheless, their use has been the cause of a paradoxical bronchoconstriction, which is a rare and potentially serious adverse reac- tion. The aim of this study is to report a case of paradoxical bronchoconstriction caused by β 2 adrenergic agonists. Methods: This case is about a 50-year-old asthmatic patient who describes a history of repeated acute asthma attacks after salbutamol inhalation or terbutaline nebulization. A double-blind crossover study was performed over 3 days, in order to compare the effects of each bronchodilator. Forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), and maximal expiratory flow 25-75 (MEF25-75) were measured. Results: On the first day, a bronchoconstriction caused by deep and repeated inhalations was eliminated. On the second day, an airway obstruction was confirmed by a decrease in FEV 1 at 40% from baseline values after nebulization of a standard dose of terbutaline. On the third day, a spirometry was performed before and after nebulization of a standard dose of ipratropium bromide, and there were no significant changes in the spirometric parameters. Finally the patient was discharged with a written warning mentioning the danger of salbutamol and terbutaline use. Conclusion: Salbutamol and terbutaline are generally well-tolerated β 2 adrenergic agonists. Nevertheless, in rare cases, these substances can cause a paradoxical bronchoconstriction. Doctors must therefore remain vigilant about its side effect and possibly investigate each case. Keywords: Asthma, Bronchoconstriction, Bronchodilators, β 2 adrenergic agonists, Spirometry Received: September 21, 2020 Accepted: September 28, 2020 Published online: October 5, 2020 Corresponding author: Khadija Ayed 12 Avenue Farhat Hachèd Soliman 8020 Nabeul - Tunisia ayed_khadija@yahoo.fr light chain kinase hydrolysis. In addition, it promotes the ex- change of calcium/sodium, which results in a decrease in in- tracellular calcium concentration, and stimulates the Na+/K+ adenosine triphosphatase (ATPase) pump. This discovery justifies the use of these substances as a pillar of the treatment of bronchial obstruction in addition to their safety and efficiency (1-5). Nevertheless, use of salbutamol and terbutaline has been the cause of paradoxical bronchoconstriction, which is a rare and potentially serious adverse event requiring vigilance by treating physicians (6,7). We describe a case of paradoxical bronchoconstriction in an asthmatic patient caused by β 2 -adrenoceptor agonists objectively demonstrated with an appreciable decrease of forced expiratory volume in one second (FEV 1 ) in a double- blind crossover study. Methods and Results This case is about a 50-year-old asthmatic patient with no other past medical history and whose body mass index was 20.7 kg/m2. He described a history of repetitive acute attacks of asthma after inhalation of salbutamol. Asthma was Background Salbutamol and terbutaline are both short-acting β 2 - adrenoceptor agonists that are believed to exert their max- imal therapeutic effect through bronchodilation. Activated β 2 -adrenergic receptors promote their binding to a stimu- lating G protein called Gs. This binding stimulates adenylyl cyclase, which in turn activates the intracellular cyclic ade- nosine monophosphate (cAMP) that phosphorylates several relaxation proteins. In bronchial smooth muscle, activated protein kinase inhibits both myosin and phosphoinositide Ayed et al 13 © 2020 The Authors. Published by AboutScience diagnosed 5 years earlier, based on clinical arguments with- out neither atopy nor spirometric confirmation. The patient was then treated with inhaled corticosteroids and salbuta- mol for 3 years. During this period, the patient continued to have respiratory symptoms such as wheezing and dry cough after taking medication. In April 2016, the patient presented dramatic symptoms after taking a standard dose of terbuta- line via nebulizer and developed a respiratory failure requir- ing intubation and hospitalization in an intensive care unit. As part of the follow-up of his disease, the patient was sent to our pulmonary function department in August 2017. Spirometry and bronchodilator reversibility test were carried out by a “CareFusion MicroLab” spirometer, and spirometry was performed by experts in respiratory functional explora- tion according to the latest American Thoracic Society (ATS)/ European Respiratory Society (ERS) recommendations. Pre- dicted values were obtained according to reference equa- tions from the work of Stocks and Quanjer (8). Baseline spirometry revealed a small airways obstruction, which is defined by a normal forced vital capacity (FVC), a normal FEV 1 /FVC ratio, and a decrease of at least one forced expiratory flow (FEF): FEF50%, FEF25%, or FEF between 25% and 75% of the FVC (FEF25-75). During bronchodilator re- versibility test, the patient developed an explosive cough and dyspnea just after salbutamol inhalation (400 µg) by metered dose inhaler (MDI). A decrease in FEV 1 at 25% from baseline was noticed (Tab. I). An administration of ipratropium bro- mide via nebulizer restored basic spirometric values. In the light of this ascertainment, we studied the influ- ence of terbutaline and ipratropium bromide on bronchial reactivity. A double-blind crossover study was performed, over 3 days; neither the patient nor the technician knew the composition of the nebulization in order to compare the ef- fects of each bronchodilator on bronchial reactivity. An infor- mal consent was obtained and the patient was asked to avoid using bronchodilators for at least 12 hours prior to the study. FEV 1 , FVC, and FEF25-75 were measured and the patient was monitored by blood oxygen saturation. On the first day, a basic spirometry was performed with eight measurements in order to eliminate bronchoconstric- tion due to deep inhalation during spirometry testing. No significant changes compared to baseline spirometry were found (Tab. II). On the second day, a spirometry was planned before and 15 minutes after a nebulization of a standard dose of terbu- taline made up to a total volume of 5 mL with 0.9% saline solution (5 mg/unit). The patient was initially asymptom- atic, but nebulization was interrupted because of important dyspnea, coughing, wheezing, and discrete cyanosis. Physi- cal examination revealed a wheezing, sinusal tachycardia at 110 per minute, and blood oxygen saturation at 85%. There was no urticaria, pruritus, or macular rash. The spirometry was performed earlier because of the reaction and revealed an airway obstruction confirmed by a decrease in FEV 1 at 40% from baseline spirometry (Tab. III). On the third day, a spirometry was performed before and 30 minutes after a nebulization of a standard dose of ipratropium bromide made up to a total volume of 5 mL with 0.9% saline solution (0.5 mg/unit). There were no significant clinical or spirometric changes (Tab. IV). Finally, the patient was discharged with a written warning mentioning the dan- ger of salbutamol and terbutaline use via MDI or nebulizer solutions. Discussion Currently, inhaled β 2 -adrenoceptor agonists are generally used in the treatment of acute asthma attacks, based on their effectiveness and relative safety. However, in rare cases, they may cause unexpected adverse effects such as paradoxical bronchoconstriction. Paradoxical bronchoconstriction was recorded in this pa- tient each time he used β 2 -adrenoceptor agonists, whether with salbutamol via MDI or terbutaline via nebulizer. Many TABLE I - Spirometric parameters before and after salbutamol inhalation Spirometric parameters Baseline spirometry After salbutamol Measured % Predicted Measured % Predicted % Changing FEV 1 2.36 L 74 1.76 L 55 −25 FVC 3.57 L 91 3.36 L 86 −6 FEV 1 /FVC 66% – 52% – −21 FEF25-75 1.34 L 36 0.68 L 18 −49 FEF25-75 = FEF between 25% and 75% of the FVC; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity. TABLE II - Spirometric parameters during repeated spirometry testing FEV 1 FVC FEV 1 /FVC (%) Baseline or 1st spirometry 2.41 L (75%) 3.27 L (83%) 73 2nd spirometry 2.36 L (74%) 3.11 L (79%) 75 3rd spirometry 2.29 L (71%) 3.15 L (80%) 73 4th spirometry 2.35 L (73%) 3.19 L (81%) 73 5th spirometry 2.30 L (71%) 3.11 L (79%) 73 6th spirometry 2.42 L (75%) 3.22 L (82%) 75 7th spirometry 2.31 L (71%) 3.20 L (81%) 72 8th spirometry 2.35 L (73%) 3.22 L (82%) 72 FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity. Paradoxical bronchoconstriction caused by bronchodilators14 © 2020 The Authors. Published by AboutScience factors have been excluded before reaching the conclusion of paradoxical bronchoconstriction. First, in some asthma patients, deep inhalation can pro- duce paradoxical bronchoconstriction during spirometry test- ing (9). This is why we performed the test on the first day with more than three measurements, but no spirometric changes were found. Second, double-blind crossover study was performed to avoid psychological response to spirome- try testing. In fact, psychological stress can exacerbate clinical symptoms in patients with asthma (10). Third, several studies suggested that excipients (as chlorofluorocarbon propellants and surfactants) or preservatives (as benzalkonium chloride) in MDIs have been incriminated in paradoxical bronchocon- striction due to a bronchial irritation (11,12). In our case, this possibility was rejected because the same response was seen after nebulization of terbutaline solution, which did not contain foreign substances as preservatives or stabilizers. In fact, excipients of our terbutaline solution were sodium chloride, sodium edetate, and hydrochloric acid. In addition, osmolarity of liquids of nebulization may in- duce bronchoconstriction. Hyperosmolar buffers have been shown to cause histamine release from normal human ba- sophils and mast lung cells (13,14). Saline solutions that are hypotonic or hypertonic are both able to induce bronchocon- striction (15). For these reasons, we used isotonic saline in all nebulizer solutions. This bronchoconstriction was most likely related to an adverse reaction to β 2 -adrenoceptor agonists. It is, however, difficult to specify their exact action mechanism on bronchi during this paradoxical reaction. A number of questions re- main to be answered with a biocellular study. All possibilities should be taken into account. It is danger- ous to reject a possible cause of asthma mortality. Doctors and patients should be aware that although β 2 -adrenoceptor agonists do not generally produce adverse effects, it may ag- gravate symptoms. This adverse reaction needs to be consid- ered as one of the possible causes of sudden death or acute asthma attack. Finally, some precautions should be taken with the use of β 2 -adrenoceptor agonists. Since short-acting β 2 -adrenoceptor agonists represent the first-line treatment of acute asthma (2,3), any discrepancy between a good adherence to treat- ment and refractory symptoms should lead the physician to suspect paradoxical bronchoconstriction. In this case, the pa- tient should be treated with other bronchodilators such as anticholinergics. Similar reactions should lead to a new assessment includ- ing a full spirometric study with bronchial reversibility tests as well as the above-cited protocol, in order to define the causative agent. Conclusion β 2 -adrenoceptor agonists are an important and well- tolerated pharmacological class in the management of asthma. In rare cases, salbutamol and terbutaline may cause unusual paradoxical bronchoconstriction, whose mechanism remains unknown. Therefore, physicians must be vigilant about this potentially serious side effect and investigate each case. Disclosures Conflict of interest: The authors declare that there is no conflict of interest. Financial support: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. TABLE III - Spirometric parameters before and after terbutaline nebulization Spirometric parameters Baseline spirometry After terbutaline Measured % Predicted Measured % Predicted % Changing FEV 1 2.36 L 74 1.41 L 44 −40 FVC 3.11 L 79 2.82 L 72 −9 FEV 1 /FVC 75% – 40% – −35 FEF25-75 2.22 L/s 51 0.79 L/s 18 −64 FEF25-75 = FEF between 25% and 75% of the FVC; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity. 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