ACEP COVID-19 Field Guide

Alternative treatments for acute asthma during COVID

Author: Bryan G. Kane, MD, FACEP, Associate Professor of Medicine, University of South Florida Morsani College of Medicine; Assistant Program Director (Research), Lehigh Valley Health Network Emergency Medicine Residency

With the onslaught of COVID-19, emergency physicians will unfortunately need to cope with shortages of medications.¹ One such shortage is albuterol, specifically metered-dose inhalers (MDIs).² MDIs are preferred with COVID-19, as they have decreased aerosolization of the virus compared to nebulized delivery.³ Should emergency physicians wish to order bronchodilators without the risk of aerosolization, there are studies of intramuscular (IM) options in the literature.

Terbutaline is a beta-2 agonist that can be used to treat asthma.⁴ There are several publications that address the use of terbutaline in acute bronchospasm. When administered subcutaneously, terbutaline results in clinical improvement similar to epinephrine.^5,6,7 One study noted a slightly higher rate of tachycardia in injected terbutaline versus injected epinephrine.⁸ Focusing on acute, rather than chronic, use of terbutaline, a prospective study did not find elevations in troponin.⁹ This small cohort of 29 critically ill children did note ECG changes during intravenous (IV) infusions. The Chiang study was one of three studies included in a 2017 systematic review on the safety of pediatric asthma medications.¹⁰ This review identified 14,560 citations, included 46 randomized controlled trials, and found a total of 11 reported adverse drug reactions with terbutaline (4 with IV infusion and 7 with PO administration). No adverse drug events were identified with subcutaneous injection. When treating adults, a 1988 study of 108 asthmatics ages 18 to 96 did not identify a relationship between age and ventricular dysrhythmia when treated with subcutaneous epinephrine (0.3 mg 1:1000).¹¹

Based on available evidence, injected terbutaline or epinephrine appears to be a viable alternative to nebulized bronchodilators for acute asthma exacerbations during the COVID pandemic. It should be noted that the subcutaneous terbutaline injection site used in the studies noted here is the deltoid. For adults, IM injection of epinephrine in the thigh has been demonstrated to lead to significantly higher peak plasma levels as compared to IM or subcutaneous injection in the upper extremity.¹² The superiority of IM injection over subcutaneous injection for epinephrine has also been demonstrated in children.¹³ In one study from 1974, terbutaline was administered IM.¹⁴ In this crossover study of 20, 7 patients had side effects such as tremor or restlessness after terbutaline. Recommended dosing of terbutaline for asthma varies from 0.25 to 0.5 mg subcutaneously in the deltoid. The dosage of epinephrine varies in the studies noted. One advantage of using 0.3 mg of 1:1000 epinephrine (0.15 mg for pediatrics) is staff familiarity with this dosage due to its usage in the treatment of anaphylaxis.

Additional resources

• FDA news release “FDA Approves First Generic of a Commonly Used Albuterol Inhaler to Treat and Prevent Bronchospasm”: The FDA has approved the first generic version of an albuterol sulfate inhaler (marketed as Proventil HFA) used to prevent and treat bronchospasm in patients 4 years and older with reversible obstructive airway disease. It is also indicated to prevent exercise-induced bronchospasm in the same population. 
• The American College of Allergy, Asthma and Immunology has also released “A Message to Asthma Sufferers About a Shortage of Albuterol Metered Dose Inhalers.”

References

1. FDA. Drug shortages. Updated 2020 Apr 1. 
2. American College of Allergy, Asthma and Immunology. A message to asthma sufferers about a shortage of albuterol metered dose inhalers. Published 2020 Mar 20.
3. CMAJ. RE: transmission of corona virus by nebulizer — a serious, underappreciated risk! Published 2020 Mar 3.
4. Lexicomp.
5. Phanichyakarn P. Comparison of subcutaneous injections of terbutaline, salbutamol and adrenaline in acute asthmatic attacks in children. J Med Assoc Thai. 1989;72(12):692-696. 
6. Khaldi F, Salem N. Comparaison de l'effet de l'injection sous-cutanée d'adrénaline et de terbutaline dans la crise d'asthme du nourrisson [Comparison of the effect of subcutaneous injection of adrenaline and terbutaline in asthma crisis in infants]. Arch Pediatr. 1998;5(7):745-748. doi:10.1016/s0929-693x(98)80056-0
7. Spiteri MA, Millar AB, Pavia D, Clarke SW. Subcutaneous adrenaline versus terbutaline in the treatment of acute severe asthma. Thorax. 1988;43(1):19-23. doi:10.1136/thx.43.1.19 
8. Sly RM, Badiei B, Faciane J. Comparison of subcutaneous terbutaline with epinephrine in the treatment of asthma in children. J Allergy Clin Immunol. 1977;59(2):128-135. doi:10.1016/0091-6749(77)90214-7
9. Chiang VW, Burns JP, Rifai N, Lipshultz SE, Adams MJ, Weiner DL. Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: a prospective assessment. J Pediatr. 2000;137(1):73-77. doi:10.1067/mpd.2000.106567
10. Leung JS, Johnson DW, Sperou AJ, et al. A systematic review of adverse drug events associated with administration of common asthma medications in children. PLoS One. 2017;12(8):e0182738. Published 2017 Aug 9. doi:10.1371/journal.pone.0182738
11. Cydulka R, Davison R, Grammer L, Parker M, Mathews J 4th. The use of epinephrine in the treatment of older adult asthmatics. Ann Emerg Med. 1988;17(4):322-326. doi:10.1016/s0196-0644(88)80772-8
12. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001;108(5):871-873. doi:10.1067/mai.2001.119409
13. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. 1998;101(1 Pt 1):33-37. doi:10.1016/S0091-6749(98)70190-3
14. Johansen S. Clinical comparison of intramuscular terbutaline and subcutaneous adrenaline in bronchial asthma. Eur J Clin Pharmacol. 1974;7(3):163-167. doi:10.1007/bf00560376