Reply to “Subcutaneous terbutaline as an alternative to aerosolized albuterol”

To the Editor:

We appreciate the comments and perspective expressed by Dr. Strauss regarding our recent pandemic contingency guidance,¹ and we agree that in the setting of acute severe asthma or impending respiratory failure, both nebulized albuterol and subcutaneous terbutaline are important clinical considerations. Although evidence suggests that inhaled albuterol through a metered dose inhaler can be as effective as nebulized albuterol, alternative bronchodilator delivery may be needed in some situations.^{2 , 3} Although subcutaneous terbutaline may be an option, if nebulized therapy is required due to patient impairment and ineffective drug delivery by the metered dose inhaler, it would be an appropriate consideration if felt to be essential in patient management. In this context, for a patient with potential SARS-CoV-2 infection, it would be appropriate to consider administering nebulized therapy in a negative pressure room with appropriate airborne precautions—complete personal protective equipment (PPE) including an N95 respirator.¹ In the setting of acute severe asthma, it is important to ensure availability of emergency medical services and/or additional intensive care resources that may be required for patient management, including supplemental oxygen, aggressive bronchodilator therapies (both intramuscular and intravenous beta-agonists, anticholinergics, and other smooth muscle inhibitors including magnesium sulfate), anti-inflammatory medications including early administration of corticosteroids, and supportive measures such as noninvasive positive pressure ventilation and helium-oxygen gas mixtures.⁴

Terbutaline is a beta-agonist that preferentially stimulates beta-2 receptors in the bronchi to a greater degree than beta-1 receptors in the heart. Although terbutaline is effective at a dose of 0.5 mg (0.5 mL) subcutaneously in adult patients presenting with acute severe asthma, it is also notable that epinephrine at a dose of 0.5 mg (0.5 mL) has been shown to have similar benefit with a comparable adverse effect profile.^{5 , 6} Dosing of subcutaneous terbutaline and subcutaneous epinephrine is similar (0.01 mg/kg/dose), with an adult dose of 0.25 mg for terbutaline and 0.3 to 0.5 mg for epinephrine every 20 minutes for 3 doses recommended by the 3rd Expert Panel Report (EPR3).^{7 , 8} Notably, when administered subcutaneously, evidence suggests that terbutaline loses its beta-selectivity and offers little advantage over epinephrine,⁶ which may be more readily available in many office settings; however, terbutaline subcutaneously may be preferred over subcutaneous epinephrine in pregnancy.⁹ In addition, if both subcutaneous epinephrine and terbutaline are available, terbutaline may be preferred as its effect on forced expiratory volume in 1 second and forced vital capacity may be more pronounced and of longer duration as a result of its slower rate of inactivation, because it is not metabolized by either catechol-o-methyl transferase or monoamine oxidase as is epinephrine.⁶ The recently released GINA guidelines¹⁰ and EPR3⁸ recommend nebulized or inhaled short-acting beta-agonists for the initial treatment of acute asthma exacerbation; EPR3 stated that injected epinephrine or terbutaline had “no proven advantage” compared with aerosol therapy.⁸ Properly designed studies demonstrating superior therapeutic utility of terbutaline for acute asthma are required to alter this recommendation; however, in the setting of the current SARS-CoV-2 pandemic and the need to implement droplet and situational airborne precautions, administration of injected bronchodilator therapy may merit consideration. The benefits of using subcutaneous terbutaline or subcutaneous epinephrine in acute severe asthma may outweigh the increased risks of SARS-CoV-2 infection by nebulizer therapy, especially in an increasingly common scenario of PPE shortages throughout North America. Importantly, when delivering bronchodilator therapy in the setting of acute asthma, supplemental oxygen may be needed because approximately one-third of patients may experience a decrease in PaO₂, and patients who are already hypoxic may be at greater risk due to ventilation-perfusion mismatch.⁶ In this setting, beta-agonists may increase perfusion relative to ventilation through cardiac output and pulmonary vasodilation.⁶ In the context of supplemental oxygen therapy, recommendations for PPE for patients with suspected SARS-CoV-2 infection would also apply.¹

During the COVID-19 pandemic, each clinician must treat the patient in front of him or her, managing each unique situation in its appropriate context. Although subcutaneous beta-agonists may have a role in managing some asthma exacerbations during the pandemic, COVID-19 is not an absolute contraindication to any medication or management strategy urgently needed in delivering optimal care. Still, Dr. Strauss highlights an important and often overlooked aspect in the management of acute asthma exacerbations and we greatly appreciate this insight.