The first step in managing difficult-to-treat asthma is to confirm the diagnosis of asthma.[6,7] This typically includes spirometry before and after bronchodilation to seek objective evidence of reversible airway obstruction. If baseline spirometry is normal, bronchial-provocation testing may be performed.
The second step is to investigate factors contributing to symptoms and exacerbations. It is imperative that these modifiable factors—poor inhaler technique, smoking, medication noncompliance, environmental exposures, and comorbidities that are not optimized (gastroesophageal reflux, rhinosinusitis, sleep apnea, immunoglobulin deficiency, cardiac disease, etc.)—be addressed before further actions are considered.[6,7]
The third step is the use of an interdisciplinary team to optimize management.[6,7] Education should be provided regarding asthma pathobiology, self-assessment of control, understanding asthma medications, proper inhaler technique, and a home action plan when control is lost. Additionally, asthma therapy should be optimized to include inhaled combination therapy comprising high-dose inhaled corticosteroids plus long-acting beta agonists and rescue therapy; consideration of add-on therapies such as a long-acting muscarinic agent or a leukotriene receptor antagonist; consideration of nonpharmacologic interventions such as weight loss, mucus clearance, and vaccinations; and referral to an asthma specialist or clinic. Table 1 provides a summary of asthma inhaler therapy.
If severe asthma persists despite optimization, the fourth step is to assess the specific severe-asthma phenotype, i.e., allergic versus eosinophilic.[6,7] This typically involves assessment of blood and sputum eosinophils, measurement of serum immunoglobulin E (IgE), skin-prick testing, and (where available) fractional exhaled nitric oxide testing. Consideration of add-on biological therapies, when appropriate and available, is also part of this step. Biological therapies that target the inflammatory pathways involving IgE (omalizumab [Xolair]), interleukin (IL)-5 (mepolizumab [Nucala], benzralizumab [Fasenra], reslizumab [Cinqair]), and IL-4/IL-13 (dupilumab [Dupixent]) have been shown to reduce the risk of exacerbation. Patients who are not candidates for biological therapy may be evaluated for bronchial thermoplasty, a series of three outpatient bronchoscopy sessions involving the use of radiofrequency to ablate airway smooth muscle.
Once control is achieved, the patient should be maintained on that regimen for 3 to 6 months, and if stability persists an organized approach to therapy deescalation should be employed. This generally includes stopping oral corticosteroids first and then discontinuing other add-on medications, followed by reducing the inhaled corticosteroid to moderate-dose therapy, and, finally, considering cessation of biological therapy.
Various therapies that should be considered in cases of severe asthma are described in the sections that follow.
Inhaled Short-Acting Bronchodilation: Because, by definition, severe asthma is more aggressive and harder to control, acute exacerbations are more frequent in this population and are associated with more morbidity and mortality. Inhaled short-acting bronchodilation is the mainstay of treatment for moderate and severe exacerbations. Compared with intermittent administration via metered-dose inhaler, continuous nebulized inhaled beta2-agonist use reduces hospital admission rates without notable changes in pulse, blood pressure, or tremor. Randomized, controlled trials and one meta-analysis of studies comparing beta2-agonist monotherapy with a beta2 agonist given in conjunction with inhaled anticholinergics found that adding multiple doses of anticholinergic medication improves lung function and reduces hospitalizations.[10,11]
Supplemental Oxygen: All patients should be given supplemental oxygen to maintain pulse oximetry at 94% or greater. Although a mixture of helium and oxygen (Heliox) is reported to flow more easily through constricted airways because of its lower density, data supporting improved outcomes are insufficient, and the use of this medication is not routinely endorsed for acute exacerbations.
Corticosteroids: The administration of systemic corticosteroids within 1 hour of emergency department (ED) presentation reduces the need for hospitalization regardless of the route of administration (IV hydrocortisone, IV methylprednisolone, or oral prednisone), and more pronounced effects are seen in patients with severe exacerbations. There is presently insufficient evidence to make definitive recommendations regarding the use of inhaled corticosteroids in place of systemic corticosteroids in severe acute exacerbations.
Magnesium Sulfate: The addition of IV magnesium sulfate to standard asthma care has been shown to have divergent results in adults and children. In adults with severe exacerbations (peak expiratory flow [PEF] <30% predicted), magnesium therapy leads to slightly improved lung function but does not reduce hospitalization. However, in children, magnesium sulfate at a dosage of 25 mg/kg to 100 mg/kg has shown marked improvements in lung function and reduced hospitalization rates. Neither oral nor nebulized magnesium has shown a benefit for pulmonary function or any other outcome.[14,15]
Methylxanthines: The use of methylxanthines (aminophylline, theophylline) in acute asthma is associated with increased adverse effects (arrhythmias, palpitations, vomiting) without any reduction in hospitalizations. Data are insufficient to either support or recommend against routine empiric antibiotic therapy for acute asthma exacerbations. Ketamine, which is an anesthetic with bronchodilating properties, also requires further study in severe asthma, as current publications are limited to case reports and case series.
Beta Agonists: After an 8-year absence, the inhaled beta agonist epinephrine (Primatene Mist HFA [hydrofluoroalkane]) has recently been reintroduced in the U.S. market for the treatment of mild intermittent asthma in patients older than 12 years. This product is available without a prescription. Proper technique includes shaking or priming the inhaler before each use and cleaning it after each administration. Frequent use of this agent may be an indicator of poor asthma control. This product should not be used in patients taking monoamine oxidase inhibitors. Beta agonists may also be given parenterally in the setting of acute asthma exacerbations. Parenteral beta agonists are less efficacious than inhaled beta agonists, and they carry an increased risk of tachyarrhythmias and myocardial injury. Although guidelines continue to recommend against parenteral beta agonists in the setting of acute asthma exacerbations, their use is endorsed when anaphylaxis is suspected.
The decision to admit a patient with an acute asthma exacerbation to the hospital versus discharge to home is difficult for the following reasons: 1) healthcare professionals both overestimate and underestimate the severity of patients' asthma exacerbations; 2) exacerbation severity and asthma severity are separate entities; and 3) multiple comorbidities—pneumonia, heart failure, pneumothorax, myocardial infarction—mimic and/or worsen asthma exacerbations.[17,18] Historical factors that affect triage decisions include recent poor control or asthma exacerbations, previous ED visits or hospitalizations, previous need for mechanical ventilation, medication compliance, social support, recent use of oral corticosteroids, health literacy, and other comorbid conditions.[7,19,20]
Objective measures that can help the healthcare professional assess the severity of the patient's asthma exacerbation and, ultimately, the decision to admit or discharge the patient include tachypnea (>20 breaths/minute); need for supplemental oxygen to maintain oxygen saturation >92%; arterial blood gas with a partial pressure of carbon dioxide >40 mmHg in the setting of increased respiratory rate; and PEF measures (Table 2). It should be noted that it may be impractical to measure PEF values during acute exacerbations. Furthermore, no single measure is best for assessing severity or predicting hospital admission.
If the patient is ultimately discharged home, there must be a clear and comprehensive care plan that includes 1) follow-up with the primary care physician or pulmonologist in 3 to 5 days; 2) reinforcement of risk-factor modification (e.g., smoking cessation, trigger avoidance); 3) reinforcement of medication compliance and proper use; and 4) creation or modification of an asthma action plan outlining peak flow monitoring, home symptom assessment, medication changes, and red flags that should prompt a return to the ED.
Patients should be instructed to use a handheld peak flow meter each morning before medication administration as part of the asthma action plan. Peak flow meters can detect obstruction changes in the airways before physical symptoms occur. A personal best peak flow is the highest number observed by the patient when the asthma is well controlled and no symptoms are present. A decrease in peak flow of 20% to 30% of the patient's personal best may indicate the start of an asthma exacerbation and requires communication with the asthma provider and potential medication adjustment. A peak flow below 50% of personal best indicates a medical emergency, and the patient should seek immediate care.
US Pharmacist. 2019;44(7):HS 2-HS 7. © 2019 Jobson Publishing