US Pharm. 2019;44(7):HS2-HS7.
ABSTRACT: Asthma is a common respiratory disorder, and the presentation of patients with acute, poorly controlled asthma remains a clinical challenge. In current guidelines, severe asthma represents a subset of difficult-to-treat asthma that, despite treatment of contributing factors and patient compliance with optimized therapy, remains uncontrolled, or asthma that worsens when high-intensity therapy is decreased. Acute exacerbations are managed with inhaled bronchodilators, inhaled corticosteroids, and oral corticosteroids. Patient-specific pharmacotherapy to prevent acute exacerbations includes the use of inhaled corticosteroids plus a long-acting bronchodilator, a short-acting bronchodilator for rescue, a long-acting muscarinic, a leukotriene antagonist, and biologics.
Asthma is a chronic disorder of the airways that is characterized by variable and recurring airway inflammation and bronchial hyperresponsiveness. In this common condition that affects people in all age groups, the resulting bronchoconstriction, airway-wall edema, and excessive mucus secretion collectively lead to airway obstruction and symptoms that include some constellation of cough, wheezing, chest tightness, and dyspnea. As with any disease, asthma has a spectrum of severity. Although severe asthma occurs in 3% to 10% of the asthmatic population, the care of these patients accounts for more than 60% of the total costs attributed to asthma.1-3 These costs, which are primarily related to medication, are higher per person than those associated with chronic obstructive pulmonary disease or type 2 diabetes.3,4 This review will focus on the management of patients presenting with acute, poorly controlled asthma.
Since 2014, clinicians have made increasing efforts to distinguish asthma severity from asthma control.2 Asthma control denotes the degree to which the clinical manifestations of asthma are minimized, and asthma severity alludes to the intrinsic intensity of the disease process. Severity and control are distinct entities, as one patient may have mild asthma that is treatment refractory and consequently poorly controlled, whereas another patient may have more severe asthma that is treatment responsive and well controlled.
All patients with asthma are at risk for acute exacerbations. A patient is said to have uncontrolled asthma if he or she has poor symptom control (frequent rescue-inhaler use, activities limited by asthma, nocturnal awakening due to asthma) or has frequent exacerbations (two or more courses of oral corticosteroids in 12 months, one or more asthma-related hospitalizations in 12 months).5
Asthma is considered difficult-to-treat if the patient remains uncontrolled despite compliance with medium-dose or high-dose inhaled corticosteroids in combination with a second controller; the patient requires oral corticosteroids to achieve control; or the patient remains uncontrolled despite oral corticosteroids.2
Severe asthma is a subset of difficult-to-treat asthma wherein the disease either remains uncontrolled despite treatment of contributing factors and adherence to maximally optimized therapy or worsens when high-intensity therapy is decreased.2 Historically, severe asthma has been referred to as severe refractory asthma, asthma emergency, asthma attack, or status asthmaticus. Under current guidelines—and with the introduction of biological therapies—these terms are incorrect, inaccurate, or lacking in specificity.
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.8 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.7 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.9 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.12
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.13 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.7
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.5 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.16 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).17 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.17
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.17
The Pharmacist’s Role
It is essential that pharmacists stay abreast of current asthma treatment guidelines and be conversant with contemporary pharmacotherapy for severe asthma. As part of the interdisciplinary team, pharmacists have a role in optimizing asthma management and improving therapeutic outcomes. Asthma disease education, patient self-assessment of control, and an understanding of asthma medications are key elements of each patient interaction. Pharmacists can demonstrate proper inhaler technique, assess refill requests, monitor for drug interactions, reinforce medication adherence, and assist with product selection and insurance coverage.
Asthma is a major chronic disease that affects individuals in all age groups. All patients with asthma are at risk for acute exacerbations. Pharmacists in all healthcare settings should be conversant with evidence-based pharmacotherapy for the management of acute exacerbations of and preventive therapy for severe asthma. Acute exacerbations are managed with inhaled bronchodilators, inhaled corticosteroids, and oral corticosteroids. Patient-specific pharmacotherapy to prevent acute exacerbations includes the use of inhaled corticosteroids, often in combination with a long-acting bronchodilator, a short-acting bronchodilator for rescue, a long-acting antimuscarinic antagonist, a leukotriene antagonist, and biologics. Biological therapies represent a treatment option for patients with severe asthma unresponsive or intolerant to traditional treatments.
1. Hekking PP, Wener RR, Amelink M, et al. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896-902.
2. Chung KF, Wenzel SE, Brozek JR, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-373.
3. Sadatsafavi M, Lynd L, Marra C, et al. Direct health care costs associated with asthma in British Columbia. Can Respir J. 2010;17:74-80.
4. O’Neill S, Sweeney J, Patterson CC, et al. The cost of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic Society Difficult Asthma Registry. Thorax. 2015;70:376-378.
5. Global Initiative for Asthma. Difficult-to-treat & severe asthma in adolescent and adult patients: diagnosis and management. V2.0, April 2019. www.ginasthma.org. Accessed May 31, 2019.
6. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377:965-976.
7. Global Initiative for Asthma. Global strategy for asthma management and prevention. Updated 2019. https://ginasthma.org/wp-content/uploads/2019/04/GINA-Severe-asthma-Pocket-Guide-v2.0-wms-1.pdf. Accessed May 31, 2019.
8. Ramsahai JM, Hansbro PM, Wark PAB. Mechanisms and management of asthma exacerbations. Am J Respir Crit Care Med. 2019;199:423-432.
9. Camargo CA Jr, Spooner CH, Rowe BH. Continuous versus intermittent beta-agonists in the treatment of acute asthma. Cochrane Database Syst Rev. 2003;(4):CD001115.
10. Plotnick LH, Ducharme FM. Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev. 2000;(4):CD000060.
11. Rodrigo GJ, Rodrigo C. First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med. 2000;161:1862-1868.
12. Rodrigo G, Pollack C, Rodrigo C, Rowe BH. Heliox for nonintubated acute asthma patients. Cochrane Database Syst Rev. 2006;(4):CD002884.
13. Rowe BH, Spooner C, Ducharme FM, et al. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev. 2001;(1):CD002178.
14. Silverman RA, Osborn H, Runge J, et al. IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest. 2002;122(2):489-497.
15. Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J. 2007;24:823-830.
16. FDA. CDER conversation: safely using the newly available OTC asthma inhaler Primatene Mist. www.fda.gov/drugs/news-events-human-drugs/cder-conversation-safely-using-newly-available-otc-asthma-inhaler-primatene-mist. Accessed May 31, 2019.
17. National Heart, Lung and Blood Institute. Guidelines for the diagnosis and management of asthma (EPR-3). www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of-asthma. Accessed May 31, 2019.
18. Maselli DJ, Peters JI. Medication regimens for managing acute asthma. Respir Care. 2018;63:783-796.
19. Fergeson JE, Patel SS, Lockey RF. Acute asthma, prognosis, and treatment. J Allergy Clin Immunol. 2017;139:438-447.
20. Lazarus SC. Emergency treatment of asthma. N Engl J Med. 2010;363:755-764.
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