An Update on the Emergency Department Management of Asthma Part I: Pathophysiology and Management Strategies
An Update on the Emergency Department Management of Asthma Part I: Pathophysiology and Management Strategies
Authors: Larissa I. Velez, MD, Assistant Professor, Division of Emergency Medicine, University of Texas Southwestern, Dallas; Fernando L. Benitez, MD, Assistant Professor, Division of Emergency Medicine, University of Texas Southwestern, Dallas; Charles W. Todd, MD, Division of Emergency Medicine, University of Texas Southwestern, Dallas; and Jeremy G. Spinks, MD, Division of Emergency Medicine, University of Texas Southwestern, Dallas.
Peer Reviewers: Sandra M. Schneider, MD, FACEP, Professor and Chair, Department of Emergency Medicine, University of Rochester School of Medicine, Rochester, NY; and David A. Kramer, MD, FACEP, FAAEM, Program Director and Vice Chair, Department of Emergency Medicine, York Hospital, York, PA.
This issue begins a two-part series on management of asthma. Part I will focus on pathophysiology and emergency department management strategies, including beta agonists, steroids, and magnesium. Part II will conclude with a look at anticholinergics, methylxanthines, ketamine, leukotriene receptor antagonists, and heliox as well as with a discussion of managing asthma in special populations.
The Editor
Introduction
In the United States during 2002, asthma accounted for 12.7 million physician visits; 1.9 million emergency department (ED) visits; 484,000 hospitalizations; and 4,261 deaths.1 The prevalence of asthma in our society has led it to be the eleventh most common diagnosis in the ED.2 The direct and indirect costs of the disease are estimated to exceed $14 billion annually in the United States alone.3
Almost 30 million Americans have been diagnosed with asthma at some time in their lives. The lifetime prevalence is 10.4% in all U.S. adults according to a Centers for Disease Control and Prevention (CDC) study with data from 1999-2004. Although the incidence of pediatric asthma has reached a plateau, the morbidity and mortality continue to increase.4 It is estimated that 0.5-2% of pediatric asthma patients admitted to the hospital will require intensive care unit treatment.4
With the wide availability of treatment modalities for asthma, and a thorough understanding of the disease, physicians should achieve a high rate of symptom control. However, in a recent study of asthmatic patients in Canada, only 24% had adequate disease control.5 Fifty-seven percent of patients fell in the category of "poorly controlled" asthma.5 Fifty-one percent reported having sought urgent care for their asthma at least once during the past year; but surprisingly, 91% considered their asthma "adequately controlled."5
Relapse rates, defined as another episode of asthma requiring emergency care or hospitalization, ranging from 10% within 7 days after ED discharge to 31% 10-21 days after ED discharge, have been reported.6 For this reason, emergency physicians must not only be adept at treating asthma in the ED, but also should be familiar with the proper medication regimen that their patients need after discharge. This article will review the recent literature on the ED management of asthma.
Pathophysiology and Definitions
According to the Canadian asthma consensus guidelines, asthma is "characterized by paroxysmal or persistent symptoms, such as dyspnea, chest tightness, wheezing, sputum production and cough associated with variable airflow limitation and airway hyperresponsiveness to endogenous or exogenous stimuli."7 Status asthmaticus is at the end of the spectrum of severity and is defined as "a state of progressive bronchospasm unresponsive to conventional therapy."4
Asthma is considered well-controlled when the following are true: the patient has daytime symptoms fewer than four days per week; night-time symptoms less than one night per week; physical activity is normal; exacerbations are mild and infrequent; there are no reported absences from school or work due to asthma; the patient needs fewer than four doses per week of beta agonists; the FEV1 or PEF is 90% of personal best or greater; and the PEF diurnal variation is less than 10-15%. All patients not meeting these criteria need maintenance treatment, which will be discussed later in the text.7
Several historical factors should be obtained from asthma patients presenting to the ED, since these factors place the patient at high risk of death from asthma: history of sudden, severe exacerbations; prior intubation or intensive care unit admissions for asthma; two or more hospitalizations for asthma in the past year; three or more ED visits in the past year; one hospitalization or ED visit in the past month; use of more than two beta agonist canisters per month; current use or recent withdrawal from systemic steroids; difficulty in perception of the severity of the obstruction; comorbidities (chronic obstructive pulmonary disease [COPD], congestive heart failure [CHF], cardiovascular disease); serious psychiatric or psychosocial problems; and illicit drug use, especially cocaine or heroin.8 (See Table 1.)
| Table 1. Historical Factors that May Place Patients at High Risk of Death from Asthma8 |
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The pathophysiology of asthma has three key components: airway hyperresponsiveness, bronchial smooth muscle spasm, and airway inflammation (edema, mucus secretion, influx of inflammatory cells).9 Compared to normal individuals, people with asthma have a disproportionate amount of bronchospasm when exposed to triggers. This is mediated by beta adrenergic receptors. Stimulation of the beta receptors causes bronchodilation, and beta adrenergic blockade results in bronchoconstriction. Alpha stimulation, on the other hand, does not produce significant bronchoconstriction. In some patients, even with aggressive management, there is only partial reversibility of airflow obstruction. This phenomenon may be due to airway structure remodeling over time.9
Airway inflammation now is considered to play a central role in asthma. This inflammatory reaction is mediated by histamine, prostaglandins, leukotrienes, cytokines, and enzymes. A prolonged inflammatory response is known to be mediated by T helper cells (Th2 cells). Thus, the goals of ED management of asthma are to: relieve bronchoconstriction, initiate management of the inflammation, and treat any precipitating factors, such as infections. Table 2 classifies the severity of asthma.
| Table 2. NAEPP Classification of Asthma Severity Before Treatment |
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ED Management Strategies for the Acute Asthma Patient
Beta agonists. Beta agonists are the mainstay of acute asthma therapy in both adults and children because they are efficacious, their side effects are minor, and their margin of safety is wide.10 These beta agonists function via beta receptors on the bronchial tissue via a beta2 receptor which is a G protein that functions to increase cAMP. This then activates various enzymes that serve to sequester cytosolic calcium, resulting in smooth muscle relaxation and symptom relief. Although this is their main role, additional functions of beta agonists currently are being investigated, such as inhibiting isolated human lung mast cell release, increasing mucociliary clearance, and reducing plasma exudation to the airway.11,12
There are many beta agonists that can be used to treat bronchoconstriction, but the preferred one in the acute setting is a short-acting, beta2 selective agonist (SABA), such as albuterol (salbutamol, Ventolin, Proventil, Volmax).
The preferred method of delivery is via the inhaled route.13 This can be achieved through the metered dose inhaler (MDI) or by powered nebulizer. Both have been shown to be equally effective as long as the MDI is used with a chamber.14,15 In pediatric patients, the use of MDI has fewer systemic side effects and similar efficacy to nebulizer use.16,17 In addition to this, MDIs with holding chambers are more widely available and less expensive than nebulizers.16 Nebulizer treatment would be a more logical means if the patient lacked the experience or ability to use an MDI, as an acute event is not the time to teach proper use of the MDI. After the acute event is over, MDI teaching should begin.
For most patients, nebulizer therapy is equally as effective as a continuous or intermittent treatment. In a recent review of patients presenting to the ED with asthma, there was no difference in efficacy between hourly vs. continuous nebulizer treatments.15 In contrast, another study found that in those with FEV1 less than 40%, continuous treatment resulted in a significant improvement over hourly treatment, with either high dose (7.5 mg/hour) or standard dose (2.5 mg/hour) albuterol.14,18
Dosing has been an issue of debate, as there is a paucity of evidence regarding proper beta adrenergic dose. Current recommendations are based upon convention rather than on evidence. The guidelines in the United States recommend 2.5-5.0 mg of albuterol every 20 minutes, then 2.5-10 mg every 1-4 hours.19 British guidelines favor 5.0 mg every 20 minutes.20 For pediatric patients, the recommended dosing is 2.5 mg (0.5 mL) of albuterol per dose for patients weighing fewer than 10 kg, and 5.0 mg (1 mL) per dose for those weighing more than 10 kg. Six puffs of albuterol via MDI (100 mcg per puff, or 600 mcg total) is an estimated equivalent to a dose of 2.5 mg of nebulized albuterol. The MDI should be shaken before each delivery, and deliveries should be at least one minute apart from each other, delivered just before inhalation and then cleared from the spacer with a minimum of five tidal breaths between actuations.21
There has not been a definitive difference in efficacy among various dosages for the SABAs.19,22 However, in one study, when patients were stratified into those with the most severe disease (FEV1 less than 40%), there does seem to be a more significant improvement with high-dose intermittent albuterol (7.5 mg every 20 minutes).14 This is an area that needs more study before evidence-based recommendations can be made. However, it appears that standard doses of short-acting beta adrenergic agents delivered intermittently or continuously are at least as effective as higher doses.
There has been great debate among researchers and among those with anecdotal experience regarding the efficacy of racemic albuterol (both the R and S stereoisomers) vs. levalbuterol (the R isomer) (Xopenex). Albuterol is a medication that consists of two chemicals that are identical with the exception of one carbon that is known as a chiral carbon. The rotation of this chemical about this carbon creates two molecules that are exact mirror /ahc/img that cannot be superimposed and are called stereoisomers. These stereoisomers are designated as the R and S isomers. In nature, there are many such compounds. Usually, one of the stereoisomers is biologically active. There has been much discussion over the clinical effect of the albuterol isomers.23 Although in the laboratory there has been evidence that the S enantiomer has potential negative effects on tissue, this has not been validated clinically.23 The reported negative effects of S-albuterol include increased smooth muscle reactivity, increased intracellular calcium in airway bronchial smooth muscle, increased bronchoreactivity in animals in vitro, and increased production of histamine.24
To date, there have been several studies comparing levalbuterol and albuterol.24-28 One demonstrated lower admission rates and decreased costs associated with the use of levalbuterol.26 Another showed similar results in a pediatric population, with a reduction of admission from 45% to 36%.29 The results of these two trials have been disputed due to study limitations such as the retrospective observational nature of the study by the first study or admission rates for patients that were double or triple the national average in the data from the second study.26,29 One recent double-blind, randomized, controlled study did not show any difference between the two medications either in side effects or efficacy in relieving symptoms.30 Given the data at hand, the routine use of levalbuterol over racemic albuterol is neither supported by the literature nor by guidelines. It may be useful, however, in patients who are experiencing side effects to albuterol.31
Common side effects of the beta agonists include muscle tremor, hypokalemia, and tachycardia.14 The muscle tremor is via stimulation of the beta2 receptor on skeletal muscle. This same receptor also is responsible for the hypokalemia, since it causes potassium uptake in the skeletal muscle. The hypokalemia does not represent a decrease in total body potassium, since it is due to redistribution. The hypokalemia is more significant in those receiving higher doses of albuterol and those receiving continuous nebulized albuterol. There are no reports of significant cardiac dysrhythmias secondary to beta adrenergic-induced hypokalemia, although it is prudent to place the high-risk cardiac patients on a monitor and consider checking serum potassium concentrations after prolonged or aggressive treatment. In one study there was one incident of hypokalemia (2.8 mEq/L) with high-dose nebulizer treatment. There were no complications, but the potassium was repleted.14
There is minimal to no role for intravenous (IV) and oral beta agonists in treating acute asthma. A recent Cochrane review totaling 584 patients failed to show any benefit to the IV route.32 Another literature review showed only a benefit in the trials that had compared IV beta adrenergics with placebo. The data also showed an increased rate of adverse events when using the IV route.33 Intravenous beta adrenergic agents have been shown to increase VQ mismatch by blunting the pulmonary hypoxic vasoconstriction. This can result in worsened pulmonary gas exchange.4,34
The Other Beta Agonists. Terbutaline (Brethine, Bricanyl) is a beta2 adrenergic agonist that has been used in asthma. Stephanopoulos used IV infusions of terbutaline at greater than 4 mcg/kg/min in pediatric patients with status asthmaticus. The treatment was well tolerated.4 There is a concern for cardiotoxicity from the IV use of terbutaline. A recent case series of pediatric patients, however, did not show any cardiotoxicity.35 Overall, terbutaline IV should be reserved for the pediatric patient unresponsive to therapy.
Epinephrine, a nonselective adrenergic agonist, also has been used occasionally in the treatment of severe, life-threatening asthma. A recent chart review in young adults showed no adverse effects form the addition of epinephrine to standard treatment. This study, however, was small and only looked at rates of complications. No statements as to effectiveness can be drawn at this time.36
According to Spiteri et al, epinephrine and terbutaline are equally efficacious and, surprisingly, 0.5 mg of SQ epinephrine has the same symptom profile as 0.5 mg of SQ terbutaline (i.e., there is no difference between terbutaline, a beta2 selective molecule, and epinephrine, a nonselective adrenergic agonist).37
The long-acting beta agonists (LABAs), such as salmeterol (Serevent Diskus, Advair Diskus) and formoterol (Foradil Aerolizer, Oxeze), recently have received attention for their potential to result in severe asthma exacerbations and increased asthma-related deaths if used alone (see FDA.gov).38 They are neither recommended in the acute setting nor as single maintenance therapy in the chronic asthma patient.
Overall, beta agonists are safe and effective in treating asthma and are an integral part of acute asthma exacerbation treatment.
Steroids (Dose, Route Type, Frequency). Asthma is a chronic inflammatory disease with periodic acute exacerbations. The acute exacerbations have an early and a late response. The early response is thought to be due to stimulation of sensitized mast cells, which then release preformed mediators of disease including histamine, prostaglandins, leukotrienes, platelet-activating factor, and TNF-alpha.39 The late phase of the disease is thought to be dominated by Th2 cells that are effector cells producing effects via direct mediators (interleukins) and secondary mediators on eosinophils, mast cells, B cells, and other T cells.39 It is in this realm that steroids are active in treating disease.
The term steroid is a generic term for a four-ringed structure that is the foundation of many of the body's hormones. The hormone cortisol (hydrocortisone) is synthesized in the adrenal cortex and has both glucocorticoid and mineralocorticoid properties. By manipulating the ring structure, the glucocorticoid effects are amplified and the mineralocorticoid effects are minimized. These steroids, prednisolone (Delta-Cortef, Prelone, Pediapred, Orapred) and dexamethasone (Decadron, Dexone), represent the newer generation of steroids. Further manipulation yields steroids that are active via the topical and inhalator routes, such as beclomethasone (Vanceril, QVAR), flunisolide (AeroBid, AeroBid-M), and triamcinolone (Azmacort). Relative to the treatment of asthma, it is thought that corticosteroids lead to decreased synthesis of the pro-inflammatory mediators such as IL (3-5, 9, 10, and 13), GM-CSF, Platelet activating factor, and TNF-alpha, among others, and increase the synthesis and release of beta2 receptors on pulmonary tissue.
Given that asthma is an inflammatory process, it is not surprising that steroids have been used to treat asthma for the past 60 years.40 There is such a preponderance of evidence since then supporting the use of steroids in the acute exacerbation of asthma that they now are part of both the United States and the British protocols.10,20,41-43
There is little evidence to support a specific dosage for steroid use in the ED population. However, in a recent Cochrane Collaboration, there was no difference in efficacy when treating hospitalized patients with high-, moderate-, or low-dose steroids. Low dose was defined as less than 80 mg oral methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol) per day.44 Most research shows a therapeutic benefit at 40-60 mg of oral prednisone per day, although some may require up to 80 mg PO per day.45 Dosage in the U.S. protocol calls for prednisolone, methylprednisolone, or prednisone (Deltasone, Meticorten, Pred-pack, Sterapred) 40-60 mg per day for a 3-14 day course.10 According to one review, it is unlikely that there is efficacy below 30 mg per day of methylprednisolone or its equivalent.45
There is no evidence of a difference in efficacy or onset of action among IV, IM, and oral routes.46-49 It previously was thought that steroids take about 4-6 hours to begin to have an effect; however, recent data suggest their onset of action may be as soon as 2 hours.50 Intramuscular corticosteroids have been shown to be as effective as oral administration.42,48 A single IM injection of a depot steroid has the advantage of bypassing the issues of patient compliance and prescription filling.48 It is clear that the early use of systemic corticosteroids in both adult and pediatric patients decreases the need for hospitalization, especially when the therapy is initiated within 1 hour of ED arrival.43,45 Patients who are discharged should be sent home with a short course of oral corticosteroids, preferably for about 3-10 days. The oral steroid dosage does not have to be tapered after short-course "burst" therapy if the patient is receiving inhaled steroid maintenance therapy.10
Currently there is some evidence to show that the addition of inhaled corticosteroids to oral dosing is beneficial in acute asthma exacerbations.51 There is no role yet for inhaled steroids replacing oral steroids for acute exacerbations in the ED, and they have been shown to have less effectiveness in at least one study.52,53 At this point, it is also unclear if the inhaled corticosteroids can replace the oral corticosteroid dosing after discharge from the ED.54 However, all patients not adequately controlled or with severe asthma should be prescribed an inhaled corticosteroid on discharge.55,56 A recent survey of ED practices indicated that only 32-34% of physicians follow this practice.57 Appropriate inhaled corticosteroids have been approved for use in children as young as 1 year of age.
Concerns about long-term growth retardation from steroids as they currently are used in the treatment of pediatric asthma appear to be unfounded.31 In fact, poor asthma control that results from inadequate controller therapy can adversely affect linear growth, and one study showed that glucocorticoids actually improved growth in children with asthma.58,59
Magnesium. Magnesium sulfate first was used in the treatment of asthma by the Uruguayan physician Rosello in 1935.60 Its mechanism remains elusive but may occur via sequestration of intracellular bronchial smooth muscle calcium, resulting in smooth muscle relaxation.61,62 Additionally, beta agonist therapy can decrease serum magnesium. It is possible that normalization of serum magnesium levels in the setting of albuterol treatment contributes to its bronchodilating effect.63 Other mechanisms have been hypothesized, however it still is not clear exactly how magnesium affects the asthma patient.62,64 Interestingly, a difference in serum magnesium levels between patients with asthma and those without has not been shown. Rather, after an acute exacerbation, the intracellular magnesium is reduced in acute asthma patients. This decreased intracellular magnesium concentration resolves when symptom control is achieved.64
Systematic reviews of the available data have shown that only severe acute asthma patients (FEV1 less than 25%) will respond to intravenous magnesium treatment.65,66 There were no reported adverse effects from the treatment. Based on these reviews and a multi-center, randomized trial, IV magnesium should be used in the severely ill asthma patient (FEV1 less than 25%).62 The study has been criticized for not using ipratropium but, given the evidence at hand, IV magnesium appears to be a beneficial adjunct in the very ill patient.67
Magnesium sulfate is given IV at 1.2-2 grams over 20-30 minutes. Bronchodilating effects appear about 20 minutes after infusion and may persist for up to 3 hours.21 Caution must be used since hypotension may result, secondary to the relaxing effect magnesium can have on vascular smooth muscle. Finally, a review of the literature (6 prospective randomized trials and 1 observational study) did not show any benefit of nebulized magnesium.68 A systematic review of the literature was only able to show a trend in decreased admission with the used of nebulized magnesium.69 The routine use of nebulized magnesium cannot be recommended.
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In the United States during 2002, asthma accounted for 12.7 million physician visits; 1.9 million emergency department (ED) visits; 484,000 hospitalizations; and 4,261 deaths. The prevalence of asthma in our society has led it to be the eleventh most common diagnosis in the ED. The direct and indirect costs of the disease are estimated to exceed $14 billion annually in the United States alone.Subscribe Now for Access
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