Authors: Jill M. Baren, MD, FACEP, FAAP, Assistant Professor of Emergency Medicine, Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia; Attending Physician, Department of Emergency Medicine, The Hospital of the University of Pennsylvania; Attending Physician, Division of Emergency Medicine, Department of Pediatrics, The Children’s Hospital of Philadelphia; Amy Puchalski, MD, Fellow, Division of Emergency Medicine, Department of Pediatrics, The Children's Hospital of Philadelphia.
Peer Reviewer: Steven Krug, MD, Associate Professor of Pediatrics, Northwestern University School of Medicine; Director, Pediatric Emergency Medicine, Children’s Memorial Hospital, Chicago.
Asthma is the most common chronic disease of childhood, with patients suffering substantial morbidity and frequent emergency department (ED) utilization.1 Understanding the current recommendations for appropriate treatment of these patients in an acute setting is vital for all emergency care providers, and is based on a clear understanding of the underlying epidemiology and pathophysiology of asthma. The aim of this review is to summarize current concepts in the identification, evaluation, and treatment of children presenting with acute asthma exacerbations in the ED setting.—The Editor
Introduction
Asthma is a chronic inflammatory disease characterized by airflow obstruction (which is at least partially reversible by medication), exacerbations, and remissions.2 The National Heart, Lung and Blood Institute (NHLBI) of the National Institute of Health (NIH) has developed a set of guidelines for the evaluation and management of asthma, which are known as the National Asthma Education and Prevention Program (NAEPP) Guidelines.3 These guidelines were derived primarily from expert opinion from a broad range of generalists and specialists who treat asthma and are partially evidence-based. The NAEPP guidelines state three general requirements for the diagnosis of asthma. First, a child must have intermittent symptoms of airflow obstruction, which is identified by several key indicators, including history of nighttime cough, recurrent wheeze, or chest tightness. Second, reversible airflow obstruction must be documented by pulmonary function testing, worsening symptoms in the presence of any of several triggers, or symptoms that occur at night. It is important to note that documented changes in pulmonary function are an important component of this definition. Finally, all other possible diagnoses considered by the clinician need to be excluded.3
A recent survey found that many physicians may not adhere to some aspects of these recommendations. Only 10% surveyed felt evaluation of lung function was necessary to diagnose asthma, and many incorrectly thought asthma could not be diagnosed in a child younger than 2 years or in a febrile child with wheezing.2,4 Although unproven, failure to adhere to these suggested guidelines may result in a delay in the identification of a child with asthma and a lack of initiation of optimal preventive therapy.
The NAEPP guidelines further classify those with asthma by severity of disease. This classification is based on differences in overall symptoms, nocturnal symptoms, and lung function, and has implications for acute and chronic treatment.3 Patients are divided into those with mild intermittent disease or those with mild, moderate, or severe persistent disease. From the ED perspective, patients categorized with any one of the above classifications of baseline disease can present with an acute exacerbation and should receive treatment accordingly. Baseline severity of disease classification, however, may be beneficial for the selection of appropriate discharge medications.
Epidemiology
The overall prevalence of childhood asthma in the United States is between 4.3% and 6% of the general population. Unfortunately, this prevalence has increased during the last two decades.1,5,6 In one study, the prevalence increased from 3.5% to 5.3% in a single decade.1 Currently, asthma is the most common chronic disease in childhood, as well as the fourth leading cause of disability among children.1 In 1998, there were more than 850,000 ED visits made by pediatric asthma patients.7 Among all ED visits by children in the United States, 5-10% are attributed to asthma.1,2,6 In 1998, there were approximately 90,000 hospitalizations for pediatric asthma, a number that has been increasing, particularly among children ages 1-4 years.2,6,7 Asthma also is one of the most frequent causes of school absence among children, accounting for more than 10 million lost school days annually.4,8
Annual fatalities due to asthma in 1998 totaled 4657, with 158 occurring in children younger than 14 years.9 According to the National Center of Health Statistics, asthma fatalities doubled among 5- to 14-year-olds between 1980 and 1998, but in recent years have appeared to be stabilizing.10,11 The NAEPP guidelines have identified risk factors for fatal asthma, which are summarized in Table 1. Identification of these risk factors is important in any child with asthma.
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There has been much speculation about the reasons for the overall increases in the prevalence of, hospitalization from, and mortality rate of childhood asthma. Changes in various risk factors for asthma, such as higher rates of prematurity, lack of breast feeding, more exposure to air pollution and smoking, or changes in socioeconomic status, may partially account for these increases.1 The prevalence of asthma also is disproportionately large among African American and urban children.1,6 The most recent National Health and Nutrition Examination Survey demonstrated a prevalence of asthma in African American children that was twice as high as in Caucasian children, with evidence of higher rates of hospitalization, readmission, and mortality, as well.1 Gender differences also are seen in asthma, with more males affected by asthma prior to adolescence and more females during adolescence and adulthood.1 Overall, approximately 30% of children will have persistent symptoms of asthma into early adulthood, and once symptoms continue beyond age 20, they are unlikely to resolve.1
Etiology
Multiple etiologic agents have been implicated in the initiation of an asthma exacerbation in children, many of which can be identified by the child’s caretaker during initial history. Some of the more common triggers for asthma include tobacco smoke, air pollutants, animal allergens, dust mites, viral respiratory infections, cockroach allergens, weather changes, molds, outdoor allergens, and gastroesophageal reflux.2,3 Upper respiratory tract infections (URIs), in particular, are one of the leading causes of asthma exacerbations in infants and younger children, with respiratory syncytial virus (RSV)being particularly common in the pre-school age group and mycoplasma being more common among school-age children.12,13 The rate of viral URIs can vary between 14% and 63% in children with an acute wheezing episode.12 Wheezing usually begins within about 40 hours of the onset of upper respiratory symptoms and can last up to four days, giving some indication of expected length of asthma symptom persistence.14 Viral infections appear to be an even more prominent trigger of severe asthma exacerbations relative to those that are mild.15 The question as to whether viral infections early in life predispose a child to asthma is controversial, and various studies have shown conflicting results.12
The role of other risk factors in the development of childhood asthma also has been evaluated. A meta-analysis evaluating the role of environmental allergens showed no evidence that allergen exposure during infancy increased the risk of asthma after age 6 years.16 In a cross-sectional survey of families with children younger than 6 years of age, presence of asthma was associated with a family history of atopy, child’s history of allergy to a pet, use of a gas stove, presence of a dog at home, and history of tobacco smoke exposure.17 The causal nature of tobacco smoke exposure is further supported by a Swedish cross-sectional survey showing greater prevalence of childhood exposure to smoke in adult asthmatics than in those without asthma.18 The role of day care and exposure to other children was examined in a prospective cohort study of more than 1000 children followed from birth to age 6 years. Within the cohort, attending daycare in the first 6 months of life or having older siblings at home was protective against having asthma after age 6.19 In summary, there does not appear to be a single common pathway by which all children develop asthma, but rather a combination of genetic predisposition and environmental exposures that are responsible for the initial development and subsequent exacerbations of asthma.
Pathophysiology
The underlying pathophysiology of asthma is rather complex, involving many aspects of acute and chronic inflammation and airway hyperresponsiveness. The partially reversible airflow obstruction of asthma is due to bronchial smooth muscle constriction, airway edema, inflammation, and mucus plugging.11 Acutely, bronchoconstriction accounts for the majority of symptoms from an asthma exacerbation; however, as symptoms persist for several days, airway inflammation and edema become increasingly prominent features.20 Airway hyperresponsiveness, or exaggerated bronchoconstriction, to various etiologic agents is another important underlying cause of asthma symptoms and severity of disease.3 The histologic features of asthma include mast cell activation, denuded airway epithelium, inflammatory cell migration, and eventual collagen deposition and fibrosis below the basement membrane.3 Changes due to chronic damage from these features may eventually become permanent.3
Clinical Features
The initial information gained from the history and physical exam provide a basis for the determination of the severity of a child’s asthma exacerbation and the best approach for initial management. The clinician should be brief in the initial assessment so as not to delay initiating therapy. More detailed questions can be addressed as the patient is stabilized.
History. History first should focus on the characteristics of the child’s exacerbation symptoms. Patients may complain of wheezing, persistent coughing, chest pain or tightness, or feeling short of breath. The caretakers of young patients may express concern over feeding difficulties, post-tussive vomiting, difficulty sleeping or increased fussiness more than other classic respiratory symptoms. The onset, duration, and severity of symptoms should be clarified.2,3,20 The clinician should verify a past diagnosis of asthma in the patient and age of onset. Important issues relevant to past exacerbations include frequency of exacerbations, number of hospitalizations and ED visits in the last year, history of intensive care unit (ICU) admissions or intubation for an exacerbation, as well as what usually triggers exacerbations.
The clinician should then focus on medication use, including recent b2-agonist usage for the current exacerbation, as well as baseline use, the last time oral steroids were required, and the use of any preventive medications.20 Other comorbid conditions, such as congenital heart disease, also must be identified in the past history. A strong family history of atopy may provide support to a diagnosis of asthma in a child whose family is not clear on the diagnosis.3 Many aspects of the social history are informative as well. The family should be questioned about the presence of various triggers in the child’s environment, adherence to any preventive medication prescribed, extent of social support in the child’s life, day care attendance, and the understanding of the role of preventive and rescue medications, as well as their availability to the family.2,3 When treating the acutely ill child, the priority of historical facts that should be obtained are: 1) history of current symptoms; 2) verification of the diagnosis of asthma; and 3) b2-agonist use prior to arrival.20
Physical Exam. In pediatric asthmatic patients, the physical exam should focus on vital signs, accessory muscle use, mental status, inspiratory to expiratory (I:E) ratio, and degree of aeration.21 Auscultory findings, particularly in infants and small children, do not always reveal a characteristic high-pitched, expiratory wheeze. Breath sounds may be coarse, sound like upper airway congestion, or be nearly absent in the case of severe exacerbations. In children with mild symptoms, or those with chronic cough, a wheeze may not be appreciated until after a b2-agonist treatment provides some relief of airflow obstruction.
Vital Signs. Respiratory rate is often the best indicator of the degree of airway obstruction in younger children who are not able to increase tidal volume in response to respiratory difficulty.22 Instead, they become tachypneic to increase functional vital capacity in the presence of airway obstruction.20 It is important to know the age-appropriate normals for respiratory rate in both awake and sleeping patients, as this vital sign has been shown to be state-dependent.20 Children often are tachycardic during exacerbations due to a combination of anxiety, increased work of breathing, and hypoxia. Hypotension may be present in those with impending respiratory failure due to diminished venous return and elevated pleural pressures. Pulsus paradoxus, an exaggeration of the normal drop in blood pressure with inspiration is present in 40% of asthmatics and correlates well with forced expiratory volume in one second (FEV1).23 From a practical standpoint, pulsus paradoxus is very difficult to assess in children, especially in a noisy ED, and therefore, it is of limited use.20
Accessory Muscle Use. Retractions and paradoxical abdominal and chest wall movements often are prominent in pediatric patients with asthma and easy to appreciate due to the thin, compliant chest wall. Subcostal, intercostal, and supraclavicular retractions may be noted. Supraclavicular retractions usually develop last and indicate significant work of breathing. Nasal flaring also is common in young children with moderate or severe exacerbations and is an indication of hypoxia.2 Infants frequently are noted to have abdominal breathing, characterized by protrusion of the abdomen on inspiration.20
Mental Status. As with many pediatric illnesses, a smiling or playful child can be reassuring. Conversely, alteration in mental status in conjunction with respiratory distress is extremely concerning for impending respiratory failure. Irritability, combativeness, lethargy, confusion, and agitation may be signs of both hypoxia and hypercarbia, and should be cause for immediate concern.20
I:E Ratio. In pediatric patients with mild asthma exacerbations, a prolonged expiratory phase may be the only indication of active disease. More severely ill children will have a pronounced expiratory phase characteristic of airway obstruction.
Aeration. As previously stated, absence of wheezing may be due to severely diminished aeration in children with severe exacerbations. A child’s ability to speak or cry also is related to how well he can aerate, and should be noted on initial assessment.
Completing the Physical Assessment. Two important concepts should be kept in mind when completing the physical assessment of an asthmatic child. First, a great deal of information can be gathered merely by observing the child from a distance. Initially, one can assess general appearance, mental status, overall work of breathing, and degree of breathlessness without a "hands-on" approach. This may prove to be valuable in gaining the trust of the patient, and in avoiding a worsening of the respiratory status. Second, a thorough physical examination ultimately should be conducted to determine severity, response to therapy, and to rule out other causes of respiratory distress. For example, one should listen for stridor and a murmur or gallop on auscultation, and should check for peripheral edema, rashes, or hepatomegaly, which may indicate alternative diagnoses or co-morbid conditions.
Diagnostic Tests
The vast majority of important information relevant to an asthma exacerbation in a pediatric patient is found in the history and physical exam. At times, additional diagnostic studies are helpful in assessment and management.
Pulse Oximetry. Measuring oxygen saturation with pulse oximetry is probably the most useful of all adjunctive tests in children presenting with an asthma exacerbation, and it should be checked intermittently or continuously throughout the ED course, depending on the severity of the patient’s condition. Hypoxia, as measured by pulse oximetry, reflects the degree of atelectasis and intrapulmonary shunting in a patient.2 Studies of the value of pulse oximetry in predicting the outcome of an acute exacerbation have had conflicting results. Geelhoed et al demonstrated that an oxygen saturation of less than 91% was predictive of hospital admission.24 Other data indicate that pulse oximetry may be a more discriminating predictor for hospitalization than peak flow monitoring.25 Still other investigations have maintained that pulse oximetry has a poor sensitivity and specificity for predicting exacerbation outcome.2
Important to keep in mind is that pulse oximetry provides no information regarding ventilation, and it is less accurate in the face of peripheral vasoconstriction.2 In the setting of poor perfusion, readings may be inaccurate. Overall, the inconsistent results of pulse oximetry as a predictor of outcome are outweighed by its clinical advantages, particularly in the pediatric population. It is non-invasive, and it can detect changes in oxygen saturation, which may allow the clinician to rapidly respond and avert a potential worsening of the patient’s condition. Pulse oximetry monitoring is recommended for all asthma patients.
Peak Expiratory Flow (PEF) Monitoring. The 1997 NAEPP guidelines stress the importance of PEF monitoring, both for long-term management of asthma and to assist in evaluating patients during an exacerbation.3 The PEF is a measure of obstruction in large caliber airways, and is an approximation of FEV1.2 As air trapping worsens, however, PEF does not correlate as well with FEV1, in part because it is an effort-dependent measure. FEV1 is effort-independent and reflects the obstruction in both large- and medium-caliber airways.26
Despite its inherent limitations, PEF monitoring is a fairly simple procedure that can be taught to patients and performed easily in the ED. The procedure should be attempted in every child older than 5 years. Children should be asked to take a deep breath and blow out as forcefully as possible. The patient should be standing for optimal measurement. The best of three readings should be recorded.27 The readings are interpreted relative to a child’s past personal best or a predicted value based on the child’s height. A value greater than 80% of predicted is consistent with a mild exacerbation; 50-80% a moderate exacerbation; and less than 50% a severe exacerbation.3 Measurements can be done multiple times during ED treatment as the primary assessment of the patient’s response to therapy. Generally, values greater than 70% of predicted are the goal in considering discharge to home.3 The only real disadvantages of PEF monitoring include the inability to use it in young children and its effort dependence. In children who clearly are in severe distress, it may be impossible or not prudent to perform PEF testing initially in lieu of immediate therapy.
Chest Radiographs. Chest radiographs are of limited utility in the emergent management of the pediatric asthma patient. Patients who may warrant radiography include severely ill patients, those who are not responding to therapy as expected, those with persistent focal findings on lung exam after several treatments with inhaled b2-agonists, and those with concern for barotrauma or other suspected complications of asthma (i.e., pneumothorax).2,11,21,22 Infants with a first episode of wheezing also frequently warrant a chest radiograph to exclude alternative diagnoses (i.e., foreign bodies, congenital heart disease, or congenital lung anomalies).21 The presence of fever alone should not be the sole indication for chest x-ray in patients with asthma, as viral infections are one of the most common triggers for childhood asthma exacerbations.
Arterial Blood Gases (ABG). ABG monitoring rarely is necessary and never is routine in pediatric asthma patients. Initially, patients may be mildly hypoxic secondary to intrapulmonary shunting and mildly hypocarbic due to hyperventilation.2,11 Patients in impeding respiratory failure will become normo- or hypercarbic; however, clinical signs such as fatigue or worsening accessory muscle use or mental status should alert the clinician to a deteriorating condition well before an ABG is drawn. In this case, an ABG would be considered only supporting evidence for the clinical diagnosis of respiratory failure.22 Blood gas monitoring is important for the rare child who requires intubation for treatment of status asthmaticus.
Differential Diagnosis
Many diseases cause symptoms of wheezing and respiratory distress that can be mistaken for asthma. In infants, there is a broad differential diagnosis which must be considered in a child with these symptoms. Infectious respiratory illnesses such as croup, pneumonia, pertussis, and bronchiolitis all have similar symptoms. Bronchiolitis can be particularly difficult to distinguish from asthma. Historical information such as age, past history of wheezing episodes, past response to bronchodilators, and family history of atopy can help to differentiate the two entities.
Several congenital anomalies may mimic asthma, including choanal atresia, vascular rings, congenital lobar emphysema, pulmonary sequestrations, and congenital cystadenomatoid malformations. Tracheomalacia, which is relatively common in infants, often is perceived as wheezing by family members. Airway foreign bodies and anatomical conditions like hemangiomas and papillomas may produce wheezing and respiratory distress as well. Chronic diseases, such as heart failure, cystic fibrosis, bronchopulmonary dysplasia, and gastroesophageal reflux, always must be considered. Rarely, there may be psychogenic causes of wheezing.22
Management
The general goals of treating an asthma exacerbation are to correct hypoxemia, quickly reverse airflow obstruction, and treat the underlying inflammatory response.3 The NAEPP guidelines contain a useful algorithm for the approach to an asthma exacerbation. (See Insert.) A summary of medications, their indications, and doses appears in the Insert.
Pharmacologic Therapy. Inhaled b2-Agonists. Inhaled b2-selective agonists, such as albuterol, are the mainstay of ED therapy for asthma. Albuterol exerts its effects by relaxing bronchial smooth muscle and increasing water content in bronchial mucus to promote mucociliary clearance.28 The recommended dose of albuterol is 0.15 mg/kg/dose (0.03cc/kg/dose).2 However, higher doses frequently are used for moderate and severe exacerbations, with various studies demonstrating no increase in adverse effects.2 General guidelines for albuterol dosing in moderate or severe exacerbations is 0.5 cc per nebulizer treatment in children weighing fewer than 10 kg; 0.75 cc for children 10-20 kg; and 1 cc in children weighing more than 20 kg. The initial goal is to administer a nebulization every 15-20 minutes when treating moderate to severe exacerbations, decreasing to one treatment every 1-4 hours, depending on the patient’s response.3 Undiluted albuterol nebulized treatments may be as effective as those diluted in normal saline for severe exacerbations, while allowing for a shorter treatment period.29
Delivery of b2-agonists via a metered-dose inhaler (MDI) with spacer device is an acceptable alternative to delivery with a nebulizer system. Many randomized, controlled trials in pediatric patients ages 1-17 years have demonstrated equivalent efficacy of MDI vs. nebulized treatments in the emergent treatment of asthma exacerbations.2,30-32 The recommended dosages are between 4 and 8 puffs per treatment for acute exacerbations. The advantages of the MDI include its decreased cost relative to nebulizers, reduced administration time in the ED, and its ease of portability for families.2,32 MDIs can be used effectively in infants in conjunction with a mask on the end of the spacer device.
Continuously nebulized albuterol should be considered when a child does not have adequate response to three treatments given over one hour. The recommended starting dose is 0.5 mg/kg/ hour.3 Continuous albuterol does not offer any routine advantage over intermittent albuterol; however, a study by Khine et al demonstrated more effective bronchodilation with continuous administration in pediatric patients with severe exacerbations.33
Levalbuterol is a relatively new therapeutic option that may offer diminished side effects and more effective bronchodilation relative to albuterol in some patients. Albuterol is a racemic mixture of both the R and S isomers, while levalbuterol contains only the R isomer. The R isomer primarily is responsible for bronchodilation, while the S isomer is responsible for some of the systemic side effects and may actually cause bronchoconstriction.34 Only a few small, randomized, controlled trials in children have been performed comparing the two medications. One showed improved bronchodilation with levalbuterol initially and on repeated treatments.34 Until these early trials are confirmed in patients with acute exacerbations, levalbuterol currently has no role in the ED management of asthma.
Ipratroprium. Ipratroprium bromide is an inhaled anticholinergic derived from atropinethat inhibits acetylcholine-mediated bronchoconstriction and decreases mucus production.2 It is not systemically absorbed and has very minimal side effects.11,35 It reaches peak effect in 60 minutes, so it is useful when given early in the treatment of an exacerbation.2 The medication should be administered in conjunction with albuterol in moderate and severe exacerbations.3 The NAEPP guidelines recommend a dose of 250-500 mcg via nebulizer or 4-8 puffs via MDI for three treatments given 20 minutes apart. Doses given twice in an hour have been used in children both in studies and clinical practice.2,36 Schuh et al demonstrated the efficacy of ipratropium in 120 children ages 5-17 years with an initial FEV1 of less than 50% predicted. At 20 and 120 minutes after treatment, patients who received ipratropium vs. placebo had significantly better pulmonary function. This difference was more prominent in the most severe patients and in those who received multiple, as opposed to single, doses of ipratropium.37 In addition, hospital rates were lower among the most severely affected children (FEV1 < 30%). No significant side effects were reported.37 A recent meta-analysis of ipratropium studies in children concluded that it is primarily helpful in moderate and severe exacerbations, that multiple doses decrease hospitalization rates by 30%, and that a single dose improves lung function but does not affect hospitalization.36 There is no data to support the use of ipratropium with every b-agonist treatment or in the setting of mild exacerbation.38
Corticosteroids. Corticosteroids are a vital component of asthma exacerbation therapy. They help to diminish airway inflammation and obstruction and they potentiate the bronchodilating effect of b2-agonists.2 Corticosteroids should be given to all children with moderate to severe exacerbations and to those who do not completely resolve their symptoms after a single b2-agonist treatment.3 Prednisone and prednisolone most commonly are used in children. The most popular outpatient regimen is a loading dose of 2 mg/kg in the ED followed by 1 mg/kg/dose twice a day for four more days. While the issue has not been resolved in the literature, the authors recommend a maximum dose of 60 mg per day, a dose that is used commonly in the adult population. The recommended dose for hospitalized patients is 1 mg/kg/dose every six hours for two days then 1-2 mg/kg/day until PEF is 70% of predicted.3 Intravenous (IV) methylprednisolone is an alternative in severely affected patients who require hospitalization.39 Several studies have demonstrated that IV and oral steroids have equivalent efficacy, so oral should be used whenever possible.40,41 There is also no difference in efficacy between liquid formulation and crushed tablets.42 The benefit of corticosteroids was demonstrated clearly in a trial by Scarfone et al, who showed a 32% decrease in hospitalization rate in children treated in the ED with steroids for a moderate or severe asthma exacerbation.43 Steroids should be administered as early as possible during ED treatment.37
Some studies recently have examined alternate routes of administration of steroids for acute exacerbations. One prospective trial in children ages 6 months to 7 years with mild to moderate exacerbations found intramuscular decadron to be equivalent to five days of oral prednisolone in terms of improvement in symptoms.44 This may be an alternative for outpatient therapy in children who are unable to tolerate oral steroids. Another study compared a two-day dose of oral decadron to a five-day course of prednisone. The two regimens had similar relapse rates, hospitalization rates, and symptom persistence at 10 days.45 Decadron therapy is not used widely in clinical practice, but may warrant further study. The role of inhaled steroids in the emergent treatment of asthma also has been evaluated. In 100 children with acute asthma, there was a greater improvement in FEV1 and decreased hospitalization rate in those receiving standard oral therapy, providing no justification for the administration of inhaled steroids in the ED setting.46 The great benefit of inhaled steroids comes as a preventive intervention, which clearly has been shown to decrease the risk of hospitalization and ED visits among children with asthma.47
Systemic b2-Agonists. Patients with severe exacerbations or those who fail to respond to standard therapy with inhaled b-agonists, anticholinergics, and systemic steroids require more intensive therapy with systemic b-agonist agents. Two options are subcutaneous or IV epinephrine or terbutaline. Subcutaneous epinephrine or terbutaline is most helpful when airway obstruction initially is so severe that inhaled medication cannot effectively reach the distal airways and may provide enough bronchodilation for inhaled therapy to become effective. Terbutaline is preferable to epinephrine since it is b2-selective. The dose of epinephrine is 0.01 mL/kg of the 1:1000 concentration up to a 0.5 mL maximum.48 The dose of terbutaline is 0.005-0.01 mg/kg/dose, to a maximum of 0.4 mg.48
For severely ill patients, terbutaline also can be administered as a continuous infusion. It is indicated in patients with severe exacerbations who are not responding to conventional therapy, including continuously inhaled b2-agonists, inhaled anticholinergics and systemic corticosteroids.3,11 It is strongly suggested for all children ill enough to require intubation. Terbutaline has fewer systemic side effects than epinephrine; both have the potential to cause tachycardia, flushing, tremors, hypokalemia, hyperglycemia, dysrhythmia, and hypotension.11,22 Children receiving a terbutaline infusion require continuous monitoring in an intensive care unit. Concern raised about myocardial toxicity secondary to terbutaline appears to be restricted to a minority of patients who are intubated with infusions for longer than 72 hours.49 The dose of IV terbutaline is 2-10 mcg/kg as an initial bolus over 20 minutes, followed by a continuous infusion starting at 0.08 mcg/kg/min that can be titrated up to 6 mcg/kg/min.48
Magnesium. The use of magnesium for moderate to severe asthma exacerbations remains controversial. Magnesium relaxes smooth muscle, possibly by antagonizing calcium-induced muscle contraction.2 It also may diminish histamine-induced bronchospasm.50 The side effects are minimal, but can include warmth, flushing, or nausea and vomiting during the infusion.2,51 Two randomized, controlled trials in children demonstrated the benefit of magnesium in those with moderate to severe exacerbations. In the first, a bolus of 25 mg/kg of magnesium was compared to placebo in children who already had received three nebulized treatments and steroids. They showed significant improvements in pulmonary function testing 30 minutes after the infusion and decreased hospitalization rates.51 The second used a dose of 40 mg/kg given after three albuterol treatments and steroids to children with PEF less than 70% predicted. Both at the end of the infusion and 90 minutes post-infusion, the magnesium group had significantly better pulmonary function testing and were more likely to be discharged home.50 Another randomized study in children evaluated whether or not magnesium should be given early in the treatment course to children with moderate to severe exacerbations. All children enrolled were given 75mg/kg of IV magnesium or placebo after the first albuterol treatment. There was no significant difference between the groups with regard to pulmonary index score and hospitalization rate.52 While there are no specific recommendations in the NAEPP guidelines regarding magnesium, its use should be considered strongly in patients with moderate or severe exacerbations of asthma not responding to inhaled b2-agonists, anticholinergics, and steroids.
Leukotriene Modifiers. Leukotriene modifiers are a newer class of medications that play an important role in outpatient therapy of asthma, but have not yet been shown to have a definitive role in the management of acute exacerbations. Leukotrienes are potent inflammatory mediators. They are 100 to 1000 times as potent as histamine and have longer-lasting effects.53 Leukotriene modifiers block production of the substances that cause bronchoconstriction, edema, and increased mucus production, resulting in bronchodilation and some anti-inflammatory activity. Their bronchodilating effects are additive to those of b2-agonists.50 Four randomized, controlled trials have been done in children to assess utility in outpatient therapy. All showed benefit, including fewer days of symptoms, fewer exacerbations, less steroid use, and better quality of life.53-57 Montelukast is the only leukotriene inhibitor approved for children older than 2 years of age. Both IV and oral forms have been studied in children. The IV form had a quicker onset and produced a greater improvement in FEV1 than oral. Both oral and IV routes improved FEV1 more than placebo without a greater incidence of side effects.58 While these results are promising, further research is needed to investigate the role of leukotriene modifiers in the acute treatment of asthma.
Heliox. Heliox is a mixture of helium and oxygen that may be helpful for selected patients with severe exacerbations. It is a low-density gas mixture which helps to decrease turbulent airflow, thereby decreasing airway resistance, obstruction, and ultimately work of breathing.11 To be effective, the mixture must be at least 60% helium; therefore, it has limited utility in hypoxic patients.59 In a small, randomized study in children younger than 18 years who were on continuous albuterol and IV steroids, heliox (80% helium) was compared to room air. The heliox group had greater improvement in dyspnea, peak flow, and pulsus paradoxus. The investigators felt that heliox spared three patients from intubation.59 Although not routine, heliox can be considered for a limited group of severe asthmatics who do not have a significant oxygen requirement.
Aminophylline. Aminophylline is a methlyxanthine compound that exerts its effects by relaxing bronchial smooth muscle, as well as improving mucociliary clearance and decreasing inflammation.60 It is a controversial adjuvant therapy for severe or refractory asthma patients. Several clinical trials in the last 10 years showed no benefit to the addition of aminophylline to standard hospital therapy, so its use has fallen out of favor.61 More recent studies in hospitalized patients show some benefit to its use. One randomized, controlled trial of pediatric patients in an ICU setting demonstrated a quicker recovery as shown by clinical asthma scores when IV aminophylline was added to nebulized albuterol, IV steroids, and inhaled ipratroprium.60 A similar study in patients admitted to a general pediatric service, however, showed aminophylline did not decrease length of stay or improve clinical scores compared to placebo.62 Currently, aminophylline is not recommended routinely for use in emergency treatment of asthma, given the availability of b2-selective IV agents with fewer adverse effects.
Intubation.Due to the pathophysiology of asthma, intubation of asthmatic children presents many potential complications and should be avoided whenever possible. Passage and placement of an endotracheal tube stimulates airway reflexes, potentiates hyperresponsiveness, and can result in worsening airway obstruction.2 Positive pressure ventilation in an asthmatic increases the risk for hypotension, cardiac arrest, and barotrauma.11 To ameliorate the potential complications of mechanical ventilation, it is vital to maintain intravascular volume in a patient who requires positive pressure ventilation.3
The decision to intubate should be based primarily on clinical grounds, and maximal medical therapy should be applied first, including continuous albuterol with anticholinergics, IV corticosteroids, IV or subcutaneous b2-agonists, and IV magnesium. Intubation is indicated for any of the following clinical signs: depressed mental status, severe hypoxia, worsening hypercapnea, poor respiratory effort, and, of course, respiratory or cardiac arrest.2,11 Rapid sequence intubation is the preferred method for obtaining control of the airway. Appropriate medication choices in this setting are atropine, ketamine, and a paralytic. Atropine serves as an antisialogogue and blunts the bradycardia induced by direct laryngoscopy in children. Ketamine at 2 mg/kg/dose is an ideal sedative for asthma, since it causes bronchodilation.11 Ketamine also may cause laryngospasm, so the practitioner must be aware of this potential adverse effect.
Proper ventilation technique after intubation can be very difficult. With severe airway obstruction, the patient must have sufficient time to exhale, or air trapping and the risk of barotrauma will increase. The respiratory rate should be slightly less than would otherwise be used for a child the same age, to allow enough time for exhalation. The goal for the I:E ratio is 1-1.5:5. The peak inspiratory pressure should be less than 40, and the peak end expiratory pressure should be very low or zero to minimize barotrauma. Permissive hypercapnea often is accepted in the intubated asthmatic, especially in children, who have greater tolerance of this condition.11
Summary of General Management Principles
The NAEPP recommendations for the treatment of an acute asthma exacerbation in the ED can be found in the Insert. The initial assessment should be focused and brief to establish the severity of the exacerbation and to initiate treatment without delay. Vital historical information includes the onset, duration, and severity of symptoms, use of rescue medications, most recent b2-agonist use, prior hospitalizations, ED visits, steroid use, prior intubations, and the presence of other significant comorbid conditions.3 The initial physical exam should focus on the degree of respiratory distress, mental status, work of breathing, and vital signs of the patient.
Supplemental oxygen is the single most important initial therapy for patients who are hypoxic, and should be given to all patients with oxygen saturation of less than 90%.3 Inhaled b2-selective agonists should be given to all patients via nebulizer or MDI with spacer. For moderately and severely ill patients, treatments should be administered every 20 minutes up to three treatments; frequency can be adjusted depending on the response. Continuous b2-agonists can be considered for severely ill patients not responding adequately to intermittent inhaled therapy. Inhaled anticholinergics are recommended for moderate to severe exacerbations, and, as previously discussed, are most helpful in patients with severe airflow obstruction. Ipratroprium is given concurrently with one or two of the initial three b2-agonist treatments; increased doses do not appear to increase efficacy.38
Corticosteroids need to be administered as early as possible in the course of therapy, and should be given to all children with moderate and severe exacerbations, as well as to patients with more mild exacerbations who do not have a complete response to a single b2-agonist treatment. Additional therapies, such as IV b2-agonists and magnesium, can be considered in severely ill children who are not responding to maximal inhaled therapy and steroids, and certainly should be used for those with impending respiratory failure or who are intubated. A vital part of emergent asthma therapy is frequent reassessment of the patient through physical exam and PEF rate in children able to perform the test. The patient’s response is the most important factor in determining the future course of treatment and disposition.3,21
Disposition
Clinicians must integrate aspects of a child’s history, physical exam, response to therapy, and psychosocial situation to make appropriate plans for disposition. Children with a history of frequent and/or severe exacerbations, recent ED visits and/or hospitalizations for asthma, previous intubation, or delay in seeking care for symptoms may require hospitalization irrespective of exacerbation severity or response to treatment.22 The degree of improvement in the physical exam also is important. Flow sheets, which document serial exams, may facilitate care. Accessory muscle use, dyspnea, and degree of wheezing are the best parameters to follow in younger children.22 In children who are able, PEF monitoring should be used to gauge response to therapy and facilitate disposition. PEF of 70% or greater indicates a good response; 50%-70% an incomplete response that may warrant hospitalization; and less than 50% indicates a poor response necessitating admission.3 Patients who seem stable for discharge should be observed for at least 60 minutes after their last b2-agonist treatment to ensure safety for home therapy at less frequent intervals.2
Criteria proposed for hospitalization are listed in Table 2. History of previous ICU admission, initial SaO2 less than 92%, and continued need for albuterol treatments every hour after steroids are administered are factors that have been shown to be predictive of the need for admission.63 The probability of requiring frequent albuterol therapy for more than 12 hours in patients with all three predictors present was 92-99%.64 Infants and young children often warrant greater concern than older children and adults. They are more prone to respiratory failure due to decreased functional reserve, weaker diaphragms, weaker rib cages, and smaller airways, which can become obstructed from relatively less edema and bronchospasm.22
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NAEPP criteria for continued outpatient management of an asthma exacerbation include having a PEF greater than 70% predicted; minimal or no symptoms at least 30 minutes, and preferably 60 minutes, after ED therapy; access to medications; and available follow-up within a few days.3 Several studies have looked at the rate of relapse of asthma after an ED visit as well as risk factors for relapse. Rates of relapse varied from 4% to 30% among children.3,63,65 Risk factors for relapse include increased frequency of ED visits for asthma in the past year, older age, use of second-line asthma medications, and exposure to tobacco smoke.63,66 Psychosocial issues always should be considered when discharging a child with asthma. The family’s understanding of medications and their ability to obtain them, the availability of a telephone and transportation, and the ability of the caretaker to assess the child are all necessary for proper home treatment and monitoring.66 If concerns exist in any of these areas, hospitalization should be strongly considered.
A prospective cohort study of short-term outcomes of asthma in children illustrated that many have persistent symptoms two weeks after an ED visit.6 Despite the presence of symptoms, however, only 29% made or planned to make a follow-up visit with their doctor.6 Other studies also have illustrated low rates of follow-up for asthmatics.65 Every effort should be made to ensure appropriate follow-up care, preferably before the course of corticosteroids is completed.3
Usual medications prescribed at ED discharge are b2-agonists and oral corticosteroids. Inhaled b2 agonists routinely are given every four hours for several days, and then changed to dosing as needed.2 Families should be cautioned not to continue frequent, routine treatments indefinitely. Oral corticosteroids should continue for a total of five days, unless a longer course is needed for more severe disease. Concerns about the side effects of asthma medications are common, so every effort should be made to answer questions to prevent non-compliance.5 Non-compliance is not rare. One retrospective cohort study documented that fewer than one-half of children prescribed steroids after discharge from an ED visit for asthma filled their prescriptions, with higher rates among African American and older children.67 In another survey of pediatric patients, 85% reported they followed most of the physician’s recommendations regarding asthma, but 34-54% doubted the efficacy of the medications.68,69 In addition, only 60% made a follow-up visit with their primary care provider, and only one-third of parents made an effort to keep their children away from known triggers.68
These data indicate that education is vital to disposition planning. Although time often is limited in the ED, important issues listed in Table 3 should be addressed whenever possible. Children with greater baseline severity of disease may require additional medications for long-term control of asthma beyond b-agonist and oral corticosteroids. Urban children, in particular, are under-medicated with preventative therapy (i.e., inhaled corticosteroids, leukotriene modifiers, long-acting bronchodilators). One survey showed that even though 37% of children in urban settings with asthma had been to the ED in the last six months, only 11% were on preventive therapy.68 Although there are no current studies defining the role of these medications in the ED visit, it may be helpful for emergency physicians to suggest to families, patients, and physician providers that these medications may provide benefit.70
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References
1. Camargo CA, Richardson LD. Epidemiology of asthma. In: Brenner BE, ed. Emergency Asthma. New York: Marcel Dekker; 1999:59-80.
2. Baren JM, Zorc JJ. Contemporary approach to the emergency department management of pediatric asthma. Emerg Med Clin North Am February 2002;20: 115-138.
3. National Asthma Education and Prevention Program. Expert panel report 2: Guidelines for the diagnosis and management of asthma. DHHS pub # NIH 97-4051. 1997.
4. Werk LN, Steinback S, Adams WG, et al. Beliefs about diagnosing asthma in young children. Pediatrics 2000;105:585-590.
5. Mansour ME, Lanphear BP, Dewitt TG. Barriers to asthma care in urban children: Parent perspectives. Pediatrics 2000;106:512-519.
6. Stevens MW, Gorelick MH. Short-term outcomes after acute treatment of pediatric asthma. Pediatrics 2001:107: 1357-1362.
7. National Center for Health Statistics. New Asthma Estimates: Tracking Prevalence, Health Care, and Mortality. 2001. (http://www.cdc.gov/nchs).
8. American Lung Association. Trends in asthma morbidity and mortality. January 2001. (http://www.lungusa.org).
9. National Vital Statistics Report. Number of deaths from 113 selected causes by age. United States, 1999. 49;8: Sept. 21, 2001.
10. National Center for Health Statistics, Final Vital Statistics Report, 1979-1998. (http://www.lungusa.org).
11. Werner H. Status asthmaticus in children: A review. Chest 2001;119: 1913-1929.
12. Baren JM. Respiratory infections: The major cause. In: Brenner BE, ed. Emergency Asthma. New York: Marcel Dekker; 1999:113-125.
13. Henderson FW, Clyde WA Jr, Collier Am, et al. The etiologic and epidemiologic spectrum of bronchitis in pediatric practice. J Pediatr 1979:95:183-190.
14. Mertsola J, Ziegler T, Ruuskanen O. Recurrent wheezy bronchitis and viral respiratory infections. Arch Dis Child 1991;66:124-129.
15. Horn MEC, Reed SE, Taylor P. Role of viruses and bacteria in acute wheezy bronchitis in childhood: A study of sputum. Arch Dis Child 1979;54:587-592.
16. Pearce N, Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000;55(5): 424-431.
17. Lanphear BP, Aligne CA, Auinger P, et al. Residential exposures associated with asthma in U.S. children. Pediatrics 2001;107: 505-511.
18. Larsson ML, Frisk M, Hallstrom J, et al. Environmental tobacco smoke exposure during childhood is associated with increased prevalence of asthma in adults. Chest 2001;120:711-717.
19. Ball TM, Castro-Rodriguez JA, Griffith KA, et al. Siblings, daycare attendance, and the risk of asthma and wheezing during childhood. N Eng J Med 2000;343:538-543.
20. Brenner BE, Tyndall JA, Crain EF. The clinical presentation of acute asthma in adults and children. In: Brenner, BE, ed. Emergency Asthma. New York: Marcel Dekker; 1999:201-232.
21. Scarfone RJ, Fuchs S. Management of acute asthma in children. In: Brenner BE, ed. Emergency Asthma. New York: Marcel Dekker; 1999:429-441.
22. Baren JM. The acute asthmatic in the pediatric emergency department: To admit or discharge? In: Brenner BE, ed. Emergency Asthma. New York: Marcel Dekker; 1999:505-517.
23. Rebuck AS, Pengelly LD. Development of pulses paradoxus in the presence of airways obstruction. N Engl J Med 1973;288:66-69.
24. Geelhoed GC, Landau LI, LeSouef PN. Predictive value of oxygen saturation in emergency evaluation of asthmatic children. BMJ 1988:297:395-396.
25. Geelhoed GC, Landau LI, LeSouef PN. Oximetry and peak flow in assessment of acute childhood asthma. J Pediatr 1990:117: 907-909.
26. Eid N, Yandell B, Howell L, et al. Can peak expiratory flow predict airflow destruction in children with asthma? Pediatrics 2000:105: 354-358.
27. Polgar G, Promadhat V. Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia; W.B. Saunders Co:1971.
28. Nelson HS. Adrenergic therapy of bronchial asthma. J Allergy Clin Immund 1986:77:771.
29. Gutglass DJ, Hampers L, Roosevelt G, et al. Undiluted albuterol aerosols in the pediatric emergency department. Pediatrics 2000; 105:e67.
30. Mandelberg A, Tsehari S, Houri S, et al. Is nebulized aerosol treatment necessary in the pediatric emergency department? Comparison with a metal spacer device for metered-dose inhaler. Chest 2000; 117:1309-1313.
31. Schuh S, Johnson DW, Stephens D, et al. Comparison of albuterol delivered by a metered dose inhaler with spacer versus a nebulizer in children with mild acute asthma. J Pediatr 1999;135:22-27.
32. Leversha AM, Campanella SG, Aickin RP, et al. Cost and effectiveness of spacer versus nebulizer in young children with moderate and severe acute asthma. J Pediatr 2000;136:497-502.
33. Khinett H, Fuchs SM, Saville AL. Continuous vs. intermittent nebulized albuterol for emergency department management of asthma. Acad Emerg Med 1996;3:1019-1024.
34. Nelson HS. Third-generation beta agonists: Changing of the guard. Clinical experience with levalbuterol. J Allergy Clin Immunol 1999; 104:577-584.
35. Anderson WM. Hemodynamic and non-bronchial effects of ipratroprium bromide. Am J Med 1986;81:45-52.
36. Qureshi F, Pestain J, Davis P, et al. Effect of nebulized ipratropium on the hospitalization rates of children with asthma. N Eng J Med 1998; 339:1030-1035.
37. Schuh S, Johnson DW, Callahan S, et al. Effect of frequent nebulized ipratroprium bromide added to frequent high-dose albuterol therapy in severe childhood asthma. J Pediatr 1995;126:639-645.
38. Plotnick LH, Ducharme FM. Should inhaled anticholinergics be added to b2 agonists for treating acute childhood and adolescent asthma? A systematic review. BMJ 1998;317:971-977.
39. Tal A, Levy N, Bearman JE. Methylprednisolone therapy for acute asthma in infants and toddlers: A controlled clinical trial. Pediatrics 1990;86:350-356.
40. Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in acute exacerbation’s of asthma: A meta-analysis. Am J Emerg Med 1992;10:301-310.
41. Barnett PL, Caputo GL, Baskin M, et al. Intravenous versus oral corticosteroids in the management of acute asthma in children. Ann Emerg Med 1997;29:212-217.
42. Lucas-Bouwman ME, Roorda RJ, Jansman FGA, et al. Crushed predisone tablets or oral solution for acute asthma? Arch Dis Child 2001;84:347-348.
43. Scarfone RJ, Fucho S, Nagers AL, et al. Controlled trial of oral prednisone in the emergency department treatment of children with acute asthma. Pediatrics 1993;92:513-518.
44. Gries DM, Moffitt DR, Pulos E, et al. A single dose of intramuscularly administered dexamethasone acetate is as effective as oral prednisone to treat asthma exacerbations in young children. J Pediatr 2000;136:298-303.
45. Qureshi F, Zaritsky A, Poirier M. Comparative efficacy of oral dexamethasone versus oral prednisone in acute pediatric asthma. J Pediatr 2001;139:20-26.
46. Schuh S, Reisman J, Alshehri M, et al. A comparison of inhaled fluticasone and oral predisone for children with severe acute asthma. N Eng J Med 2000;343:689-694.
47. Adams RJ, Fuhlbrigge A, Finkelstein JA, et al. Impact of inhaled anti-inflammatory therapy on hospitalization and emergency department visits for children with asthma. Pediatrics 2001;107:706-711.
48. Jew R, ed. Pharmacy Handbook and Formulary. The Children’s Hospital of Philadelphia. Lexi-comp Inc., 2001-2002.
49. Chiang VW, Burns JP, Rifai N, et al. Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: A prospective assessment. J Pediatr 2000;137:73-77.
50. Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Ped Adol Med 2000;154:979-983.
51. Ciarallo L, Sauer AH, Shannon MW. Intravenous magnesium therapy for moderate to severe pediatric asthma: Results of a randomized, placebo-controlled trial. J Pediatr 1996;129:809-819.
52. Scarfone RJ, Loiselle JM, Joffe MD, et al. A randomized trial of magnesium in the emergency department treatment of children with asthma. Ann Emerg Med 2000;36:572-578.
53. Bisgaard H. Leukotriene modifiers in pediatric asthma management. Pediatrics 2001;107:381-390.
54. Bisgaard H, Nielsen KG. Bronchoprotection from leukotriene receptor antiogonist in asthmatic pre-school children. Am J Respir Crit Care Med 2000;162:187-190.
55. Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6 to 14 year old children: A randomized double-blind trial. JAMA 1998; 279:1181-1186.
56. Knorr B, Frarchi LM, Maspero JF, et al. Montelukast (MK-0476) improves asthma over a 3 month treatment period in 2- to 5-years-old. Am J Respir Crit Care Med 2000 Abstract.
57. Kemp JP, Dockhorn RJ, Shapiro GG, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14 -year-old children with asthma. J Pediatr 1998;133:424-428.
58. Dockhorn RJ, Baumgartner RA, Leff JA, et al. Comparison of the effects of intravenous and oral montelukast on airway function: A double blind, placebo controlled, three period, crossover study in asthmatic patients. Thorax 2000;55:260-265.
59. Kudukis TM, Manthous CA, Schmidt GA, et al. Inhaled helium-oxygen revisited: Effect of inhaled helium-oxygen during the treatment of status asthmaticus in children. J Peditr 1997;130:217-224.
60. Keogh KA, Macarthur C, Parkin PC, et al. Predictors of hospitalization in children with acute asthma. J Pediatr 2001;139:273-277.
61. Ream RS, Loftis LL,Albers GM, et al. Efficacy of IV theophylline in children with severe status asthmaticus. Chest 2001;119:1480-1488.
62. DiGuilio GA, Kercsmar CM, Krug SE, et al. Hospital treatment of asthma: Lack of benefit from theophylline given in addition to nebulized albuterol and intravenously administered corticosteroid. J Pediatr 1993;122:464-469.
63. Emerman CL, Cydulka RK, Crain EF, et al. Prospective multicenter study of relapse after treatment for acute asthma among children presenting to the emergency department. J Pediatr 2001;138(3):318-324.
64. Needleman JP, Kaifer MC, Nold JT, et al. Theophylline does not shorten hospital stay for children admitted for asthma. Arch Ped Adol Med 1995;149:206-209.
65. Batz AM, Eggleston P, Alexander C, et al. Outcomes of emergency room treatment of children with asthma. J Asthma 1991;18:255-264.
66. Crain EF. Follow-up and prevention of relapse in children after disposition from the ED. In Brenner BE, ed. Emergency Asthma. New York: Marcel Dekker, Inc.;1999:533-543.
67. Cooper WO, Hickson GB. Corticosteroid prescription filling for children covered by Medicaid following an emergency department visit or hospitalization for asthma. Arch Pediatr Adolesc Med 2001;1559:1111-1115.
68. Leickly FE, Wade SL, Crain E, et al. Self-reported adherence, management behavior, and barriers to care after an emergency department visit by inner city children with asthma. Pediatrics 1998;101:917-918.
69. Eggleston PA, Malveaux FJ, Butz AM, et al. Medications used by children with asthma living in the inner city. Pediatrics 1998;101:349-354.
70. Rowe BH, Bota GW, Fabris L, et al. Inhaled budesonide in addition to oral corticosteroids to prevent asthma relapse following discharge from the emergency department: A randomized controlled trial. JAMA 1999;281:2119-2126.