Asthma Update: Managing Asthma in the Pediatric Emergency Department
Asthma Update: Managing Asthma in the Pediatric Emergency Department
Authors: Blake Bulloch, MD, Fellow, Division of Emergency Medicine, Children's Hospital Medical Center, Cincinnati, OH; Richard M. Ruddy, MD, Professor of Clinical Pediatrics, Director, Division of Emergency Medicine, Children's Hospital Medical Center, Cincinnati, OH.
Peer Reviewer: Jeffrey Linzer, MD, Assistant Professor of Pediatrics, Emory University School of Medicine; Associate Medical Director, Pediatric Emergency Care Center, Hughs Spalding Children's Hospital, Atlanta, GA.
The American Thoracic Society defines asthma as "a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of treatment".1 While this definition was first used in 1962, it remains appropriate today.
In order to establish the diagnosis of asthma, the clinician should determine that 1) the patient has intermittent or recurring symptoms of airflow obstruction, 2) that the obstruction to airflow is reversible, and 3) that the airflow obstruction is not due to other diagnoses.2 Remember that "all that wheezes is not asthma" and that you must consider other disease entities in acutely wheezing children.3,4
To better guide the clinician's assessment of asthma severity and to optimize the management of patients with asthma, guidelines by an expert panel at the National Institutes of Health and the National Heart, Lung, and Blood Institute were published initially in 1991 and updated in 1997.2 In the 1997 report, the classification of asthma severity has been changed from mild, moderate, and severe to the new classification of mild intermittent, mild persistent, moderate persistent, and severe persistent. This more accurately reflects the clinical and chronic manifestations of asthma. The panel does emphasize that no matter what classification of asthma a patient has, they can have mild, moderate, or severe exacerbations. (See Table 1.) An asthma exacerbation is a worsening of symptoms, which can be either abrupt in onset or gradual, but which is always associated with a decrease in expiratory airflow. This review will approach the diagnosis, clinical evaluation and management of children presenting to the emergency department (ED) with an acute asthma exacerbation.
-The Editor
Epidemiology
Asthma is the most common chronic disease of childhood with a prevalence of 5-10%.3,5 Analysis of national data from the CDC during the years 1980 through 1993 indicated that asthma-related mortality and hospitalization rates increased among people younger than 25 years of age.6 Asthma accounted for approximately 4000 deaths in people younger than 24 years of age during this 14-year interval. During that interval, annual hospitalizations for asthma in this group increased 28% with a large proportion of this increase in children younger than 4 years of age.7
Despite recent advances in treatment, asthma continues to be a substantial economic burden and the leading cause of missed school days. Weiss and associates estimated the direct and indirect costs of asthma in all age groups to be $6.2 billion in 1990.8 They found children 17 years of age and younger made up approximately 50% of all visits to the ED for asthma-related complaints at a cost of $90.4 million annually. Average inpatient stays for children were five days in length and accounted for greater than $250 million in costs. Asthma resulted in the estimated loss of more than 10 million school days in 1990 in children between 5 and 17 years old with accompanying loss of workdays for the primary care giver. Overall, the costs attributed to asthma in this age group amounted to more than $1 billion per year without including medication costs.
Etiology
Episodes of wheezing associated with respiratory infections are common in the first year of life. Many of these infants will have bronchiolitis, an infectious etiology of wheezing, but some have asthma. Martinez and colleagues prospectively studied factors affecting wheezing before the age of 3 years and their relation to wheezing at 6 years of age.12 They gathered data on four groups of patients: a) patients who never wheezed (51.5%); b) transient wheezers-those with at least one episode of wheezing in the first three years of life associated with a lower respiratory tract infection but no wheezing at 6 years of life (20%); c) late wheezers-children who had wheezing with a lower respiratory tract infection at 6 years of age but none in the first three years of life (15%); and, d) persistent wheezers-children who had wheezing in the first three years of life and at 6 years of age (13%). Factors found to be independently associated with persistent wheezing were: maternal asthma, maternal smoking, rhinitis apart from colds, eczema during the first year of life, male sex, and Hispanic background. Among the children with non-recurrent (transient) wheezing, maternal smoking was the only independent factor.
Other studies have revealed that infants with documented viral infections of the lower respiratory tract are at greater risk for wheezing later in life.13 This includes not only those infants who had severe episodes of bronchiolitis but also those with mild forms of viral lower respiratory tract infections that were managed in the office setting. As well, patients born with impaired lung function at birth may be more susceptible to these infections and, therefore, to wheezing. In contrast, lower respiratory tract infections from bacterial causes do not seem to predispose children to asthma.
Conditions that predispose or that may worsen lower airway disease include rhinitis and sinusitis. With this in mind, patients and parents should be questioned about nasal obstruction, nasal discharge, frequent colds, day and night coughing with post-nasal drip, and sore throat. Treatment of sinusitis will often result in improvement in airway obstruction. Management includes the use of antihistamines, decongestants, and antibiotics for common pathogens.14 Gastroesophageal reflux may also cause symptoms of dyspnea and wheezing often within a couple of hours of feeding and shortly after being laid supine. These infants often have histories of recurrent vomiting or regurgitation and must be considered as a cause of wheezing in infants.
Pathophysiology
Regardless of the severity, asthma is a chronic inflammatory disorder of the tracheobronchial tree. (See Figure 1.) In general, a variety of physiologic triggers including inhalant allergens, tobacco smoke, pollutants, viral infections, exercise, and emotions enhance the release of the preformed mediators of inflammation from the mucosal mast cells.15 These mediators include histamine, chemotactic factors, leukotrienes, prostaglandins, and platelet activating factor. These mediators lead to contraction of bronchial smooth muscle and increased vascular permeability leading to edema of the airways and increased mucus production.16-18 This is the early asthma response, which consists of bronchoconstriction, lasts 1-2 hours, and can be reversed with high-dose beta-agonists.19
Up to 80% of patients will go on to develop a late asthma reaction within four hours of exposure to the trigger and lasting up to a week.4 This late-phase is due to the effect of inflammatory cells attracted to the airways (polymorphonuclear leukocytes, eosinophils, and monocytes) that release proteolytic enzymes leading to mucosal injury and further inflammation.16-18 It has been shown that cromolyn sodium and corticosteroids may contribute to the alleviation of symptoms in the late phase.
The physiologic consequences of the above include bronchoconstriction and increased mucus production leading to obstruction of both the large and small airways. Due to the airway obstruction, patients experience increased air-trapping that increases dead space ventilation, placing the patient on the compliance/resistance curve at a point where the work of breathing can dramatically increase. This results in ventilation/perfusion mismatching with hypoxia. Lack of effective treatment may lead to patient fatigue, and minute ventilation may decrease leading to CO2 retention and respiratory failure.
Clinical Evaluation
The clinical evaluation of a patient who presents with an asthma exacerbation should begin with a rapid cardiopulmonary assessment and immediate institution of rescue therapy when required. Focus the assessment on the degree of respiratory distress, which determines the amount of airway obstruction and ventilatory compromise. Ventilation/perfusion changes, spirometry, and patient symptoms have been shown to poorly correlate with each other in a variety of situations. However, in each individual patient, assessing the degree of obstruction is best done by measuring the severity of symptoms and signs displayed on physical exam combined with an objective measure of airway obstruction such as peak expiratory flow rates.
History. The most common presenting symptoms in asthmatics include shortness of breath (SOB), wheezing, cough, and chest tightness. Patients frequently feel SOB although it is not entirely clear why. The chest is hyperinflated due to the air trapping. Because of increased elastic recoil at this distended lung volume, the work of exhalation is lessened but the work of inspiration is greatly increased.20 Tonic activity of the inspiratory muscles throughout inspiration and expiration has been shown in patients with asthma exacerbations, and this is a major contributor to the sensation of dyspnea. Dyspnea can be clinically assessed by determining the effect on the child's normal speech (i.e., the ability to speak in normal sentences without breaths).
Table 1. Classification of the Severity of Acute Asthma Exacerbation (Modified from NIH Guidelines, Figure 3-92)
| Signs/Symptoms | Mild | Moderate | Severe |
| Dyspnea (speed/feeding) | None; talks in sentences | Short of breath with talking; difficulty breathing | Can only speak in 1-2 word sentences; may refuse feeds |
| Alertness | May be agitated | Usually agitated | Agitated to decreased level of consciousness |
| Respiratory rate* | Increased | Increased | Increased |
| Respiratory distress | None | Moderate | Severe |
| Wheeze | Often only end-expiratory | Loud and throughout expiration | Often both inspiratory and expiratory |
| Heart rate_ | < 100 | 100-200 | > 120 |
| Pulsus paradoxus | Absent | 10-20 mmHg | Often 20-40 mmHg |
| PEFR | > 80% predicted | < 80% predicted | < 50% predicted |
| Oxygen saturation on R/A | > 95% | 91-95% | < 91% |
| PaCO2 | < 42 mmHg | < 42 mmHg | > 42 mmHg |
| * Guide to rates of breathing in awake children | _ Guide to normal pulse rates in children | ||
| Age | Normal rate | Age | Normal rate |
| < 2 months | < 60/min | 2-12 months | < 160/min |
| 2-12 months | < 50/min | 1-2 years | < 120/min |
| 1-5 years | < 40/min | 2-8 years | < 110/min |
| 6-8 years | < 30/min | ||
Chest tightness is a manifestation of stimulation of vagal nerve irritant receptors. Subtle airway obstruction may have cough as the only clinical manifestation of an acute exacerbation. In mild cough-variant episodes as described, there may be no wheezing or prolonged expiration on clinical exam. Asthma with acute cough should be enough of a symptom complex to provide the patient with a trial of bronchodilators.
Other important historical data to obtain include the onset and duration of the current exacerbation and possible triggers of the episode. Triggers can be allergic, infectious, or irritant in nature. Viral URI is more common in infants and young children, while environmental allergens/irritants are more common in older children and adolescents. Duration of symptoms for greater than 24 hours is likely to suggest a greater component of inflammation. Obtain an inventory of current medications and the dose and frequency of each drug, including the use of systemic corticosteroids over the past several months. Identify patients who have had previous hospital admissions including the need for intensive care to identify the most high-risk patients. Factors that have been identified that increase a patient's risk of a fatal asthma exacerbation include: previous life-threatening exacerbations, hospital admission for asthma in the last 12 months, suboptimal medical management, poor access to medical care, psychological or psychosocial problems, overuse of beta-agonists, black race, and age (with teenagers at increased risk).9-11 Finally, seek a history of allergies to help identify triggers. Some authors report that up to 90% of children may have allergy/atopy as part of their asthma.21
Physical exam. Initially, the physical exam should be brief and focused. Always begin by assessing the child's general appearance. Work of breathing as evidenced by the presence of chest wall retractions and abdominal excursion, skin color, and level of consciousness can be assessed within seconds and is a good indicator of the severity of respiratory compromise. Assess for an increase in the anterior-posterior diameter of the chest, the "barrel-chest," to estimate the severity of air trapping. Observe the patient's respiratory rate and look for nasal flaring as a sign of distress. Occasionally, patients may grunt if there is significant pneumonia or atelectasis. Evaluate the use of accessory muscles by looking for intercostal, subcostal, and suprasternal retractions. The accessory muscles work to lift the entire rib cage cephalad. This generates high-negative intrapleural pressures in patients whose airways are partially obstructed to assist in ventilation. Use of the accessory muscles of respiration in this fashion places a larger metabolic demand on the child. This leads to more CO2 production and fatigue that may contribute to respiratory acidosis.
Expiration is impaired in asthma due to intrathoracic small airway obstruction. Prolonged expiration is often subtle in mild asthma but can be pronounced in severe episodes. Most characteristic, but least prognostic, is the degree of wheezing on exam. Wheezing may be auscultated and is caused by rapid, turbulent airflow through the narrowed airways. Wheezing may be heard on both inspiration and expiration and tends to vary in intensity and pitch over time and often changes from place to place. After bronchodilator therapy, it may be louder due to improvement of the obstruction. Be aware of the patient in whom no wheezing is auscultated, as wheezing is not heard when airflow has diminished over severely obstructed airways.
Table 2. Wood-Downes' Clinical Asthma Score
| Parameter | |||
| Cyanosis (PaO2) | None (> 70 mmHg in room air) | Present in room air (< 70 mmHg in room air) | Present in 40% O2 (< 70 mmHg in 40% O2) |
| Inspiratory air entry | Normal | Decreased or asymetric | Decreased or absent |
| Accessory muscle use | None | Moderate | Severe |
| Expiratory wheezes | None | Moderate | Severe |
| Cerebral function | Normal | Agitated or depressed | Comatose |
On physical exam, it is useful to calculate a standard score such as a clinical asthma score.22 (See Table 2.) Clinical asthma scores, such as the Wood-Downes' score shown in table 2, were designed to predict patients at high risk for respiratory failure. Many authors have tried to validate updated scores, but only a few have shown reasonable trends. However, these scores are still useful in following the individual patient's response to treatment during an acute exacerbation. The Wood-Downes' clinical system can assist the clinician by showing that a score of greater than 5 is indicative of impending respiratory failure, while a score of greater than 7 indicates existing respiratory failure. Obtain oxygen saturation by pulse oximetry to detect hypoxia and to assist in demonstrating the effect of small airways disease on oxygen shunting.
Measurement of pulsus paradoxus is useful in recognizing severe episodes, although it may be difficult to obtain in children. A paradoxical pulse is measured by inflating an appropriate sized blood pressure cuff above the systolic blood pressure, slowly deflating it until you hear the first systolic sounds during expiration. Note this pressure and then continue to lower the pressure until you can hear the systolic sounds throughout the respiratory cycle. The difference is normally less than 4-5 mmHg and is the change in systolic blood pressure between inspiration and expiration. A pulsus paradoxus is present when this value is 10 mmHg or greater and is accurate in identifying patients with a greatly diminished FEV1.
Laboratory studies. Bedside pulmonary function tests provide a rapid, objective assessment of the patient and serve as a guide to the effectiveness of therapy. In moderate-to-severe obstruction, these tests may be delayed until after bronchodilators are administered and the patient shows some improvement. The forced expiratory volume in one second from maximal inspiration (FEV1) and the peak expiratory flow rate (PEFR) can be measured in the ED. These studies directly measure the degree of large airway obstruction. Patient cooperation is required for these tests to be reliable. Sequential measurements may be taken to monitor.
Peak expiratory flow (PEF) monitoring has been shown to play a useful role in the ED management of childhood asthma. It is effort dependent and takes practice, so it is not always useful in children under 5 years of age. Appropriate normal values for age, corrected for height, are available. A decrease in PEFR to less than 50% of the patient's personal best indicates a severe exacerbation.2 Following improvement in PEFR by the titration of rescue medications to response can decrease ED admits when performed well.23
Pulse oximetry is a useful adjunct in the monitoring of patients with exacerbations, especially in those children younger than 5 years of age who are unable to perform PEFR. It is a noninvasive, painless method of assessing a patients oxygenation and small airways disease. It is unreliable in cool, underperfused states, and it can be sensitive to movement and lighting. Some literature suggests that patients with initial oxygen saturation less than 91% who respond to treatment well enough to be discharged home from the ED have a higher incidence of relapse with return visits and often hospitalization. On the other hand, patients with an initial oxygen saturation of 95% or higher rarely relapse acutely.24 A disadvantage is that pulse oximetry does not reflect a decreased PaO2 until it has decreased to less than 80 mmHg. It is not reliably consistent when the O2 saturation is less than 75-80%.
Arterial blood gas (ABG) analysis has not been a good predictor of clinical outcome in patients with acute asthma exacerbations.25 Hypoxia is a major concern in children with asthma. Pulse oximetry is useful and more convenient for assessing oxygenation, but an ABG is the only way to get an accurate measurement. It is the patient with an acute severe exacerbation in whom we are concerned about respiratory failure (increasing PCO2 and respiratory acidosis) and who has a significant O2 requirement in which the ABG may be useful. As such, the ABG can be reserved for those patients who may require intubation and mechanical ventilation or who are clinically difficult to assess. Keep in mind that obtaining an ABG may be difficult, especially in a child younger than 2 years of age, and may further aggravate the patient's respiratory distress.
The use of chest radiographs in patients with wheezing remains controversial. Radiographic findings of hyperinflation, peribronchial thickening, increased central lung markings, and subsegmental atelectasis are frequent findings in asthma exacerbations and usually do not change patient management. Chest radiography has been previously recommended for patients presenting with their first episode of wheezing. However, Gershel and colleagues found 94.3% of radiographs in first-time "wheezers" to be normal.26 They found that patients with first-time wheezing and a respiratory rate above 60 or a pulse above 160, localized rales or localized decreased breath sounds before treatment, and localized rales and localized wheezing after bronchodilator treatment were more likely to have positive films. Those in support of radiographs argue correctly that all that wheezes is not asthma. However, history and physical examination most often lead the clinician in the right diagnostic direction. It seems wise to follow the patient's response to medical management and, if the clinical picture seems discordant with the history, consider obtaining the radiographs. If a patient fails to respond to medical management or has fever, a radiograph is wise to help exclude pneumonia, pneumomediastinum, or the rare pneumothorax. Sinusitis may be an important co-morbid factor for an asthma exacerbation and, occasionally, it is beneficial to obtain a CT or radiograph of the sinuses.
The need for blood analysis is limited in patients with asthma exacerbations. While a CXR will detect cases of pneumonia, a white blood cell count is a nonspecific indicator of toxicity or of accompanying bacteremia in patients with pneumonia. Keep in mind that the use of corticosteroids or sympathomimetics will result in demargination of white blood cells and possibly cause leukocytosis. As such, the CBC is not a good indicator of infection in asthmatic patients. Beta-agonists have been shown to decrease serum levels of potassium, magnesium, and phosphate, although this is not usually of clinical significance in otherwise healthy children. Beta-agonists stimulate beta2-adrenergic receptors that are linked to membrane-bound sodium-potassium ATPase. In activating this enzyme, there is a direct influx of potassium into cells leading to a decreased serum potassium concentration. Catecholamines have also been shown to cause intracellular shifts of phosphate ions.27 If a patient is on theophylline at home, it is prudent to check a serum level.
Patients in status asthmaticus may have increased levels of plasma anti-diuretic hormone (ADH). This may occur secondary to hypovolemia, decreased left atrial pressures, or stimulation by adrenergic drugs. If given hypotonic fluids, patients have developed clinically significant hyponatremia. Therefore, hypotonic fluids should be avoided in patients with severe exacerbations, especially if they are not showing a significant response to therapy. ADH levels return to normal once there is relief of the airway obstruction.28
On occasion, moderately severe asthma may affect serum electrolytes such as potassium, magnesium, or phosphate. Severe asthmatic patients are hypoxic and may have a respiratory alkalosis from hyperventilating. This, combined with low serum potassium and/or magnesium, may precipitate cardiac dysrrthymias. Hypophosphatemia is reported to cause respiratory muscle fatigue and to cause a decrease in tissue oxygen extraction in patients with asthma exacerbations. Whether the decreases in serum concentrations of potassium, magnesium, or phosphate are clinically significant is unknown, and measurement of these electrolytes on a routine basis is not indicated.
Differential Diagnosis
Wheezing reflects an obstruction to airflow with turbulent flow producing the ausculatory findings. A variety of other conditions may present with wheezing in infants and children as shown in table 3.3,29 The wheezing associated with these conditions is rarely rapidly reversible and is often not paroxysmal. For example, the sudden onset of respiratory distress with cough and dyspnea, especially in the child with no prior history of obstructive airway disease, suggests foreign body aspiration. The exam may reveal stridor, unequal air entry, or unilateral chest wall expansion as a means of differentiating it from asthma. A history of possible aspiration should be carefully obtained.
Bronchiolitis is caused by a viral infection, most notably the respiratory syncytial virus (RSV), and presents in a manner clinically similar to asthma. It tends to affect children younger than 2 years and, often, infants who are younger than 6 months. There is often a 1-2 day prodrome of upper respiratory tract infection symptoms, low-grade fever, and similar symptoms in other family members. Recurrent episodes are unusual. The chest radiograph is similar to asthma in that they both may show hyperinflation with focal atelectasis. It is possible to identify the RSV antigen by immunoflorescence of nasopharyngeal aspirates.
Cystic fibrosis (CF) can mimic asthma, especially in the first year of life. Both result in an obstructive respiratory pattern, and chest radiographs may appear similar. Exacerbations are often triggered by infections. Viral infection may exacerbate CF, but bacterial infection ensues from Staphylococcus or Pseudomonas organisms. Some CF patients have a good response to bronchodilators. Other findings associated with CF include steatorrhea causing failure to thrive, recurrent pneumonia, digital clubbing, rectal prolapse, chronic cough, and nasal polyposis. The definitive diagnosis for CF is the sweat chloride test.
Table 3. Differential Diagnoses of Wheezing*
ALLERGIC
Asthma
Anaphylaxis
ACQUIRED
Foreign body aspiration
Bronchopulmonary dysplasia
Gastroesophageal reflux
Aspiration syndrome
CARDIAC
Congestive heart failure
Mitral stenosis, cor triatriatum
CONGENITAL
Laryngotrachomalacia
Tracheoesophageal fistula
Cystic fibrosis
Tracheal of bronchial stenosis
Bronchomalacia
Vascular rings
INFECTIONS
Bronchiolitis
Bacterial, Mycoplasma, or Viral pneumonia
TB endobronchitis
* Most common conditions encountered in infants and children but not all inclusive.
Bronchopulmonary dysplasia is still a common pulmonary problem. It results from prolonged endotracheal intubation, mechanical ventilation, and high-inspired oxygen concentrations in premature infants with respiratory distress syndrome. Some respond well to bronchodilator therapy and corticosteroids. Often, the pulmonary symptoms will resolve by 5 years of age.
Gastroesophageal reflux is caused by a laxity in lower esophageal sphincter tone. This may lead to symptoms of dyspnea and wheezing often within a couple of hours of feeding and shortly after being laid supine. These infants often have a history of recurrent vomiting or regurgitation and may develop recurrent pneumonia. Aspiration as a cause of coughing and wheezing in infants must be considered. Tests that may be useful in determining if reflux is present include a 24-hour pH probe or barium swallow.
Other causes of wheezing to consider include fixed obstruction from vascular disease, congenital heart disease, and endobronchial masses such as from bronchogenic cysts or secondary-to-enlarged paratracheal nodes from tuberculosis.
Medications
Asthma medications are now divided into two groups. The first group is the quick-relief or "rescue" medications used to treat acute symptoms and exacerbations.2 Medications in this group consist of the short-acting beta2-agonists, anticholinergics, and systemic corticosteroids and will be the focus of this section. (See Table 4.) The second group is referred to as the long-term control medications and are used to achieve and maintain control of persistent asthma.
Quick-relief medications. Beta-agonists act by increasing levels of cAMP in bronchial smooth muscle and in mast cells by activating the enzyme adenylate cyclase. Increased cAMP leads to increased binding of intracellular calcium to the endoplasmic reticulum, which decreases myoplasmic calcium and causes bronchial smooth muscle relaxation.16 High-dose, short-acting beta2-agonists, specifically albuterol, remain the treatment of choice for relief of acute symptoms.19 Bitolterol and pirbuterol are also inhaled short-acting beta2-agonists, but they have not been sufficiently studied. Possible adverse effects from beta-agonist therapy can include a decrease in PaO2 due to a transient worsening of the ventilation/perfusion ratio, cardiac stimulation (i.e., tachycardia and ectopy), skeletal muscle tremor, and central nervous system stimulation.
Ipratropium bromide (Atrovent) is a quaternary ammonium derivative of atropine that limits its systemic absorption and decreases the side effects that were seen with the use of atropine. As such, it is the only anticholinergic currently used in the treatment of acute asthma exacerbations. It is delivered by aerosolization and inhibits smooth muscle contraction and mast cell mediator release. It has a slower onset of action than beta2-agonists with a peak effect occurring over two hours but lasting up to six hours.30,31 When compared directly to albuterol, it is not as potent a bronchodilator. Osmond and Klassen reported a meta-analysis of randomized controlled trials using ipratropium bromide with beta2-agonists and found a statistically significant improvement in percentage predicted FEV1 over beta2-agonists alone.30 The studies did not find a clinically significant difference, but patients were compared after only one dose of ipratropium bromide and with the use of low-dose beta-agonists. Schuh and colleagues later performed a triple armed, randomized, double-blind placebo controlled trial comparing ipratropium bromide 0.25 mg every 20 minutes for three doses, with a second group receiving one dose of ipratropium bromide during the first hour, and a third group received placebo.31 All patients received high-dose albuterol (0.15 mg/kg) every 20 minutes for the first hour. Patients showed a statistically significant improvement in FEV1 with the use of frequently administered ipratropium bromide, and the difference was more marked the more severe the exacerbation.
Table 4. Medications for the Treatment of Asthma Exacerbations in the ED
Medication Dosage Comments
Oxygen FiO2 to maintain saturation > 90%
SympathomimeticsAlbuterol ebulizer solution 0.15 mg/kg q 15-20 min for Deliver at 6/L min with O2 (5 mg/mL) 3 doses (min. dose 2.5 mg, to ensure small particle max dose 5 mg/nebulization), size and optimal delivery then 0.15-0.3 mg/kg up to 10 mg q 1-4 h prn, or 0.5 mg/kg/h by continuous nebulization MDI (90 mcg/puff) 4-8 puffs q 20 min up to 4 h, Always use with spacing then q 1-4 h prn deviceTerbutaline (1 mg/mL) 0.01 mL/kg subcutaneously Both terbutaline and q 15-20 min to a maximum epinephrine may be used of 0.25 mL q 15-20 min for 3 doses subcutaneously. However,Epinephrine 0.01 mL/kg subcutaneously there is no proven (1:1000 solution) q 15-20 min to a maximum advantage over inhaled dose of 0.3 mL beta-agonists
Anticholinergics 0.25 mg q 20 min for 3 doses May be mixed in same Ipratropium Bromide then q 2-4 h prn ebulizer as albuterol (0.25 mg/mL)
Corticosteroids 2 mg/kg initially then 1 mg/kg o clear advantage in Prednisone q 6 h for 48 h, then 1-2 mg/kg/d administering IV over po if Prednisolone in 2 divided doses with a the patient is able to keep Methylprednisolone maximum dose of 60 mg for the medication down, is 3-10 d ot in severe distress, or has an ileus
It is currently recommended that ipratropium bromide be used as a quick relief medication along with beta2-agonists. It may be repeated with the first three beta2-agonist treatments during an acute exacerbation, as it appears there may be a dose response curve. It is available as both a nebulizer solution (0.25 mg/mL) and as an MDI (18 mcg/puff). Only the nebulizer solution is recommended for use in acute asthma exacerbations since the MDI has not been studied under these conditions.
Corticosteroids appear to work by the inhibition of phospholipase A2 activity, which blocks the release of inflammatory mediators, thereby suppressing the migration of polymorphonuclear leukocytes. They also increase the number and affinity of beta-adrenergic receptors, and reverse the increased capillary permeability seen in exacerbations. A number of studies have verified that systemic corticosteroids improve exacerbations and reduce length of symptoms. They should be routinely prescribed to all asthmatics experiencing an exacerbation.
A meta-analysis by Rowe and colleagues that examined the role of corticosteroids in acute asthma exacerbations came to the following conclusions:32 Corticosteroid treatment results in a decreased relapse rate in the first week to 10 days. Administration of steroids within 30 minutes in the acute care setting leads to a reduced admission rate.32,33 Based on their calculations, the number of children you would need to treat early in an ED visit in order to prevent one hospital admission would be 6-11 children based on a baseline admission rate of 20%.32 There is no evidence to suggest that route of administration of the corticosteroid (oral vs intravenous) improves the patient's outcome. Despite this conclusion, clinicians treating severe asthma exacerbations would likely still choose the IV route in specific patients with vomiting, ileus, or evidence of other factors that may delay steroid delivery.
Prednisone, or its active form prednisolone, is the oral corticosteroid of choice while methyprednisolone is the IV steroid of choice. Side effects from the short-term use of corticosteroids are more limited than with chronic use. These include mood changes, hypertension, fluid retention, and an increase in appetite, all of which will resolve with discontinuation of the corticosteroids. Unusual complications of steroid therapy include peptic ulcer disease or aseptic necrosis of the hip.34 Most children have minimal effect from 3-4 courses of five-day corticosteroid therapy over a year. Children requiring more than four courses of corticosteroids in a year are at greater risk for adrenal suppression and adverse effects on bone calcium. Care needs to be taken to not extend courses to greater than 10 days, nor to fail to initiate corticosteroid therapy because of concern over side effects. Repeated use would be good reason for an allergy or pulmonology referral.
Management
The approach to the child who presents to the ED with an acute asthma exacerbation as outlined by the expert panel report shown in table 5.2 As mentioned previously, the initial evaluation begins with a rapid cardiopulmonary assessment with institution of therapy as indicated. A thorough history and physical examination with emphasis on color, ausculatory findings, use of accessory muscles, respiratory rate, and heart rate is performed. Oxygen saturation should be measured, and PEF and FEV1 should be considered except in children with severe obstruction or in children younger than 5 years of age.
If the patient is in mild-to-moderate distress or has a PEF or FEV1 50% or greater predicted, then inhaled beta2-agonist by MDI with spacer device or nebulizer is given. Patients should receive up to three treatments in the first hour. Oxygen should be administered as necessary to maintain a saturation of 90% or greater. If the patient does not clear completely with the first dose of beta-agonist, then oral corticosteroid should be given. If there are continued moderate symptoms, then inhaled short acting beta2-agonists should be continued hourly. A good response is indicated by an FEV1 or PEF 70% or higher that is maintained for at least one hour from the time of the last treatment, no respiratory distress, and a normal physical exam. If the patient demonstrates a good response they may be discharged home.
Patients who present with a severe exacerbation or an FEV1 or PEF lower than 50% predicted should be treated aggressively. Administer supplemental oxygen to maintain their saturation above 90-95% and initiate high-dose beta2-agonist therapy and anticholinergic continuously for one hour. Corticosteroids should be given parenterally in moderate-to-severe exacerbations and orally in children with mild-to-moderate exacerbation or showing improvement and not vomiting. These patients need to be monitored closely, and, at the end of the first hour of treatment, their response will dictate the extent of continued beta-agonist and anticholinergic frequency.
An incomplete response is indicated by an FEV1 or PEF 50% or higher but less than 70% after therapy. These patients may benefit from hospitalization or from a short stay admission depending on the facilities available. Hospital admission is also indicated if there is persistent respiratory distress (clinical asthma score greater than 2 or tachypnea) after initial aggressive therapy. Other guidelines include: oxygen saturation less than 93% in room air, previous emergency treatment in the last 24 hours, or an inability to tolerate medications by mouth (i.e., vomiting). Children in high-risk categories should also be considered for admission to the hospital and include those with congenital heart disease, BPD, CF, or neuromuscular disorders.2,3,15,35
A poor response is defined as a physical exam that reveals the patient to remain in severe respiratory distress with a high clinical asthma score, a PCO2 42 mmHg or higher, or an FEV1 or PEF lower than 50%. These patients should be admitted to an intensive care setting for constant monitoring. Consider intensive care admission if there is 1) impending respiratory failure as evidenced by exhaustion or pulsus paradoxus higher than 25 mmHg, 2) worsening distress despite therapy, 3) requirement for continuous nebulization (beta-agonists less than 1 hour in frequency after the initial 3 treatments), 4) there is evidence of complications from an air leak.3
The Child in Respiratory Failure
Most asthma exacerbations do not involve respiratory failure, but almost all exacerbations do involve some degree of reduction in oxygen delivery. A PaO2 above 50 mmHg affects oxygen saturation much less than a PaO2 less than 50 mmHg and is part of the definition of type I respiratory failure (i.e., respiratory failure with hypoxia). As an exacerbation evolves, the patient may be unable to maintain minute ventilation due to fatigue, and, eventually, the patient's PaCO2 will begin to rise into the "normal range" and above, signifying type II respiratory failure (i.e., respiratory failure with hypoxia and CO2 retention).35,36 Treatment for these patients is limited and may involve the use of intravenous infusions of beta2-agonists and mechanical ventilation. Obviously, these patients need to be monitored closely in an intensive care setting.
At Toronto's Hospital for Sick Children, Bohn and colleagues have used IV infusions of salbutamol (albuterol) in children with imminent respiratory failure and have avoided the need for intubation and mechanical ventilation.37 It is given as a loading dose of 0.5 mcg/kg, followed by an infusion of 0.2 mcg/kg/min with increases of 0.1 mcg/kg/min every 15 minutes to a maximum of 4 mcg/kg/min monitoring for a decrease in PaCO2 or the development of cardiotoxicity. Since albuterol is not approved by the FDA for use intravenously in the United States, terbutaline can be used in a similar fashion. It is given as a 10 mcg/kg loading dose over 5-10 minutes and then as an infusion of 0.4 mcg/kg/min with increments of 0.2 mcg/kg/min up to a maximum dose of 6 mcg/kg/min.3
Intubation and mechanical ventilation is still required in a small number of patients in whom pharmacologic treatment has failed and they are unable to adequately eliminate CO2. Ketamine (1-2 mg/kg slow IV) is the sedative of choice for intubation in asthmatic patients as it relaxes bronchial smooth muscles, antagonizes the histamine response, and increases the plasma concentration of catecholamines.38 The concomitant use of benzodiazepines will reduce the risk of emergence phenomena, and the use of an anticholinergic (atropine) will reduce the risk of excessive bronchial secretions associated with the use of ketamine. Exercise caution if rapid sequence intubation with paralytics is performed. Importantly, succinylcholine and pancuronium can cause bronchoconstriction by releasing histamine (potentially worsening hypoxia), while patients with severe bronchoconstriction may be extremely difficult to bag after paralysis due to elevated airway pressures. Histamine release is rare with vecuronium, atracuronium, or rocuronium use.
When volume ventilation is utilized use a low respiratory rate and high inspiratory flow with a long expiratory time and minimal end-expiratory pressure to allow full expiration and enhance venous filling of the heart.36 You need to allow as full an expiration as possible since air trapping is the underlying problem in asthma. If full expiration is not allowed, the end expiratory pressure continues to increase with subsequent breaths, and this impairs cardiac filling and, subsequently, the patient's blood pressure will fall. By hypoventilating patients, their PCO2 may increase but they will have a longer expiratory time and be able to decrease their end expiratory pressure. "Even if the PaCO2 doubles from 40 to 80 mmHg, the serum pH will only fall from 7.4 to 7.1. Bicarbonate can be added if needed to raise the pH level to protect the heart from potential adverse effects."36 This is referred to as permissive hypercapnia and is effective in ventilating asthmatic patients.
Disposition and Follow-up
Before discharge, whether from the ED or in-patient service, patients must be educated on how to use their medications and why it is important that they closely follow the instructions. Short-acting beta2-agonists should be prescribed generally as an MDI with spacing device to be administered as 2-6 puffs every 3-4 hours as needed for symptoms of airway obstruction. Prednisone or prednisolone should be prescribed at a dose of 1 mg/kg/dose given once a day or divided twice daily for 3-10 days, up to a maximum dose of 80 mg/day. All patients older than 5 years of age should be given a peak flow meter and taught how to use it correctly. They should also be educated on the use of a diary, to obtain measurements in the morning and evening, and to record the best of three attempts each time. Signs and symptoms of recurrent airflow obstruction should be discussed with the child and family and what steps to take if they occur. It is advisable that they call their own physician within 24 hours to give a progress report and to make an appointment to be seen in follow-up within the next seven days or sooner if the patient is particularly high-risk.
Long-term Control Medications
While emergency physicians should be aware of, and understand these medications, the long-term control medications play little role in the management of acute asthma exacerbations.
The exact mechanism by which methylxanthines (theophylline and aminophylline) produce bronchodilation is unclear. Though effective bronchodilators, they have a narrow therapeutic window that limits their use. Early appearance of side effects often prevents the goal of optimal smooth muscle relaxation and bronchodilation. Toxic effects include headaches, tremor, nausea, vomiting, dysrrthymias, and seizures. Methylxanthines are no longer recommended for the treatment of acute asthma exacerbations. In several well-designed studies, methylxanthines and steroids have been shown to offer no therapeutic benefit to children with mild-to-severe symptoms but have been associated with more side effects when compared to the use of beta-agonists combined with systemic corticosteroids.39-41 In the 1997 NIH guidelines, sustained release theophylline is considered a mild-to-moderate bronchodilator and to possibly have some mild anti-inflammatory effects. Its use is primarily as an adjunct to inhaled corticosteroids in the prevention of nocturnal asthma symptoms. For acute exacerbations, unless there is evidence of theophylline toxicity, most authors would continue the long-acting drug.
The leukotriene modifiers are a new class of medications that may play a role in the prevention of symptoms in mild persistent asthma patients. Induction of asthma symptoms, such as bronchospasm, airway edema, mucus secretion, and inflammatory cell migration may be attributed to the leukotrienes. Zafirlukest (Accolate) is a leukotriene antagonist that attenuates the late response to allergens leading to an improvement in pulmonary function and a decrease in asthma symptoms. Zileuton (Zyflo) is a 5-lipoxygenase inhibitor and interferes with the production of leukotrienes. These medications have been shown to partially reverse spontaneous bronchoconstriction and to reduce asthma symptom scores in clinical trials.42 Their exact role has not yet been defined. They are only recommended for use in children older that 12 years of age.
Salmeterol (Serevent) is a long acting beta2-adrenoreceptor agonist that is 10 times more potent then albuterol in its bronchodilatory effects. It has a slow onset of action-compared to the short acting beta2-agonist requiring up to 20 minutes for effect-but has a duration for up to 12 hours. Currently, it is indicated for the long-term prevention of symptoms, especially nocturnal, in combination with an anti-inflammatory agent. It is not recommended as a rescue treatment option for acute asthma exacerbations.43,44
Cromolyn Sodium (Intal) and Nedocromil (Tilade) are mast cell membrane stabilizers that are able to suppress both the early and late onset asthma responses. They do not directly produce bronchodilation, but they do decrease bronchial hyper-reactivity and will inhibit the acute phase response from exercise and cold air. These agents require up to two weeks of use to develop therapeutic response and are extremely safe.45 They are usually initiated for chronic use before inhaled corticosteroids as the first anti-inflammatory medication in the treatment of mild persistent asthma.
Inhaled corticosteroids are useful and effective prophylactic medications that must be differentiated from systemic corticosteroids. Their clinical effectiveness has been demonstrated in numerous studies, and systemic side effects are extremely low.
Controversial Issues
The use of intravenously administered beta2-angonist has been controversial. In order for beta-agonist to be effective, it must reach the target organ, the small airways, and some investigators believe this initially occurs by systemic absorption of inhaled agents in severe exacerbations. Browne and associates recently performed a double-blind, randomized, placebo-controlled study to determine if a child with severe asthma would have a more rapid initial response to the beta2-agonists if therapeutic salbutamol concentrations could be achieved within 15 minutes of the start of therapy.46 They found that patients in the intravenous group achieved better pulmonary indices, less distress, a decreased requirement for oxygen, and faster rate of improvement to discharge than inhaled therapy alone.
Except for tremor, there were no other side-effect differences between the two groups and the tremor was not considered to be clinically significant. Despite small numbers, the results were significant in showing that a 10-minute infusion of IV salbutamol (15 mcg/kg) early in the course of treatment of an acute exacerbation may decrease clinical progression compared to inhaled therapy alone.
The use of oral beta-agonists in children with acute asthma often arises. Louridas and colleagues prospectively compared inhaled salbutamol (albuterol) to oral salbutamol in 10 patients.47 Pulmonary function tests were performed at 20, 40, 80, and 120 minutes post-medication administration. Within 20 minutes, the FEV1 in the inhalation group had increased by 7-8% vs. 2-3% in the oral group. This change was even more pronounced at 120 minutes with the FEV1 increasing by 20% in the inhalation group vs. 5-6% in the oral group. Similar responses were seen in the PEFR. It appears, therefore, that inhaled beta-agonist produces a rapid onset and prolonged upslope in bronchodilatory effects while the oral route has a slower onset and less bronchodilatory effects. The oral form also appears to have more pronounced side effects than the inhaled form. They may be of use in infants with mild asthma, in whom inhaled beta-agonist by MDI may be more difficult to deliver efficiently.
The use of nebulizer, compared to MDI, has long been the preferred method of delivery for beta2-agonists in the hospital setting. However, with the addition of spacing devices for use with MDIs, there is increasing evidence that they may be a more reliable method of medication delivery.48,49 Spacing devices extend the area between the inhaler and the mouth. This allows larger particles that would normally be trapped in the upper airway to be removed in the chamber, thereby reducing systemic absorption and increasing deposition of smaller particles in the airways. The aerosolized particles remain suspended in the spacing device for up to five seconds, which eliminates the need for coordination of MDI activation and inhalation and enhances drug delivery. It has been estimated that an MDI with spacing device delivers up to 20% of the drug to the airways vs. 10% using MDI or nebulizer alone. Current data suggest that between 10-12 inhalations by MDI with spacing device is equivalent to 5 mg of nebulized beta2-agonist.15
Amirav and Newhouse recently reviewed 10 articles comparing the use of MDI with spacing devices to nebulizers. Despite administering greater that 2-4 times the dose by nebulizer, the nebulizer never showed any superiority, and, in three of the 10 articles, the MDI with spacing devices was more efficacious.49 However, the MDI set-up has not been tested in controlled trials using patients with severe obstruction.
It has been proposed that magnesium sulfate stimulates bronchial smooth muscle relaxation by inhibiting calcium flux into smooth muscle cells through the slow calcium channels. The exact mechanism by which decreased magnesium affects bronchospasm is unknown, but there can be a significant decrease in serum magnesium after inhaled bronchodilators. It is unusual for this to be of such significance that it is necessary to measure serum magnesium levels. There have been conflicting studies on its efficacy in the treatment of asthma exacerbations in adults.50-54 Recently, Ciarallo and colleagues performed a randomized, double-blind, placebo-controlled trial evaluating the efficacy of intravenous magnesium sulfate (IV Mg) in children 6-18 years of age with moderate-to-severe asthma exacerbations.55 Patients were candidates if, after receiving three beta2-agonist treatments by nebulizer, they continued to have a PEFR less than 60% of their predicted value. Patients in the IV Mg group (25 mg/kg, maximum 2 g in 100-mL normal saline over 20 min) showed improvement by 50 minutes post-treatment. At 110 minutes post-treatment, FEV1 had improved by 75% in the Mg group vs. 5% in the placebo group. Similar results were seen in PEFR and resulted in fewer hospital admissions. The patients in either group reported no adverse effects, and there were no significant changes in blood pressure. Previously reported side effects were minimal, and these include flushing, mild fatigue, and a burning sensation at the intravenous site. These results revealed more improvement in lung function compared to previous adult studies and are encouraging.
A recent study investigated the use of Heliox (a mixture of 70% helium and 30% oxygen) in children with acute severe asthma exacerbations.56 The rationale behind its use involved the hypothesis that part of the reason for decreased airflow in asthmatics is turbulent flow. They hypothesized that if you could decrease the density of inspired gas, there should be an improvement in the air exchange. The investigators did not demonstrate a significant effect on pulmonary function.
Antimicrobials were used a great deal in the past in patients with acute asthma exacerbations. While it can be difficult to differentiate a bacterial lower respiratory tract infection from a severe asthma exacerbation, the routine use of antibiotics has not been shown to be beneficial.57 The diagnosis of pneumonia may be supported by the findings of fever and chills, a left shift in the peripheral white blood cell count, and if the child is old enough to provide a sputum sample, by the finding of a large number of neutrophils in the sputum accompanied by the heavy growth of only 1-2 organisms. Clinically significant infections, such as otitis media or sinusitis, should be treated with amoxicillin, trimethoprim-sulfamethoxazole (Bactrim or Septra), or amoxicillin-clavulanate (Augmentin). If the clinician suspects infection with Chlamydia pneumoniae (formerly the TWAR strain), then erythromycin is suggested.
Summary
Asthma is the most common chronic illness of childhood and a leading cause of morbidity. Advances continue to show that inflammation plays a major role in its pathogenesis and severity. The new guidelines by the NBHLI emphasize aggressive anti-inflammatory therapy to control acute exacerbations and chronic symptoms. First-line medications used to control patients with acute asthma exacerbations include beta2-agonists, anticholinergics, and systemic corticosteroids. Further study is needed into therapies such as intravenous magnesium sulfate and salbutamol, which may play an important role in the treatment of patients with moderate-to-severe exacerbations. Despite changes in our patients' access to medical care, asthma continues to be one of the most common ED visits for children.
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