Asthma Update: Pearls You May Have Missed

May 1, 2005

ABSTRACT: Asthma is a very serious yet very controllable illness. In acute exacerbations, bronchospasm can be reversed with nebulized albuterol (2.5 to 5 mg); give 2 additional treatments at 20-minute intervals and then every hour for the first few hours until wheezing resolves. Subcutaneous terbutaline and epinephrine are alternatives. Systemic corticosteroids may be needed to manage the acute attack (eg, 2 mg/kg of oral prednisone or pred-nisolone). In addition, an anticholinergic agent (eg, inhaled ipratropium) may be used. IV magnesium (25 to 50 mg/kg) and heliox have shown promising results in acute asthma. Maintenance therapy is indicated when daily symptoms occur more than twice per week or when nighttime symptoms occur more than twice per month; such therapy may also be warranted for an infant with exacerbations that occur less than 6 weeks apart or more than 3 times per year, or when other risk factors are present. Inhaled corticosteroids are the cornerstone of maintenance therapy and are mandatory for all patients with persistent asthma. Alternative treatments for children younger than 5 years include cromolyn and an oral leukotriene modifier (montelukast). Patient and parent education helps ensure proper drug administration, monitoring, and compliance.

A chronic inflammatory disease of the airways, asthma is one of the most common reasons why children are brought to a physician. There has been a significant worldwide increase in the prevalence of asthma--especially in developed countries.1 Asthma affects more than 26 million Americans: more than 9 million are younger than 18 years.2 Children make more than 2.7 million physician visits for asthma, and they miss more than 14 million school days per year.2 Fortunately, in 2000, deaths from asthma decreased for the first time in many years. Unfortunately, and despite our best efforts, more than 4000 people died of asthma- related complications in 2000. Among them were 233 children under 17 years of age.3

Pediatricians deal with asthma on a daily basis and must treat acute exacerbations; determine whether maintenance therapy is warranted; monitor the response to this therapy; and closely monitor the growth of the asthmatic child--especially the child taking corticosteroids.

In this article, we outline a treatment strategy for the acute asthma flare. We also discuss the most recent advances in pediatric drug therapy and provide up-to-date recommendations for the long-term management of asthma (Tables 1, 2, and 3).

PATHOPHYSIOLOGY

Asthma is the result of airway inflammation caused by infiltration of cells (mast cells, eosinophils, basophils, monocytes, lymphocytes) and mediators (IgE, cytokines, histamines, leukotrienes, prostanoids). Airway inflammation leads to edema, excess mucus production, and bronchial hyper-responsiveness and/or bronchospasm. This results in air trapping (hyperinflation), carbon dioxide retention, ventilation-perfusion mismatch, hypoxia, respiratory distress, and--in severe cases--respiratory failure. A genetic predisposition, an atopic diathesis, and certain environmental stimuli are the likely factors that predispose children to asthma. Asthma triggers include (but are not limited to) seasonal allergies, changes in weather, animals, tobacco smoke, upper respiratory tract infections, and exercise.

Some patients respond poorly to treatment with the available anti-inflammatory agents. This phenomenon is not fully understood but is probably the result of airway remodeling and associated non-reversible airflow obstruction.4 It is not clear whether airway remodeling is a consequence of chronic inflammation or whether these 2 processes occur in parallel.4 The hypothesis that early and aggressive treatment of asthma could decrease the risk of these long-term changes is currently under investigation.

EVALUATION

A detailed history is the key to accurate diagnosis; it is also crucial for characterizing the severity of asthma. The history should include a list and pattern of symptoms, precipitating and aggravating factors, and the number of emergency department visits and hospital and ICU admissions. It is important to note whether the child required intubation and ventilatory support (which is associated with increased mortality). Details about the family and social history, as well as about current treatment plans, also guide further interventions.

In the acutely ill child, monitor vital signs and check a pulse oximetry reading. Pay special attention to the respiration rate over a 1- to 2-minute period. Focus your physical examination on the signs and symptoms of respiratory distress, which include:

• Difficulty in speaking.

• Nasal flaring.

• Intercostal retractions.

• Use of accessory muscles of respiration.

• Poor air exchange.

• Wheezing.

Spirometry is helpful in evaluating the cooperative child but generally is not available in a pediatrician's office. Peak flow meters are a useful and readily available alternative. Using a chart based on the child's height, a predicted peak flow can be compared with the child's value before and after bronchodilator therapy. We have found that most children are able to perform this test appropriately by the time they are 6 years old. In infants, the diagnosis of asthma is based on the history, the physical examination findings, and response to bronchodilator therapy.

A chest radiograph is of limited value in the diagnosis of asthma but is very helpful in excluding other processes. Hyperinflation and peribronchial cuffing are typical findings in a child with asthma, although the same findings can be seen with viral respiratory infections, such as bronchiolitis (Figure). You might also consider obtaining additional studies, as suggested in an algorithm we have previously published for the evaluation of chronic cough.5 A pediatric allergist can help determine whether there are specific allergens that trigger the patient's asthma. Exclusion of these triggers can significantly decrease the patient's symptoms.

TREATMENT OF ACUTE EXACERBATIONS

The goal of acute therapy is reversal of bronchospasm and inflammation. Initially--along with addressing the ABC's of emergent care--supplemental oxygen should be provided for the wheezing child if oxygen saturation is less than 90% or if the patient is in significant respiratory distress. Administer nebulized albuterol (2.5 to 5 mg), and evaluate the patient after the first treatment. If the child is still in distress, give 2 additional treatments at 20-minute intervals, then every hour for the next few hours until wheezing resolves.6 The child must be closely monitored for evidence of fatigue, respiratory decompensation, or medication side effects.

Continuous albuterol therapy may be necessary for patients who do not respond to intermittent treatments. The dosage ranges from 0.15 to 0.45 mg/kg/h to a maximum of 15 mg/h.7 In addition to racemic albuterol sulfate, levalbuterol--the stereoisomer of albuterol and a relatively new short-acting b2-agonist--is also available to treat acute wheezing episodes (see Table 1). Note that there are conflicting data about the efficacy and side-effect profile of levalbuterol compared with racemic albuterol.8-10

Some of the common side effects of albuterol (from b-adrenergic stimulation) include tachycardia, palpitations, headache, nausea, nervousness, and dizziness. Hypokalemia, arrhythmias, and seizures are also potential complications of an albuterol overdose. Patients who do not respond to inhaled albuterol or levalbuterol are candidates for therapy with terbutaline or epinephrine.11 The dose for nebulized albuterol is age-dependent:

• The recommended dose for children younger than 2 years is 0.5 mg.

• For children between 2 and 9 years, the recommended dose is 1 mg.

• For children older than 9 years, the recommended dose is 1.5 to 2.5 mg given every 4 to 6 hours.

Terbutaline can also be given subcutaneously as follows:

• For children younger than 12 years, the recommended dose is 0.01 mg/kg (maximum, 0.4 mg) given every 15 minutes for 3 doses.

• For children older than 12 years, the recommended dose is 0.25 mg (maximum, 0.5 mg) given 3 times 15 minutes apart.

The recommended dose for subcutaneous epinephrine is 0.01 mg/kg (1:1000 dilution; maximum dose, 0.3 mL) given 3 times every 15 minutes. Both terbutaline and epinephrine can cause palpitations, tremors, nausea, vomiting, nervousness, arrhythmias, and hypertension.

Systemic corticosteroids (oral or intravenous) may be needed to manage the acute attack. For outpatient management, give 2 mg/kg (maximum dose, 80 mg) of oral prednisone or prednisolone and continue with 1 mg/kg bid for 3 to 5 days. Children who need to be hospitalized may require 0.5 to 1 mg/kg of IV methylprednisolone every 6 hours during hospitalization.

Dexamethasone, given intramuscularly in a single dose of 1.7 mg/kg, has been found to be as effective as oral prednisone given for 5 days.12 Consider this therapy for patients with a history of poor compliance. Remember that inhaled corticosteroids are not as effective as systemically administered corticosteroids in acute exacerbations of asthma.13

Airway cholinergic tone is known to increase in patients with asthma, especially during viral infections. Therefore, it is sensible to add an anticholinergic agent in the management of acute asthma. Inhaled ipratropium, an anticholinergic agent, used in combination with inhaled b2-agonists, has been shown to decrease hospitalization rates in children with severe asthma exacerbations.14 This agent is usually given in 250-µg doses, but a dose as high as 500 µg has been found to be safe and effective.14 Potential side effects of ipratropium include headache, dizziness, anxiety, cough, dry mouth, and blurred vision.

Despite aggressive outpatient care, hospitalization may be required for the patient who continues to experience significant respiratory distress. A good rule of thumb is to admit patients who require albuterol treatments more frequently than every 4 hours.

Because theophylline has potentially serious toxicity and it provides no additional benefit to currently available medications, it is not typically used to manage acute asthma. Recent studies have shown, however, that patients with severe asthma who do not respond to albuterol, ipratropium, or corticosteroids have benefited significantly from the addition of theophylline.15

Recently, intravenous magnesium sulfate has shown promising results in the management of acute asthma in children.16 Magnesium sulfate blocks calcium-mediated smooth muscle contraction, which causes bronchodilation. The recommended dose is 25 to 50 mg/kg (maximum, 2 g) given as a bolus over 20 minutes. Common associated side effects are flushing, hypotension, variation in heart rate (bradycardia and tachycardia), and muscle weakness.

Nebulized magnesium sulfate has bronchodilator effects similar to those of nebulized albuterol. However, data from trials using nebulized magnesium sulfate alone or in combination with albuterol in acute asthma in children are not available at this time.

Another treatment option for children with acute asthma is heliox, a blend of helium and oxygen. Helium, an inert gas, has no therapeutic benefits. However, 20% to 30% of helium mixed with 70% to 80% of oxygen is much less dense than air; therefore, oxygen can be delivered through the swollen, narrow airways to alveoli without significant turbulence. Currently, no data are available on the efficacy and safety of heliox in the management of acute asthma in children.

MAINTENANCE THERAPY

Maintenance therapy is indicated for persons with persistent asthma--those in whom daytime symptoms occur more than twice per week or in whom nighttime symptoms occur more than twice per month (Table 4).17 Also, consider instituting maintenance therapy for the young infant in whom exacerbations are occurring less than 6 weeks apart or more than 3 times per year, or if other risk factors are present (such as a family history of asthma).6

The reader is referred to the National Asthma Education and Prevention Program Expert Panel Report.6 This comprehensive resource describes the features of each class of asthma (mild intermittent, mild persistent, moderate persistent, and severe persistent) and provides a step-wise approach to the treatment of all classifications of asthma in all age groups. These guidelines can be used as a starting point, and the treatment plan can be modified to fit the specific circumstances of each individual patient.

When treatment is chosen, the family and child need to be educated about the disease and its management.18,19 The ability to use equipment properly (ie, a nebulizer, metered-dose inhaler, spacer, powder disk inhaler, or peak flow meter) is crucial for proper drug administration, monitoring, and compliance.

Maintenance therapy is intended to counteract the biochemical processes that cause the respiratory symptoms. As with any medical treatment, the risks and benefits must be weighed and explained to the child's caregiver.

Inhaled corticosteroids are the most important agents available today for optimal long-term asthma management.6 It cannot be overstated that controller medications need to be prescribed for all persons with persistent asthma. Parents may fear "steroids." Therefore, it is paramount to invest time in emphasizing that in most patients the benefits of inhaled corticosteroids outweigh the risks. The potential adverse effects on growth appear to be dose-related. The Childhood Asthma Management Research Group found that children managed with long-term budesonide experienced a decrease in height velocity in the first year of treatment but displayed similar growth velocity at the study's end, 4 to 6 years later.20 Although growth rates can be reduced in the first year of treatment, the final adult height is not affected.21

Reassure the parents that the child's growth will be monitored closely and that surveillance for any side effects will take place at frequent follow-up visits. We suggest monthly visits when the medication is first initiated and then every 3 to 6 months thereafter.

Although a rare occurrence, adrenal crisis associated with inhaled corticosteroids can occur and presents as seizures secondary to hypocalcemia, fatigue, lethargy, nausea, and postural hypotension.22,23 Choose an inhaled corticosteroid and determine the lowest effective dose needed to control the patient's symptoms (see Table 2). The only inhaled corticosteroid approved for children as young as 1 year is budesonide inhalation suspension, which needs to be administered separately from other medications with a compressed, air-driven jet nebulizer (not an ultrasonic nebulizer).24 You may want to choose another one of the available inhaled corticosteroids in powder or aerosol form. This includes fluticasone, which is approved for children as young as 4 years (see Table 2).

If control is not adequate with the inhaled corticosteroid alone, the suggested second step is to add a long-acting b2-agonist, such as salmeterol, which is approved for children as young as 4 years (see Table 1).6 Emphasize to the parent that long-acting b2 agents are not rescue medications and that the short-acting b2-agonists need to be available at home and school for acute exacerbations. These medicines also do not replace the inhaled corticosteroid.

In 1999, salmeterol xinafoate plus fluticasone in a single inhalation device was the first combination therapy to be approved for asthma treatment in patients aged 12 years and older (see Table 1). A device that contains 2 medications may improve compliance, but close monitoring of symptoms and side effects is still essential.

If the child cannot cooperate with or tolerate the preferred controller medications, as previously discussed, alternative treatments for children younger than 5 years include the inhaled mast cell stabilizer cromolyn, and the recently introduced oral leukotriene modifiers (see Table 1).6 Although cromolyn has a highly favorable safety profile, it must be administered multiple times per day. It is less effective than inhaled corticosteroids, and caregiver satisfaction is lower than with the steroids.25

The oral leukotriene receptor antagonist montelukast is approved for children as young as 1 year and is available in granules or chewable tablets. This medication is particularly useful in children 2 years and older who suffer from seasonal allergic rhinitis (for which it is also approved) and asthma.

Montelukast is well tolerated; possible side effects include GI upset and upper respiratory tract symptoms. In children older than 5 years, alternative treatments also include inhaled nedocromil and the oral leukotriene modifier zafirlukast.6

Oral theophylline may be the only alternative if a patient is intolerant of or noncompliant with the previously mentioned medications. Theophylline is used infrequently in the general pediatric clinic because of its potential side effects and the need to monitor serum levels.

For those patients receiving maintenance therapy, peak flow meters may be helpful at home to detect early signs of an acute flare. However, noncompliance and incorrect use of the peak flow meter limit its effectiveness for many patients.18 The need to educate and re-educate parents and mature children about the proper use of metered-dose inhalers, spacers, and peak flow meters cannot be overemphasized.

It is wise to supply parents with oral corticosteroids that may be administered when a child with a history of severe exacerbations displays signs of acute respiratory distress. Advise parents that if the child is ill enough to need oral corticosteroids, then professional medical help should be sought as soon as possible. Parents should be well supplied with a short-acting b2-agonist for emergent treatment and warned that long-acting b2-agonists are not helpful in this setting.

Most asthma symptoms can be adequately controlled by the available anti-inflammatory agents (corticosteroids, leukotriene receptor antagonists, and mast cell stabilizers). There is, however, a population of asthma sufferers who are not helped by these agents and who likely have permanent damage or remodeling of their airways. Ongoing research is exploring monoclonal antibodies against IgE and a number of cytokines, as well as immune modulators that control asthma.26,27

WORD TO THE WISE

Asthma is a very serious yet very controllable illness. Educate the parents and older child about the condition, and provide a written plan of action for an exacerbation that the family gives to all babysitters, day-care providers, and school personnel. Individual emergency care plans should be in place for the school in all school-aged children with asthma.28

Advise parents of the American Academy of Pediatrics recommendation to annually immunize children with asthma at 6 months of age or older with the trivalent inactivated influenza vaccine.29 An asthma specialist can be involved in care any step along the way. This may be especially important for a child with asthma who is younger than 1 year or who is moderately or severely affected.

References:

REFERENCES:


1. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.

Lancet.

1998;351:1225-1232.
2. Mannino DM, Homa DM, Akinbami LJ, et al. Surveillance for asthma--United States, 1980-1999.

MMWR.

2002;51:1-13.
3. Centers for Disease Control and Prevention, National Center for Health Statistics. NCHS data on asthma. Asthma deaths, 2000. Available at: www.cdc.gov/nchs/data/factsheets/asthma.pdf. Accessed April 4, 2005.
4. Davies DE, Wicks J, Powell RM, et al. Airway remodeling in asthma: new insights.

J Allergy Clin Immunol.

2003;111:215-225.
5. Nield LS, Kamat DM. Chronic cough in kids: a practical approach to the work-up.

Consultant for Pediatricians.

2003;2:315-321.
6. National Asthma Education and Prevention Program.

Expert Panel Report: Guidelines for Diagnosis and Management of Asthma--Update on Selected Topics.

Bethesda, Md: US Dept of Health and Human Services. National Heart, Lung, and Blood Institute. 2002. NIH publication 02-5074. June 2003. Available at: http://www.nhlbi.nih.gov/guidelines/ asthma/asthmafullrpt.pdf. Accessed March 25, 2005.
7. Carl JC, Kercsmar CM. Management of acute pediatric asthma.

Curr Allergy Asthma Rep.

2002; 2:468-476.
8. Nowak RM, Emerman CL, Schaefer K, et al. Levalbuterol compared with racemic albuterol in the treatment of acute asthma: results of a pilot study.

Am J Emerg Med.

2004;22:29-36.
9. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma.

J Pediatr.

2003;143: 731-736.
10. Milgrom H, Skoner DP, Bensch G, et al. Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol

. J Allergy Clin Immunol.

2001;106:938-945.
11. Lin YZ, Hsieh KH, Chang LF, Chu CY. Terbutaline nebulization and epinephrine injection in treating acute asthmatic children.

Pediatr Allergy Immunol.

1996;7:95-96.
12. Gries DM, Moffitt DR, Pulos E, Carter ER. 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.
13. Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe BH. The effectiveness of inhaled corticosteroids in the emergency department treatment of acute asthma: a meta-analysis.

Ann Emerg Med.

2002;40:145-154.
14. Qureshi F, Pestian J, Davis P, Zaritsky A. Effect of nebulized ipratropium on the hospitalization rates of children with asthma.

N Engl J Med.

1998;339: 1030-1035.
15. Ream RS, Loftis LL, Albers GM, et al. Efficacy of IV theophylline in children with severe status asthmaticus.

Chest.

2001;119:1480-1488.
16. Ciarallo L, Brousseau D, Reinert S. Higher-dose intravenous magnesium sulfate therapy for children with moderate to severe acute asthma.

Arch Pediatr Adolesc Med.

2000;154:979-983.
17. National Asthma Education and Prevention Program.

Expert Panel Report: Guidelines for Diagnosis and Management of Asthma.

Bethesda, Md: US Dept of Health and Human Services. National Heart, Lung, and Blood Institute. NIH publication 97-4051. July 1997. Available at: http://www. nhlbi.nih.gov/guidelines/asthma/asthgdln. pdf. Accessed March 28, 2005.
18. Scarfone RJ, Capraro GA, Zorc JJ, Zhao H. Demonstrated use of metered-dose inhalers and peak flow meters by children and adolescents with acute asthma exacerbations.

Arch Pediatr Adolesc Med.

2002;156:378-383.
19. Guevara JP, Wolf FM, Grum CM, Clark NM. Effects of educational interventions for self-manage-ment of asthma in children and adolescents: syste-matic review and meta-analysis.

BMJ.

2003;326: 1308-1309.
20. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma.

N Engl J Med.

2000;343:1054-1063.
21. Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma.

N Engl J Med.

2000;343: 1064-1069.
22. Todd GR, Acerini CL, Ross-Russell R, et al. Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom.

Arch Dis Child.

2002;87:457-461.
23. Todd GR, Acerini CL, Buck JJ, et al. Acute adrenal crisis in asthmatics treated with high-dose fluticasone propionate.

Eur Respir J.

2002;19:1207-1209.
24.

Physicians' Desk Reference.

58th ed. Montvale, NJ: Thomson PDR; 2004.
25. Murphy KR, Fitzpatrick S, Cruz-Rivera M, et al. Effects of budesonide inhalation suspension compared with cromolyn sodium nebulizer solution on health status and caregiver quality of life in childhood asthma.

Pediatrics.

2003;112:e212-e219.
26. Berger W, Gupta N, McAlary M, Fowler-Taylor A. Evaluation of long-term safety of the anti-immu- noglobulin E antibody, omalizumab, in children with allergic asthma.

Ann Allergy Asthma Immunol.

2003; 91:182-188.
27. Belvisi MG, Hele DJ, Birrell MA. New advances and potential therapies for the treatment of asthma.

BioDrugs.

2004;18:211-223.
28. American Academy of Pediatrics Committee on School Health. Guidelines for emergency medical care in school.

Pediatrics.

2001;107:435-436.
29. American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for influenza immunization of children.

Pediatrics.

2004; 113:1441-1447.