Re-thinking the Management of Pediatric Asthma

An early morning symposium on the management of pediatric asthma featured 4 speakers who discussed issues related to new therapeutic options.

This program was supported by an unrestricted educational grant from Sepracor Inc.

Acute and Chronic Therapy with Beta-2 Agonists in Children

“Asthma has great economic impact on our society, currently costing $18 to $20 billion yearly in the United States,” said John Carl, MD, Department of Pediatrics, Case Western Reserve University; Rainbow Babies and Children’s Hospital, Cleveland, Ohio. Forty-three percent of direct costs are due to emergency room visits and hospitalizations. 

Dr. Carl and colleagues developed an asthma care algorithm for use in the emergency room and inpatient settings in an effort to improve quality of care and control costs. This algorithm is driven by initial and intermediate assessments that allow the clinician to evaluate the evolution of a patient’s stay. These clinical examination criteria, expressed as the chest assessment score, provide a uniform tool that has been validated and can be used by physicians, nurses, and respiratory therapists. 

Components of the chest assessment score are wheezing, air exchange, accessory muscle use, and oxyhemoglobin saturation. In order to be advanced on the care algorithm, patients must score a “good” on these criteria, with no or only end expiratory wheezing, bilateral symmetric air exchange in all lobes, no accessory muscle use, and oxyhemoglobin saturations of Ž 94%. Patients who do not achieve these criteria receive beta-agonist medication. Additional assessments are performed at 20-minute intervals, with beta-agonist administered up to a total of 6 treatments, and systemic corticosteroids admin-istered if the patient fails to meet criteria after the first dose. 

Patients who do not achieve the criteria following the 6th dose are admitted to an asthma care or intensive care unit, where patient assessment is performed initially at 2-hour intervals for 12 hours, and then advanced to longer assessment intervals. Patients who fail to achieve a good chest assessment score undergo an intensification regimen, which includes a one-time administration of subcutaneous epinephrine, up to a total of 0.5 mg. High-dose albuterol aerosol or ipratropium 500 mcg and steroids at 2 mg/kg are administered, along with supplemental oxygen as required. 

“While the clinical benefits of racemic albuterol are well-known, the pharmacodynamic activity actually stems only from the R-isomer,” said Dr. Carl. The R-isomer binds to the beta receptor and decreases intracellular calcium, airway reactivity, and eosinophil activation, thus decreasing inflammation and improving lung function. The S-isomer acts by increasing cyclic GMP, increasing tri-inositol phosphate, protein kinase C, and intracellular calcium levels. This may result in paradoxical bronchospasm or airway inflammation, and given a long half-life and accumulation, may cause deterioration in lung function.

Dr. Carl and colleagues performed a randomized, double-blind study of 482 patients to compare the efficacy and safety of the R-isomer as levalbuterol with racemic albuterol consisting of 50% S-albuterol and 50% R-albuterol. Patients aged 1-17 with pre-existing diagnosis of asthma who presented with cough, wheezing or shortness of breath were randomized to receive either 1.25 mg levalbuterol or 2.5 mg racemic albuterol according to the established treatment algorithm. 

Of 234 patients randomized to receive racemic albuterol, 108 (46%) required hospitalization, while 88 (35%) of 248 patients treated with levalbuterol required hospitalization (P = 0.016). This represents a 24% relative reduction in admission rate. There was a trend toward shorter length of stay in the levalbuterol group (P = 0.06). Intensification was required in 17% of racemic albuterol patients and 7% of the levalbuterol patients (P = 0.07). No serious adverse events occurred in either group, and there were no significant between-group differences in the incidence of adverse events. “Based on 1,100 admissions per year at our institution, use of levalbuterol would result in a savings of $220,000 annually at our institution alone,” said Dr. Carl. 
 
 
 

Advances in Combination Therapy in Pediatric Asthma

“Therapy of asthma has evolved considerably over the last several years,” said Stanley Szefler, MD, Helen Wohlberg and Herman Lambert Chair in Pharmacokinetics; co-director, Clinical Research Unit, National Jewish Medical and Research Center; and professor of pediatrics and pharmacology, University of Colorado Health Sciences Center, Denver. From the initial use of epinephrine to relieve bronchospasm not more than 50 years ago, we now find ourselves in an era focused on preventing bronchospasm, resolving inflammation, and attempting to alter the course of the disease. Current goals of therapy are relief of symptoms, improvement of pulmonary function, and prevention of disease progression. As attention is shifted toward early identification and intervention, aggressive therapy must be balanced with potential adverse effects of therapy.

While mortality due to asthma has stabilized in the last few years, the number of hospitalizations, particularly in children younger than 4 years, is increasing. “We need to turn our attention to decreasing hospitalization rates in this population,” said Dr. Szefler.

Current guidelines for the treatment of asthma, last published in 1997 and currently undergoing revision, are outdated due to the introduction of new products for asthma management. The areas of greatest controversy in revision of these guidelines are related to initial therapy and when to move to combination therapy. At this time, there is no combination product that is approved for use in children under age 12, so it is necessary to turn to additive therapy to achieve the same effect. 

Products currently approved for use in young children include budesonide, montelukast, inhaled steroids, formoterol, salmeterol (dry powder form), and cromolyn. There are limited data about long-term use of some of these products, particularly the leukotriene antagonists and long-acting beta-agonists. Considerable information is available about inhaled steroids, which have emerged as first choice for long-term preventive therapy; however, concern about long-term effects limit their use in young children. The potential benefits of early inhaled steroid therapy include improved pulmonary function, decreased asthma-related hospitalizations, and greater response to inhaled treatment if started within 2 years of onset. While long-acting beta-agonists are beneficial, they do not affect the inflammatory process.

“The literature now indicates that combination therapy can achieve the benefits of high-dose inhaled corticosteroid therapy while avoiding the risk of adverse events associated with high-dose therapy,” said Dr. Szefler. A patient poorly controlled on low-to-moderate doses of inhaled steroids can have a long-acting beta-agonist or a leukotriene receptor antagonist added to the treatment regimen. Multiple studies have indicated that combination therapy, particularly with inhaled steroids and long- acting beta-agonists, results in greater improvement in lung function and results in fewer exacerbations than doubling the dose of inhaled steroids. “This is especially important in childhood asthma, given the concerns for potential adverse effects on growth and concerns about exacerbations increasing in this age group,” said Dr. Szeffler. It is likely that labeling for a combination product combining a steroid and long-acting beta-agonist will eventually be approved for children younger than 12 years. 

While most data are available for the combination of fluticasone and salmeterol, there are also growing numbers of studies indicating the efficacy of budesonide and formoterol, as well as theophylline or leukotriene receptor antagonists as add-on therapy. Given current labeling, however, combination therapy in young children necessitates the use of 2 different types of delivery systems. 

Introduction of a number of new medications for management of asthma is likely in the coming years. Investigation of the natural history of the disease, the importance of outcome measures and adverse effects on growth and development in young children, and search for critical modulators of disease are ongoing. 

Considerations Regarding Preservatives in Asthma Medications

Leslie Hendeles, PharmD, professor of pharmacy and pediatrics, University of Florida, Gainesville, discussed issues related to preservatives in albuterol formulations. Among these preservatives are benzalkonium, which is used to prevent the growth of bacteria in non-sterile solutions, and EDTA, which may be added to prevent discoloration of a solution. 

Zhang and others (Am Rev Respir Dis 1990;141:1405-1408) investigated the effects of benzalkonium on FEV-₁ in 28 patients. Of these, a substantial proportion had bronchoconstriction in response to benzalkonium alone. A single dose was associated with an approximately 30% drop in FEV-₁, and this effect lasted more than 60 minutes. The effect was dose related and occurred in patients who exhibited greatest airway reactivity as demonstrated by response to histamine challenge. 

The clinical relevance of this finding has been demonstrated by Beasley et al (Br Med J 1987; 294:1197-1198), who performed a double-blind study comparing preservative-free ipratropium bromide, commercially available ipratropium bromide, which was formulated with benzalkonium and EDTA in New Zealand, and placebo. Paradoxical bronchoconstriction occurred in the group treated with the commercial preservative-containing solution. In another study by Miszkiel et al (Br J Clin Pharmacol 1988;20:295-301) pretreatment with cromolyn, which inhibits mast cell degranulation, prevented subsequent benzalkonium-induced bronchoconstriction, suggesting that the effect of benzalkonium is mediated by release of mediators from mast cells.

Of the 5 commercially available preparations of albuterol, the 0.083 mg screw cap preparation made by Schering or its generic sold by Warrick have the highest concentration of benzalkonium. These are the most commonly dispensed albuterol formulations. Following NIH guidelines in an emergency-room setting, 2.5 to 5 mg of albuterol every 20 to 30 minutes times 3 would provide 1,800 mcg of benzalkonium to the patient within one hour.

Dr. Hendeles and colleagues conducted a randomized double-blind cross-over study (J Allergy Clin Immunol 2001; 107:68-72) in volunteers with asthma. Subjects were randomized to receive repeated doses of benzalkonium, EDTA, or placebo in amounts they would receive if they were treated with benzalkonium-containing albuterol preparations in the emergency room. The mean decrease in FEV-₁ was 17% in patients given benzalkonium; however, some subjects had decreases of 50%. The effect was dose related. No bronchoconstriction occurred with EDTA or placebo. 

One alternative for decreasing or avoiding benzalkonium exposure is use of a metered dose inhaler with a valve holding chamber. Several double-blind studies have demonstrated that increasing the dose of albuterol via a metered dose inhaler is as effective as the racemic albuterol nebulizer solution. Another alternative is prescribing a preservative-free product. Racemic albuterol is available without preservative and can be specified when prescribing as “do not dispense benzalkonium-containing product.” Xopenex® (Sepracor), a formulation of levalbuterol, is preservative free. 

 

Changes in Asthma Medications and Their Effect on Asthma Guidelines

“Our challenge is to merge the advances in medication for asthma into the guidelines for treatment of pediatric asthma,” said Joann Blessing-Moore, MD, associate clinical professor, Stanford University, Stanford, California. New medications have been introduced since the publication of the previous National Asthma Education Program guidelines, and new guidelines are evolving.

New challenges that face practitioners in the treatment of pediatric asthma are how to identify patients at risk early in the course of the disease and how to classify severity of disease. Treatment goals include not only control of symptoms but prevention of the long-term remodeling or chronic changes that can occur in these patients. In addition, education of patients and caregivers about appropriate action plans with new medications is essential.

Asthma is the leading cause of morbidity and mortality among children throughout the world, and accounts for one-third of school absences. Onset of asthma occurs at an early age, with median age at onset of approximately 4 years, and more than 50% of persistent asthma beginning before age 3. Of children younger than age 6 years who have one episode of wheezing, approximately one-third go on to have persistent wheezing. Major risk factors for persistent asthma include positive family history, atopic dermatitis, hospitalization for bronchiolitis with severe wheezing, and 3 viral illnesses with wheezing within 6 months. Two-thirds of children who have wheezing associated with croup and approximately 10% of adolescents with allergic rhinitis will develop asthma.

There are 3 relatively new medications for the treatment of asthma. Beta-agonists, which are the mainstay of treatment for acute asthma, have previously included only the racemic form of albuterol. The pure R-isomer, or levalbuterol, is now available. Only the R-isomer binds to the beta receptor, resulting in bronchodilatation with fewer side effects. In addition, this isomer has been reported to increase ciliary beat frequency and decrease eosinophil activation. The S-isomer, on the other hand, has been noted to increase intracellular calcium, eosinophil activity, mucus production, histamine, and IL-4 levels. 

Several studies in varying age groups down to 3 months have demonstrated that levalbuterol is effective in improving pulmonary function at approximately one-fourth of the dose of the racemic formulation, and is associated with significantly fewer side effects, including tremor and changes in potassium and glucose levels. “Levalbuterol is safe, effective, long-lasting, and cost-effective,” said Dr. Blessing-Moore.

The long-acting beta-agonists salmeterol and formoterol provide 12- hour bronchodilatation and increase the efficacy of inhaled steroids such that only one-half of the dose of inhaled steroid is needed. Salmeterol is active within 30 minutes and lasts 12 hours. The rapid onset and 12-hour duration of formoterol have raised the question of whether this drug should be used as first-line therapy and whether it should play a role as a rescue medication. A large, long-term trial is underway to evaluate the role of this drug in asthma therapy.

Anti-inflammatory medications are indicated for patients with persistent asthma. If patients need a bronchodilator more than 2 times a week (except for exercise) or are awakened due to asthma more than 2 times per month, anti-inflammatory medications are essential. This is the rule of twos. “The need to effectively heal the lungs and prevent remodeling with use of anti-inflammatory medication is basic to the care of the asthmatic,” said Dr. Blessing-Moore. Budesonide (Pulmicort Respules™) is the first nebulized steroid available in the United States, and has recently been approved for use in ages 1 to 8 years.

Possible side effects of long-term use of inhaled corticosteroids, in particular their effect on growth, have always been a concern. Although long-term studies of inhaled steroids in children have demonstrated a possible decrease in growth rate within the first year of treatment, this is followed by a return to the expected growth curve. Cataracts have not been reported with use of the nebulized budesonide formulation. Studies have also demonstrated the importance of treating early for the best long-term effects on lung growth. Lower doses of inhaled steroids may be used if they are combined with long-acting beta-agonists or other anti-inflammatory medications. 

The leukotriene receptor antagonists were first introduced in 1996 in the United States. Montelukast and zafirlukast have a significant role in maintaining asthma control in children as well as adults. These agents block one of the mediators of the asthmatic/inflammatory response. They are mild bronchodilators, are bronchoprotective, and help in the control of exercise-induced as well as environmentally induced symptoms. 

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