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The effectiveness of anti-leukotriene agents in childhood asthma: evidence to guide clinical practice. (Evidence-Based Practice).

Asthma continues to be the leading public health problem in pediatrics, affecting 8 million children in the United States (American Lung Association [ALA] 2001). In comparison to children without asthma, children affected by this chronic disease have 2.2 times more emergency room visits and 3.5 times more hospitalizations (Lozano, Sullivan, Smith, & Weiss, 1999). The financial cost of asthma in the United States averages 6 billion dollars per year, which includes direct health care costs (e.g., hospitalizations, office visits, medications) as well as indirect health care costs (e.g., school absenteeism by children and lost work time by parents) (Ratcliffe, 1997).

An important goal of asthma management is to provide optimal pharmacological treatment in order to maintain normal pulmonary functioning and normal activities of daily living as well as to prevent further asthma exacerbations. Antileukotriene agents, which interrupt the action of leukotrienes, have been found to be effective in the treatment of chronic asthma in adults. This is a key inhibitory mechanism because leukotrienes, which are produced and released by pro-inflammatory cells (e.g., mast cells and eosinophils), are approximately 1,000 times more potent in producing bronchoconstriction than histamine (Griffin et al., 1983).

Despite the fact that anti-leukotriene agents are being prescribed for children with asthma, there are no firm recommendations on the use of these agents by the National Institutes of Health (NIH) (NIH, 1999). Therefore, a search for the best and latest evidence was conducted to answer the clinical question: "Are anti-leukotriene agents effective in the treatment of asthma in children and adolescents?"

The Search for Evidence

The objective of this search was to find and critically appraise the best and latest evidence on the therapeutic effectiveness of the anti-leukotriene agent montelukast (i.e. Singulair[R]) in the treatment of childhood asthma. A systematic search of the literature began with the Cochrane Data Base of Systematic Reviews and then proceeded to Medline and CINAHL, using the medical subject headings (MESH) "childhood asthma," "leukotriene receptor antagonist," "montelukast" and text keywords "systematic reviews" and "randomized controlled trials." A study was considered eligible for inclusion in this review if it: (a) was a randomized controlled trial, (b) included human pediatric or adolescent subjects ages 6 years and older, and (c) was written in English. The search reviewed a total of 20 studies. Review of the abstracts from these studies revealed that three of them met the inclusion criteria established for this review. However, it was decided that a randomized controlled trial by Malmstrom and colleagues (1999) would not be included in this review because of the wide age range of subjects (i.e., 15 to 85 years) included in the study.

Presentation of the Evidence

Study # 1. In a study conducted by Reiss and colleagues (1998), 681 healthy, non-smoking participants who were 15 years of age or older with at least I year of specified daytime asthma symptoms and short acting beta-agonist use were randomly assigned to receive either montelukast or a placebo. The patients who were randomized had to meet the inclusion criteria established for the study: (a) a forced expiratory flow in 1 second (FE[V.sub.1]) between 50-85% of the predicted value after withholding their beta agonist for at least 6 hours, (b) 15% FE[V.sub.1] improvement 20-30 minutes after beta-agonist use in at least two pre-study evaluation visits, and (c) demonstrated competence using a peak flow meter and a diary card used to track asthma symptoms. Patients were excluded if they had an active upper respiratory infection (URI), a recent hospitalization or visit for asthma, mast cell stabilizer use 2 weeks prior to the study, theophylline use, long-acting inhaled beta-agonist use, or anticholinergic use within 1 week of the study. Other exclusions included astemizole use within 3 months and immunotherapy initiated within the past 6 months. In this study, 25% of the patients were allowed to engage in concomitant steroid usage.

The study was a multi-center, randomized, double blind, placebo-controlled, three period clinical trial comparing montelukast to placebo. Period one was a 2-week placebo run-in period followed by a 12-week active treatment period involving montelukast or placebo (i.e., period two) and ending with a 3-week wash out period (i.e., period three). Subjects were seen in the clinic every 2 weeks during period one and every 3 weeks thereafter.

The participants for this study were recruited from 50 study centers in the United States between October 1994 and August 1995, with the majority being White (i.e., 89%). The subjects were randomized by a computerized randomization process. A longitudinal design was created to assess the effectiveness of montelukast over a 12-week period. Quality control was ensured using a standardized spirometer approved by the American Thoracic Society as well as the use of a daily diary card, which has been supported as reliable in previous studies. The treatment group received montelukast 10 mg orally, once daily at bedtime. The placebo group received an identical appearing placebo pill administered once daily at bedtime. The intervention was self- administered at home over the 12-week period.

The main dependent variables measured in this study were FE[V.sub.1] and asthma symptom scores, as recorded by subjects on a daily record card. Other outcomes included self-reports of morning and evening peak expiratory flow rate, daily use of beta agonists, frequency of nocturnal awakenings, asthma-specific quality of life, as well as change in peripheral blood eosinophil counts. In addition, at the end of period two (i.e., week 12), physicians and subjects made global evaluations of the change in their asthma status. The measurement of FE[V.sub.1] was assessed by a computerized spirometer at each clinic visit, which was conducted between 6 and 9 a.m., 10 to 12 hours after the prior dose of study medication. The largest FE[V.sub.1] from at least 3 maneuvers was the subject's value for each clinic visit. The information from the spirometer was sent via modem to a quality control center for review of the data to ensure adherence to the American Thoracic Society standards of acceptability and reproducibility.

An Analysis of Variance (ANOVA) statistical model was used to compare the difference in responses between the treatment groups. Variances taken into consideration for the analyses included study demographics and inhaled corticosteroid use. Main outcome variables were FE[V.sub.1] and daytime asthma symptoms. Findings revealed that FE[V.sub.1] was improved by 13.1% in the montelukast group compared to 4.2% in the placebo group (p < 0.001). Montelukast also improved patient-reported daytime asthma symptoms and the need for intermittent beta agonist use (p < .001) compared with placebo. In addition, subjects taking montelukast had significantly decreased blood eosinophil counts in comparison to those taking the placebo (p < .001). The most frequent adverse effects included headaches and URIs, although these effects were not significantly more in the montelukast group than the placebo group. Less than 15% of both groups dropped out of the study. Reasons for attrition included adverse effects, pregnancy, consent withdrawal, protocol deviations, and unavailability. The investigators concluded that montelukast was more effective in controlling daily asthma symptoms than the placebo with few adverse events.

Study #2. Knorr and colleagues (1998) performed a study to determine the efficacy and safety of montelukast with 336 children, ages 6 to 14 years, all of whom had a history of intermittent or persistent asthma symptoms. Subjects were eligible for participation in the study and randomization into groups was done by the same inclusion criteria as in the previous study by Reiss and colleagues (i.e., FE[V.sub.1] between 50% to 85% of the predicted value, at least 15% reversibility after inhaling a beta-agonist). Concomitant inhaled steroids were used in 39% of the subjects receiving montelukast and 33% receiving the placebo. Exclusion criteria for this study consisted of a recent URI; recent emergency room visit, intubation, or hospitalization for asthma; and current use of one of several specified medications.

This study was a multi-center, longitudinal, randomized, double blind clinical trial conducted over 8 weeks. Subjects were recruited from 47 centers (i.e., private practices or academic medical centers) in the U.S. and Canada and were randomly assigned to treatment or placebo groups via computer-generated randomization with two subjects receiving the placebo for every three subjects receiving montelukast.

The intervention was a 5 mg montelukast chewable tablet administered at home once each night over an 8-week treatment period verses an identical placebo pill administered at the same time. The primary outcome variable, FE[V.sub.1], was measured according to the same procedure as was used in the prior study by Reiss and colleagues.

The FE[V.sub.1] was obtained at clinic visits every 2 weeks and transmitted to a centralized quality control location. Other outcome variables included daytime asthma symptoms; morning and evening peak expiratory flow rates; daily use of inhaled, short-acting beta-agonists; nighttime awakenings; quality of life; and physician, parent, and patient reports of asthma status as well as change in peripheral blood eosinophil counts and school days lost.

Statistical analysis revealed no differences in baseline demographic and clinical variables between the two study groups. Results indicated a significant improvement in percent of change in FE[V.sub.1] by the treatment group (i.e., 8.23% in the treatment group and 3.58% in the placebo group, p < 0.001). In addition, montelukast was shown to have a significant positive effect on daily asthma symptoms, including a decreased need for beta-agonists within the first 24 hours of treatment, as well as quality of life, parental global evaluations, and peripheral blood eosinophil levels. Montelukast also was found to be more effective than placebo in treating childhood asthma in various subgroups of children, including children of various ages, different gender and races, and history of exercise-induced asthma.

The most common adverse effects, which occurred at similar rates between the montelukast and placebo groups, were headache, asthma exacerbations, and URI. Allergic rhinitis was the one adverse effect that significantly differed between groups, occurring more frequently in the placebo group. Comparable percentages of subjects in the montelukast and placebo groups did not complete this study at 12.6% and 10.7%, respectively. Reasons for attrition included withdrawal of consent, protocol deviation, unavailability, and adverse experiences.

Overall, the findings indicated that montelukast significantly improved FE[V.sub.1] in 6- to 14-year-old children. As a result, the investigators concluded that long-term treatment of chronic asthma with montelukast can be effective in children in reducing asthma exacerbations. They also concluded that, since montelukast showed similar improvements in patients who were and were not on inhaled corticosteroids, montelukast would be an appropriate complementary therapy to inhaled corticosteroids in the treatment of chronic asthma in children.

Critique of the Evidence

The use of a randomized controlled, double blind, clinical trial in both of the studies reviewed is the strongest experimental design to control for extraneous variables as well as to support a cause and effect relationship between the treatment (e.g, montelukast) and outcome variables (e.g., asthma symptoms). Thus, the internal validity of these studies is strong, which enhances confidence in the findings that there were true differences in outcomes between the subjects who received montelukast in comparison to those who received the placebo.

Although approximately a quarter to a third of the subjects in the studies reviewed were using corticosteroids concomitantly, the use of random assignment equally distributed those subjects between the montelukast and placebo groups, which decreases the chance of corticosteroid usage confounding the results. The median age of the participants in the study by Reiss and colleagues was 31 years, but it is not known how many adolescents actually participated in this study. In order to determine the effectiveness of montelukast specifically in teens, it will be important to conduct randomized controlled trials in the future specifically with this developmental age group.

A strength of both of the studies reviewed is that a combination of self-report and observation measures were used to tap the outcome variables. Convergence of self-report measures (e.g., asthma symptoms, frequency of night awakenings, peak flow meter readings) and observation outcomes (e.g., FE[V.sub.1] as measured during the clinic visits, peripheral blood eosinophil counts) increases the credibility of their findings.

One of the greatest strengths of the study by Knorr and colleagues (1998) was that it was designed to be specific to children and early adolescents, ages 6 to 14 years of age. Since this study also was a randomized controlled, double blind trial, the results provide a strong level of evidence upon which to guide clinical practice decisions. However, additional randomized controlled trials conducted with school-age children and adolescents are needed in order to accumulate further evidence regarding the more long-term safety and efficacy and of montelukast in the treatment of chronic childhood asthma.

Further research comparing inhaled corticosteroids with leukotriene antagonists also would be beneficial in supporting the use of leukotriene antagonists as either alternative or add-on therapy in the treatment of chronic asthma.

Implications for Clinical Practice

Asthma is the most common chronic disease in childhood, one in which pediatric nurse practitioners and nurses can assume a key role in assisting children and their families with individual management plans that are most effective in controlling asthma symptoms. As such, it is critical for them to be familiar with the evidence regarding effectiveness of various asthma medications.

From the evidence presented in this review, it can be concluded that pediatric nurse practitioners and nurses can be comfortable in using or recommending the use of leukotriene antagonists, such as montelukast, in the treatment of chronic childhood asthma. Specifically, appropriate use of leukotriene antagonists in childhood asthma may be especially beneficial in cases where inhaled corticosteroid therapy has not adequately managed the child's condition or as an adjunct to corticosteroid usage. Examples in which montelukast also could be particularly beneficial is with children who are having difficulty with correct inhaler usage or those who may be more compliant with oral versus inhaled therapy.

In summary, montelukast seems to be both an effective and safe treatment in the short-term management of chronic childhood asthma. Further research is needed with children and adolescents to determine its long-term effectiveness and safety.


American Lung Association (ALA). (2001). National health interview survey. Retrieved from data_102000.html

Griffin, M., Weiss, J.W., & McFadden, E.R., Corey, E.J., Austen, K.F., & Drazen, J.M. (1983). Effects of leukotriene D4 on the airways in asthma. New England Journal of Medicine, 308, 436-439.

Knorr, B., Natz, J., Bernstein, J., Nguyen, H., Seidenberg, B., Reiss, T., & Becker, A. (1998). Montelukast for chronic asthma in 6-to 14-year-old children: A randomized, double-blind trial. JAMA, 279, 1181-1186.

Lozano, P., Sullivan, S.D., Smith, D.H., & Weiss, K.B. (1999). The economic burden of asthma in U.S. children: Estimates from the National Medical Expenditure survey. Journal of Allergy & Clinical Immunology, 104, 957-963.

Malmstrom, K., Rodriguez-Gomez, G., Guerra, J., Villaran, C., Pineiro, A., Wei, L., Seidenberg, B., & Reiss, T. (1999). Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: A randomized, controlled trial. Annals of Internal Medicine, 130, 487-495.

National Institutes of Health (NIH). (1999). Stepwise approach to managing asthma long term for adults and children more than 5 years of age. Retrieved on April 9, 2002 from

Polit, D., & Hungler, B. (1999). Nursing research: Principles and methods (6th ed.). Philadelphia, PA: Lippincott.

Ratcliffe, M.M. (1997). Asthma. In J.A. Fox (Ed.), Primary health care of children (pp. 836-848). St. Louis: Mosby Year-Book.

Reiss, T., Chervinsky, P., Dockhorn, R., Shingo, S., Seidenberg, B., & Edwards, T. (1998). Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: A multicenter, randomized, double-blind trial. Archives of Internal Medicine, 158, 1213-1220.

Glossary of Terms

Analysis of variance (ANOVA)--a statistical procedure for testing mean differences among two or more groups by comparing the variability between groups with the variability within groups.

Attrition--the loss of participants during the course of a study, which can introduce bias by changing the composition of the sample initially drawn.

Internal validity--the extent to which it can be said that the independent variable is responsible for the change in the dependent variable, not other extraneous variables.

P value--in statistical testing, the probability that the obtained results are due to chance alone: the probability of committing a type I error. For example, a p < .001 means that the probability that the results occurred by chance is less than I in 1,000.

Note: From Polit & Hungler (1999).

Julie Berkhof, BSN, RN, is a Graduate Student, Family Nurse Practitioner Program, University of Rochester School of Nursing, Rochester, NY.

Karen Parker, BSN, RN, is a Graduate Student, Family Nurse Practitioner Program, University of Rochester School of Nursing, Rochester, NY.

Bernadette Mazurek Melnyk, PhD, RN, CPNP, FAAN, is Associate Dean for Research and Professor; Director, Center for Research & Evidence-Based Practice and PNP Program, University of Rochester School of Nursing, Rochester, NY.
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Author:Berkhof, Julie; Melnyk, Bernadette Mazurek; Parker, Karen
Publication:Pediatric Nursing
Geographic Code:1USA
Date:Jan 1, 2003
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