Comparison of Nebulized Budesonide with Intravenous Dexamethasone in the Treatment of Young Children Hospitalized with Acute Asthma

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1 J Med Sci 2005;25(5): Copyright 2005 JMS Shu-Tse Lai, et al. Comparison of Nebulized Budesonide with Intravenous Dexamethasone in the Treatment of Young Children Hospitalized with Acute Asthma Shu-Tse Lai 1, Yi-Ming Hua 2, Yuan-Sheng Lai 2, Chun-Jung Chen 2, and Chih-Hsing Hung 2* 1 Department of Pediatrics, Catholic Mercy Hospital, Hsin Chu, 2 Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China Background: Asthma is an airway inflammatory disease and, when acute attack, systemic steroids are considered an essential component of its treatment. Methods: Eighteen young children hospitalized with acute asthma were assigned randomly into budesonide (Pulmicort) and dexamethasone (Decadron) treatment groups. The budesonide group received nebulized terbutaline plus nebulized budesonide and the dexamethasone group received nebulized terbutaline plus intravenous dexamethasone. Pulmonary index scores (PIS), including respiratory rate, wheezing, inspiration/expiration ratios and the use of accessory muscles during respiration, were measured on the first and the second days of hospitalization, and on the day of discharge. Changes in blood pressure, blood glucose, and serum potassium were also evaluated as adverse effect indices at the same time points. Results: There were no significant differences in PIS, blood pressure, blood glucose or serum potassium between the two groups, and no difference in the total hospital stay or the total amount of terbutaline used during treatment. The total doses of budesonide and dexamethasone used during treatment were 5.53±1.73 mg and 22.10±7.65 mg, respectively (P=0.02). The follow-up mean height gains, blood pressure and blood glucose also showed no statistical differences between groups. Conclusions: Nebulized budesonide is as effective as intravenous dexamethasone in the treatment of young asthmatic children, without obvious adverse effects, but the fewer doses of budesonide required may give the benefits of lower systemic effects. Key words: asthma, corticosteroid, nebulizer INTRODUCTION Asthma is a persistent, chronic inflammatory disorder of the airways 1, and control of inflammation has become the cornerstone of treatment during acute exacerbation 2. Parenteral or oral corticosteroids are equally effective in the emergency room treatment of adults and children with acute asthma, and are efficacious in speeding recovery 3, reducing the hospitalization rate 4 and decreasing early relapse 5. Early intervention using corticosteroids helps to slow the chronic progression of the disease and diminish the likelihood of permanent lung damage 6. However, systemically administered corticosteroids cannot be used in the long term without adverse effects 7. These factors prompted the consideration of nebulization as a means of Received: December 2, 2004; Revised: March 31, 2005; Accepted: April 6, * Corresponding author: Chih-Hsing Hung, Department of Pediatrics, Tri-Service General Hospital, 325, Cheng-Gong Road Section 2, Taipei 114, Taiwan, Republic of China. Tel: ; Fax: ; ped@ mail.ndmctsgh.edu.tw delivering the drug. Budesonide (Pulmicort Respules, AstraZeneca) was the first nebulized corticosteroid developed, and is approved by the Food and Drug Administration in the United States for use in children with asthma younger than 4 years 8. For inhaled corticosteroids, the efficacy depends on the topical activity of the drug that reaches the target areas, whereas the adverse events depend on both oral deposition and systemic activity. The systemic activity of the drug depends on the amount of the drug absorbed through the gastrointestinal tract or through the lungs 9, as well as during first-pass hepatic degradation 10. The amount of drug delivered to the lungs depends on the inhalation technique 11, the type of inhaler used and the fine-particle fraction dose of the drug 12. Either nebulization 13 or the use of a large volume spacer 14 offers the advantages of a better peripheral deposition and convenient administration. In children, a high dose of inhaled budesonide does not produce adrenal suppression 15 and this was considered to be because of its rapid systemic biotransformation, low glucocorticoid activity of its hydrolyzed products 16 and its short half-life in serum 17. To date, the use of nebulized corticosteroid to treat acute 223

2 Nebulized pulmicort for childhood asthma Table 1 Pulmonary index scores Score Respiratory Rate < >60 Wheezing None Terminal expiration, with stethoscope Entire expiration, with stethoscope Inspiration and expiration, without stethoscope Inspiratory-expiratory ratio 5/2 5/3 ~ 5/4 asthma has not been well studied, although aerosolized dexamethasone proved effective for children presenting in emergency rooms with croup 18. Most reported studies regarding the comparison of the clinical effectiveness via different route of administration are limited to the field of emergency room management, and there are few reports concerning inpatient service. We conducted this study to compare the clinical efficacy and adverse effects of corticosteroids, given by nebulized administration, with those produced by intravenous administration. MATERIALS AND METHODS Accessory muscle use Patients and Study Design The study used a randomized design, and informed consent was obtained from the parents of the subjects. The children recruited for this study were in the pre-school age group, between 1 and 5 years old. A diagnosis of childhood asthma was made according to the criteria defined by the National Asthma Education and Prevention Program, Expert Panel Report II, Guidelines for the Diagnosis and Management of Asthma. These included recurrent viralassociated wheezing (>3 episodes during the past 12 months), being responsive to β 2 adrenergic agonist treatment and repeated coughing at night and on exertion 2. Subjects who had acute febrile respiratory tract infections or other systemic illnesses and those who did not respond to β 2 adrenergic agonists were excluded. From June 1, 2003, to May 31, 2004, 20 children who were eligible for the study were assigned randomly into two treatment groups. The budesonide group patients received nebulized terbutaline sulfate (2.5 mg/ml; Bricanyl, AstraZeneca, Sodertalje, Sweden) at 0.25 mg/kg every 6 1/1 <1/1 0 ± If no wheezing due to minimal air exchange, score 3. Accessory muscle use was scored by assessment of sternocleidomasoid activity: 0, no apparent activity; plus or minus sign, questionable increase; double plus signs, increase apparent; and triple plus signs, maximal activity. This table was copied from Becker et al. s original paper 20. Table 2 Demographic data on admission Age (years) Sex (M/F) FAHS* Serum IgE (class)** Total eosinophil counts/ul Serum potassium (mg/dl) BP (systolic) (mmhg) BP (diastolic) (mmhg) Blood glucose (mg/dl) PIS*** Pulmicort Group Decadron Group P value 2.4 ± 1.3 5/4 0.6 ± ± ± ± ± ± ± ± ± 1.2 5/4 0.4 ± ± ± ± ± ± ± ± * FAHS: family allergy history scores; BP: blood pressure. **Serum IgE was expressed as classes defined by the Phadiotop s classification, which has been described in P224. ***PIS: pulmonary index score. hours as required to a maximum of 5 mg, and nebulized budesonide inhalation suspension (1 mg/2 ml; Pulmicort Respules, AstraZeneca, Sodertalje, Sweden) at 0.05 mg/kg every 12 hours 17. The dexamethasone group of patients was given the same terbutaline regimen plus intravenous dexamethasone at 0.1 mg/kg every 8 hours 19. On admission, a personal and family allergy history was recorded. Blood was taken for the determination of serum total IgE concentration, measured using a unicap-100 auto-analyzer (Phadiotop, Pharmacia, Sweden), and total eosinophil counts and biochemistry. Total serum IgE values were divided into six classes for analysis: class 0, <0.35 ku/l; class 1, ku/l; class 2, ku/l; class 3, ku/l; class 4, ku/l; class 5, ku/l; and class 6, >100 ku/l. Pulmonary index scores (PIS), total hospitalization days and total amount of terbutaline administered were used as parameters to evaluate clinical efficacy. Changes in blood pressure, blood glucose, and serum potassium upon admission and on discharge were used as parameters to compare any adverse effects. The PIS values were calculated based on respiratory rate, wheezing, inspiration/expiration ratio, and the need to use accessory muscles 20. In the scoring system, a score of 0 to 3 was assigned to each variable. The final scores ranged from 0 to 12, with the worst condition at 12 (Table 1). The PIS was recorded at the first and second hospitalization days, and on the day of discharge. The decision to permit discharge from the ward was made based on the loss of morning wheezing and clinical symptoms. The follow-up study lasted from January 5 to January 20, All enrolled patients were called back to the outpatient department for a checkup. The recorded data included the mean interval between the date of study and follow-up (in months), total increase in height (centimeters), 224

3 Shu-Tse Lai, et al. A C B D Fig. 1 Changes in total pulmonary index scores (A), respiratory rates (B), wheezing scores (C), inspiration/expiration ratios (D), and the use of accessory muscles (E) on days 1, 2 and on discharge. E mean rate of growth (centimeters per month), blood pressure (millimeters of mercury), and blood glucose concentration (milligrams per deciliter). Statistical Analysis Demographic data, including age, sex, family allergy history, serum IgE, total eosinophil count, PIS, potassium, blood glucose, and blood pressure, were recorded and analyzed using one-way analysis of variance. The changes of PIS and peak expiratory flow in the same group were analyzed using the Wilcoxon signed-rank test. Differences between the two groups were analyzed by using the nonparametric Mann-Whitney test. A two-tailed P value less than 0.05 was considered significant. RESULTS Demography Twenty patients were enrolled; 2 were excluded because of fever episodes. There were no significant differences between the two study groups (Table 2). Changes in Pulmonary Function No significant difference in PIS was seen be-tween the two treatment groups on day 1 (9.2±1.8 vs 8.1 ±1.3; P=0.122), day 2 (5.6±2.2 vs 5.3±2.6; P=0.974) or on discharge (2.0±1.1 vs 2.1±0.9; P=0.758) (Fig. 1A). The respiratory rate decreased steadily with time. There were no statistically significant differences in either group on day 1 (43.9±13.3 vs 37.6±9.8; P=0.078), day 2 (36.4 ±9.6 vs 31.9±7.7; P=0.62) or on discharge (26.0±3.7 vs 26.4±3.0; P=0.917) (Fig. 1B). A significant overall improvement in wheezing scores was found in both groups, but there were no significant differences between groups on day 1 (2.1±0.7 vs 2.1±0.3; P=0.14), day 2 (0.7±0.8 vs 0.8±0.9; P=0.899) or on discharge (0 vs 0; P>0.05). This sharp downward slope indicated remarkable clinical improvement (Fig. 1C). The inspiration/expiration ratios decreased steadily after treatment started, but there were no differences between groups on day 1 (3.0±0 vs 2.7±0.5; P>0.05), day 2 (2.4 ±1.1 vs 2.1±0.9; P=0.131) or on discharge (0.8±0.8 vs 1.2±0.6; P=0.131) (Fig. 1D). Obvious overall improvements in sternocleidomastoid activity were found in both groups of patients (Fig. 1E). The scores in both groups diminished similarly. The scores were 2.8±0.4 vs 2.4±0.5 (P=0.193) on day 1, 1.4±0.8 vs 1.7±0.7 (P=0.732) on day 2, and 0.7±0.5 vs 0.7±0.7 (P=1.000) on discharge. 225

4 Nebulized pulmicort for childhood asthma Table 3 Comparison of clinical and laboratory parameters on admission and discharge BP (mmhg) (systolic) (i) BP (mmhg) (systolic) (o) BP (mmhg) (diastolic) (i) BP (mmhg) (diastolic) (o) Blood glucose (mg/dl) (i) Blood glucose (mg/dl) (o) K (mg/dl) (i) K (mg/dl) (o) Total hospital day (day) Total bricanyl use (mg) Total steroid use (mg) Changes in Clinical and Laboratory Parameters on Admission and Discharge The measures of blood pressure (systolic and diastolic), blood glucose and serum potassium revealed no significant changes between admission and discharge in either group of patients (Table 3). Thus, there were no adverse effects in these patients. The number of days spent in hospital and the total amount of terbutaline used were very similar between the two groups; clearly the two treatments showed equal clinical efficacy. The total amounts of budesonide and dexamethasone used during treatment were 5.53 mg ±1.73 and mg±7.65 (P=0.02), respectively. Table 4 also shows that there were no significant differences in the mean interval of follow-up, total height growth, mean rate of height increase, systolic or diastolic blood pressure, or blood glucose between the treatment groups. DISCUSSION Pulmicort Group Decadron Group P Value 99.6± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±7.65 BP: blood pressure, (i): on admission, (o): the day of discharge * Asthma is a complex condition resulting from the interactions of a variety of environmental factors, acting on a background of genetic predisposition. It is characterized by chronic airway inflammation, reversible airway obstruction and airway hyper-responsiveness to a variety of stimuli 2. The diagnosis of asthma in children is more difficult than in adults, because no practical tests can be done in children under the age of 5 years. The diagnosis should be based largely on clinical judgment, and symptomatology and physical findings. It is generally accepted that a therapeutic trial with β 2 adrenergic agonists is the most reliable means to diagnose asthma in children 2. Empirically, the presence of repeated coughing, especially at night, with exercise, and with viral illness or evidence of prolonged cough that lasts for more than 10 days on most episodes of colds in young children, with or without atopy, Table 4 Clinical and laboratory parameters on follow-up Interval (month) Total height growth (cm) Mean height growth (cm/month) BP(systolic)(mmHg) BP(diastolic)(mmHg) Blood glucose (mg/dl) BP: blood pressure. Pulmicort Group Decadron Group P value 12.33± ± ± ± ± ± ± ± ± ± ± ± should raise asthma as a probable diagnosis 2. Our patients had histories of recurrent wheezing during the previous 12 months and had positive family histories of allergy. All of them showed remarkably reduced PIS values after treatment using β 2 adrenergic agonists. This indicates a positive therapeutic trial for reversibility. Current guidelines for the assessment of acute asthma in adults require the measurement of peak expiratory flow 20. This is a physically demanding test, and may be technically difficult to obtain from young children. Two scoring systems have been used to assess and follow the severity of asthma attacks and predict the impending respiratory failure in children 20,21. The Pulmonary Index proposed by Becker et al. in is a modification of an earlier scoring system by Pierson et al. in , and contains 4 items: respiratory rate, wheezing, inspiration/expiration ratio, and the use of accessory muscles. It seems simpler than the childhood asthma severity scale (CHAS) proposed by Ortega et al., which has 3 domains and 14 items 21. We used Becker s Pulmonary Index to assess the severity of asthma at entry and to evaluate its clinical progression. For patients with acute asthmatic exacerbation, systemic steroids are considered an essential component of treatment 4. The most common methods of steroid administration are the parenteral (either intramuscular or intravenous) and the oral routes. The use of inhaled cortisone was first reported in , and this was chiefly used as a controlled regimen for chronic asthma 24, but few studies have assessed its efficacy for acute asthma. In addition, many trials have shown that parenteral steroids produce the same clinical effects as oral steroids among patients presenting in emergency rooms with acute asthma 3. Nebulized dexamethasone is as effective as oral prednisolone in the emergency room treatment of moderately ill children with acute asthma, and is associated with more rapid clinical improvement, more reliable drug delivery and fewer relapses 25. Patients who receive β 2 adrenergic agonists and oral prednisolone have a substantially lower hospitalization rate than those who received β 2 adrenergic agonist alone (31% vs 49%)

5 Shu-Tse Lai, et al. The efficacy of corticosteroids on asthmatic patients depends largely on topical activity over target tissues. Thus, inhaled budesonide has stronger and longer topical effects than intravenous dexamethasone 27,28. It was postulated that the inhaled budesonide reaches the peripheral lungs and binds to lipophilic glucocorticoid receptors, whereas intravenous dexamethasone binds to hydrophilic glucocorticoid receptors. There have been two large studies concerning the adverse effects of the long-term use of inhaled budesonide. The mean durations of study were 4.3 years 29 and 9.2 years 30. Both studies concluded that there was transient growth depression in the first year of treatment, but no difference on final adult height. Other studies have examined the effects on bone mineral density and adrenal suppression in children with asthma receiving long-term treatment with inhaled budesonide 31. This reported no significant suppressive effects. In our study, the follow-up mean height growth was 0.54±0.20 cm/month in the budesonide group and 0.64±0.19 cm/month in the dexamethasone group. This is similar to the normal growth pattern of 0.5 cm/ month, so there was no evidence of growth suppression in these children. As for adrenal depression, we monitored blood pressures and blood glucose levels and found no significant abnormalities. The dosage of dexamethasone was according to the recommended dosage in Nelson s Textbook of Pediatrics 19. The use of nebulized budesonide was based on the instructions from the manufacturers 17. There is no direct measure of the biopotency of budesonide versus dexamethasone, but the two can be compared with that of cortisol. Budesonide has 1000-fold higher topical anti-inflammatory potency than cortisol, and 40 times higher systemic activity than cortisol when given subcutaneously: 25 times higher than cortisol by the oral route 32. Dexamethasone has times the glucocorticoid potency of cortisol 33. Therefore, we can assume that nebulized budesonide has lower systemic activity than intravenous dexamethasone, but has stronger topical effects. In our study, the total amount of budesonide used during treatment was 5.53±1.73 mg, and the total amount of dexamethasone used was 22.1±7.65 mg (P=0.02). Thus, fewer doses of nebulized budesonide are needed to produce the same clinical effect as intravenous dexamethasone. Our study showed equal clinical effects using both routes of steroid administration (nebulized and intravenous), and the fewer overall doses of budesonide required may lead to fewer systemic effects. In addition, we detected no obvious side effects or toxicity from the short-term use of corticosteroids. However, further research with more subjects is required to verify our conclusions. REFERENCES 1. Barnes PJ, Chung KF, Page CP. Inflammatory mediators of asthma: an update. Pharmacol Rev 1998;50: National Institutes of Health: National Heart Lung and Blood Institute, National Asthma Education and Prevention Programme. Expert panel report II: guidelines for the diagnosis and management of asthma. NIH publ No Bethesda, MA: National Institutes of Health, Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med 1986;314: Rowe BH, Keller JA, Oxman AD. Effectiveness of steroid therapy in acute exacerbation of asthma: a meta-analysis. Am J Emerg Med 1992;10: McNamara RM, Robin JM. Intramuscular methylprednisolone acetate for the prevention of relapse in acute asthma. Ann Emerg Med 1993;22: Pedersen S, Szefler S. Pharmacological interventions. Childhood asthma. Eur Respir J 1998;27(Suppl) :S Adinoff AD, Hollister R. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med 1983;309: Szefler SJ. Pharmacodynamics and pharmacokinetics of budesonide: a new nebulized corticosteroid. J Allergy Clin Immunol 1999;104: Lipworth BJ. New perspectives on inhaled drug delivery and systemic bioactivity. Thorax 1995;50: Lipworth BJ. Pharcokinetics of inhaled drugs. Br J Clin Pharmacol 1996;42: Dolovich M, Ruffin RE, Roberts R. Optimal delivery of aerosols from metered dose inhalers. Chest 1981;80: Chrystyn H. Is total particle dose more important than particle distribution? Respir Med 1997;91: Lodrup Carlsen KC, Nikander K, Carlsen KH. How much nebulized budesonide reached infants and toddlers? Arch Dis Child 1991;67: Jackson C, Lipworth B. Optimizing inhaled drug delivery in patients with asthma. Br J Gen Pract 1995;45: Bisgaard H, Dankjoer-Nielsen M, Andersen B. Adrenal function in children with bronchial asthma treated with beclomethasone dipropionate or budesonide. J 227

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