Inhaled budesonide for the treatment of acute wheezing and dyspnea in children up to 24 months old receiving intravenous hydrocortisone

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1 Inhaled budesonide for the treatment of acute wheezing and dyspnea in children up to 24 months old receiving intravenous hydrocortisone Flávio Sano, MD, a Geny K. Cortez, MD, a Dirceu Solé, MD, b and Charles K. Naspitz, MD b São Paulo, Brazil Background: Inhaled corticosteroids are highly effective in the treatment of asthma at all ages, and their use in younger children is increasing. There are no data currently available on the treatment of infants with acute wheeze and dyspnea with nebulized budesonide. Objective: Our purpose was to assess the clinical effect of nebulized budesonide in infants with acute wheeze and dyspnea. Methods: A prospective study was performed comparing the addition of nebulized budesonide 0.25 mg every 6 hours (group A, n = 32) and nebulized ipratropium bromide 0.1 mg every 6 hours (group B, n = 39) with the normal treatment regimen with intravenous fluid, hydrocortisone, and nebulized fenoterol. A clinical score was made at admission and every 12 hours. The score included wheezing and costal retraction (0-6) and respiratory rate (counts per minute). Results: Seventy-one infants aged 3 to 24 months were studied (42 boys). A statistically significant reduction was seen in clinical score and respiratory rate in both groups 12 hours after admission. The children who received budesonide improved significantly faster than the children who received ipratropium bromide, and the hospitalization period was significantly lower in the budesonide group (66.4 hours) compared with the ipratropium bromide group (93 hours) (P <.01). Three patients from the budesonide group and 2 from the ipratropium bromide group were readmitted within the first 4 weeks. Conclusion: Treatment of infants with acute wheeze with nebulized budesonide is associated with faster clinical improvement and reduction in hospital stay period. (J Allergy Clin Immunol 2000;105: ) Key words: Asthma, budesonide, inhaled steroids, efficacy, infants Acute episodes of wheezing and dyspnea are common among infants and young children. Although most of these children will spontaneously outgrow these symptoms after the age of 3 years, some children will have persistent symptoms, suggesting that episodes of wheezing and dyspnea early in life may indicate predisposition for asthma in a proportion of these patients. 1 From the a Hospital Nipo-brasileiro and the b Division of Allergy and Clinical Immunology and Rheumatology, Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil. Received for publication June 10, 1999; revised Dec 1, 1999; accepted for publication Dec 1, Reprint requests: Flávio Sano, MD, Av Onze de Junho, 685, apto 166, Cep: , São Paulo, SP, Brazil. Copyright 2000 by Mosby, Inc /2000 $ /1/ doi: /mai There is evidence for an inflammatory reaction underlying the episodes of wheezing and dyspnea in infants. Recently, inflammatory mediators including TNF-α, thromboxane B 2, PGE 2, and eosinophil cationic protein have been detected in bronchoalveolar lavage fluid from infants with acute attacks of wheezing. 2,3 It has been shown that the release of these mediators from activated mast cells in vitro could be inhibited by the addition of dexamethasone. 2 Long-term benefits from the use of inhaled corticosteroids in infants and young children have been demonstrated. Inhaled budesonide has been shown to be effective in controlling persistent respiratory symptoms in children when used for up to 12 months. 4-6 In addition, inhaled flunisolide has also been used to treat wheezing babies with persistent symptoms. 7 Although inhaled budesonide has been shown to be useful for the treatment of acute episodes of croup, 8-10 acute attacks of asthma in older children, 11,12 and recurrent wheezing episodes in young children, 13 its use in the treatment of acute episodes of dyspnea and wheezing in infants and young children has not been systematically investigated. One uncontrolled study showed that the use of nebulized budesonide resulted in shorter hospital stays and a decreased need for intravenous medications in hospitalized babies with bronchiolitis. 14 Recently, it was shown that budesonide inhalation suspension is an effective and safe treatment for 178 young children (4-8 years old) with inhaled steroid dependent persistent asthma. 15 The aim of the current study was to evaluate the clinical efficacy of inhaled budesonide in association with fenoterol for the treatment of hospitalized wheezing babies already receiving intravenous hydrocortisone and to compare this association with a combination of fenoterol and ipratropium bromide, without budesonide, for the treatment of these patients. METHODS Patients We studied 71 children aged 3 to 24 months old who were admitted to the hospital with a severe acute attack of wheezing and dyspnea that did not improve after at least 3 nebulizations with a β 2 - agonist agent in the emergency department. Demographic and clinical data are shown in Table II. Children were randomly assigned to receive treatment with either fenoterol plus budesonide or fenoterol plus ipratropium bromide by nebulization, in addition 699

2 700 Sano et al J ALLERGY CLIN IMMUNOL APRIL 2000 TABLE I. Clinical score Score Wheeze None End- Expiratory Inspiratory expiratory and expiratory Retractions* None Few Moderate Intense *Use of accessory muscles, suprasternal retractions. to treatment with intravenous hydrocortisone. Consecutive patients were assigned to alternate treatment groups, following the order of admission. Informed consent was obtained from each patient signed by a parent or legal guardian and Institutional Review Board approval was received before the start of the study. Study design A physician prescribed the treatment, which was administered by the nursing staff, and another physician, who evaluated all patients throughout the study, was blinded to the medication used. All 71 children received inhaled fenoterol mg/kg every 4 hours, intravenous hydrocortisone 40 mg/kg/d, intravenous hydration 100 ml/kg/d, and oxygen when necessary. Thirty-nine of these children (21 boys) received 0.25 mg of inhaled budesonide suspension 4 times daily to a total dose of 1 mg/d throughout the hospitalization period. The other 32 children (21 boys), received 0.1 mg ipratropium bromide 4 times daily to a total dose of 0.4 mg/d throughout the hospitalization period. The dosages of either budesonide suspension or ipratropium bromide were administered together with 4 of the 6 dosages of fenoterol. Nebulization was performed with a continuous flow of oxygen at 5 L/min and 3 ml of 0.9% saline solution until the end of the volume was nebulized. Children with radiologic findings of pneumonia or receiving antibiotics were excluded from the study. Those who showed no improvement after 3 nebulizations with a β 2 -agonist and with signs of respiratory insufficiency were sent to the intensive care unit for treatment and were not included in the study. Patients were assessed and scored every 6 hours by a trained nurse and every 12 hours by an assistant physician. The respiratory rate and the clinical score were used for patient evaluation on the basis of the National Institutes of Health, National Heart, Lung, and Blood Institute 1997 guidelines. 16 A clinical score was attributed to the patients on the basis of the presence of wheezing (0-3 points) and retractions (0-3 points), with a maximal score of 6 (Table I). Children were evaluated throughout the period of hospitalization and were discharged when considered to be well enough to be followed up as outpatients. After discharge, all patients were followed up clinically for a period of 4 weeks. Statistical analysis The Mann-Whitney test was used to compare clinical score, respiratory rate, and mean length of hospital stay between the groups treated with budesonide or ipratropium bromide for each of the time intervals throughout the evaluation period. The chi-square test was used to compare the percentage of patients who remained in the hospital over time, according to the treatment modality they received. In both tests a P value of <.05 was considered significant. RESULTS At enrollment there were no significant differences between the 2 study groups regarding age, sex, time since the onset of symptoms, number of previous wheezing episodes, and baseline clinical scores (Table II). TABLE II. Clinical characteristics of the patients in the study A significant reduction in the clinical scores and respiratory rates was observed in both treatment groups after 12 hours compared with baseline. However, a significantly greater reduction in the clinical scores was observed in the budesonide group compared with the ipratropium bromide group after 12 hours (Fig 1). In addition, a significantly greater reduction in the respiratory rates was seen in the budesonide group compared with the ipratropium bromide group after 24 hours of treatment (Fig 2). The mean length of hospital stay in the budesonidetreated group (66.4 hours) was significantly lower than in the ipratropium bromide treated group (93 hours), representing a 28.7% difference (P <.01). After 72 hours of treatment 84.3% of the patients treated with ipratropium bromide remained in the hospital, whereas only 53.8% of those treated with budesonide were hospitalized (P <.01). There was a progressively lower percentage of patients remaining in the hospital in the budesonide group from 72 hours onward compared with the ipratropium bromide group (Fig 3). Within a period of 4 weeks after discharge, 3 patients from the budesonide group and 2 patients from the ipratropium bromide group required readmission to the hospital. DISCUSSION Ipratropium Statistical Budesonide bromide signifi- (n = 39) (n = 32) cance Mean age (range in months) NS Boys (%) NS Time of onset of NS symptoms (h) No. of previous wheezing NS episodes Clinical score at admission NS NS, Not significant. Acute episodes of wheezing in infants and young children, particularly caused by bronchiolitis, are among the major causes of morbidity requiring vigorous treatment. An ideal treatment regimen would be at one time effective and safe and would result in fast clinical improvement, thus decreasing hospital admission rates and abbreviating length of hospital stay. The currently recommended therapy for these patients includes the use of β 2 -agonists, anticholinergics, oxygen, and oral and systemic corticosteroids. 16 Efficacy in relieving acute wheezing in children has been demonstrated for inhaled β 2 -agonists and ipratropium bromide. 20,21 It has been previously demonstrated that a combination of ipratropium bromide and fenoterol caused significant improvement of dyspnea and wheezing in children less than 2 years old compared with

3 J ALLERGY CLIN IMMUNOL VOLUME 105, NUMBER 4 Sano et al 701 FIG 1. Mean values of clinical scores in children treated with nebulized budesonide or ipratropium bromide over time in the hospital. Clinical scores were assigned to each child on basis of presence of wheezing (0-3 points) and retractions (0-3 points), with a maximum score of 6. Children treated with ipratropium bromide had significantly higher clinical scores than those treated with budesonide, at times 12 to 84 hours after admission, as indicated (two asterisks) (Mann-Whitney test, P <.01). FIG 2. Mean values of respiratory rates in children treated with nebulized budesonide or ipratropium bromide over time in the hospital. Children treated with ipratropium bromide had significantly higher respiratory rates than those treated with budesonide at 24 and 36 hours (two asterisks) (Mann-Whitney test, P <.01) and 48 hours (asterisk) (Mann-Whitney test P <.05) after admission, as indicated.

4 702 Sano et al J ALLERGY CLIN IMMUNOL APRIL 2000 FIG 3. Percentage of patients staying in hospital over time among children with acute wheezing treated with either nebulized budesonide or ipratropium bromide. There was progressively lower percentage of patients remaining in hospital in budesonide group from 72 hours onward compared with ipratropium bromide group (chi-square test, P <.01) (two asterisks). fenoterol alone. 22 More recent studies have shown that a combination of ipratropium bromide and salbutamol reduced hospital admissions in patients with moderate to severe asthma exacerbations. 23,24 On the other hand, a recent trial has failed to demonstrate any incremental benefit resulting from adding ipratropium bromide compared with high doses of salbutamol for children with mild or moderate asthma attacks. 25 Other studies have suggested that therapy with inhaled corticosteroids is beneficial in controlling symptoms 4-6 and exacerbations of wheezing in these patients. An emergency department study of children with moderately severe asthma exacerbations revealed that the use of high doses of inhaled budesonide had similar efficacy to oral prednisolone, yet with a shorter onset of action. 26 In this study patients treated with budesonide did not have a decrease in serum cortisol levels, which occurred in the prednisolone-treated group. Similar studies in adults have reported clinical improvement and lack of changes in levels of biochemical markers of corticosteroidinduced suppression of the hypothalamic-pituitaryadrenal function, such as urinary cortisol and osteocalcin. 27 Our results demonstrate that nebulized budesonide has an additive effect when administered in conjunction with a bronchodilator and intravenous corticosteroid in the treatment of young children hospitalized with severe wheezing. The effect was superior to the administration of bronchodilators alone in conjunction with intravenous corticosteroid. In our study budesonide-treated children showed faster clinical improvement, as judged by the evaluation of accessory respiratory muscle use and respiratory rate. In addition, the 28.7% reduction in length of hospital stay seen in the budesonide-treated patients is relevant for reduction of the cost of care and decreasing the risk of acquiring nosocomial infections. Our results are in keeping with previous observations that treatment with inhaled budesonide reduces the length of hospital stay in young children with acute attacks of dyspnea and wheezing. 14 Our results suggest that inhaled corticosteroids may have a more efficient action on the underlying inflammation present in the airways of these young children with acute wheezing. 2,3 Alternatively, inhaled corticosteroids may have promoted an increased β 2 -adrenergic receptor function, resulting in a better response to β 2 -agonist drugs. 28 A study of children with bronchiolitis revealed that those who received either inhaled cromolyn or budesonide for 8 weeks after the acute episode had a reduction in the number of subsequent episodes of dyspnea and wheezing. 29 On the other hand, another study of children in a similar age range failed to demonstrate reduction in acute symptoms or prevention of wheezing in children treated with inhaled budesonide for 6 weeks after the acute episode of bronchiolitis. 30 In our study children did not receive any anti-inflammatory treatment after hospital discharge, and we have not found any differences in readmission to the hospital in patients treated with budesonide compared with those treated with ipratropium bromide. There were 3 readmissions of children from the budesonide group and 2 from the ipratropium bromide group within the 4-week follow-up period. In conclusion, our results showed that the addition of nebulized budesonide to a treatment regimen of inhaled bronchodilator and intravenous corticosteroid resulted in faster clinical improvement and reduction in the length of hospital stay in young children hospitalized for severe attacks of dyspnea and wheezing. Our results support the

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