Pediatrics International (2004) 46, 539544

Original Article

Additive effects of dexamethasone in nebulized salbutamol or L-epinephrine treated infants with acute bronchiolitis
SEMANUR KUYUCU, SELMA UNAL, NECDET KUYUCU AND ESAT YGLGOR Department of Pediatrics, Faculty of Medicine, Mersin University, Mersin, Turkey
Abstract Background: Although it is the most common lower respiratory infection of infancy, the optimal treatment for acute bronchiolitis is still controversial. The aim of this study was to compare the early and late effects of nebulized L-epinephrine (EPI) and intramuscular dexamethasone (DEX) combination therapy with nebulized salbutamol (SAL) and dexamethasone combination and bronchodilators alone in outpatients with acute bronchiolitis. Methods: A total of 69 infants aged 221 months who were admitted to the Pediatrics Department of the Faculty of Medicine, Mersin University, with acute bronchiolitis were included in a randomized, placebocontrolled, prospective trial study. Patients were assigned to receive either nebulized L-epinephrine (3 mg) or salbutamol (0.15 mg/kg) and 15 min later, either dexamethasone 0.6 mg/kg or placebo (PLA), intramuscularly, in a double-blind randomized fashion. The study groups were: epinephrine + dexamethasone group (group 1, n = 23), salbutamol + dexamethasone group (group 2, n = 23), epinephrine + placebo group (group 3, n = 11), and salbutamol + placebo group (group 4, n = 12). The outcome measures were heart rate, respiratory rate and Respiratory Distress Assessment Instrument (RDAI) score determined at 30, 60, 90 and 120 min, 24 h, and 5 days after the first therapy. Patients were then followed-up during the subsequent 2 months for the prevalance of respiratory complaints regarding bronchial hyperreactivity. Results: There were no significant differences between the outcome variables of the four groups within the first 120 min and at 24 hours, or between the rates of requirement of a second dose of the same bronchodilator. However, fifth day RDAI score values of both DEX groups were significantly lower than that of SAL + PLA group (P = 0.000 and P = 0.01, respectively). The fifth day score value of group 1 was also significantly better than that value of EPI + PLA group but not different from group 2. Conclusions: A single dose of intramuscular dexamethasone added to nebulized L-epinephrine, or salbutamol therapies resulted in better outcome measures than bronchodilators alone in the late phase (fifth day) of mild to moderate degree bronchiolitis attack. However, effects of EPI + DEX combination was not different from SAL + DEX combination. bronchiolitis, dexamethasone, L-epinephrine, salbutamol.

Key words

Acute bronchiolitis is the most common lower respiratory tract infection of infancy. Although signs and symptoms may be serious, most infections are self-limited and improvement occurs within several days. Approximately 12% of affected infants less than one year of age require hospitalization.1 Treatment of hospitalized patients with bronchiolitis includes supportive measures, such as supplementary oxygen and adequate hydration in addition to antiviral chemotherapy in
Correspondence: Semanur Kuyucu MD, Mersin University Faculty of Medicine, Department of Pediatrics, Zeytinlibahe, 33079, Mersin, Turkey. Email: semanurkuyucu@yahoo.com Received 14 July 2003; revised 19 January 2004; accepted 26 February 2004.

selected cases.13 The optimal therapy for bronchiolitis is controversial. Although some studies suggest a positive response to 2-agonists,2,4,5 many reports discourage their use because of the lack of a proven therapeutic effect.68 The pathophysiological changes that occur during acute bronchiolitis are inflammatory obstruction in the small airways with submucosal edema, cellular infiltration, epithelial necrosis, and mucous plugging. It is not yet understood to what degree the bronchoconstriction (or smooth muscle contraction) contributes to the obstruction of airways during acute viral infection.9 Treatment with a combined and agonist and/or steroids should theoretically be beneficial.10 Some clinical trials have shown epinephrine to be superior to placebo and/or salbutamol in acute bronchiolitis.1113

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room air for at least 15 min. The RDAI score is based on two respiratory variables, wheezing and retraction, and is scored using the following scales: expiratory wheezing (04 points); inspiratory wheezing (02 points); location of wheeze (02 points); supraclavicular retraction (03 points); intercostal retraction (03 points); and subcostal retraction (03 points).16 The same patient was assessed by two independent observers and the mean of the two scores was used for data analysis. Eligible patients were randomly assigned to receive either 0.15 mg/kg of a 1-mg/mL solution of salbutamol (Ventolin) added to 0.9% saline solution to make a total of 3 mL, or 3 mL (3 mg) of 1 : 1000 L-epinephrine (Epinephrine) solution. Solutions were given through a compressed type nebulizer (Medic-Aid Ltd, West Sussex, UK) with continuous flow of oxygen 56 L/min for 10 min. Fifteen minutes following the administration of both nebulized medications, dexamethasone 0.6 mg/kg, or a placebo was given intramuscularly in a randomised fashion independent of the first randomization. Medication doses were based on previous clinical trials in patients with either bronchiolitis or croup.2,5,11,15 Preparation and administration of nebulized solutions were performed by a trained emergency department nurse. Parents and investigators remained blinded to administered medications throughout the study period. The clinical assessment was performed on admission and repeated 30, 60, 90 and 120 min after the first treatment. If the patients had not experienced an improvement in the RDAI score of at least 4 points by 120 min, they were given the same medications (epinephrine or salbutamol) in the same doses again and reassessment was then performed 30 and 60 min after the second dose. After the completion of the first part of the study the patients were discharged and reassessed at 24 hours, and 5 days later by the same observer (N.K.). In addition, they were followed-up by regular hospital visits during the subsequent two months in regards to respiratory complaints such as exercise-induced cough and wheezing. For continuous variables, an independent two-tailed t-test was performed by using pooled or separate variance estimates as appropriate. Dichotomous events were analyzed by using the chi-squared test. All statistical analyzes were conducted with SPSS for Windows, Release 10.0 (SPSS 19891992).

Tal et al. showed that combined salbutamol and dexamethasone treatment significantly improved the clinical condition of infants hospitalized with acute wheezing.14 However, Klassen et al. did not find an adjunctive effect of oral dexamethasone therapy on the clinical course of salbutamoltreated inpatients with acute bronchiolitis.15 To our knowledge, corticosteroid and epinephrine combination has not been evaluated before in the therapy of acute bronchiolitis. The aim of our study was to compare the short and long-term effects of nebulized L-epinephrine and intramuscular dexamethasone combination therapy with nebulized salbutamol and dexamethasone combination and bronchodilators alone in outpatients with acute bronchiolitis.

Patients and Methods

The study was conducted in pediatric outpatient clinics and the emergency department of the Faculty of Medicine, Mersin University, during the winter months. Patients were eligible for the study if they met the following criteria: aged between 2 and 21 months; they were admitted with their first episode of wheezing; clinical findings compatible with acute bronchiolitis (acute onset wheezing with or without cough, tachypnea, and increased respiratory effort, accompanied by clinical evidence of a viral illness such as coryza and fever); and Respiratory Distress Assessment Instrument (RDAI)16 score 4. Patients were excluded from the study if they had: a history of prior wheezing; previous treatment with bronchodilators; a previous diagnosis of asthma or allergic bronchitis by a physician; a personal history of atopic dermatitis or allergic rhinitis; any chronic cardiac or pulmonary disease; any steroid treatment within the previous 2 weeks; signs of severe respiratory disease as evidenced by a pulse rate 200 beats/min, a respiratory rate of 100 breaths/min, a RDAI score of 15, or profound lethargy; clinical and/or radiological evidence of a bacterial infection; or a parental history of asthma or atopic disease. Informed consent was obtained in all cases and the study was approved by the research ethics committee of the hospital. Enrollment occurred between approximately 08.00 hours and 17.00 hours when, after the initial assessment, the attending pediatrician called one of the investigators. History regarding the recent symptoms, duration of illness, infectious contact, recent similar symptoms of the siblings, smoking habits of the parents and socioeconomic status were obtained from parents. A complete physical examination, complete blood counting and chest X-rays were performed. Primary outcome measures included respiratory rate, heart rate and RDAI score, which were assessed by investigators when the infants were relatively calm and had been breathing

Results
A total of 69 children, aged 221 months, completed the total study duration of 5 days. The distribution of participants according to study groups were as follows; epinephrine + dexamethasone group (group 1, n = 23), salbutamol + dexamethasone group (group 2, n = 23), epinephrine + placebo group (group 3, n = 11), and salbutamol + placebo group

Dexamethasone in bronchiolitis
Table 1 Admission characteristics of the study groups EPI + DEX (n = 23) Age (mo) Temperature (C) Duration of illness (d) Sibling history Passive smoking 7.2 0.8 37.7 0.1 2.5 0.1 6 (26%) 18(78.2%) SAL + DEX (n = 23) 7.9 1.0 37.4 0.1 3.5 0.3* 3 (13%) 19(82.6%) EPI + PLA (n = 11) 9.6 1.3 37.3 0.2 2.6 0.2 5(50%) 8(72.5%) SAL + PLA (n = 12) 9.9 1.7 37.4 0.1 2.6 0.2 2 (16.7%) 8 (66.7%)

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EPI, nebulized epinephrine; DEX, dexamethasone im; SAL, nebulized salbutamol; PLA, placebo im. Values are expressed as mean SEM and n (%); recent similar symptoms among siblings. *Signicantly different from group 1, P < 0.01.

Table 2 Variable

Comparison of outcome variables at different time points EPI + DEX (n = 23) 148.5 2.7 134.5 3.3 130.9 2.2 121.7 1.3 72.2 1.94 48.2 1.3 44.9 2.4 33.1 1.2 7.3 0.2 3.8 0.2 3.4 0.2 2.3 0.1** SAL + DEX (n = 23) 141.8 3.2 135.0 2.5 134.2 2.7 123.7 1.7 69.6 1.95 50.6 2.2 49.0 2.7 37.7 1.8 7.2 0.2 4.0 0.3 3.9 0.3 2.5 0.1* EPI + PLA (n = 11) 144.5 3.3 138.6 2.3 131.6 3.1 125.4 2.4 68.0 2.6 49.6 2.9 44.2 3.2 36.5 2.3 7.4 0.1 4.2 0.3 3.7 0.3 2.9 0.2 SAL + PLA (n = 12) 149.0 3.7 138.2 3.1 132.8 2.0 128.5 2.6 66.5 3.2 45.6 1.9 42.0 2.5 41.1 2.9 7.7 0.1 4.4 0.4 3.8 0.3 3.4 0.2

Heart rate (beats/min) Baseline 120 min 24th hour 5th day Respiratory rate (breaths/min) Baseline 120 min 24th hour 5th day RDAI score Baseline 120 min 24th hour 5th day

All values are expressed as mean SE. *Signicantly different from group 4 (P = 0.01); **signicantly different from group 3 (P = 0.02) and group 4 (P = 0.000).

(group 4, n = 12). Three patients from group 1, one patient from group 2, eight patients from group 3 and nine patients from group 4 did not come to control visits on either the 24th hour, or fifth day and hence, were not included in the analysis. The reasons for drop-outs were not known. The four groups were similar with respect to age, temperature, baseline clinical measurements and RDAI scores (Tables 1 and 2). The disease duration before admission in group 2 was longer than group 1, but it was similar for the other groups When the response to therapy was evaluated longitudinally within each of the groups, the 120th minute hearth rate, respiratory rate and RDAI score values were found to be significantly better than the baseline values of these parameters for every group (P < 0.05). The 90-minute heart rate value (137.6 2.6) of group 2 was significantly lower than that (144.1 1.5) of group 3 (P = 0.04). Other heart rate, respiratory rate, and RDAI score values of all groups at 30, 60, 90 and 120 min were similar (P > 0.05) (Table 2). Fifth day RDAI score value of group 1

[2.3 0.1(mean SE)] was significantly lower than group 3 (2.9 0.2) and group 4 (3.4 0.2) (P = 0.02 and P = 0.000, respectively). The fifth day score value of group 2 (2.5 0.1) was also significantly better than group 4 (P = 0.01) and, though not statistically significant, group 3 (P = 0.09). The fifth day RDAI score values of group 1 and group 2 were not significantly different. A second dose of same medication (epinephrine or salbutamol) was given to five (21.7%) patients from group 1, eight (34.8%) patients from group 2, five (45.4%) patients from group 3 and four (33.3%) patients from group four, since they did not show a substantial (4 points) improvement in RDAI score at 120 min. There were no significant differences between the retreatment rates of each group (P > 0.05). All of these patients showed a decrease 4 points in their scores 60 min after the second dose of medication when compared to the score at baseline. None of the patients in any group required hospitalization. During the subsequent two months, 17 patients from group 1, 16 patients from group 2, and a total of 13 patients

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had more beneficial effects than salbutamol on clinical index and pulmonary mechanics in acute bronchiolitis. Two recent reports comparing nebulized epinephrine and/or nebulized salbutamol to placebo in moderate to severe bronchiolitis revealed that these bronchodilators were no more effective than placebo.19,20 We could not find any significant differences between the short-term RDAI scores and single physiologic variable values of salbutamol and epinephrine-treated groups. However, both treatment modalities were equally effective in improving these parameters from baseline values. A virushost immune system interaction through the respiratory airways during viral infection results in inflammation of the small airways with cellular infiltration and secretion of inflammatory substances such as virus-specific IgE, free O2 radicals, arachidonic acid metabolites, histamine and eosinophil cationic protein (ECP).9,2123 Leucotriene C4 was demonstrated in nasopharyngeal secretions of infants with acute bronchiolitis reaching peak levels 38 days after the onset of the illness.24 This inflammatory process have an important role in the pathogenesis of acute bronchiolitis, and is not only responsible for the acute stage, but also for the late effects such as postbronchiolitis wheezing and airway hyperreactivity.9,23,25,26 A recent in vitro study has demonstrated the inhibitory effects of fluticasone propionate on RSV-induced increases of IL-8 and RANTES (regulated on activation, normal T expressed and secreted).27 These findings relevant to inflammation form the rationale in favor of anti-inflammatory treatment, namely glucocorticoids, in acute bronchiolitis. The results of studies about the efficacy of corticosteroids in acute bronchiolitis remains controversial. Some studies showed that parenteral or oral steroids, alone or together with salbutamol, had no significant effect on the outcome measures in infants hospitalized with bronchiolitis.15,28,29 However, long-term follow-up of these patients after the acute attack were not performed. Cade et al. found no significant differences in the late and long-term outcome measures of acute RSV bronchiolitis treated with inhaled steroids.30 Age of the patient is one of the important determinants of the response to steroids. Martinez et al. demonstrated the correlation between intrinsically smaller airways or preexisting impaired lung function with an increased frequency of wheezing in infancy.31 Infants and children <2 years of age who wheeze because of intrinsically smaller airways can be expected to be less responsive to steroid effects than others. However, those with a combination of congenitally smaller airways and further obstruction caused by the release of inflammatory mediators might show, at least partly, relief or prevention of inflammation as a response to corticosteroids. Tal et al. reported that a combination of salbutamol and dexamethasone was significantly superior to salbutamol alone, dexamethasone alone, or placebo suggesting a synergistic
L-epinephrine11

from group 3 and group 4 were followed-up. Four patients (23.5%) from the epinephrine + dexamethasone group, three patients (18.8%) from salbutamol + dexamethasone group and six patients (46.2%) from the placebo group showed respiratory complaints such as exercise-induced cough and mild wheezing. Although these symptoms were more prevalent in patients who were given placebo + bronchodilator than in those treated with dexamethasone plus epinephrine or salbutamol, the differences were not statistically significant. No side-effects such as pallor, vomiting or tremor were encountered in the patients.

Discussion
This prospective double-blind placebo-controlled trial showed that a single dose of dexamethasone added to nebulized L-epinephrine or salbutamol treatments on admission resulted in better outcome measures than bronchodilators alone, on the fifth day after intervention in mild to moderate cases of acute bronchiolitis. However, bronchodilator plus dexamethasone regimens were not superior to bronchodilators for the first two hours or at the 24th hour. Neither nebulized L-epinephrine nor salbutamol was more beneficial than the other. One of the limitations of this study was the relatively small number of patients in the placebo groups. Either treatment failure or treatment success may have led to the reluctance of patients in the placebo group to return for follow-up. However, the highly significant statistical differences between dexamethasone and placebo groups may overcome this issue. Studies examining the effectiveness of bronchodilators in bronchiolitis have shown variable and conflicting results.2,5,8,1113 Some reports have demonstrated that short-term effects of either nebulized salbutamol or epinephrine were better than placebo in the treatment of acute bronchiolitis.2,4,5,12,14 Other studies did not show a significant improvement in clinical scores, SaO2 or pulmonary mechanics with regular nebulized salbutamol in bronchiolitis.68,13,17 However, these studies exclusively included hospitalized patients, and one study used only oxygen saturation as the primary outcome measure.6 Recently, a meta-analysis evaluating eight randomized controlled trials of inhaled 2-agonists in bronchiolitis could not determine any evidence that conclusively supported the efficacy of 2-agonist therapy for bronchiolitis.18 Studies evaluating the effects of nebulized epinephrine on bronchiolitis have shown more encouraging results. Nebulized racemic epinephrine or L-epinephrine resulted in significant clinical improvement, lower hospitalization rates, and/or significant improvement in pulmonary resistance.1113 Two of these studies have found that nebulized racemic epinephrine13 and

Dexamethasone in bronchiolitis
effect of this combination on clinical improvement in infants with acute wheezing.14 They reported that no differences in the course of the disease or response to treatment had been found between infants who were diagnosed with asthma and those diagnosied with bronchiolitis. Sheth et al. showed that dexamethasone reversed the chronic virus-induced airway obstruction characterized by airway hyperreactivity, increased production of airway eicosanoids and increased number of bronchiolar mast cells in experimental rats.25 Reijonen et al. demonstrated that early anti-inflammatory therapy with nebulized budesonide or with cromolyn sodium significantly decreased wheezing episodes after bronchiolitis.26 Those children with high nasopharyngeal ECP concentrations (>870 ng/g) benefited especially from anti-inflammatory therapy.21 A recent meta-analysis investigating the role of systemic corticosteroids in infants hospitalized with an attack of bronchiolitis, most of whom were experiencing their first attack, revealed a statistically significant improvement in clinical symptoms, length of stay and duration of symptoms.32 They found that the response rate was better in those with higher symptom scores at admission. There is further evidence supporting the hypothesis that the likelihood of response to corticosteroids increases with severity of the disease.33 These data may explain the lack of a significant additive response by intramuscular dexamethasone in the early phase of our study which included mild to moderate cases not requiring hospitalization. However, the dexamethasone-treated groups of the present study showed significantly lower score values on the fifth day examination, when compared to placebotreated groups. Hence, beneficial effects of parenteral dexamethasone treatment may be more pronounced in the late phase of the disease among milder bronchiolitis cases. The rationale for using intramuscular dexamethasone is that it's quickly absorbed when given intramuscularly, achieving high plasma levels within 15 min and has a higher potency than other corticosteroids. However, clinical effects may peak after 34 h and dexamethasone has a long half-life of 3672 h.27,34 Therefore, a single dose of dexamethasone should be sufficient for a bronchiolitis attack. For research purposes, bronchiolitis is often defined as first time wheezing associated with clinical evidence of a viral infection in infants.4,11 However, some of these children are infantile asthmatics who will continue to wheeze therafter, and this is difficult to predict when they are first seen. Castro-Rodriquez et al. have developed a clinical index to define the risk of asthma in early wheezer infants.35 A loose index required any wheezing in the first 3 years of life plus two major criteria (parental asthma and physiciandiagnosed atopic dermatitis), or one major and one minor criteria. This index gave a specifity of 84.7% and a negative predictive value of 73.2%. Since our trial excluded infants with recurrent wheezing, family history of atopic disease,

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personal history of atopic disease and wheezing without colds, we can predict that at least 75% of our study group will not develop asthma. Hence, the significant clinical improvement obtained by bronchodilator therapies during the first few hours and the late beneficial effects of dexamethasone adjunctive therapy cannot be explained by an response of the asthmatic effect in the present study. In conclusion, a single high dose of intramuscular dexamethasone given as adjunctive to nebulized bronchodilators early in the course of mild to moderate bronchiolitis cases may diminish the ongoing inflammatory processes which are responsible for the late effects of the infection and hence, result in a more favorable and shortened disease process. However, larger studies including acute bronchiolitis cases with varying degres of severity are needed in order to determine the differential effects of corticosteroids according to severity and phase of the disease.

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