The efficacy of nebulized salbutamol, hypertonic saline and salbutamol/hypertonic saline combination in moderate bronchiolitis

Pulmonary Pharmacology & Therapeutics The efficacy of nebulized salbutamol, hypertonic salineand salbutamol/hypertonic saline combination in moderate bronchiolitisq,qq Ilke Ozahı Ipek , Emek Uyur Yalcin , Rabia Gonul Sezer ,, Abdulkadir Bozaykut a Department of Pediatrics, Istanbul Medipol University, School of Medicine, Turkeyb Department of Pediatrics, Zeynep Kamil Maternity and Childrens Diseases Training and Research State Hospital, Tepegöz sok. Burhanettinbey apt. No:28/10, 34730, Göztepe-Çiftehavuzlar, Istanbul, Turkey Background: The mainstay of treatment in bronchiolitis includes oxygenation, aspiration of secretions from the respiratory tract and maintenance of hydration. The first choice medical agent in clinical practice is nebulized bronchodilators, although their place in treatment is controversial.
Objectives: We investigated the therapeutic benefit of nebulized hypertonic (3%) saline (HS), by comparing four different nebulized regimens in the treatment of bronchiolitis in the emergencydepartment.
Methods: A total of 120 infants were included in this randomized, double-blind, prospective study. Infants were grouped according to the nebulized treatment they received: group 1 - salbutamol þ normal saline (NS), group 2 - salbutamol þ HS, group 3 - HS, group 4 - NS. Heart beat, Clinical Bronchiolitis Severity Score (CBSS) and oxygen saturation of the patients were determined beforeand after the nebulizations and at 48e72 h after admission by the designated study physician.
Results: Post-treatment mean CBSS were significantly lower than pre-treatment scores in all groups(p ¼ 0.0001) with no significant difference within groups. Improvement percentages for CBSSs weresignificantly higher in infants without a history of atopy treated with HS and NS (p ¼ 0.023, p ¼ 0.0001,respectively).
Conclusions: The CBSSs of all the infants improved after three doses of nebulized therapy regardless of thetreatment regimens. The combination of salbutamol with hypertonic saline did not lead to an additiveeffect in the improvement of CBSSs compared to the standard salbutamol þ NS combination. Atopicchildren benefited from salbutamol/NS combination whereas non-atopic children improved with HS andNS nebulizations based on improvement percentages of CBSS.
Ó 2011 Elsevier Ltd. All rights reserved.
recommend the routine use of any medication for bronchiolitis, theuse of various medical therapies is still frequent . Besides Acute bronchiolitis is the most common cause of lower respi- supportive care, nebulized bronchodilators (salbutamol, epineph- ratory tract disease in infancy. The importance of the disease is rine, ipratropium bromide) and corticosteroids are commonly used associated with its high frequency, asthma-like clinical signs, and in clinical practice. Antiviral treatment (ribavirin), heliox, surfac- potential recurrence. The mainstay of treatment in bronchiolitis tant, cysteinyl leukotriene receptor antagonists and extracorporeal includes supportive care such as oxygenation, aspiration of secre- membrane oxygenation are also used in the treatment of bron- tions from the respiratory tract and maintenance of hydration.
chiolitis e. Since the efficacy and cost-effectiveness of the Despite current clinical practice guidelines, which do not treatment have recently become of great importance, any treat-ment that could decrease the severity of the disease with minimumcost is always preferred.
q The research was primarily done in Istanbul Zeynep Kamil Maternity and Hypertonic (3%) saline (HS) solution, by absorbing water from Children’s Diseases Training and Research State Hospital where Dr Ipek was also the submucosa and thereby decreasing edema, improves muco- ciliary function. It has been shown that HS in vitro and in vivo qq This study was presented in poster format in Excellence in Paediatrics 2010, accelerates mucus transport rates . Since HS is inexpensive, easy to acquire, and applicable for use for ambulatory patients, we * Corresponding author. Tel.: þ90 5335448313; fax: þ90 2163910677.
investigated the therapeutic benefit and safety of nebulized HS in 1094-5539/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi: I.O. Ipek et al. / Pulmonary Pharmacology & Therapeutics 24 (2011) 633e637 Family or individual history of atopy were defined as positive Evaluation of clinical bronchiolitis severity score.a when any of the parents, siblings or the patient has been suffering from asthma, allergic rhinitis, atopic dermatitis or any documented allergy. Supportive care including oxygen supplementation, aspi- ration, and hydration when necessary were provided to all patients.
Heart and respiratory rates of the infants were measured using a bedside monitor (SC 6002 XL Multiparameter Monitor; Siemens; Germany). Each of the 120 patients enrolled in the study was given 4 mL of a nebulized solution via a compressor nebulizer through a facemask with continued flow of oxygen at 4e5 L/min (Mini- compressor nebulizer, CN-02WD, Ace-Tec Co., Ltd., Guangdong, China). All eligible patients were randomly assigned to one of four groups according to the consecutive order of their admission to the short-stay unit: group 1 received 0.15 mg/kg salbutamol plus NS, group 2 received 0.15 mg/kg salbutamol plus HS, group 3 receivedonly HS and group 4 received only NS. The nebulized solution was the emergency department. In this study, The Clinical Bronchiolitis administered in a double-blind setting every 20 min until 3 doses Severity Scores (CBSSs) were compared based on the four different had been administered (0, 20 and 40th min). A second assessment treatment regimens and the atopy history of the infants.
was performed 20 min after the last nebulization (at 60th min). All We aimed to test the hypothesis that inhaled salbutamol and/or patients completed the treatment protocol, none of them with- HS would improve CBSS in infants with acute bronchiolitis. A secondary aim was to determine if the presence of atopy could The primary outcome for this study was the changes in CBSSs of each group after the treatment. Difference between pre- and post-treatment values were compared to pre-treatment values and defined as improvement percentage. Corticosteroid need, hospi-talization ratios, and clinical assessment at 48e72 h were also This double-blinded, randomized, controlled, clinical trial was assessed in the study. The decision of corticosteroid use and conducted between October 2009 and March 2010 in the short-stay hospitalization is made when CBSS deteriorated and/or arterial unit of the Pediatric Emergency Department of a training and oxygen saturation (SaO2) detected <85 on room air after the research hospital. Inclusion criteria were: age < 2 years, a history of treatment. Children necessitating hospitalization were continued preceding viral upper respiratory infection followed by wheezing on nebulized salbutamol/NS treatment and the others were dis- and crackles on auscultation, and a CBSS of 4e8 on admission charged without any treatment. Children were asked to return at (). Viral respiratory infection was diagnosed on clinical 48e72 h after the admission. All the children were reexamined at grounds. Exclusion criteria were: infants with CBSS <4 or >8, 48e72 h by the same physician and CBSSs were rescored.
oxygen saturation < 85% on room air, chronic cardiac illness, The secondary outcome was the comparison of the improve- premature birth, birth weight < 2500 g, history of recurrent ment percentages of children with and without a history of atopy.
wheezing episodes, proven immune deficiency, severe neurological Heart beat, CBSS and SaO2 of the patients were determined disease, age < 1 month or >2 years, consolidation or atelectasis on before and after the nebulizations and at 48e72 h after admission a chest roentgenogram. Signed informed consent was obtained by the designated study physician who was blinded to the contents from the parents of each infant and the study was approved by the Ethics Committee of Zeynep Kamil Maternity and Children’sTraining and Research State Hospital. A standard follow-up form, which included data on age, gender, cause of admission, type ofnutrition, number of household persons, exposure to tobacco The NCSS 2007 statistical software was used to analyze the data smoke, family or individual history of atopy, type of heating, Descriptive analyses were completed for the overall study response to treatment, necessity of corticosteroid administration population and for each group separately. Categorical variables and hospitalization was completed for each child.
were examined by Â2 test; one-way analysis of variance (ANOVA) Table 2Baseline clinical characteristics.
Family/Individual History of atopy [n(%)] I.O. Ipek et al. / Pulmonary Pharmacology & Therapeutics 24 (2011) 633e637 Table 3The comparison of the groups according to respiratory and heart beat rates, oxygen saturation and clinical bronchiolitis severity scores.
The statistically significant results are represented with bold.
and Tukey’s multiple comparison test were used for continuous Respiratory and heart rates, oxygen saturation and CBSS values variables. Groups with and without a history of atopy were of the groups were separately analyzed with regard to the presence compared using the ManneWhitney non-parametric U test. A p of a family or individual history of atopy. Atopic children benefited value < 0.05 for the two-tailed t test was considered statistically from salbutamol/NS combination whereas non-atopic children improved with HS and NS nebulizations based on improvementpercentages of CBSS ().
One hundred twenty infants (mean age 7.96 Æ 3.91 months) met Our study shows that combination of nebulized salbutamol with the inclusion criteria and were enrolled in the study. All patients NS or HS and administering HS or NS alone are all effective in were previously healthy e it was their first episode of wheezing.
decreasing the CBSS in the first attack of moderate bronchiolitis in Baseline clinical characteristics of the groups were shown in There were no significant difference between groups when To date, majority of the studies investigating the use of nebu- baseline age, gender, number of household persons, exposure to lized HS solution in bronchiolitis were conducted in hospitalized tobacco smoke, family or individual history of atopy, type of home infants. There are 3 previously published trials on the use of heating, type of nutrition and symptoms at the time of admission nebulized HS in bronchiolitis in ambulatory setting. In the first study published in 2002, the authors compared the utility of HS and Evaluating the socioeconomic factors, we found that the median NS with adjunctive terbutaline and concluded that aerosolized HS value for household populations was 5 persons (min ¼ 3; plus terbutaline is effective in decreasing symptoms as compared to max ¼ 10), that 60.8% of the patients were exposed to tobacco NS plus terbutaline in nonasthmatic, mild-to-moderate viral smoke, and that 45.8% were heating with coal stoves. The vast bronchiolitis . Differently from our study, the treatments were majority (83.3%) of subjects were breast-fed so it was not possible performed 3 times a day for 5 days. In another study conducted in to determine if there was a relationship between breast-feeding the emergency department setting, patients were randomized to receive nebulized racemic epineprine in either hypertonic ornormal saline . Although the co-administered bronchodilator was different from ours, the authors also reported no differentialbenefit for HS compared with NS similar to our result .
Reasoning from the hypothesis that a HS concentration >3% could 2 and CBSS values were evaluated at baseline and 20 min after the last nebulization. Baseline values of the be more efficacious, the authors compared the efficacy and safety of aforementioned parameters were not significantly different nebulized 5%, 3%, and 0.9% saline mixed with epineprine in between the groups (p > 0.05) ().
Post-treatment mean CBSS were significantly lower than pre- treatment scores in all groups (p ¼ 0.0001) with no significant The data concerning the necessity of corticosteroid administration, hospitalization ratios and clinical assessment at 48e72 h.
Pre- and post-treatment oxygen saturation levels were within normal limits in all groups so higher post-treatment values observed in groups 3 and 4 (p ¼ 0.0001 and p ¼ 0.037, respectively) The mean post-treatment heart rates were significantly lower in group 3 (p ¼ 0.044), while it was significantly higher in groups 1 and 2 treated with salbutamol (p ¼ 0.0001).
Of the 120 children, 13 were hospitalized and the rest were asked to return for reassessment at 48e72 h with no treatment.
1 - Clinical Bronchiolitis Severity Scores (CBSS) lower than post-treatment values.
Groups were compared for the necessity of corticosteroid admin- 2 - CBSS same as the post-treatment values.
istration, hospitalization ratios and clinical assessment at 48e72 h 3 - CBSS higher than post-treatment values.
I.O. Ipek et al. / Pulmonary Pharmacology & Therapeutics 24 (2011) 633e637 higher than baseline values in our NS and HS groups while the pre/ The comparison of the improvement percentages of respiratory and heart beat rates, post differences in the salbutamol groups were not significant. An oxygen saturation and clinical bronchiolitis scores of groups according to the explanation might be that the large decreases in SaO2 were observed in only a few patients and so the post-treatment mean Improvement percentage Improvement percentage p SaO2 value was not deeply affected. And as patients with moderate bronchiolitis had normal SaO2 levels at baseline, this was a limita- tion about evaluating the improvement in saturation.
A majority of the studies and meta-analyses comparing the efficacy of b2-agonist nebulization with other bronchodilators and placebo did not recommend the routine use of b2-agonist nebuli- zation in bronchiolitis e. In a systematic review of the effectiveness of commonly used treatment regimens for bron- chiolitis, King et al. reported that there were no signi differences in outcome measures such as the decision to hospitalize and the duration of hospitalization between b2-agonist recipients and controls. Tachycardia and temporarily decreased SaO2 were reported as adverse effects of treatment with the same review. Tachycardia was also observed in group 1 and 2, but was not detected in NS and HS groups.
RR: Respiratory rate, SatO2: Oxygen saturation, HR: Heart beat rate, CBS: Clinical values for all treatment groups, but no significant difference was The statistically significant results are represented with bold.
detected between the groups. This means that salbutamol and HSare no more effective than NS in improving CBSS, and combiningthem does not produce any additive benefit.
a recently published study (2010) and found 5% HS superior to 3% Despite lack of evidence for their efficacy, corticosteroids are HS and NS for improving the bronchiolitis severity score used in the management of bronchiolitis on the basis of the The effect of nebulized HS in improving clinical score was found suggestion that the anti-inflammatory action of corticosteroids to be greater among outpatients than inpatients Although no might alleviate the symptoms of bronchiolitis. In line with the adverse event related to HS nebulization was reported, the authors findings of a meta-analysis describing a statistically significant suggested the use of the salbutamol/HS combination as a possible improvement in clinical symptoms, length of hospital stay, and way to avoid the potential bronchospasm effect of HS in patients for duration of symptoms on the course of bronchiolitis with cortico- whom asthma was not ruled out On the other hand, higher steroids, we also used steroids in case of clinical deterioration .
concentrations (5%, 7%) of nebulized HS solutions were also In our study, corticosteroid need, hospitalization ratios and clinical considered safe . All HS recipients in our study group assessment at 48e72 h were not statistically significant when the completed the treatment protocol without bronchospasm, aggra- vated wheezing or cough, so we suggested that HS is a safe treat- Bronchodilator responsiveness is a feature of asthma so the ment for infants with moderate bronchiolitis.
beneficial effect of salbutamol only in infants with a history of atopy The place of nebulized bronchodilators in treatment of bron- may be attributed to the presence of bronchoconstriction. The chiolitis is controversial. Some authors reported that bronchodila- relationship between atopy and bronchodilator responsiveness has tors were as effective as an oral placebo in the management of been discussed in many studies . Chavasse et al. re- bronchiolitis, while others found it safe and effective in relieving the ported no beneficial effect of salbutamol in atopic infants but their respiratory distress of young infants A Cochrane review of study group consisted of infants with well documented persistent or bronchodilators for bronchiolitis stated that they provide small, recurrent wheeze. Our study included infants with acute moderate short-term improvements in clinical scores. Thus, the decision to bronchiolitis which may be reason for the different results.
use bronchodilators should be made by weighing this small benefit Young non-atopic wheezers were proposed to have poor lung against the costs and adverse effects of these agents Further- function with structural changes that predispose to wheezing with more, Hofhuis et al. determined that inhaled beta-2 agonists viral infection . Non-atopic infants with smaller airways would cause a significant reduction in mean forced expiratory flow rates in be expected to demonstrate high airways resistance. Reticular infants with recurrent wheezing. In our study group, which did not basement membrane thickening and eosinophilic inflammation, include any recurrent wheezers, no significant difference was which are characteristics of asthma, were not present in the airway detected between salbutamol/NS, salbutamol/HS, HS and NS groups pathology of atopic infants with reversible airflow obstruction .
for post-treatment values of respiratory rate, oxygen saturation and Atopic children responding to bronchodilator treatment better than CBSS. Additionally, we compared the response to four treatment nonatopics may also be related to the smaller airways of non-atopic protocols of patients with and without individual or family histories of atopy. Contrary to the previous reports, we observed that with Our study has some limitations. Since the study was conducted nebulized salbutamol/NS, improvement percentages of respiratory in a single-center setting in infants with moderate bronchiolitis, the rate and CBSS were higher in infants with a history of atopy .
results could not be generalized to all infants with bronchiolitis.
This difference might be associated with the characteristics of the The same results might not have been seen if the infants with study groups as the mentioned studies were conducted on persis- severe bronchiolitis had enrolled the study group.
Ho et al. observed desaturation after salbutamol and saline nebulization. The decrease in SaO2 was greater and more prolongedwith salbutamol than with saline. They concluded that salbutamol A combination of salbutamol with HS instead of NS (the control) nebulization during acute bronchiolitis cannot be recommended does not provide any additive benefit in the improvement of CBSS . The mean post-treatment SaO2 values were significantly compared to the control group. In infants with a history of family I.O. Ipek et al. / Pulmonary Pharmacology & Therapeutics 24 (2011) 633e637 atopy, improvement percentages for respiratory rate and clinical [11] Al-Ansari K, Sakran M, Davidson BL, El Sayyed R, Mahjoub H, Ibrahim K.
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