Effectiveness of erdosteine, a second generation mucolytic agent, in children with acute rhinosinusitis: a randomized, placebo controlled, double-blinded clinical study PDF

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Acta Pædiatrica ISSN 0803–5253 REGULAR ARTICLE Effectiveness of erdosteine, a second generation mucolytic agent, in children with acute rhinosinusitis: a randomized, placebo controlled, double-blinded clinical study E Unuvar ([email protected])1, Z Tamay1, I Yıldız1, S Toprak2, A Kılıc3, S Aydın...

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Acta Pædiatrica ISSN 0803–5253

REGULAR ARTICLE

Effectiveness of erdosteine, a second generation mucolytic agent, in children with acute rhinosinusitis: a randomized, placebo controlled, double-blinded clinical study E Unuvar ([email protected])1, Z Tamay1, I Yıldız1, S Toprak2, A Kılıc3, S Aydın1, G Kılıc1, N Guler1, F Oguz3, M Sıdal3 1.Department of Pediatrics, Istanbul School of Medicine, Istanbul University, Capa, Istanbul, Turkey 2.Department of Forensic Medicine, University of Gazi Osman Pas¸ a, Tokat, Turkey 3.Department of Pediatrics, Institution of Child Health, Istanbul University, Capa, Istanbul, Turkey

Keywords Children, Erdosteine, Infection, Mucolytic, Rhinosinusitis

Abstract Aim: To evaluate whether mucolytic agents have an adjuvant role with antibiotics in the treatment of children with rhinosinusitis. Methods: Ninety-two children with rhinosinusitis were recruited for this randomized, placebo

Correspondence Emin Unuvar, Tunusbagi Caddesi, Melek Isik Ap. No 6 D 3 Dogancilar, Uskudar, TR-34605, Istanbul, Turkey. Tel: +90 536 359 9526 | Fax: +90 212 531 0529 | Email: [email protected]

was administered to 49 children, and 43 children received placebo. Changes in symptoms were

Received 30 June 2009; revised 14 November 2009; accepted 23 November 2009.

40 in the placebo group. The average S5 scoring value at the onset of study was 11.0 in treatment group and 12.1 in placebo group. On day 14, mean scores were 3.1 in the treatment group and 2.8

DOI:10.1111/j.1651-2227.2009.01646.x

controlled, double-blinded clinical trial. Mean age was 8.5 ± 3.2 years. Erdosteine (5–8 mg ⁄ kg ⁄ day) recorded with the standard S5 scoring for 14 days. Complete resolution of symptoms on day 14 was considered to be clinical improvement. Results: Eighty-one participants completed the study. Forty-one were in the treatment group and

in the placebo group. Complete improvement was 78% in the treatment group and 74.4% in the placebo group. There was no significant difference between the groups. There were no clinically detected serious side effects or complications in both groups. Conclusion: Use of erdosteine as a mucolytic agent in children with acute rhinosinusitis does not directly affect the success of treatment.

INTRODUCTION Acute rhinosinusitis is a common infection that occurs after a viral upper respiratory tract infection in 10–15% of patients (1,2). Although rhinosinusitis commonly causes morbidity, it rarely results in mortality. The diagnosis of sinusitis in children mainly depends on clinical symptoms (3,4). Antibiotics are effective in the treatment of sinusitis, and they significantly improve the clinical outcomes compared with placebo groups (5,6). However, other studies demonstrated minimal efficacy of antibiotics in the treatment of acute rhinosinusitis (7–9). The differences in the outcomes of these clinical trials are likely because of the heterogeneity of the patients’ clinical presentations. It is now clear that patients with severe symptoms benefit from antibiotherapy. Antibiotics improve the symptoms, radiological findings and prognosis of the acute rhinosinusitis (10). The effectiveness of adjuvant therapies in addition to antibiotics is not clear in paediatric age group (11). Nasal saline irrigation may provide relief for a short period of time, but this effect is not different compared with placebo (12). Nasal corticosteroids, decongestant drugs, mucolytic agents, inhibitors of leukotrienes are commonly prescribed, but none of them offers additional benefit in the treatment

of rhinosinusitis (1,13). Topical steroids are only effective in chronic allergic rhinitis (14). In the medical literature, the adjuvant effect of mucolytic agents in childhood rhinosinusitis is not well documented (1–4). The aim of our study is to evaluate whether mucolytic agents have an adjuvant role with antibiotics in the treatment of children with rhinosinusitis. This randomized, placebo controlled, double blinded clinical trial was planned to determine the effect of erdosteine, a mucolytic agent, in children with clinically diagnosed rhinosinusitis.

METHODS Patient population and institution This clinical trial was carried out among children who were between 3 and 12 years of age and were clinically diagnosed to have acute rhinosinusitis from October 1, 2007 to May 31, 2008 in the outpatient clinic of Department of Pediatrics at Istanbul Faculty of Medicine. The research clinic is a university paediatrics clinic where paediatric patients are cared. Our trial was planned and carried out in full compliance with CONSORT regulations harbouring the basic principles of randomized drug trials (15).

ª2009 The Author(s)/Journal Compilation ª2009 Foundation Acta Pædiatrica/Acta Pædiatrica 2010 99, pp. 585–589

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Mucolytic agent in rhinosinusitis

Unuvar et al.

Eligibility criteria for participants Patients older than 3 years of age presenting to the Pediatrics Outpatient Clinic during working hours (9 am–4 pm) and diagnosed with acute rhinosinusitis were consecutively enrolled. Participants suitable for the trial were included in the study. Inclusion criteria were as follows: (1) Age older than 3 years and younger than 12 years; (2) symptoms of upper respiratory tract infection (running nose, cough, fever etc.) lasting longer than 10 days and not exceeding 30 days; (3) presence of severe symptoms of marked rhinosinusitis including fever of 39C, purulant anterior or retronasal rhinitis, halitosis, tender sinuses on palpation, facial asymmetry and orbital oedema; (4) not diagnosed and treated with antibiotics within the last 30 days; (5) absence of diagnosis of chronic rhinosinusitis; (6) absence of serious malformations in the nose and sinuses; (7) absence of chronic diseases such as cystic fibrosis, respiratory tract allergy, immune deficiency and diabetes; (8) absence of an illness severe enough to require hospitalization; (9) no history of allergy to erdosteine; and (10) family signed consent form. Trial plan Qualified participants were randomized into two groups: group 1 took erdosteine, and group 2 received placebo. Erdosteine, which has mucolytic properties, is licensed for use in children in Turkey. Mucolytic agents are useful in decreasing the viscosity of mucus. In addition, erdosteine has antioxidant properties (16–18). Erdosteine was chosen because of its availability in syrup form, twice daily dosage and its favourable taste. Erdosteine was orally administered in the suspension form (Erdostin suspension; Sandoz Drug GmBH, Istanbul, Turkey; 175 mg ⁄ 5 mL) in two divided doses (daily dose is 5–8 mg ⁄ kg for children). Placebo drug samples had similar taste and size but did not contain erdosteine. The aim of this clinical trial was primarily to determine the activity of mucolytic agents (1) in the relief of symptoms and (2) in clinical cure. Both drugs and placebo drug samples were prepared and provided by Sandoz Drug GmBH. Both doctors evaluating the patients and participant families were blinded to the group assignment. Clinical scoring At the onset of the study, the clinical examination of the patients was carried out by the senior physician. The S5 scoring system, which has been used previously, was used for clinical scoring. The five symptoms of rhinosinusitis (nasal obstruction, day cough, night cough, headache or facial ache and coloured nasal discharge) were taken as the S5 criteria previously used (7). On the scale, symptoms were graded as 0 no symptoms, 1 moderate problem, 2 a severe condition and 3 extremely severe condition. The patients were asked to score their symptoms every day during the treatment. The patient responses were ‘always the same’, ‘a little better’, ‘getting better’, ‘good’, ‘very good’, ‘bad’ or ‘very bad’. Good or better was evaluated as improvement, no problems left as complete cure, not good ⁄ always the same as failure of treatment. The patients were examined for a total of three times (at the onset, 3rd

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and 14th day of study) by a physician (Dr. I.Y.) during their follow-up, and signs of sinusitis were recorded. Improvement of symptoms, which were present at the initial examination, was also evaluated objectively. S5 scoring, a subjective criterion, was also tested objectively with clinical findings. On day 14, decrease in S5 score, complete improvement of clinical findings and complete disappearance of all the complaints were accepted as cure, and doing better as improvement. Randomization method Subjects fulfilling the inclusion criteria and providing voluntary consent were randomized according to list prepared in a computerized medium regarding the sample size. The entire randomization list was kept secret until the completion of trial numbers. Placebo drug Placebo drugs were prepared by the same drug company (Sandoz Drug GmBH). Placebo samples were undistinguishable from their bottles. The enrolling patients, their families, doctors and statistician were all blind to the drug groups. Carrying out the trial Randomized patients had their physical examinations on enrolment day (Dr. I.Y.) and re-examined on the day 3rd and 14th days of the treatment period. The evaluation was made according to clinical scoring with the likert scale previously used in rhinosinusitis trials in the literature. After the clinical evaluation, the families filled in scoring table given to them every day throughout the trial period (14 days). Evaluation results for each symptom were taken into consideration in the follow-up. Study was monitored for methodology regularly. Outcome measures As primary success criteria, complete disappearance of initial symptoms on day 14 of follow-up was regarded as cure, presence of some symptoms accepted as improvement and persistence of all symptoms was failure of treatment. Observation of an unexpected or unpredictable condition was defined as a complication. Patient compliance to treatment and drug adverse effects were taken as secondary success criteria. While drug adverse effects were defined as unexpected effects that can be related to the drug during the treatment, compliance to treatment was accepted as missing the drug dose...