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R E G U L A R A R T I C L E

Effectiveness of erdosteine, a second generation mucolytic agent, in childrenwith acute rhinosinusitis: a randomized, placebo controlled, double-blindedclinical studyE Unuvar ([email protected])1, Z Tamay1, I Yldz1, S Toprak2, A Klc3, S Aydn1, G Klc1, N Guler1, F Oguz3, M Sdal3

1.Department of Pediatrics, Istanbul School of Medicine, Istanbul University, Capa, Istanbul, Turkey2.Department of Forensic Medicine, University of Gazi Osman Pas a, Tokat, Turkey3.Department of Pediatrics, Institution of Child Health, Istanbul University, Capa, Istanbul, Turkey

Keywords

Children, Erdosteine, Infection, Mucolytic,Rhinosinusitis

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]

Received

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

DOI:10.1111/j.1651-2227.2009.01646.x

Abstract

Aim: To evaluate whether mucolytic agents have an adjuvant role with antibiotics in the treat-

ment of children with rhinosinusitis.

Methods: Ninety-two children with rhinosinusitis were recruited for this randomized, placebo

controlled, double-blinded clinical trial. Mean age was 8.5 3.2 years. Erdosteine (58 mgkgday)

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

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 and40 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

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 aftera viral upper respiratory tract infection in 1015% of

patients (1,2). Although rhinosinusitis commonly causesmorbidity, 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 com-pared with placebo groups (5,6). However, other studies

demonstrated minimal efficacy of antibiotics in the treat-

ment of acute rhinosinusitis (79). The differences in the

outcomes of these clinical trials are likely because of the

heterogeneity of the patients clinical presentations. It isnow clear that patients with severe symptoms benefit from

antibiotherapy. Antibiotics improve the symptoms, radio-

logical 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 oftime, 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, theadjuvant effect of mucolytic agents in childhood rhinosinus-

itis is not well documented (14). The aim of our study is toevaluate whether mucolytic agents have an adjuvant role

with antibiotics in the treatment of children with rhinosi-

nusitis. This randomized, placebo controlled, double

blinded clinical trial was planned to determine the effect oferdosteine, 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 uni-versity paediatrics clinic where paediatric patients are

cared. Our trial was planned and carried out in full compli-

ance with CONSORT regulations harbouring the basic

principles of randomized drug trials (15).

Acta Pdiatrica ISSN 08035253

2009 The Author(s)/Journal Compilation 2009 Foundation Acta Pdiatrica/Acta Pdiatrica201099, pp. 585589 585


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Sample size

Efficacy of the placebo drug was predicted to be 30%, andthe contribution of the mucolytic agent to the treatment was

30%. By taking a beta error margin as 0.20 and alpha value

as 0.05 and estimating a 30% patient loss, sample size was

calculated as 130 with 80% power.

Ethic aspect

After planning the trial, it was presented to the Ethics Com-mittee of Istanbul University, Istanbul Faculty of Medicine.

After obtaining approval from The Ethics Committee, the

trial was started.

Statistical methods

Categorical variants were analysed by chi-square test. Stu-

dentst-test was used for comparing group scores. All statis-tical tests were performed using the SPSS 12.0 (licensed by

Istanbul University) package for Windows (SPSS Inc, Chi-cago, IL, USA).

RESULTS

During the course of the trial, 130 patients were diagnosed

to have acute bacterial rhinosinusitis. Thirty-eight of these

patients did not meet the inclusion criteria. Ninety-two eli-

gible participants were randomized. Forty-nine participants

were assigned to group 1 (erdosteine drug group), and 43were assigned to group 2 (placebo group). During follow-

up, eight patients in group 1 and three patients in group 2

were dropped out from the study protocol (Fig. 1). Forty-

one participants from group 1 and 40 participants from

group 2 completed the clinical trial. Therefore, the data of

81 patients out of 92 enrolled were used in statistical analy-sis. The attrition rate was 12% (1192).

The basic demographic characteristics of participants are

shown in Table 1. Forty-three percentage of the patients

were women. Mean age was 8.5 3.2 years. In responses to

treatment, clinical scores declined during the 14-day follow-

up in both group 1 and group 2. Before the treatment, the

mean scores of group 1 and group 2 were not significantlydifferent and were 11.0 5.4 (mean SD) and 12.1 4.5

respectively. On the 14th day of follow-up, mean scores

were 3.1 4.1 in group 1 and 2.8 2.6 in group 2, andthere was no statistically significant difference (Table 1 and

Fig. 2). When the patients were evaluated according to pri-

mary and secondary outcome criteria, 78% of the patients

in group 1 achieved complete cure, while in group 2 thisrate was 74.4%. The difference between the groups did not

reach statistical significance. Erdosteine created a differencein clinical improvement compared with placebo, although

this was not statistically significant. During the course of

treatment, there were no complications requiring hospital

administration in both groups.

DISCUSSION

The treatment of rhinosinutis in children and the efficacy ofthe medications are controversial. There are few random-

ized clinical drug efficacy trials about the treatment of sinus-

itis in the paediatric age group (19). These studies are

particularly focused on the efficacy of antibiotics (5,6). The

place and efficacy of adjuvants in the treatment of rhinosi-

nusitis are also controversial, and there are very few ran-domized clinical drug efficiency trials carried out in

children. These are either about the efficiency of topicalNumber of patientssuitable for the trial

n: 130

Excluded patients

n: 38

Not harboring inclusion criteria: 23

Not giving voluntary consent: 15

Entering randomization

n: 92

Group-1: Receiving

erdosteine n: 49

Group-2: Placebo

n: 43

Leaving on follow-

up n: 8

Leaving on follow-

up n: 3

Entering analysis

n: 41

Entering analysis

n: 40

Figure 1 Flow chart of patients in the study.

Table 1 General characteristics, S5 clinical scores and responses to treatment

in erdosteine and placebo groups (n = 81)

Variables

Group 1 using

erdosteine (n = 41)

Group 2 placebo

(n = 40) p

Gender (number of girls, %) 21 (51.2) 14 (35.0) 0.53

Age (years; mean SD) 9.4 2.8 8.6 3.1 0.42

Weight (kg; mean SD) 25.6 10.2 27.8 11.4 0.34

Height (cm; mean SD) 124.0 19.0 122.1 25.9 0.58

Clinical S5 score*

Onset of treatment 11.0 5.4 12.1 4.5 0.32

Day 3 of treatment 7.5 6.0 7.1 4.0 0.73

Day 14 of treatment 3.1 4.1 2.8 2.6 0.67

Improvement ratesTotal cure (%) 78.0 74.4 0.69

Improvement (%) 19.6 23.1 0.25

No response (%) 2.4 2.5 0.44

Complication (%)

= No case.

*S5 clinical scoring system: 5 symptoms of rhinosinusitis (nasal obstruction,

day cough, night cough, headache or facial ache and coloured nasal discharge)

were taken as criteria in clinical scoring. In the scale, 0 no symptoms, 1 moder-

ate problem, 2 severe condition and 3 extremely severe condition. The

patients were asked to score their symptoms accordingly every day. Total

scores were obtained for each day.

Unuvar et al. Mucolytic agent in rhinosinusitis



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corticosteroids or normal saline (14,20). To our knowledge,

our research is the first randomized clinical trial investigat-ing the efficacy of mucolytic agents like erdosteine in the

treatment of rhinosinusitis in children. The reason for

choosing erdosteine was its anti-inflammatory and antioxi-

dant effects in addition to its mucolytic effect, and evidenceof its beneficial effect in minimizing mucosal damage

(17,19). Furthermore, twice daily dosing, availability of a

suspension form and a favourable taste were the other rea-

sons for our choice.The randomized, placebo controlled and double blinded

nature of our trial increases its validity. The S5 clinical scor-

ing system, which has been used in previous trials, was usedin the evaluation of our patients. The limitation of our and

the previous studies was the determination of clinical suc-

cess in sinusitis with a rather subjective evaluation like S5that was only based on the information from the families.

However, another method has not been used as the stan-

dard so far. Apart from using this method known as the

standard, the patients were also evaluated by a physicianduring their follow-up and not only those assessed by the

family but also the clinical findings observed by the physi-

cian were taken into evaluation.

When S5 clinical scoring values were taken into consider-

ation during the follow-up of the patients, there was a differ-

ence between the values on day 14 among the groups usingthe placebo and the drug, but this was not statistically signif-

icant (3.1 vs. 2.8). The mucolytic agent does not seem to

have a significant contribution to the success of treatment.

There are no significant differences among the groupsregarding possible drug adverse effects. There were no cases

with clinically relevant serious adverse effects and conse-

quent hospitalization. No change was noted in the coughing

symptom that was predicted to worsen because of the

mucolytic effect. Vomiting or bronchospasm were not

observed in either group.

The limitation of our study is the small number of patientsin each group. If the study was carried out with more

patients and was designed as a multicenter study, the exter-

nal validity of our findings would be higher and could be

more generalized. However, when previous randomized

clinical studies carried out in children are considered, the

number of patients in our trial is not too small.

In conclusion, the use of erdosteine as a mucolytic agent

in children with acute rhinosinusitis does not directly affectthe success of the treatment.

ACKNOWLEDGEMENTS

We thank Prof.Dr. Mary Lu Angelilli for her contribution in

the English adaptation of the article and we also thank

Prof.Dr. Nermin Guler, Prof.Dr. Fatma Oguz and Prof.Dr.Mujgan Sdal for their cooperation.

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0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days

S5c

linicalscore

Placebo

Erdosteine

Figure 2 Comparison of trends of values obtained with the S5 scoring scale

based on the information provided by the families during the treatment and

the change with the treatment over the days among the erdosteine and pla-

cebo groups.

Mucolytic agent in rhinosinusitis Unuvar et al.

588 2009 The Author(s)/Journal Compilation 2009 Foundation Acta Pdiatrica/Acta Pdiatrica201099, pp. 585589


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