Antibiotics for otitis media with effusion in children
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness of antibiotics in children with OME.
Background
Description of the condition
Symptoms, prevalence and aetiology
Otitis media with effusion (OME) is one of the most common diseases in early childhood. OME is characterised by an accumulation of fluid in the middle ear behind an intact tympanic membrane, without the symptoms or signs of acute infection (NICE 2008).
The lack of symptoms with OME makes it difficult to estimate its true prevalence, but the point prevalence of middle ear effusion on screening tests at ages 0 to 18 years is about 20% (Casselbrant 2003). OME has the first and largest prevalence peak of 20% at two years of age and a second peak of approximately 16% at around five years of age (Zielhuis 1990); approximately 90% of children have had OME at some time before the age of four years (Paradise 1997).
With newly detected OME natural resolution (i.e. disappearance of the fluid from the middle ear) within three months is seen in 28% of children, but rates of improvement or spontaneous resolution in children with OME after an episode of acute otitis media (AOM) are much higher (Rosenfeld 2003a). Recurrence of OME, however, is also common, with an estimated rate of 50% within 24 months (Teele 1989).
In most cases OME causes mild hearing impairment of short duration. When experienced in early life, and in cases of persistent or recurrent and bilateral episodes of OME, the associated hearing loss may be significant and have a negative impact on speech development and psychological health (Gouma 2011; Roberts 2004; Sabo 2003;Shekelle 2002).
Although the pathophysiology of OME is not fully understood, it is thought to be an expression of middle ear dysfunction related to inflammation of the middle ear mucosa and immature or poor Eustachian tube function (Rovers 2004).
Description of the intervention
While most cases of OME will resolve spontaneously, children with persistent middle ear effusion and associated hearing loss may need treatment. To that end there are two management options: surgical or medical.
A recent Cochrane Review on the effectiveness of ventilation tube insertion in children with OME suggests that ventilation tubes only offer a short‐term hearing improvement in children with uncomplicated OME (Browning 2010). The review authors found no effect on speech and language development. Another recent Cochrane Review shows that adenoidectomy is effective in the resolution of middle ear fluid in OME, but the benefit to hearing is small (van den Aardweg 2010).
Since the benefits of surgery in OME are limited, it is particularly relevant to establish the effectiveness of non‐surgical therapies for OME. Perera et al reviewed the effectiveness of autoinflation, a non‐invasive intervention, in OME and concluded that its costs are low and there are no adverse effects, but that the duration of treatment and the long‐term impact in children deserves further study (Perera 2006).
In terms of medical management, the Cochrane Review by Griffin et al has not shown that antihistamines or decongestants alone or in combination are effective in OME (Griffin 2006). In a recent trial of topical intranasal corticosteroids in OME, Williamson et al found no benefit after one and three months of treatment (Williamson 2009). Simpson et al in their Cochrane Review on oral and topical intranasal steroids in OME, show that oral steroids, especially when used with an oral antibiotic, lead to a quicker resolution in the short‐term (< one month). No evidence was found of benefit from treatment of OME with topical steroids, alone or in combination with an antibiotic (Simpson 2011).
The rationale for using antibiotics in OME is the polymicrobial origin of the disease; a bacterial pathogen is identified in approximately one out of three children with OME (Poetker 2005). Potential benefits of antibiotics in OME, however, need to be balanced against the adverse effects and the risk of bacteria becoming resistant to antibiotics (Tähtinen 2011).
In 2003, Rosenfeld reviewed the effects of antibiotic therapy in OME and concluded that there is evidence for short‐term efficacy, but long‐term efficacy is doubtful (Rosenfeld 2003b). Mandel et al in their review, published in 2004, came to a similar conclusion (Mandel 2004). In a recent double‐blind study in Aboriginal infants with OME, Leach et al show that children receiving continuous amoxicillin had more aerated middle ears and fewer perforations (Leach 2008).
Since 2004, the effectiveness of antibiotics in the management of OME has not been reviewed systematically. We aim to do so in this Cochrane Review.
Objectives
To assess the effectiveness of antibiotics in children with OME.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
We will include studies evaluating children aged 18 years or under with a diagnosis of unilateral or bilateral OME at time of randomisation. The clinical diagnosis has to be made by a combination of otoscopy (including pneumatic otoscopy and otomicroscopy), tympanometry and/or audiometry. We will exclude studies that randomised on the basis of acute otitis media even though OME was also studied in follow up. We will also exclude studies in children with tympanostomy tubes present, chronic suppurative otitis media, known immune deficiency, Down syndrome or craniofacial anomalies (including cleft palate).
Types of interventions
Intervention
Antibiotics (all types).
Control
The comparators are no treatment and placebo. We will exclude studies comparing one antibiotic versus another antibiotic because we aim to determine whether antibiotics are effective in OME and not which antibiotic is most effective.
Additional therapies, such as steroids, for which short‐term (< one month) benefit has been shown (Simpson 2011) will be allowed as long as they are identical in the treatment and in the control group.
Antihistamines, decongestants and mucolytics, which demonstrate no specific effect on the resolution of OME (Griffin 2006; Pignataro 1996), will be allowed as co‐treatment or comparator of antibiotics.
Types of outcome measures
Our principle endpoint for analysis is two to three months after initiation of treatment. However, we will search studies for data on the effects of antibiotic treatment at different time points including end of treatment, short‐term (two to four weeks) and long‐term (≥ six months).
Our outcomes of interest are as follows.
Primary outcomes
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Complete resolution of OME (complete treatment success) after two to three months, defined as resolution of OME in the affected ear in children with unilateral OME at randomisation and resolution of OME in both ears in children with bilateral OME at randomisation, based on at least a combination of otoscopy and tympanometry.
Secondary outcomes
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Complete resolution of OME (complete treatment success) at all possible time points.
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Partial or complete resolution of OME (partial or complete treatment success) at all possible time points, defined as resolution of OME in the affected ear in children with unilateral OME at randomisation and resolution of OME in one or both ears in children with bilateral OME at randomisation, based on at least a combination of otoscopy and tympanometry.
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Hearing level.
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Language and speech development.
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Cognitive development.
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Quality of life.
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Need for ventilation tubes.
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Tympanic membrane sequelae.
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Adverse effects related to use of the antibiotics, notably diarrhoea, vomiting and skin rash.
Search methods for identification of studies
We will conduct systematic searches for randomised controlled trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear, and we will arrange translations of papers where necessary.
Electronic searches
We will identify published, unpublished and ongoing studies by searching the following databases from their inception: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; Web of Science; BIOSIS Previews; ISRCTN; ClinicalTrials.gov; ICTRP and Google.
We will model subject strategies for databases on the search strategy designed for CENTRAL (see Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by the Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2, Box 6.4.b. (Handbook 2011)).
Searching other resources
We will scan the reference lists of identified publications for additional trials and contact trial authors if necessary. In addition, we will search PubMed, TRIPdatabase, NHS Evidence ‐ ENT & Audiology, and Google to retrieve existing systematic reviews relevant to this systematic review, so that we can scan their reference lists for additional trials. We will search for conference abstracts using the Cochrane Ear, Nose and Throat Disorders Group Trials Register.
Data collection and analysis
We will conduct the review according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 (Handbook 2011).
Selection of studies
One review author will screen all titles and abstracts obtained from the database searches. Two review authors will review the full text of the potentially relevant titles and abstracts against the inclusion criteria. They will assess the eligibility of the trials independently and any differences in opinion will be settled by consensus.
Data extraction and management
Two review authors will independently extract study characteristics and outcomes from the included studies using standardised data extraction forms. We will resolve disagreements by discussion. When there is insufficient information we will contact study authors in an attempt to obtain further information. If necessary we will also arrange translations via the Cochrane Ear, Nose and Throat Disorders Group.
Assessment of risk of bias in included studies
Two authors will independently assess the risk of bias of the included studies using the Cochrane Collaboration’s tool for assessing risk of bias in RevMan 5.1 (RevMan 2011), as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We will consider the following six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other sources of bias. For all included trials, we will judge the risk of bias for each domain as 'low risk', 'high risk' or ‘unclear’. When there is insufficient information we will seek contact with the study authors for clarification.
Assessment of heterogeneity
We will assess heterogeneity using the I² statistic and with visual inspection of the forest plots. When heterogeneity is present (between 25% and 75%) we will reanalyse the data using the random‐effects model. If heterogeneity is greater than 75% we will not pool data. We will consider reporting biases using a funnel plot if a sufficient number of trials is identified (n > 20).
Data synthesis
We will carry out all the analyses on the basis of intention‐to‐treat, assuming treatment failure for missing data (worst‐case analysis). We will use RevMan version 5.1 (RevMan 2011) to carry out the meta‐analyses for comparable trials and outcomes.
For continuous outcomes (i.e. mean hearing loss and time with effusion) we will calculate mean differences (MD) or standardised mean differences (SMD) and their corresponding 95% confidence intervals (CI).
For dichotomous outcomes we will analyse treatment effects as risk differences (RD), as well as risk ratios (RR), with their corresponding 95% CIs.
We will stratify the results of our analyses for risk of bias by (1) treatment allocation (randomisation and concealment) (yes versus no), (2) blinding of outcome measurement (yes versus no), (3) completeness of data (yes versus no), (4) additional therapies (yes versus no), (5) level of randomisation (patient, group, cross‐over).
If possible we will perform stratified analyses for age, duration of OME and the definition of resolution of OME by three possible tympanogram types (type A; type A and C1; type A, C1 and C2).
