Otitis media with effusion - Cochrane ENT · Web viewMontelukast versus inhaled mometasone for treatment of otitis media with effusion in children: a randomized controlled trial

Otitis media with effusion – Scoping document

Otitis media with effusion

1. THE REMITThe aim of this prioritisation exercise is to inform the selection of the contents of a suite of Cochrane Reviews on the effectiveness of treatments for otitis media with effusion (OME). The objectives are:

1. to identify current interventions for OME, using expert input; 2. to identify randomised controlled trials (RCTs), systematic reviews and guidelines relating to

these interventions for OME, either since the most recent Cochrane Review (if one exists), or with no time restriction (for interventions not currently included in a Cochrane Review);

3. to rank interventions for OME by priority order, based on clinical importance and using input from a range of stakeholders, in order to identify the most important interventions to include in a new suite of Cochrane Reviews.

2. CLINICAL NEED FOR THE REVIEW OF EVIDENCE2.1 Epidemiology / burden of disease2.1.1 Description of populations and impact (outcomes)OME is a common condition in early childhood. Its key clinical feature is hearing loss, but it is frequently asymptomatic [1]. The condition, also known as ‘glue ear’, is caused by inflammation of the upper airways that leads to Eustachian tube dysfunction and fluid in the middle ear [2]. OME is often related to acute otitis media (AOM), either as a precursor or a consequence of AOM. In OME there are no symptoms or signs of active infection and the tympanic membrane remains intact, so the child does not suffer from symptoms such as fever, ear pain and ear discharge that are common with AOM [3].

It is thought that up to 90% of children have had OME by the time they start school [4], with a decline in prevalence beyond the age of six [3]. Most cases resolve without intervention within three months, and 95% within a year [3]. The condition is more common in children with craniofacial malformations, such as those characteristic of children with Down syndrome or cleft palate [1].

Children with OME may suffer from hearing loss in one or both ears. When this persists this may impact on speech and language development, and lead to behavioural problems in some children [1].

2.2 Current practiceIn the UK and many other countries, children will typically be diagnosed by clinical examination including (pneumatic) otoscopy in primary care. Primary care may be provided by different specialists: family physicians or general practitioners (GPs), or paediatricians. If the child is seen in secondary care, otomicroscopy, tympanometry and hearing tests may help to diagnose OME. Tympanometry is available in primary care in some countries, for example in Italy. In other countries, like Japan, access to Ear, Nose and Throat (ENT) specialists is directly available [5]. Diagnosis may not be available in many low- and middle-income countries.

Initially, there will be a period of active observation, usually for at least three months, during which time the care provider may offer one of the primary care interventions listed in Section 2.2.1. If OME has not resolved within the three-month observation period, the child may be referred to secondary

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care for assessment by an ENT specialist and a hearing test, but recommendations vary by country. The ENT specialist may then offer one of the secondary care options listed in Section 2.2.1.

2.2.1 Description of interventions Several interventions are available within community, primary or secondary care settings:

1. decongestants; 2. antihistamines 3. antibiotics;4. topical steroids;5. oral steroids;6. leukotriene inhibitors (montelukast);7. mucolytics;8. proton pump inhibitors, and other reflux medications;9. herbal, homeopathic and alternative remedies.10. autoinflation.

If children are referred to ENT specialists in secondary care, the options for treatment are:

11. hearing aids;12. myringotomy alone;13. myringotomy plus ventilation tubes;14. adenoidectomy;15. a combination of adenoidectomy and myringotomy with and without ventilation tubes;16.balloon dilation of the Eustachian tube.

2.2.2 How different interventions workThe physiopathology of OME can be described in terms of the body’s inflammatory and immune response to upper respiratory (nasopharyngeal) infection; the involvement of biofilms; and the possible role of respiratory allergies, gastro-oesophageal reflux, genetic predisposition, and external factors like pollution and second-hand smoke exposure [2]. The immaturity of the Eustachian tube is also a factor. This broad range of possible underlying causal mechanisms has led to a wide range of interventions, each targeting a different mechanism. The section below describes the rationale underlying several treatment options, but is not exhaustive.

The rationale for using antibiotics is to treat a bacterium that is identified in up to one-third of children with OME [5, 6]. Steroids have been used, with the intention of reducing the inflammatory cascade that causes Eustachian tube dysfunction and middle ear effusion [2]. Antihistamines and decongestants have been used in an attempt to reduce oedema and swelling of the mucous membranes and so improve Eustachian tube function [7]. Other medical interventions include proton pump inhibitors, which aim to treat gastro-oesophageal reflux as a potential cause of OME.

The most commonly recommended surgical treatment for children with OME who suffer from hearing loss is placement of ventilation/tympanostomy tubes (‘grommets’) [2]. Insertion of the ventilation tubes helps the middle ear fluid to drain, aerates the middle ear, and balances the pressures on each side of the tympanic membrane, improving the child’s ability to hear [2]. The ventilation tubes generally extrude within a year, and may need replacing when OME recurs. In certain cases, early extrusion occurs. Adenoidectomy is sometimes carried out, either with grommet

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placement or as a stand-alone procedure. The aim of this procedure is to remove the adenoid as a source of chronic inflammation, remove physical obstruction of the Eustachian tube, restore mucus drainage, and equilibrate pressure in the middle ear [2].

Traditional behind-the-ear hearing aids may be offered to children with OME. This type of hearing aid has a microphone to pick up sound, which then gets amplified and sent into the child’s ear. Another type of aid - bone conduction hearing aids on a head band - conduct sound from a microphone through the skull to the inner ear, and help overcome the hearing loss associated with OME [8].

Balloon autoinflation offers a mechanical approach to treating OME: the child blows up a balloon via their nose to raise intranasal pressure and partially re-open the Eustachian tube [9]. This is done several times per day at home. The device can be prescribed in primary care.

By contrast, the mechanical procedure of balloon dilation of the Eustachian tube is a surgical intervention carried out under general anaesthesia. This involves insertion of a balloon catheter into the Eustachian tube orifice, filling it with saline to increase pressure for about two minutes, and then emptying and removing it. The aim is to widen the Eustachian tube and improve its function [10]. A recent Cochrane protocol of balloon dilation of the Eustachian tube described how the procedure may crush unhealthy mucosa and promote the growth of normal tissue [11].

2.3 Clinical issues / variations in practiceThis section summarises the approach recommended by various international guidelines for each of the interventions identified for this prioritisation project. We looked at guidelines from the UK [1, 12, 13], Japan [14], the USA [15, 16], Denmark [17], France [18], Germany [19] and Spain [20]. We also consulted an international consensus report (ICON) that compared guidelines and clinical practice in different areas of the world. The ICON report found that, overall, regional differences were minor [21].

NICE’s clinical guideline on surgical interventions for OME (CG60) was published in 2008 [1]. Many of the recommendations in the more recent NICE Clinical Knowledge Summary report (which includes both surgical and non-surgical management) [12] were based on the 2008 report, and are described below. However, NICE is currently in the process of updating CG60 and has produced a surveillance report that describes the likely impact of new evidence (including from Cochrane Reviews) [13]. Key differences between this update and the earlier version (and international guidelines) are likely to concern the use of antibiotics, and recommendations for adenoidectomy.

Antihistamines and decongestantsAntihistamines and decongestants are currently included in a single Cochrane Review [7]. Since the Cochrane Review was published, five of the reviewed international guidelines have recommended against using antihistamines or decongestants for OME [12, 16, 18, 20, 21]. Japanese guidelines mention that second-generation antihistamines and decongestants should be considered as an option for patients with allergic rhinitis suffering from OME, but do not recommend first-generation antihistamines because the risks outweigh the benefits [14].

AntibioticsThere is a Cochrane Review on the use of antibiotics to treat OME [6]. Six of the eight international guidelines reviewed recommend against using antibiotics for OME [12, 16, 18-21]. NICE is currently

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reviewing CG60, which also recommends against the use of antibiotics at present [13]. Japanese guidelines state that antibiotic treatment is indicated for bacterial infection of the surrounding organs (including rhinosinusitis), although note that antibiotic treatment for OME is not covered by the Japanese health insurance system [14].

International rates of prescribing antibiotics for OME vary considerably [22], despite international guidelines mostly advising against their use in OME.

Oral and topical steroidsThere is no guideline recommending treatment of OME with intranasal or systemic steroids [12, 16, 18, 20, 21, 23]. Japanese guidelines recommend against the use of corticosteroids for OME in children, but mention that inhaled nasal steroids may be considered for those also diagnosed with allergic rhinitis [14].

Leukotriene inhibitors (montelukast)Montelukast is a leukotriene inhibitor used to treat asthma and allergy. As a recent treatment modality, it is not mentioned in NICE and most other international guidelines, but is used in both primary and secondary care. Spanish and US guidelines mention a lack of evidence for leukotriene inhibitors’ effectiveness in treating OME, but make no specific recommendation about their use [16, 20].

MucolyticsMucolytics are not recommended by NICE [12]. The French OME guideline mentions that they can improve OME in one-third of children in the short-term, but comments that there is no evidence for their long-term efficacy [18]. Japanese guidelines mention that carbocysteine, a mucokinetic agent, can be used while waiting for surgical treatment [14]. Similarly, the international consensus statement mentions that mucolytics can be used whilst waiting for further treatment [21]. Spanish guidelines recommend that mucolytics should not be used to treat OME, based on the limited available evidence [20].

Proton pump inhibitors and reflux medication The US guideline recommends against medicines for acid reflux [16] for children with OME. Spanish guidelines state that the lack of research on anti-reflux treatment for OME means they cannot recommend their use [20]. Other guidelines reviewed do not appear to mention this treatment option.

Herbal, homeopathic and alternative remediesNICE mentions that there is no proven benefit from any complementary or alternative therapies, but makes no specific recommendation about their use [12]. The US guideline states that “no benefits have ever been shown for chiropractic therapy, special diets, herbal remedies, complementary medicine, or alternative (natural) therapies” [16]. Complementary or alternative remedies do not appear to be mentioned in the French [18] or German guidelines [19], or in those of other countries where complementary and alternative medicine is popular, such as Japan or South Korea. Spanish

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https://cks.nice.org.uk/otitis-media-with-effusion


guidelines mention that early results from trials of probiotics need to be replicated before their use can be recommended [20].

AutoinflationAutoinflation has support in international guidelines for use during the surveillance period whilst waiting for referral to ENT specialists [12, 16, 18]. The recent review of NICE CG60 indicates that more recent evidence supports the use of autoinflation, possibly extending NICE’s original position that it may be considered during the active observation period to the stronger recommendation to ‘offer autoinflation’ [13]. Spanish guidelines state that it might be a useful treatment for OME, but mention that it is difficult for small children to perform it [20]. The international consensus statement describes this as an interesting method requiring further research to develop a standardised, cheap and easy-to-use device [21].

Secondary care interventionsHearing aidsNICE recommends offering hearing aids to children with persistent bilateral OME and hearing loss who are not suitable for surgical treatment [12]. The US guideline also mentions them as an option for children with hearing loss [16]. Other guidelines reviewed for this report do not appear to mention hearing aids.

Myringotomy aloneNICE CG60 does not include evidence for myringotomy alone, stating that this is not used (as a stand-alone treatment) for OME [1]. French guidelines suggest that radiofrequency or laser myringotomy are not indicated for OME management [18]. US guidelines only mention myringotomy as an adjuvant to adenoidectomy [16], and other guidelines reviewed for this report do not refer to myringotomy as a stand-alone procedure.

Myringotomy plus ventilation tubesNICE describes myringotomy and insertion of ventilation tubes (with or without adenoidectomy) as the most common surgical option for OME [12]. NICE’s criteria for surgical treatment state that: “Children with persistent bilateral OME documented over a period of 3 months with a hearing level in the better ear of 25–30 dBHL or worse averaged at 0.5, 1, 2 and 4 kHz (or equivalent dBA where dBHL not available) should be considered for surgical intervention.” [1].

NICE recommends that children with cleft palate who have OME and persistent hearing loss should be offered ventilation tubes as an alternative to hearing aids. For children with Down syndrome, NICE only recommends ventilation tubes as an alternative to hearing aids after consideration of the child’s age and severity of hearing loss, the practical issues relating to grommet insertion, and associated risks [12]. US guidelines describe ventilation tubes as the recommended surgical option for a child with OME who is under four years of age, and either ventilation tubes, adenoidectomy, or both, for a child over four years of age [16]. The international consensus statement mentions that ventilation tubes significantly improve hearing, and recommends basing any decision to insert ventilation tubes on the results of auditory tests and the child’s overall hearing difficulties [21].

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French guidelines give quite specific indications for placement of bilateral ventilation tubes [18]. These are either conductive or mixed hearing loss (air-bone gap > 10 dB) associated with delayed speech acquisition due to another cause (sensorineural hearing loss, language delay, developmental delay) or conductive or mixed hearing loss of more than 30 dB HL in the better of the two ears. They also state that ventilation tubes should be proposed for children with posterior tympanic membrane retraction associated with OME.

Danish guidelines [17] recommend offering ventilation tubes to children with bilateral OME and hearing problems, with or without concurrent speech problems; and children with OME and behavioural problems, vestibular problems or lowered quality of life if the child has normal hearing (but only after careful consideration, as the effect is uncertain). They recommend careful consideration for offering ventilation tubes to children with OME but no other symptoms, since there is no evidence of a beneficial effect for this group.

Adenoidectomy aloneGuideline evidence focusses on the combination of adenoidectomy and ventilation tubes, rather than adenoidectomy alone.

A combination of adenoidectomy and ventilation tubesNICE originally recommended against adjuvant adenoidectomy (to myringotomy and insertion of ventilation tubes) in the absence of persistent or frequent upper respiratory tract symptoms (or both) [12]. This recommendation is currently being reviewed, incorporating the 2010 Cochrane Review findings [24].

The US guideline recommends adenoidectomy (or ventilation tubes, or both) as a surgical option for treating OME in a child aged four or over, in particular for those who require repeat surgery after prior grommet insertion [16]. For under fours, adenoidectomy is not recommended unless there is a distinct indication (nasal obstruction, chronic adenoiditis). International guidelines recommend considering adjuvant adenoidectomy in children over four years of age, and in those with significant nasal obstruction or infection [21]. Danish guidelines only recommend offering adjuvant adenoidectomy to children having their first ventilation tubes for OME after careful consideration, as the effect is uncertain [17]. French guidelines recommend adenoidectomy (unless contraindicated by velar abnormality or clotting disorders) for children aged four years or over who have enlarged adenoids [18].

Balloon dilation NICE has recently published guidance on balloon dilation for chronic Eustachian tube dysfunction in children and adults, recommending that the evidence regarding its safety and efficacy is adequate to support its use [10]. The data were mostly from studies in adults; there were only three case-series that included children. None of the international guidelines reviewed mention balloon dilation as a treatment for OME.

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2.3.1 Description of where the evidence isThere have been 10 Cochrane Reviews and one Cochrane protocol published about treatments for OME in children (Appendix 1). Many of these are out of date and may require updating. There are also some interventions that have never been included in a Cochrane Review.

We conducted scoping searches for randomised controlled trials (RCTs), systematic reviews and Health Technology Assessment (HTA) reports in November 2019. In January 2020, we extended this to include a full search of MEDLINE and Embase, using the search terms described in Appendix 2.

The results of the scoping searches are described below for each intervention of interest to the prioritisation exercise.

Primary care interventions

Antihistamines and decongestantsThese are the subject of a joint Cochrane Review [7], with searches to February 2011. The review included 16 comparisons in 14 RCTs: two compared an antihistamine versus placebo, two compared a decongestant versus placebo or no treatment, eight compared an antihistamine/decongestant combination versus placebo or another control, and two were multi-arm studies that compared placebo versus combined treatment versus treatment with an antihistamine alone, or with a decongestant alone.

The Cochrane Review authors found no evidence of efficacy for antihistamines or decongestants, either alone or in combination, for the management of OME. The analysis showed no benefit and some harm from their use.

Scoping searches identified three RCTs that may be of relevance to this topic:

A combination treatment of montelukast with evocetirizine (an antihistamine) versus placebo [25];

Combination of a nasal antihistamine azelastine hydrochloride and corticosteroid fluticasone propionate with an oral antibiotic amoxicillin/clavulanate potassium versus antibiotic alone;

combination of nasal olopatadine (antihistamine) with an oral antibiotic amoxicillin/clavulanate potassium versus antibiotic alone.

The majority of identified trials used a combination of antihistamines and decongestants. However, the published Cochrane Review did also include separate comparisons of antihistamines and decongestants as single treatments.

AntibioticsThere is a Cochrane Review for the use of antibiotics to treat OME [6], which excluded children with pre-existing or past ventilation tubes, cleft palate or Down syndrome. The study included 25 RCTs, with searches to April 2016. The Cochrane authors concluded that oral antibiotics are associated with an increased chance of complete resolution of OME at two to three months post-randomisation (moderate-quality evidence). The authors also found low to moderate-quality evidence for complete resolution at any time point (10 days to 6 months). However, there was a higher incidence of adverse effects associated with antibiotics. The authors found uncertain evidence for improvements in short-term hearing, and did not find evidence that children treated with antibiotics had fewer

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grommet insertions. They found no data on outcomes such as speech, language and cognitive development, or quality of life.

Scoping searches have identified three abstracts of studies of antibiotics for OME published since the Cochrane Review, but these do not appear to be RCTs.

Oral and topical steroidsThe existing Cochrane Review [26] covered both oral and topical steroids (as separate interventions), with searches to August 2010. The review included a total of 12 RCTs (9 for oral steroids and 3 for topical intranasal steroids). The Cochrane authors found that oral steroids may lead to quicker short-term resolution of OME (particularly when combined with an oral antibiotic), but found no longer-term benefit, and no evidence of an impact on hearing loss. The review authors found no evidence of a benefit from topical intranasal steroids.

Scoping searches identified 22 articles of interest: 11 references about topical nasal steroids, six references (of two RCTs) about oral steroids, one RCT which compared oral versus nasal steroids, and three abstracts about intratympanic injection, and one about systemic steroids.

From the number of identified RCTs, it would be feasible to look at oral and topical steroids as separate interventions.

Leukotriene inhibitors (montelukast)Montelukast is a leukotriene inhibitor used to treat asthma and allergens. It is not currently included in a Cochrane Review as an intervention for OME. Scoping searches identified two studies that compared montelukast to placebo [27, 28]. One trial looked at a combination treatment of montelukast with evocetirizine (an antihistamine) versus placebo [25]. Another trial compared montelukast to inhaled mometasone (a steroid) [29]. Scoping searches did not identify any systematic reviews of montelukast for OME.

MucolyticsThese are not currently the subject of a Cochrane Review. Scoping searches identified three RCTs of relevance [30-32].

Proton pump inhibitors and reflux medication There is no Cochrane Review on the use of reflux medication or proton pump inhibitors for OME. Scoping searches have identified two RCTs of proton pump inhibitors [33, 34] and an older abstract relating to proton pump inhibitors [35]. There is also a meta-analysis on anti-reflux therapy for secretory otitis media in progress [36].

Herbal, homeopathic and alternative remediesThere is not currently a Cochrane Review for herbal, homeopathic or alternative remedies for OME, although there is a published systematic review of complementary and alternative medicines for otitis media [37].

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Scoping searches identified 24 references (not necessarily RCTs) that relate to some form of alternative therapy; 17 related to herbal or dietary supplements, including zinc, antioxidants, echinacea; three homeopathy; one acupuncture; and four other interventions.

There is an ongoing systematic review of herbal medicines for OME registered on PROSPERO, but this protocol was registered in 2014 and has not yet been published in full [38]. PROSPERO also lists an ongoing systematic review of probiotics for preventing AOM and OME in children [39].

AutoinflationA Cochrane Review of autoinflation for OME included eight RCTs, based on searches to April 2013 [9]. The review concluded that the intervention could be considered, and recommended further research into duration of treatment, the long-term impact on developmental outcomes, and additional quality of life measures.

Scoping searches have identified seven abstracts published since then, including five publications about the Earpopper device, and two publications relating to an RCT of nasal balloon autoinflation with the Otovent device. Searches also identified two clinical trial registries about a Swedish study of the Otovent device [40, 41]. The recent review of NICE CG60 indicates that more recent evidence supports the use of autoinflation, possibly extending its recommendation to ‘offer autoinflation’ [13].

Secondary care interventionsHearing aidsThere is no Cochrane Review of the evidence for the use of hearing aids in children with OME. Scoping searches identified a trial registry for a pilot study of a soft band bone conduction hearing aid [8].

Myringotomy aloneThere is no Cochrane Review investigating the use of myringotomy as a stand-alone procedure, although the Cochrane Review on ventilation tubes included three RCTs that compared unilateral ventilation tubes with no surgery or myringotomy in the other ear as control [42]. Scoping searches identified two abstracts of interest that investigate the use of myringotomy for OME [43, 44].

Myringotomy plus ventilation tubesThe largest body of evidence exists for the use of ventilation tubes in children with OME, although the Cochrane Review was last updated 10 years ago [42]. The review included three RCTs that randomised by ear, to compare unilateral ventilation tubes with no surgery or myringotomy in the other ear as control, and seven RCTs that randomised by child, comparing bilateral ventilation tubes with no ventilation tubes. The Cochrane authors concluded that the effect of ventilation tubes on hearing was small and diminished after six to nine months (by which time the hearing of children without ventilation tubes had improved due to natural resolution). The authors found few data on other outcomes, and identified a lack of trials conducted in children with established speech, language, learning or developmental problems.

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Since the Cochrane Review was published in 2010, there have been two HTA reports that include ventilation tubes [45, 46], and four other systematic reviews [3, 47-49]. Scoping searches for RCTs of ventilation tubes identified 12 abstracts of interest published since the Cochrane Review.

AdenoidectomyThe Cochrane Review of adenoidectomy [24] looked at three different comparisons, including one that compared adenoidectomy (with or without myringotomy) against non-surgical treatment or myringotomy only. Searches were to March 2009. The authors found a small beneficial effect of adenoidectomy on resolution of effusion.

Scoping searches have identified one RCT published since the Cochrane Review [50]. There has also been an NIHR HTA report that includes an individual patient data meta-analysis of adenoidectomy with or without ventilation tubes for children with otitis media [51].

A combination of adenoidectomy and ventilation tubesThe existing Cochrane Review of adenoidectomy [24] looked at three different comparisons, two of which included a combination of adenoidectomy and grommet insertion:

1. adenoidectomy with unilateral tympanostomy tube versus unilateral tympanostomy tube only;2. adenoidectomy with bilateral ventilation tubes versus bilateral ventilation tubes only.

The Cochrane Review included 14 studies, but there was limited opportunity for meta-analysis due to heterogeneity. The authors found evidence of a beneficial effect on the resolution of middle ear effusion, but only a small benefit to hearing. Currently this review does not include a comparison with a non-surgical control group.

Scoping searches have identified 12 abstracts of RCTs published since the Cochrane Review. There has also been an NIHR HTA report that includes an individual patient data meta-analysis of adenoidectomy with or without ventilation tubes for children with otitis media [51], and six systematic reviews published since the Cochrane Review [3, 46, 48, 49, 52, 53].

Balloon dilation Balloon dilation, or balloon Eustachian tuboplasty, has not been included in a Cochrane Review of OME treatments. Scoping searches have identified one published RCT of balloon dilation in children [54], one trial registration of an RCT of balloon dilation in children with OME [55], and two trial registrations of RCTs of balloon dilation in adults [56, 57]. Searches also identified an RCT that compared balloon Eustachian tuboplasty alone versus balloon Eustachian tuboplasty with tympanocentesis [58]. There is a German HTA report [59], one systematic review [60], and a Spanish consensus paper [61] about balloon dilation, but not specifically about its use for treating OME in children.

There is a systematic review registered on PROSPERO of balloon dilation tuboplasty for Eustachian tube dysfunction [62].

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Other Cochrane Reviews in this areaThere are three Cochrane Reviews [63-65] and one Cochrane protocol [66] relating to care of children with ventilation tubes. There is also a Cochrane Review about identification of children in the first four years of life for early treatment for OME [67]. These have not been included in the list of interventions for this scoping exercise.

Particular groupsThere are two NIHR HTA reports relating to particular groups of children who are at risk of OME: one focused on the feasibility of research into the management of OME in children with cleft palate [68] and the other in children with Down syndrome [69]. There has also been a recent study into service provision for children with Down syndrome who suffer from hearing loss associated with OME [70]. Searches identified three systematic reviews looking specifically at placement of ventilation tubes in children with cleft palate [71-73].

The SIUTIT trial is looking at the effects of ventilation tubes for recurrent acute otitis media or chronic otitis media with effusion in Greenlandic children [74]. The INFLATE trial is looking at nasal balloon autoinflation for OME in Aboriginal and Torres Strait Islander children [75].

2.3.2 Description of which areas most require an updated evidence synthesis (why is it important to do this review?)

The prioritisation exercise involved 12 professionals and two parents of a child with OME who were asked to rank the 16 interventions in order of importance, based on their clinical practice or experience. The professional consultation group included nine ENT surgeons, and three people with expertise in primary care or paediatrics. Each intervention was awarded a score based on its ranked position for each participant (16 points for the top ranked intervention, 1 point for the lowest ranked intervention). The totals were summed across all participants to give a total score. Some participants preferred not to rank some interventions (either because they did not think they were relevant to clinical practice, or because they were not sufficiently familiar with them to make an informed ranking choice). In such cases, the interventions received a score of 0 from that participant. Results are shown in Table 1.

Table 1 Results of the prioritisation exercise

Intervention Total scoremyringotomy plus ventilation tubes (grommets) 204a combination of adenoidectomy and ventilation tubes 173autoinflation 165adenoidectomy 144topical steroids 136hearing aids 115decongestants 114antibiotics 108myringotomy alone 102balloon dilation of the Eustachian tube 96oral steroids 92leukotriene inhibitors (montelukast) 91

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antihistamines 89mucolytics 81proton pump inhibitors and other reflux medications 62herbal, homeopathic and alternative remedies 59

Red line indicates top five interventions, based on prioritisation by 14 people.

Based on the results of the ranking exercise and consideration of clinical practice, guidelines and likely available RCT evidence, the core team proposed the following areas to be in most need of an up-to-date Cochrane Review:

The top priority is for a review of ventilation tubes, since the most recent Cochrane Review of this widely used procedure dates from 2009. Scoping searches identified 12 abstracts of interest, so a review of current evidence is timely.

A previous Cochrane Review included both adenoidectomy and adenoidectomy plus ventilation tubes as interventions of interest. Although we listed these as separate interventions for the scoping exercise, both were ranked highly by consultees. Discussions within the review team indicated that it would be preferable to include both interventions within the same Cochrane Review.

Autoinflation was the third-highest ranked intervention in the prioritisation exercise. The existing Cochrane Review was undertaken in 2013, and scoping searches identified at least two RCTs and two clinical trial registrations in this area. NICE’s review of NICE CG60 indicates that their recommendations on this treatment may be more positive in their updated guidance [13]. This intervention was ranked as the top priority for one of the parents we consulted for this exercise, who indicated that they were keen to avoid surgical treatment if possible.

Topical steroids were ranked more highly than oral steroids in terms of requiring an up-to-date Cochrane Review. However, discussions within the scoping team suggest that it is pragmatic to conduct a new Cochrane Review that covers both oral and topical steroids, with both being used in clinical practice. A large RCT of oral steroids as treatment for OME was published in 2018 (the OSTRICH study [76]).

Antibiotics were not ranked particularly highly during the prioritisation exercise, but the scoping team considers this to be an important area for an up-to-date review. There are a large number of trials in this area. The last Cochrane Review was carried out in 2016 and found some evidence that oral antibiotics are associated with an increased chance of complete resolution of OME at two to three months post-randomisation (moderate-quality evidence). The authors also found low to moderate-quality evidence for complete resolution at any time point (10 days to 6 months). International guidelines currently generally advise against the use of antibiotics for OME, but NICE are currently reviewing their guidance and may reconsider their original recommendation against antibiotics [13].

The scoping team considered some of the high ranked interventions to be less of a priority at this time, for the following reasons:

Although hearing aids were ranked within the top 10 interventions requiring a Cochrane Review, scoping searches and a further check in March 2020 found no RCTs of this intervention. It would therefore be likely to be an empty review if undertaken at this time. Although it would be important to highlight the lack of available RCT evidence, the resources required for such a review could be spent on other priority areas.

Some participants in the prioritisation exercise ranked ‘myringotomy alone’ quite highly, whereas others gave this a very low ranking. Consultation suggests that one reason for looking

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at myringotomy as a stand-alone procedure is that there could be subgroups of people for whom this might work. One consultee commented that, since OME is biologically and cytologically a very variable disorder, myringotomy and suction of effusion may work in a subset of cases (such as adults with serous effusion). However, due to our Cochrane reviews focusing on children with OME, group consensus was not to include this intervention as a priority.

3. PROPOSED SCOPE OF REVIEWS

This section sets out the proposed setting, population, interventions and outcomes for the suite of reviews on OME.

3.1 SettingWe will include evidence from all settings, including community settings, primary and secondary care.

3.2 Population3.2.1 Populations that will be includedThe aim is to include all children with OME, regardless of any comorbidity such as Down syndrome or cleft palate. Children with OME are prone to episodes of AOM, and the distinction between OME and AOM is not always formally made. Some trials may include both children with (persistent) OME and those with (recurrent) AOM. We will include these if a majority of participants have OME, or if it is possible to obtain subgroup data for the children with OME.

We propose the following subgroup analyses:

children with OME treated in primary care versus those treated in secondary care (ENT and hearing services);

children with a first OME diagnosis versus those with a repeated OME diagnosis after 3 months or longer (reflecting persistent OME);

children with OME and hearing loss in the better hearing ear of 25 dB or worse versus those with hearing loss less than 25 dB;

children with allergy versus those without (using the trials own definition); children with Down syndrome versus those without; children with cleft palate versus those without.

Unless trials report these subgroups, or make individual participant data available, it will be necessary to carry out the subgroup analysis at the study level, i.e. group the studies according to the characteristics of the majority of their participants.

3.2.2 Populations that will not be includedWe will exclude studies that only include children with (recurrent) AOM. We will exclude studies that only include adults with OME, defined as participants aged 18 or over.

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If a study includes a mixed population (e.g. both children with OME and AOM or both children and adults with OME), we will include the study if the majority of children have OME, or if it is possible to retrieve data for this subgroup separately.

3.3 Interventions3.3.1 Types of interventions to be included in the reviews Ventilation tubes. Adenoidectomy, either alone or in combination with ventilation tubes. Autoinflation. Topical and oral steroids. Antibiotics.

3.3.2 Types of interventions to be excluded from the reviewsInitial discussions within the core prioritisation team excluded aerosol therapy. The team also decided to exclude thermal therapy, which a French guideline mentions in the form of sulphurous water insufflations but does not recommend as first-line treatment for OME [18]. Scoping searches identified three abstracts relating to thermal therapy.

Following the prioritisation exercise, the following interventions will not be included in the initial suite of Cochrane Reviews, but may be considered at a later date if resources are available:

balloon dilation of the Eustachian tube; leukotriene inhibitors (montelukast); mucolytics; hearing aids; myringotomy alone; decongestants; antihistamines; proton pump inhibitors, and other reflux medications; herbal, homeopathic and alternative remedies.

3.4 Main outcomes3.4.1 Background on core outcome setResearchers on the mOMEnt study undertook a comprehensive assessment of outcome measures used in studies of the treatment of OME [77]. They then conducted a three-round Delphi study, a consensus meeting and a workshop with parents to identify outcomes of relevance to children with OME and cleft palate. Based on the mOMEnt study, a Core Outcome Set (COS) has also been developed for OME in children who don’t have cleft-palate [78], following extensive consultation with health professionals and focus groups of parents/guardians of children with OME.

3.4.2 Proposed outcomes for Cochrane ReviewsBased on the outcomes identified as most important in the above two studies, we propose to use the following outcomes for the new set of Cochrane Reviews.

1. Hearing, measured by pure tone audiometry or speech recognition thresholds (in dB HL).2. Listening skills, e.g. listening to stories and instructions effectively.

14


3. Receptive language skills, measured by Peabody-revised picture vocabulary test or the relevant domains of the Reynell Developmental Language Scales [79], Preschool Language Scale (PLS) [80], or Sequenced Inventory of Communication (SCID) [81].

4. Speech development, or expressive language skills, measured by Schlichting test or Lexi test, or the relevant domains of the Reynell Developmental Language Scales, PLS or SCID.

5. Psychosocial outcomes, measured by the Social Skills Scale of the Social Skills Rating System [82].

6. Presence of OME (persistence or recurrence of OME at 3, 6, 9, 12 months), measured by pneumatic otoscopy, tympanometry, otomicroscopy.

7. Number of doctor-diagnosed AOM episodes within a specified time frame. 8. Side effects of treatment

a. Side effects of ventilation tubes, i.e. changes to the tympanic membrane and perforation, measured by otoscopy.

b. Adverse events likely to be related to the study medications, e.g. ototoxicity, skin rash, epistaxis, pain (as reported in the trial).

9. Quality of lifea. Disease-specific quality of life using a standardised instrument, e.g. OM8-30, Otitis

Media-6.b. Generic health-related quality of life using a validated instrument, e.g. EQ-5D; Infant

Toddler Quality of Life Questionnaire; Child Heath Questionnaire.

4. PLANNED COCHRANE REVIEWS

Table 2 describes the proposed Cochrane Reviews.

Table 2 Proposed Cochrane Reviews

(Tentative) review short name

Pair Intervention Comparator

1. Ventilation tubes for otitis media with effusion in children

1. Bilateral ventilation tubes

Non-surgical treatment

2. Bilateral ventilation tubes

Myringotomy alone

3. Unilateral ventilation tubes

Non-surgical treatment in the other ear

4. Unilateral ventilation tubes

Myringotomy alone in the other ear

Adenoidectomy 6. Adenoidectomy alone Non-surgical treatment7. Adenoidectomy and

bilateral ventilation tubes

Non-surgical treatment

8. Adenoidectomy and bilateral ventilation tubes

Bilateral ventilation tubes

9. Adenoidectomy with unilateral ventilation tube

Unilateral ventilation tube only

Autoinflation for 10. Autoinflation No treatment

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otitis media with effusion in children

11. Autoinflation Ventilation tubes

Topical and oral steroids for otitis media with effusion in children

12. Topical steroids Placebo or no topical treatment 13. Oral steroids Placebo or no oral treatment

Antibiotics for otitis media with effusion in children

14. Oral antibiotics Placebo or no oral treatment

5. REVIEW METHODSWe will conduct the systematic reviews and meta-analyses using the methodology described in the Cochrane Handbook for Systematic Reviews of Interventions (version 6.0) [83]. We will produce a detailed protocol for each Cochrane Review that ranked highly in the prioritisation exercise. The section below gives a broader summary of the general methodological approach we will take.

5.1 SEARCHESThe Cochrane ENT Information Specialist will search the following databases from their inception to identify published, unpublished and ongoing RCTs:

the Cochrane ENT Register (search via the Cochrane Register of Studies to date); the Cochrane Central Register of Controlled Trials (CENTRAL) (search via the Cochrane

Register of Studies to date); Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid

MEDLINE(R) Daily and Ovid MEDLINE(R) (1946 to date); Ovid EMBASE (1974 to date); Web of Science, Web of Science (1945 to date); LILACS (Latin American and Caribbean Health Science Information

database), lilacs.bvsalud.org (search to date); CNKI, www.cnki.com.cn (search via Google Scholar 1999 to date); ClinicalTrials.gov (search via the Cochrane Register of Studies and clinicaltrials.gov to date); World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)

(search via the Cochrane Register of Studies and www.who.int/ictrp to date); Ovid AMED (1985 to date; if relevant to identify alternative therapies); EBSCO CINAHL (1982 to date; if relevant for any interventions commonly delivered by nurses

or allied health professionals).

We will consider using Cochrane's Screen4Me workflow to help assess the search results, depending on the number of results retrieved from the database searches. Screen4Me comprises three components:

1) known assessments, a service that matches records in the search results to records that have already been screened in Cochrane Crowd and been labelled as 'an RCT' or as 'not an RCT';

2) the machine learning classifier (RCT model) [84], available in the Cochrane Register of Studies (CRS Web), which assigns a probability of being a true RCT (from 0 to 100) to each ‐citation. We will assume that any citations assigned a probability score below the cut point ‐

16

https://community.cochrane.org/sites/default/files/uploads/S4M_webinar_slides_Feb_2019.pdf

http://www.who.int/ictrp

http://clinicaltrials.gov/

http://www.cnki.com.cn/

http://lilacs.bvsalud.org/


at a recall of 99% are non RCTs. For those that score on or above the cut point, we will ‐ ‐either manually dual screen these results or send them to Cochrane Crowd for screening;

3) Cochrane Crowd, Cochrane's citizen science platform, where the Crowd help to identify and describe health evidence.

5.2 TYPES OF RESEARCH DESIGNS CONSIDERED FOR REVIEWWe will include randomised controlled trials (RCTs), whether randomised at the level of the individual participant or by cluster (e.g. by clinic or GP practice). Where relevant, we will also include studies that randomise by ear, rather than by person (for example, reviews considering ventilation tubes or myringotomy). Due to the self-limiting nature of the condition, trials that use a cross-over design are unlikely to be appropriate. If we do identify any such trials, we will only use data from the first phase.

5.3 DATA EXTRACTION AND MANAGEMENTThe outcomes identified in Section 3.4.2 are of general relevance to the proposed suite of Cochrane Reviews on OME. If the list needs to be tailored for each individual Cochrane Review, we will describe this clearly in the relevant protocol.

We will develop a common data extraction form that can be used across all the reviews. We will use this to collect the characteristics of each study’s population and treatment regimen, and also collect data on the core outcomes of relevance to each review.

5.4 RISK OF BIAS ASSESSMENTWe will use Cochrane’s ‘Risk of bias’ tool, as described in the 2011 version of the Cochrane Handbook for Systematic Reviews of Interventions [85] to assess the following domains as ‘high, ‘low’ or ‘unclear’ risk of bias:

sequence generation; allocation concealment; blinding; incomplete outcome data; selective outcome reporting; and other sources of bias.

5.5 ANALYSIS AND POOLING OF EVIDENCEEach of the Cochrane Reviews will include an assessment of the clinical heterogeneity among the included studies. If we think these are sufficiently similar for a pooled analysis to be meaningful, we will combine the studies in a meta-analysis. We will consider the degree of similarity between studies when deciding whether to use a fixed-effect model or a random-effects model for the meta-analysis. We will follow standard Cochrane methods to conduct the analysis [83]. If we have included studies that randomise by ear rather than by child, we will use appropriate methods to account for this [86, 87]. We will also undertake a sensitivity analysis that excludes such trials.

5.6 RATING OF CERTAINTY OF EVIDENCEWe will use the GRADE approach to rate the overall certainty of evidence using GRADEpro GDT (https://gradepro.org/). The certainty of evidence reflects the extent to which we are confident that an estimate of effect is correct, and we will apply this in the interpretation of results. There are four

17

https://gradepro.org/


possible ratings: high, moderate, low and very low. A rating of high certainty of evidence implies that we are confident in our estimate of effect and that further research is very unlikely to change our confidence in the estimate of effect. A rating of very low certainty implies that any estimate of effect obtained is very uncertain. We will consider the following domains when rating the certainty of the evidence:

study limitations (risk of bias); inconsistency; indirectness of evidence; imprecision; and publication bias.

5.7 OUTPUT OF THE EVIDENCE REVIEWThe aim is to undertake Cochrane Reviews from the prioritised list, with the number of reviews dependent on the availability of resources.

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33. Dewan K, Lieu J. A clinical trial of proton pump inhibitors to treat children with chronic otitis media with effusion. Journal of International Advanced Otology 2018; 14(2): 245-9.

34. Rukholm G, et al. Role of empiric anti-reflux therapy in pediatric otitis media with effusion-a pilot study. European Journal of Pediatrics 2016; 175(11): 1658.

35. Saigusa H, et al. Therapeutic proton pump inhibitor trails for otitis media with effusion in children. 5th Extraordinary International Symposium on Recent Advances in Otitis Media . Amsterdam, The Netherlands, April 24-27, 2005, 2005: p. 204, Abstract No. P.09.03.

36. Wang J. Anti-reflux therapy for the treatment of secretory otitis media: a meta-analysis of randomized controlled trials. PROSPERO 2016 CRD42016045646. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42016045646, 2016.

37. Marom T, et al. Complementary and Alternative Medicine Treatment Options for Otitis Media: A Systematic Review. Medicine 2016; 95(6): e2695.

38. Kim YH, et al. Oral administration of herbal medicines for the treatment of otitis media with effusion: protocol for a systematic review. 2014. 1.

39. Walls T. Probiotics for preventing otitis media in children. PROSPERO 2018 CRD42018089926. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018089926, 2018.

40. Ejnell H. A comparison of surgical and a new non-surgical treatment methods for secretory otitis media in children- hearing and socioeconomic aspects. Https://clinicaltrials.gov/show/nct02546518, 2015.

41. Ejnell H. The effect of early non-surgical treatment of children with middle ear effusion on the hearing level and the health economics. Https://clinicaltrials.gov/show/nct02549612, 2015.

42. Browning GG, et al, Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children. Cochrane Database of Systematic Reviews 2010;(10).

43. Sujatha S, Venugopalan PG. Evaluation of effectiveness of myringotomy and myringotomy with ventilation tube insertion as treatment of otitismedia with effusion in children. Journal of Evolution of Medical and Dental Sciences-JEMDS 2015; 4(29): 5003-9.

44. Yousaf M, Malik SA, Haroon T. Laser myringotomy versus ventilation tubes in otitis media with effusion. Journal of Ayub Medical College, Abbottabad 2016; 28(4): 773-5.

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48. Cheong KH, Hussain SS. Management of recurrent acute otitis media in children: systematic review of the effect of different interventions on otitis media recurrence, recurrence frequency and total recurrence time. Journal of Laryngology & Otology 2012; 126(9): 874-85.

49. Wallace IF, et al. Surgical treatments for otitis media with effusion: a systematic review. Pediatrics 2014; 133(2): 296-311.

50. Capaccio P, et al. Endoscopic adenoidectomy in children with otitis media with effusion and mild hearing loss. Clinical and Experimental Otorhinolaryngology 2016; 9(1): 33-8.

51. Boonacker CW, et al. Adenoidectomy with or without grommets for children with otitis media: an individual patient data meta-analysis. Health Technol Assess 2014; 18(5).

52. Mikals SJ, Brigger MT. Adenoidectomy as an adjuvant to primary tympanostomy tube placement: a systematic review and meta-analysis. JAMA Otolaryngology-Head & Neck Surgery 2014; 140(2): 95-101.

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53. Tian X, et al. A systematic review of adenoidectomy in the treatment of otitis media with effusion in children. Journal Of Clinical Otorhinolaryngology, Head, & Neck Surgery 2014; 29(8): 723-5.

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63. Venekamp RP, et al. Interventions for children with ear discharge occurring at least two weeks following grommet (ventilation tube) insertion. Cochrane Database of Systematic Reviews 2016;(11).

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67. Simpson SA, et al, Identification of children in the first four years of life for early treatment for otitis media with effusion. Cochrane Database of Systematic Reviews 2007;(1).

68. Bruce I, et al. The management of Otitis Media with Effusion in children with cleft palate (mOMEnt): a feasibility study and economic evaluation. Health Technol Assess 2015; 19(68).

69. Fortnum H, et al. Assessment of the feasibility and clinical value of further research to evaluate the management options for children with Down syndrome and otitis media with effusion: a feasibility study. Health Technology Assessment (Winchester, England) 2014; 18(60): 1-147, v-vi.

70. Hall A, et al. A mixed-methods study of the management of hearing loss associated with otitis media with effusion in children with Down syndrome. Clin Otolaryngol 2019; 44(1): 32-8.

71. Felton M, et al. Early placement of ventilation tubes in infants with cleft lip and palate: a systematic review. Otolaryngol Head Neck Surg 2018; 158(3): 459-64.

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72. Kuo CL, et al. Grommets for otitis media with effusion in children with cleft palate: a systematic review. Pediatrics 2014; 134(5): 983-94.

73. Ponduri S, et al. The management of otitis media with early routine insertion of grommets in children with cleft palate -- a systematic review. Cleft Palate Craniofac J 2009; 46(1): 30-8.

74. Demant MN, et al. The effects of ventilation tubes versus no ventilation tubes for recurrent acute otitis media or chronic otitis media with effusion in 9 to 36 month old Greenlandic children, the SIUTIT trial: study protocol for a randomized controlled trial. 2015.

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76. Francis NA, et al. Oral steroids for resolution of otitis media with effusion in children (OSTRICH): a double-blinded, placebo-controlled randomised trial. Lancet 2018; 392(10147): 557-68.

77. Harman NL, et al. The Importance of Integration of Stakeholder Views in Core Outcome Set Development: Otitis Media with Effusion in Children with Cleft Palate. PLoS ONE 2015; 106(6): e0129514.

78. Liu PZ, Ismail-Koch H, Stephenson K, Donne AJ, Fergie N, Derry J, et al. A core outcome set for research on the management of otitis media with effusion in otherwise-healthy children. Submitted 2019.

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80. Zimmerman IL, Steiner VG, Pond RE. Preschool Language Scale-3. 1992, San Antonio, TX: The Psychological Corporation.

81. Hedrick DL, Prather EM, Tobin AR. Sequenced Inventory of Communication Development. 1984, Seattle, WA: University of Washington Press.

82. Gresham FM, Elliott SN. Social Skills Rating System. 1990, Circle Pines, MN: American Guidance Service.

83. Higgins JP, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. 2019, Chichester (UK): John Wiley & Sons.

84. Wallace BC, et al. Identifying reports of randomized controlled trials (RCTs) via a hybrid machine learning and crowdsourcing approach. J Am Med Inform Assoc 2017; 24(6): 1165-68.

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7. APPENDIX 1 – list of existing Cochrane Reviews

Review Date of search Included studies

Adenoidectomy for otitis media in children [24] 30 March 2009 14Antibiotics for otitis media with effusion in children[6] 14 April 2016 25Antihistamines and/or decongestants for otitis media with effusion (OME) in children [7]

1 Feb 2011 16

Autoinflation for hearing loss associated with otitis media with effusion [9]

12 April 2013 8

Grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children [42]

22 March 2010 10

Identification of children in the first four years of life for early treatment for otitis media with effusion [67]

30 June 2009 3

Interventions for children with ear discharge occurring at least two weeks following grommet (ventilation tube) insertion [63]

23 June 2016 9

Interventions for the prevention of postoperative ear discharge after insertion of ventilation tubes (grommets) in children [64]

3 July 2012 15

Interventions for the prevention of postoperative grommet (ventilation tube) obstruction [PROTOCOL] [66]

n/a n/a

Oral or topical nasal steroids for hearing loss associated with otitis media with effusion in children [26]

26 Aug 2010 12

Water precautions for prevention of infection in children with ventilation tubes (grommets) [65]

1 September 2015

2

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8. APPENDIX 2 - SEARCH STRATEGIESCochrane ENT Register (CRS) Medline (Ovid) Embase (Ovid1 MESH DESCRIPTOR Otitis Media with Effusion EXPLODE ALL AND INREGISTER2 ("otitis media" adj6 effusion):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER3 (Secretory otitis media):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER4 (Serous otitis media):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER5 (Middle-ear effusion):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER6 (glue ear):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER7 (middle ear perfusion):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER8 MESH DESCRIPTOR Otitis Media AND INREGISTER9 (otitis media):TI,TO AND INREGISTER10 #8 OR #9 AND INREGISTER11 (((effusion or Recurrent or persistent or serous or secretory or perfusion) adj3 otitis)):AB,EH,KW,KY,MC,MH,TI,TO AND INREGISTER12 #10 AND #11 AND INREGISTER13 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #12 AND INREGISTER

1 exp Otitis Media with Effusion/2 ("otitis media" adj6 effusion).ab,ti.3 Secretory otitis media.ab,ti.4 Serous otitis media.ab,ti.5 Middle-ear effusion.ab,ti.6 Glue ear.ab,ti.7 middle ear perfusion.ab,ti.8 Otitis Media/9 "otitis media".ti.10 8 or 911 ((effusion or Recurrent or persistent or serous or secretory or perfusion) adj3 otitis).ab,ti.12 10 and 1113 1 or 2 or 3 or 4 or 5 or 6 or 7 or 1214 randomized controlled trial.pt.15 controlled clinical trial.pt.16 randomized.ab.

1 exp secretory otitis media/2 ("otitis media" adj6 effusion).ab,ti.3 Secretory otitis media.ab,ti.4 Serous otitis media.ab,ti.5 Middle-ear effusion.ab,ti.6 glue ear.ab,ti.7 middle ear perfusion.ab,ti.8 otitis media/9 otitis media.ti.10 8 or 911 ((effusion or Recurrent or persistent or serous or secretory or perfusion) adj3 otitis).ab,ti.12 10 and 1113 1 or 2 or 3 or 4 or 5 or 6 or 7 or 1214 (random* or factorial* or placebo* or assign* or allocat* or crossover*).tw.15 (control* adj group*).tw. 16 (trial* and (control* or comparative)).tw.17 ((blind* or mask*) and (single or double or triple or treble)).tw.18 (treatment adj arm*).tw.19 (control* adj group*).tw.20 (phase adj (III or three)).tw.21 (versus or vs).tw22 rct.tw.23 crossover procedure/24 double blind procedure/25 single blind procedure/26 randomization/27 placebo/28 exp clinical trial/29 parallel design30 Latin square design/31 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22

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or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 3032 exp ANIMAL/ or exp NONHUMAN/ or exp ANIMAL EXPERIMENT/ or exp ANIMAL MODEL/33 exp human/34 32 not 3335 31 not 3436 13 and 35

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Otitis media with effusion - Cochrane ENT · Web viewMontelukast versus inhaled mometasone for treatment of otitis media with effusion in children: a randomized controlled trial