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Grommets (ventilation tubes) for recurrent acute otitis media in children

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To establish the effects of grommet insertion (with or without concurrent adenoidectomy) for children with rAOM.

Background

Description of the condition

Acute otitis media (AOM) is one of the most common childhood illnesses and is defined as the presence of middle ear fluid together with an acute onset of signs and symptoms of middle ear inflammation (Lieberthal 2013). Bulging of the ear drum or new onset of ear discharge not caused by acute otitis externa are the cardinal signs of AOM, while ear pain, fever, irritability, and problems feeding and sleeping are among the typical AOM symptoms (Lieberthal 2013). AOM is one of the most frequent reasons for primary care visits (Ashworth 1995), and the prime indication for antibiotic prescription in UK and US children (Finkelstein 2000; Grijalva 2009; Williamson 2006). AOM is also associated with substantial non‐healthcare costs due to lost days from work for parents and the use of over‐the‐counter medications (Alsarraf 1999; Niemelä 1999), in addition to its considerable impact on direct healthcare costs (Ahmed 2014; Bondy 2000).

While many children suffer from incidental AOM episodes, an important group suffer from recurrent AOM (rAOM), defined as three or more episodes in six months, or four in one year with one episode in the last six months (Goycoolea 1991). In this subset of children AOM poses a true burden through frequent episodes of ear pain, general illness, sleepless nights and time lost from nursery/school. Moreover, AOM is closely related to otitis media with effusion (OME); children with OME are at risk of AOM recurrences (Alho 1995), and following AOM children have OME for some time (Tapiainen 2014), extending the burden of rAOM to OME and hearing loss‐related developmental outcomes (Bennett 2001). The impact of rAOM on quality of life equals that of childhood asthma (Brouwer 2005), and parents of children with rAOM repeatedly seek medical attention to relieve their child's symptoms and prevent future episodes.

Epidemiological studies of otitis media demonstrate that the first two years of life represent the period of greatest risk for the first as well as recurrent episodes of infection (Teele 1989). Age‐specific incidence is highest during the second six months of life, which coincides with the lowest level of serum immunoglobulin (antibody) concentrations. There is further evidence to suggest that the function of the developing immune system is key in protecting young children against rAOM. Children fed with breast milk, rich in maternal antibodies capable of providing passive immunity, are at lower risk of otitis media in the second six months of life (Rovers 2004). Children prone to AOM may have lower age‐specific immunoglobulin levels, which may reflect a generalised poorer antibody response (Veenhoven 2004). Environmental factors including day care, low socio‐economic status and passive smoking, have been causally related to AOM (Alpert 2011; Rovers 2004). A family history of recurrent ear disease, craniofacial malformations like cleft palate and early onset of acute otitis media have also been associated with increased susceptibility to rAOM.

Preventive strategies have had a modest effect on rAOM (Fortanier 2014); for example the seven‐valent pneumococcal conjugate vaccine reduces rAOM by 10%. Antibiotic prophylaxis and surgical procedures are being used to prevent AOM recurrence. Antibiotic prophylaxis has some benefit (number needed to treat to benefit (NNTB) 5) (Leach 2006; Williams 1993), but concerns about common side effects (skin rash and gastrointestinal upset) and emerging antibiotic resistance speak against routine adoption (Gillies 2015; Laxminarayan 2013). The surgical procedures offered to children with rAOM are (a) myringotomy and insertion of grommets (ventilation tubes), (b) adenoidectomy or (c) concurrent myringotomy with insertion of grommets, and adenoidectomy. The role of adenoidectomy in reducing rAOM is not fully established (Boonacker 2014; van den Aardweg 2010). A recent individual patient data meta‐analysis suggested that children with rAOM below two years of age are most likely to benefit from adenoidectomy; the proportion of children failing treatment at 12 months was 16% (44/281) in the adenoidectomy group versus 27% (120/438) in the control group (NNTB 8). In contrast, adenoidectomy was of no significant benefit in children with rAOM aged two years and over (treatment failure at 12 months: 8/44 (18%) in the adenoidectomy group versus 1/40 (3%) in the control group) (Boonacker 2014).

Description of the intervention

Grommets are tiny plastic ventilation tubes commonly inserted under general anaesthesia in children as a day‐case procedure. An operating microscope or other magnification is used to visualise the tympanic membrane (ear drum) where a small incision is made (myringotomy), and the grommet is placed in the incision after aspiration of middle ear fluid subject to need and surgical preference. Grommets usually remain in place for six to nine months, facilitating middle ear ventilation and providing a route for drainage of middle ear fluid. They reverse and prevent the formation of middle ear effusions by providing a surrogate to the under‐functioning Eustachian tube and so create a less favourable environment for viruses and bacteria to cause recurrent middle ear infections (Rosenfeld 2013). Grommets are also thought to reduce the severity of potential AOM recurrences by allowing for drainage of middle ear fluid that might otherwise build up during an acute infection, and thereby preventing ear pain caused by pressure against the ear drum. Furthermore, they allow for local treatment of any AOM recurrence (topical antibiotics), thereby avoiding the side effects of systemic antibiotics and potentially reducing the risk of antimicrobial resistance (Weber 2004).

Why it is important to do this review

Recommendations regarding the use of grommets in children with rAOM vary. Two recent US guidelines list grommets as an option in children with rAOM (Lieberthal 2013; Rosenfeld 2013), although the latter states that grommets should not be offered to children with a history of rAOM when there is no effusion at the time of evaluation for surgery. While NICE guidance is available for the use of grommets in selected children with persistent OME (NICE 2008), specific guidance for those with rAOM is lacking.

The absence of clear guidance on the use of grommets in rAOM may lead to practice variation nationally and internationally. A recent pilot study indicated that across the UK there is a 40‐ to 60‐fold variation in the use of grommets for rAOM across Primary Care Trusts, compared with eight‐ to nine‐fold for grommets for OME (Bohm 2013, personal communication). Furthermore, the surgical rates for grommets in children with rAOM vary widely across Western countries, with the UK being among the countries with the lowest surgical rates for grommets (Schilder 2004).

An up‐to‐date, comprehensive systematic review is therefore urgently needed, summarising the available evidence on the effects of grommets with or without concurrent adenoidectomy for children with rAOM.

Objectives

To establish the effects of grommet insertion (with or without concurrent adenoidectomy) for children with rAOM.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) irrespective of the randomisation method and blinding procedure used.

Types of participants

Children up to age 16 years with rAOM, defined as three or more episodes in six months, or four in one year with one episode in the last six months (Goycoolea 1991). We will include all children whether or not there is evidence of a middle ear effusion at the time of study enrollment.

Types of interventions

Intervention

  • Grommet insertion (of any type).

  • Adenoidectomy is only allowed as a co‐intervention when used in both treatment arms.

Comparator

The comparator will be no surgical treatment: either AOM episode‐specific treatment with analgesia +/‐ antibiotics or antibiotic prophylaxis for a minimum period of three months.

The main comparison pair will be:

  • grommet insertion versus AOM episode‐specific course of analgesia with or without antibiotics.

Other possible comparison pairs include:

  • grommet insertion with concurrent adenoidectomy versus adenoidectomy alone;

  • grommet insertion versus antibiotic prophylaxis for a minimum period of three months.

In both the intervention and comparator groups AOM recurrences may be treated with analgesics and antibiotics routinely or in selected cases.

We anticipate that some children allocated to initial observation may undergo surgery before the end of the trial (i.e. cross over into the surgery group).

Types of outcome measures

We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies.

Primary outcomes

  • Treatment success, defined as the proportion of children who have no AOM recurrences at three to six months post‐randomisation (intermediate‐term).

  • Significant adverse effect: a tympanic membrane perforation persisting for three months or longer after initial observation.

Secondary outcomes

  • Treatment success, defined as the proportion of children who have no AOM recurrences at six to 12 months post‐randomisation (long‐term).

In the short (less than three months), intermediate (three to six months) and long term (six to 12 months) post‐randomisation:

  • Total number of AOM recurrences.

  • Disease‐specific health‐related quality of life of the child and its parents or carers (using any validated instrument; see Brouwer 2007).

  • Generic health‐related quality of life of the child and parents (using any validated instrument).

  • Presence of middle ear effusion.

  • Other adverse effects: ventilation tube misplaced in middle ear, otorrhoea within one week of ventilation tube placement, myringosclerosis.

We will discuss and include within our outcomes other adverse effects and complications recorded in RCTs but not listed above.

Search methods for identification of studies

The Cochrane ENT Trials Search Co‐ordinator (TSC) will conduct systematic searches for randomised controlled trials and controlled clinical trials. There will be no language, publication year or publication status restrictions.

Electronic searches

The TSC will search:

  • the Cochrane ENT Trials Register (searched via the Cochrane Register of Studies);

  • the Cochrane Register of Studies Online (search to date);

  • Ovid MEDLINE (1946 to date):

    • Ovid MEDLINE (In‐Process & Other Non‐Indexed Citations);

    • PubMed (as a top up to searches in Ovid MEDLINE);

  • Ovid EMBASE (1974 to date);

  • Ovid CAB Abstracts (1910 to 2014 week 43);

  • EBSCO CINAHL (1982 to date);

  • LILACS, lilacs.bvsalud.org;

  • KoreaMed (via Google Scholar);

  • IndMed, www.indmed.nic.in;

  • PakMediNet, www.pakmedinet.com;

  • Web of Knowledge, Web of Science (1945 to date);

  • ClinicalTrials.gov (via the Cochrane Register of Studies);

  • ICTRP, www.who.int/ictrp;

  • Google Scholar, scholar.google.co.uk;

  • Google, www.google.com.

The subject strategies for databases will be modelled on the search strategy designed for CENTRAL (Appendix 1). Where appropriate, these will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, 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, the Trials Search Co‐ordinator will search PubMed, TRIPdatabase, The Cochrane Library 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 ENT Trials Register and EMBASE.

Data collection and analysis

Selection of studies

Two review authors (LL and PTM) will independently screen titles and abstracts obtained from the database searches and the reference lists of relevant systematic reviews to assess their potential relevance for reviewing the full text. The same review authors will independently review the full text of potentially relevant articles against the inclusion and exclusion criteria. We will resolve any disagreements by discussion with a third review author (RPV).

Data extraction and management

Two review authors (LL and PTM) will independently extract data from the included studies using standardised data extraction forms. We will extract the following data from each study:

  • Trial characteristics: setting, design, method of data analysis.

  • Participants: study population, number of children in each group, participant characteristics such as age and gender.

  • Interventions: type of surgery including pre‐operative, intra‐operative and postoperative treatment.

  • Outcomes: primary and secondary outcomes recorded, time points, adverse effects and complications related to the intervention and comparators.

  • Aspects of methodology relating to risk of bias (see below).

We will also extract the following summary statistics for each trial and each outcome:

  • For continuous data: the mean values, standard deviations and number of patients for each treatment group. Where endpoint data are not available, we will extract the values for change from baseline.

  • For binary data: the numbers of participants experiencing an event and the number of patients assessed at the time point.

  • For ordinal scale data: if the data appear to be approximately normally distributed or if the analysis that the investigators performed suggests parametric tests were appropriate, then we will treat the outcome measures as continuous data. Alternatively, if data are available, we may convert them into binary data.

We have prespecified the time points of interest for the outcomes in this review. While studies may report data at multiple time points, we will only extract the longest available data within the time points of interest. For example, for 'intermediate‐term' follow‐up periods, our time point is defined as 'three to six months' post‐randomisation. If a study has reported data at three, four and six months, we will only extract and analyse the data for the six‐month follow‐up.

We will contact the authors of the original publication in case of missing data and we will resolve any discrepancies by discussion. Where a study has more than one publication, we will retrieve all publications to ensure complete extraction of data. If extracted data are suitable for pooled analysis two authors (PTM and RVP) will conduct this.

Assessment of risk of bias in included studies

Three review authors (AGMS, RPV and DAN) will independently assess the methodological quality of the included studies and resolve any disagreements by majority opinion. Guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011), we will take the following items into consideration:

  • random sequence generation (selection bias);

  • allocation concealment (selection bias);

  • blinding of participants and personnel (performance bias);

  • blinding of outcome assessment (detection bias);

  • incomplete outcome data (attrition bias);

  • selective reporting (reporting); and

  • other sources of bias.

We will present the results of the 'Risk of bias' assessment in a 'Risk of bias' graph and summary figure.

Measures of treatment effect

We will express the pooled measures of treatment effect for dichotomous outcomes as risk ratio (RR) with accompanying 95% confidence intervals (CI). For the key outcomes that we will present in the 'Summary of findings' table, we will also express the results as absolute numbers based on the pooled results and compared to the assumed risk. We may also calculate the number needed to treat to benefit (NNTB) using the pooled results.

We will express continuous outcome variables either as a mean difference (MD) with 95% CIs, if reported on the same scale, or as a standardised mean difference (SMD) with 95% CIs, if different continuous scales were used.

Unit of analysis issues

This review will not use data from phase II of cross‐over studies or from studies where the patient is not the unit of randomisation, i.e. cluster‐randomised trials or studies where 'ears' (right versus left) were randomised.

Dealing with missing data

We will contact trial authors in order to obtain additional information in case of missing data. We will only analyse the available data based on the intention‐to‐treat (ITT) principle. For continuous outcomes, we will calculate missing statistics, such as standard deviations (SDs), from other available statistics (e.g. P values) according the methods described in Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011).

Apart from imputations for missing standard deviations, we will conduct no other imputations. We will extract and analyse all data using the available case analysis method.

Assessment of heterogeneity

We will primarily assess the level of clinical diversity between trials by reviewing them for potential differences in the types of participants recruited, interventions used and outcomes measured. Secondly, we will assess statistical heterogeneity for each outcome by using the Chi2 test, with a significance level set at P value < 0.10, and the I2 statistic, with I2 values over 50% suggesting substantial heterogeneity (Higgins 2003).

Assessment of reporting biases

We will search the internet, ClinicalTrials.gov (http://clinicaltrials.gov/) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/trialsearch) for available study protocols to determine whether outcomes reported were pre‐defined and whether all outcomes listed in the study protocol were reported in the trial publications. If there are sufficient trials, we propose a more formal method of assessing reporting bias, i.e. by using funnel plots

Data synthesis

We will analyse the data according to the intention‐to‐treat principle, i.e. by analysing all participants in the groups to which they were originally randomised. Where data are missing or there was loss to follow‐up, we will conduct an available case analysis.

We will consider pooling the results for meta‐analysis using Review Manager 5.3 (RevMan 2014), in the absence of significant clinical diversity, i.e. where we judge participants, interventions, comparisons and outcomes across trials to be sufficiently similar. We will calculate treatment differences with the Mantel‐Haenszel method using a fixed‐effect model where no substantial statistical heterogeneity is present (I2 < 50%). If substantial statistical heterogeneity is detected but unresolved by sensitivity analysis and pre‐specified subgroup analyses, we will calculate treatment differences with the Mantel‐Haenszel method using a random‐effects (DerSimonian and Laird) model to provide a more conservative effect estimate. For dichotomous outcomes, we will calculate the NNTB using the results of the meta‐analysis (which itself uses risk ratio) based on the average risk of the control groups in the included studies ('study population') (Handbook 2011).

Subgroup analysis and investigation of heterogeneity

If possible, we will perform pre‐planned subgroup analyses even if statistical heterogeneity is not observed. We have planned these analyses as the factors indicated are suspected to be potential effect modifiers. They include:

  • type of surgery (grommets only versus grommets and concurrent adenoidectomy);

  • presence of middle ear effusion at randomisation or at the time of surgery (yes versus no).

In addition to the subgroups above, we will conduct the following subgroup analysis in the presence of statistical heterogeneity:

  • age (below two years of age versus two years and older);

  • type of grommet (short‐term versus intermediate/long‐term).

Sensitivity analysis

To assess the robustness of the review findings, we will perform a sensitivity analysis in which RCTs with a high risk of bias are excluded. We will define high risk of bias as high risk of allocation concealment bias or attrition bias (overall loss to follow‐up of more than 20% or differential follow‐up observed, or both). In further sensitivity analysis, we propose to calculate the effects of grommets by excluding any AOM recurrences that occurred between the date of randomisation and the date of surgery.

GRADE and 'Summary of findings'

We will use the GRADE approach to rate the overall quality of evidence for each outcome. We will judge the quality of evidence as high, moderate, low or very low. We will judge evidence from RCTs that do not have serious limitations as high quality. However, we may downgrade the quality of evidence to moderate, low or very low based on the following factors:

  • study limitations (risk of bias);

  • indirectness of evidence (directness of evidence);

  • imprecision (precision of results);

  • inconsistency (consistency of results);

  • publication bias (existence of publication bias).

We will include a 'Summary of findings' table, which we will construct according to the recommendations described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2011). We will report the following seven outcomes:

  • treatment success, defined as the proportion of children who have no AOM recurrences at three to six months post‐randomisation (intermediate‐term);

  • significant adverse effects: a tympanic membrane perforation persisting for three months or longer after initial observation;

  • treatment success, defined as the proportion of children who have no AOM recurrences at six to 12 months post‐randomisation (long‐term);

  • total number of AOM recurrences at three to six months post‐randomisation (intermediate‐term);

  • disease‐specific health‐related quality of life at three to six months post‐randomisation (intermediate‐term);

  • generic health‐related quality of life of the child and parents at three to six months post‐randomisation (intermediate‐term);

  • presence of middle ear effusion at three to six months post‐randomisation (intermediate‐term).