Evidence reviews for non-antimicrobial pharmacological interventions for children with OME

Evidence reviews for non-antimicrobial pharmacological interventions for children with OME

Otitis media with effusion in under 12s

Evidence review H

NICE Guideline, No. 233

London: National Institute for Health and Care Excellence (NICE); 2023 Aug.

ISBN-13: 978-1-4731-5338-7

Non-antimicrobial pharmacological interventions for children with OME

Review question

What is the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) for managing OME in children under 12 years?

Introduction

The aim of this review is to assess the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) in managing OME in children under 12 years.

Summary of the protocol

See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

For further details see the review protocol in appendix A.

Methods and process

Steroids

During the development of this guideline, a registered Cochrane protocol was identified which matched the committee’s intended PICO for the steroids part of the review. The Cochrane protocol differed from the committee’s intended population in that the Cochrane protocols excluded studies that did not meet their inclusion criteria for trustworthiness (that is, those identified as being potentially ‘high-risk’ using a screening tool developed by Cochrane Pregnancy and Childbirth which included specified criteria to identify studies that are considered sufficiently trustworthy), however no studies were identified that were excluded from the review on these grounds alone.

The Cochrane review team completed a review investigating the effectiveness of steroids for OME in children (Mulvaney 2023b) during guideline development and presented their results to the committee, who used them to make recommendations. Cochrane’s methods are closely aligned to standard NICE methods; minor deviations (summary of findings tables instead of full GRADE tables, defining primary and secondary outcomes as opposed to critical and important, assessing the risk of bias in primary studies using version 1 (as opposed to version 2) of the Cochrane Risk of Bias tool, how clinically important differences are determined, and including countries from a broader range of income categories than the majority of the other reviews in the guideline) relevant to the topic area were highlighted to the committee and taken into account in discussions of the evidence. Where results were reported per ear instead of per child, Cochrane used an assumed intra-cluster correlation coefficient of 0.5 to adjust the sample size. Full details of the Cochrane review, including methods, are available in the review of steroids for children with OME, see Mulvaney 2023b at https://www.nice.org.uk/guidance/indevelopment/gid-ng10193/documents.

We thank the Cochrane ENT Group for their assistance in providing the literature searches and data for review questions relating to Otitis media with effusion in under 12s.

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

The parts of the evidence review on the effectiveness of antihistamines, leukotriene receptor antagonists, mucolytics and decongestants was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1). Where results were reported per ear instead of per child, an assumed intra-cluster correlation coefficient of 0.5 was used to adjust the sample size.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

Effectiveness evidence

Included studies

Steroids

A Cochrane review on the effectiveness of steroids (Mulvaney 2023b) including 26 randomised controlled trials (RCT) (Acharya 2020; Ahmed 2022; Barati 2011; Beigh 2013; Berman 1990; Bhargava 2014; Cengel 2006; Choung 2008; Francis 2008 (OSTRICH); Hemlin 1997; Hussein 2017; Karlidag 2002; Khanam 2022; Lambert 1986; Lildholdt 1982; Macknin 1985; Mandel 2002; Niederman 1984; Podoshin 1990; Puhakka 1985; Rahmati 2017; Saffar 2001; Scadding 2014; Schwartz 1980; Stuart 1995; Williamson 2009) were considered in this review. This review was used for making recommendations by the committee, as it was considered sufficiently relevant, high quality and up to date.

Three studies compared oral steroids with no treatment (Acharya 2020; Choung 2008; Hussein 2017); 11 studies compared oral steroids with placebo (Berman 1990; Francis 2008; Hemlin 1997; Lambert 1986; Macknin 1985; Mandel 2002; Niederman 1984; Podoshin 1990; Puhakka 1985; Saffar 2001; Schwartz 1980); 7 studies compared nasal steroids with no treatment (Acharya 2020; Ahmed 2022; Barati 2011; Beigh 2013; Cengel 2006; Karlidag 2002; Rahmati 2017); and 6 studies compared nasal steroids with placebo (Bhargava 2014; Khanam 2022; Lildholdt 1982; Scadding 2014; Stuart 1995; Williamson 2009).

All studies included children aged over 4 years (Acharya 2020; Ahmed 2022; Barati 2011; Beigh 2013; Berman 1990; Bhargava 2014; Cengel 2006; Choung 2008; Francis 2008; Hemlin 1997; Hussein 2017; Karlidag 2002; Khanam 2022; Lambert 1986; Lildholdt 1982; Macknin 1985; Mandel 2002; Niederman 1984; Podoshin 1990; Puhakka 1985; Rahmati 2017; Saffar 2001; Scadding 2014; Schwartz 1980; Stuart 1995; Williamson 2009). None of the studies reported data on participants’ hearing levels at baseline, or whether participants had allergy, cleft palate, or Down’s syndrome. The Cochrane review is summarised in Table 2.

See the Cochrane review for the literature search strategy and study selection flow chart, see Mulvaney 2023b at https://www.nice.org.uk/guidance/indevelopment/gid-ng10193/documents.

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Twenty-four studies, reported in 25 articles, were included for this review; 23 RCTs (Babic 2017, Balatsouras 2005, Cantekin 1983, Choung 2008, Commins 2000, Dusdieker 1985, Edstrom 1977, Fraser 1977, Haugeto 1981, Hayden 1984, Hisamatsu 1994, Hughes 1984, Khan 1981, Kumazawa 1989, Mandel 1987, McGuiness 1977, O’Shea 1980/1982, Rahmati 2017, Ramsden 1977, Roydhouse 1981, Saunte 1978, Schoem 2010, van der Merwe 1987) and data from groups that were not crossed over in 1 cross-over RCT (Stewart 1985).

The included studies are summarised in Table 3.

Two studies compared mucolytic, decongestant and antihistamine with placebo (Hughes 1984; Khan 1981); 2 studies compared mucolytic, decongestant and antihistamine with mucolytic (Hughes 1984; Khan 1981); 1 study compared mucolytic, decongestant and antihistamine with decongestant and antihistamine (Hughes 1984); 8 studies compared mucolytic with placebo (Commins 2000; Edstrom 1977; Hughes 1984; Khan 1981; Kumazawa 1989; Ramsden 1977; Stewart 1985; van der Merwe 1987); 2 studies compared mucolytic with no treatment (Babic 2017; McGuiness 1977); 1 study compared mucolytic and antihistamine with placebo and antihistamine (Roydhouse 1981); 1 study compared mucolytic and antihistamine with placebo (Edstrom 1977); 1 study compared antihistamine with mucolytic (Edstrom 1977); 2 studies compared antihistamine with placebo (Dusdieker 1985; Edstrom 1977); 2 studies compared antihistamine with no treatment (Choung 2008; Hisamatsu 1994); 1 study compared decongestant and antihistamine with decongestant (Haugeto 1981); 1 study compared decongestant and antihistamine with mucolytic (Hughes 1984); 5 studies compared decongestant and antihistamine with placebo (Cantekin 1983; O’Shea 1980/1982; Saunte 1978; Haugeto 1981; Hughes 1984); 2 studies compared decongestant and antihistamine with no treatment (Fraser 1977; Mandel 1987); 1 study compared decongestant with antihistamine (Dusdieker 1985); 3 studies compared decongestant with placebo (Dusdieker 1985; Haugeto 1981; Hayden 1984); 1 study compared decongestant with no treatment (Fraser 1977); 1 study compared leukotrine receptor antagonist with placebo (Schoem 2010); 2 studies compared leukotrine receptor antagonist with no treatment (Balatsouras 2005; Rahmati 2017). Studies were classified as compared against no treatment when any additional treatments received (that were not of interest for the current review) were equivalent across arms.

Children in 5 studies had, on average, mild hearing loss at baseline (Choung 2008; Commins 2000; Fraser 1977; Mandel 1987; Saunte 1978), and another study included children who mostly had hearing loss <15dB (Hisamatsu 1994); 1 study included children with mild, moderate, or worse hearing loss (van der Merwe 1987); 5 studies included children with hearing loss at baseline but did not report the average severity (Edstrom 1977; Haugeto 1981; Khan 1981; O’Shea 1980/1982; Ramsden 1977); 1 study excluded children with sensory-neural or conductive hearing loss at baseline (Dusdieker 1985); and 11 studies did not report hearing thresholds at baseline (Babic 2017; Balatsouras 2005; Cantekin 1983; Hayden 1984; Hughes 1984; Kumazawa 1989; McGuiness 1977; Rahmati 2017; Roydhouse 1981; Schoem 2010; Stewart 1985).

A minority of children in 6 studies had diagnosed allergy (Cantekin 1983; Mandel 1987), history of allergy (Dusdieker 1985; Fraser 1977), allergic symptoms or positive allergic skin-prick tests (Choung 2008), or atopic heredity to allergic rhinitis to a moderate degree (Saunte 1978) at baseline; 4 studies excluded children with allergic rhinitis (Hisamatsu 1994; Rahmati 2017), proven allergy (Babic 2017) or history of allergy (Schoem 2010) at baseline; and 14 studies did not report whether participants had allergy at baseline (Balatsouras 2005; Commins 2000; Edstrom 1977; Haugeto 1981; Hayden 1984; Hughes 1984; Khan 1981; Kumazawa 1989, McGuiness 1977; O’Shea 1980/1982; Ramsden 1977; Roydhouse 1981; Stewart 1985; van der Merwe 1987).

Two studies included children aged up to 4 years (Babic 2017; Dusdieker 1985); 16 studies included both children aged up to and those aged over 4 years (Cantekin 1983; Choung 2008; Commins 2000; Edstrom 1977; Fraser 1977; Hayden 1984; Haugeto 1981; Hisamatsu 1994; Mandel 1987; O’Shea 1980/1982; Rahmati 2017; Ramsden 1977; Roydhouse 1981; Saunte 1978; Schoem 2010; Stewart 1985);; 4 studies included children aged 4 years and over (Balatsouras 2005; Khan 1981; Kumazawa 1989; McGuiness 1977); 2 studies did not report ages of participants (Hughes 1984; van der Merwe 1987).

Eleven studies excluded children with cleft palate (Choung 2008; Commins 2000; Dusdieker 1985; Stewart 1985), congenital malformations (Babic 2017), congenital craniofacial malformations (Cantekin 1983; Mandel 1987), malformations (Hisamatsu 1994), craniofacial disorders (Schoem 2010), externally obvious ear or nose deformities (O’Shea 1980/1982), or children without normal palatal function (Hughes 1984); and 13 studies did not report whether any participants had cleft palate (Balatsouras 2005; Edstrom 1977; Fraser 1977; Haugeto 1981; Hayden 1984; Khan 1981; Kumazawa 1989; McGuiness 1977; Rahmati 2017; Ramsden 1977; Roydhouse 1981; Saunte 1978; van der Merwe 1987).

Four studies excluded children with Down’s syndrome (Cantekin 1983; Commins 2000; Stewart 1985) or developmental difficulties (Choung 2008); and 20 studies did not report whether any participants had Down’s syndrome (Babic 2017; Balatsouras 2005; Dusdieker 1985; Edstrom 1977; Fraser 1977; Haugeto 1981; Hayden 1984; Hisamatsu 1994; Hughes 1984; Khan 1981; Kumazawa 1989; Mandel 1987; McGuiness 1977; O’Shea 1980/1982; Rahmati 2017; Ramsden 1977; Roydhouse 1981; Saunte 1978; Schoem 2010; van der Merwe 1987).

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review are listed, and reasons for their exclusion are provided in appendix K.

Summary of included studies

Steroids

A summary of the Cochrane review that was included in this review is presented in Table 2.

Table 2

Summary of included studies.

See the Cochrane review for characteristics of studies tables and forest plots, Mulvaney 2023b at https://www.nice.org.uk/guidance/indevelopment/gid-ng10193/documents.

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Summaries of the studies that were included in this review are presented in Table 3.

Table 3

Summary of included studies.

See the full evidence tables in appendix D and the forest plots in appendix E.

Summary of the evidence

Steroids

The Cochrane review of topical and oral steroids for children with OME investigated 4 comparisons, with the following findings:

Comparison 1: Oral steroid versus no treatment. Oral steroids had an important benefit for persistence of OME in the very short term (very low quality evidence according to GRADE criteria), but no important difference between oral steroids and no treatment for persistence of OME in the short or medium term (both low quality evidence according to GRADE criteria). There was no evidence available for this comparison for any of the other outcomes specified in the protocol.
Comparison 2: Oral steroid versus placebo. Oral steroids had an important benefit for persistence of OME in the medium term when persistence was undefined (low quality evidence according to GRADE criteria), and a possible important benefit for persistence of OME in the very short term (90% CI: 0.54 to 0.96; very low quality). There was no important difference or no evidence of an important difference between oral steroids and placebo for any of the remaining outcomes: normal hearing in the very short, short, or medium term; hearing thresholds in the very short term; disease-specific quality of life in the very short or medium term; persistence of OME in the short term, or in the medium term when persistence was defined as effusion in both affected ears; acute otitis media in the very short term; generic health-related quality of life in the very short or medium term (when assessed with PedsQL or HU13). The outcomes normal hearing in the medium term, disease-specific quality of life in the medium term, persistence of OME in the medium term, and generic health-related quality of life in the medium term were all moderate quality evidence according to GRADE criteria. The rest of the outcomes were all low to very low quality evidence according to GRADE criteria. There was no evidence available for this comparison for any of the other outcomes specified in the protocol.
- Subgroup analyses assessing the differences between oral steroid versus placebo for children with allergy versus without were done for the following outcomes: normal hearing in the very short term and persistence of OME in the very short term. Oral steroids had an important benefit for persistence of OME in the ‘no allergy’ group, but there was no important difference for those with allergy for this outcome, and no evidence of an important difference or no important difference between interventions for either group for hearing outcomes (all low or very low quality evidence according to GRADE criteria).
- Subgroup analyses assessing the differences between oral steroid versus placebo for children aged <4 versus ≥4 years were done for persistence of OME in the very short term. There was no important difference for these comparisons (low or very low quality evidence according to GRADE criteria)
Comparison 3: Topical (nasal) steroid versus no treatment. Nasal steroids had an important benefit for persistence of OME in the very short and short term (both very low quality evidence according to GRADE criteria). There was no important difference between nasal steroids and no treatment for the other outcome: final hearing threshold in the very short term (low quality evidence according to GRADE criteria). There was no evidence available for this comparison for any of the other outcomes specified in the protocol
Comparison 4: Topical (nasal) steroid versus placebo. Nasal steroids had an important benefit for persistence of OME in the medium term when persistence was undefined, final hearing threshold in the short term, and generic health-related quality of life in the medium term (very low to low quality evidence according to GRADE criteria). There was no important difference between nasal steroids and placebo for any of the other outcomes: change in hearing threshold in the short term; persistence of OME in the very short or short term, or in the medium term when persistence was defined as being in both ears; adverse event: nasal bleeding in the medium term; disease specific quality of life in the short or medium term (all low or very low quality evidence according to GRADE criteria). There was no evidence available for this comparison for any of the other outcomes specified in the protocol.

For all outcomes, time of follow-up was defined as follows: very short term: <6 weeks; short term: ≤3 months; medium term: >3 months to ≤1 year; long term: >1 year.

See the Cochrane review for summary of findings tables and full results, including all primary and secondary outcomes and sub-group analyses, Mulvaney 2023b at https://www.nice.org.uk/guidance/indevelopment/gid-ng10193/documents.

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

For the purposes of this review and analyses, interventions were considered to be compared to ‘no treatment’ when there was an additional intervention/s in the intervention arm that was the same as the comparator (provided it was not an intervention of interest). For example, antihistamine plus local treatment versus local treatment alone, and antihistamine plus antibiotic versus antibiotic, were both included under the comparison antihistamine versus no treatment. Outcomes which include comparisons like this are as follows:

Leukotriene receptor antagonist versus no treatment, presence/ persistence of OME (per child, short term) (relevant study: Balatsouras 2005). See Figure 7
Antihistamine versus no treatment, presence/ persistence of OME (per child, short term) (relevant study: Choung 2008)
Antihistamine versus no treatment, presence/ persistence of OME (per ear, short term) (relevant study: Hisamatsu 1994)
Antihistamine versus no treatment, hearing returned to normal (per ear, short term; air conduction) (relevant study: Hisamatsu 1994)
Decongestant and antihistamine versus no treatment, presence/ persistence of OME (per child, short term) (relevant studies: Mandel 1987)
Decongestant and antihistamine versus no treatment, mean final hearing threshold (per child, short term) (relevant studies: Mandel 1987)
Decongestant and antihistamine versus no treatment, mean final hearing threshold (per ear, short term) (relevant studies: Mandel 1987)
Mucolytic versus no treatment, presence/ persistence of OME (per ear, short term) (relevant studies: Babic 2017)

Results were pooled where studies reported the same class of medication or treatment received in the intervention and comparator arms for the same outcome. For example, presence/persistence of OME results from a study examining carbocisteine or bromhexine compared with placebo and another study examining bromhexine compared with placebo were pooled in an analysis examining mucolytic compared with placebo. There was no significant heterogeneity for any of the pooled outcomes and so sub-group analyses were not performed; however, in the forest plots results are presented according to the drug used. For all outcomes, time of follow-up was defined as follows: short term: ≤3 months; medium term: >3 months to ≤1 year; long term: >1 year.

Important or possible important benefits or harms

A mucolytic, decongestant and antihistamine (bromhexine and brompheniramine, phenylephrine, and phenylpropanolamine) had the possible important harm of less children having their hearing returned to normal compared with mucolytic alone (S-carboxymethylcysteine (SCMC)/ carbocisteine) in the short term, when assessed using air conduction at 0.25kHz (90% CI: 0.28 to 0.99; very low quality evidence). The same study showed that a mucolytic (SCMC/ carbocisteine) had the important benefit of more children having their hearing returned to normal compared with placebo in the short term, when assessed using air conduction at 0.25kHz (low quality evidence). For these outcomes, the children included were aged 4 years or over, all children had an air-bone gap at baseline, and information on allergy, cleft palate, and Down syndrome was not reported. A mucolytic (SCMC/ carbocisteine) had the important benefit of improving hearing thresholds compared with no treatment in the short term (very low quality evidence). For this outcome, the children included were aged 4 years or over, and information on hearing, allergy, cleft palate, and Down syndrome was not reported. A mucolytic plus an antihistamine (bromhexine and chlorpheniramine maleate) had the important benefit of less ears with presence/ persistence of OME compared with placebo plus an antihistamine (placebo and chlorpheniramine maleate) in the short term (low quality evidence). For this outcome, the children included were aged up to and over 4 years, and information on hearing, allergy, cleft palate, and Down syndrome was not reported. Only single studies reported each of these outcomes.

No important difference or no evidence of an important difference between interventions

For all the rest of the outcomes for all the comparisons, there was no important difference or no evidence of an important difference between the intervention and comparator arms. These outcomes were as follows:

Mucolytic, decongestant, and antihistamine versus placebo (all very low quality evidence):
- Presence/ persistence of OME in the short term
- Hearing returned to normal in the short term
- Hearing returned to normal in the short term
Mucolytic, decongestant, and antihistamine versus mucolytic alone (all very low quality evidence):
- Presence/ persistence of OME in the short term
- Hearing returned to normal in the short term, when assessed using air conduction at 0.5, 1, 2, 4, and 8kHz, and bone conduction
Mucolytic, decongestant, and antihistamine versus decongestant and antihistamine (very low quality evidence):
- Presence/ persistence of OME in the short term
Mucolytic versus placebo:
- Presence/ persistence of OME in the short term (per child: moderate quality evidence; per ear: very low quality evidence)
- Hearing returned to normal in the short term, when assessed using air conduction at 0.5, 1, 2, 4, and 8kHz, bone conduction, and pure-tone audiometry or free-field audiometry (all very low to low quality evidence)
- Discontinuation of treatment due to vomiting in the short term (very low quality evidence)
Mucolytic versus no treatment (very low quality evidence):
- Presence/ persistence of OME in the short term
Mucolytic and antihistamine versus placebo (very low quality evidence):
- Presence/ persistence of OME in the short term
Antihistamine versus mucolytic (very low quality evidence):
- Presence/ persistence of OME in the short term
Antihistamine versus placebo (all very low quality evidence):
- Presence/ persistence of OME in the short term
- Discontinuation of treatment due to hyperactivity and poor sleeping in the short term
Antihistamine versus no treatment (all very low quality evidence):
- Presence/ persistence of OME in the short term
- Hearing returned to normal in the short term
Decongestant and antihistamine versus decongestant (all very low quality evidence):
- Presence/ persistence of OME in the short term
- Hearing returned to normal in the short term
Decongestant and antihistamine versus mucolytic (very low quality evidence):
- presence/ persistence of OME in the short term
Decongestant and antihistamine versus placebo:
- Presence/ persistence of OME in the short term (per child: moderate quality evidence; per ear or per assessment: very low quality evidence)
- Hearing returned to normal in the short and medium term (all low to very low quality evidence)
- Change in hearing threshold from baseline in the short and medium term (all low to very low quality evidence)
Decongestant and antihistamine versus no treatment:
- Presence/ persistence of OME in the short term (moderate quality evidence)
- Mean final hearing threshold in the short term (moderate quality evidence)
- Change in hearing threshold from baseline in the short term (very low quality evidence)
Decongestant versus antihistamine (all very low quality evidence):
- Presence/ persistence of OME in the short term
- Discontinuation of treatment due to hyperactivity and poor sleeping in the short term
Decongestant versus placebo (all very low quality evidence):
- Presence/ persistence of OME in the short term
- Hearing returned to normal in the short term
- Discontinuation of treatment due to hyperactivity and poor sleeping in the short term
- Discontinuation of treatment due to acute otitis media (AOM) in the short term
- Discontinuation of treatment due to use of additional medication in the short term
- Discontinuation of treatment due to inability to tolerate medication in the short term
Decongestant versus no treatment (very low quality evidence):
- Change in hearing threshold from baseline in the short term
Leukotrine receptor antagonist versus placebo (very low quality evidence):
- Presence/ persistence of OME in the short term
Leukotrine receptor antagonist versus no treatment (very low quality evidence):
- Presence/ persistence of OME in the short term.

No evidence available

There was no evidence available for proton pump inhibitors (PPIs) and reflux medicines, and no evidence for any of the important outcomes (listening skills, receptive language skills measured using a validated scale, or disease-specific quality of life measured using a validated scale). There was no evidence for long term follow-up.

See appendix F for full GRADE tables.

Economic evidence

Included studies

Two economic studies were identified which was relevant to this question (Williamson 2009; Francis 2018).

See the literature search strategy in appendix B and economic study selection flow chart in appendix G.

Excluded studies

Economic studies not included in this review are listed, and reasons for their exclusion are provided in appendix K.

Summary of included economic evidence

See Table 4 for the economic evidence profiles of the included studies.

Table 4

Economic evidence profile of a systematic review of economic evaluations of budesonide for maintenance of remission in Crohn’s disease.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

The committee’s discussion and interpretation of the evidence

The outcomes that matter most

The primary outcomes in the Cochrane protocol for the review on steroids were hearing, disease-specific quality of life, systemic corticosteroid side-effects, and discontinuation of treatment. The committee agreed these outcomes were critical: hearing is a direct measure of any differential effectiveness associated with the use of medication; disease-specific quality of life is a measure of well-being which may capture long-term health-related outcomes associated with the effectiveness of interventions; discontinuation of treatment would capture both potential benefits and risks of the intervention depending on the reason for discontinuation of treatment (for example, because they no longer need the medication, or because the child could not tolerate the medication); systemic corticosteroid side-effects would capture the risk of adverse events (such as muscle weakness) which can happen as a result of the use of oral steroids. The primary outcomes for the review on antihistamines, leukotriene receptor antagonists, mucolytics and decongestants were similar to those for the Cochrane review on steroids; however, presence/ persistence of OME was chosen as a primary outcome instead of disease-specific quality of life, which was a secondary outcome for this review. The committee agreed that presence or persistence of OME after the use of medication directly measures the effectiveness of the intervention whereas quality of life is a less direct measure with other influences and arguably a greater subjective element. Therefore, presence of OME was kept as a primary outcome for internal consistency with other reviews conducted for this guideline, however Cochrane kept it as a secondary outcome to be consistent with their previous reviews.

The other outcomes listed in the Cochrane protocol (presence/ persistence of OME; receptive language skills; listening skills) were agreed to be important outcomes by the committee. The committee agreed that OME-related hearing loss can be associated with impairment of receptive language and listening skills, which could impact on the child’s development, and therefore the committee agreed these were important outcomes. The review on antihistamines, leukotriene receptor antagonists, mucolytics and decongestants also had receptive language and listening skills as secondary outcomes.

The quality of the evidence

Steroids

The quality of the evidence was assessed using GRADE methodology and was moderate to very low quality, mainly due to risk of bias assessed using version 1 of the Cochrane RoB tool and imprecision in the effect estimate. Where outcomes were downgraded for risk of bias, this was mainly due to selection, performance, attrition, reporting and/ or detection bias. In some cases, there was also bias arising from the randomisation process and/or measurement of the outcomes. For some outcomes, there was additionally inconsistency due to opposite directions of effect and an I-squared value >50% or >80%, and/or indirectness due to the inclusion of an indirect population.

There was no evidence for any of the following outcomes: discontinuation of treatment; listening skills, or receptive language skills measured using a validated scale. There was no evidence for long term follow-up.

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

The quality of the evidence was assessed using GRADE methodology and was moderate to very low quality, mainly due to risk of bias assessed using version 2 of the Cochrane RoB tool and imprecision in the effect estimate. Where outcomes were downgraded for risk of bias, this was mainly due to deviations from the intended interventions, missing outcome data, and/or selection of the reported result. In some cases, there was also bias arising from the randomisation process and/or measurement of the outcomes. For some outcomes, there was additionally indirectness due to the inclusion of an indirect population, outcome, or intervention, and/or suspected publication bias due to the majority of studies contributing to the outcome being industry funded.

There was no evidence available for proton pump inhibitors (PPIs) and reflux medicines, and no evidence for any of the secondary outcomes (listening skills, receptive language skills measured using a validated scale, or disease-specific quality of life measured using a validated scale). There was no evidence for long term follow-up.

Benefits and harms

Steroids

The committee discussed the evidence on steroids, in particular the moderate quality evidence comparing oral steroids with placebo for the medium-term outcomes: normal hearing, persistence of OME, disease-specific quality of life, and generic health-related quality of life. Additionally, the committee discussed the fact that oral steroids often have a stronger effect that nasal steroids. Considering the moderate quality evidence that oral steroids made no difference in terms of the above outcomes when compared to placebo and the limited, low quality evidence when compared to no treatment, the committee agreed that it was unlikely that nasal steroids, which usually have a weaker effect, would have an important hearing-, OME-, or quality of life-related benefit either. They agreed this reasoning outweighed the low to very low quality evidence that nasal steroids had an important benefit when compared to not treatment or placebo with regards to final hearing thresholds in the short term, persistence of OME in the very short, short, and (when persistence was undefined in the evidence) medium term, and generic health-related quality of life in the medium term. There was some limited evidence that oral steroids had an important benefit in terms of persistence of OME in the medium term (when persistence was undefined in the evidence) compared to no treatment, and a possible important benefit in terms of persistence of OME in the very short term. However, where there was evidence of a clinically important effect of oral steroids for any of the outcomes, the evidence was all low or very low quality, or there was uncertainty in the importance of the outcome. The committee agreed the evidence was not strong enough to recommend oral steroids when there was the potential for children to experience systemic corticosteroid side effects, especially in light of the lack of available evidence for this outcome. The committee also discussed the potential harms of using nasal steroids and agreed that, although the risks of side effects was lower than for oral steroids, nasal steroids can be difficult to administer, particularly for very young children or children with learning difficulties or other disabilities. They agreed that using nasal drops or spray could be traumatic for children and ultimately agreed the very low quality evidence showing a potential benefit on hearing or persistence of OME did not outweigh these harms. As a result, the committee recommended that nasal and oral steroids should not be used to treat OME in children.

The committee agreed the evidence base regarding the effectiveness of topical nasal steroids in the management of OME was limited and tended to focus on the outcome persistence of OME. It is therefore not clear if these are effective for improving the hearing of children with OME, and the committee agreed a research recommendation investigating the effectiveness of topical nasal steroids on OME-related hearing loss should be made, as this intervention could be a low-cost, readily accessible management option that might be preferable to other, more invasive interventions such as surgery.

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

The committee agreed that the evidence tended to show no important difference in effectiveness of antihistamines, leukotriene receptor antagonists, mucolytics, and decongestants, whether alone or in combination, for most of the outcomes when compared to any of the comparison arms. Where there was evidence of a difference between treatment groups, the evidence was of low or very low quality or there was uncertainty in the importance of the outcome, whereas all the available moderate quality evidence showed no important difference between groups. As a result, the committee agreed that these medications should not be offered to treat OME in children under 12. The committee agreed they could not make recommendations about PPIs or other reflux medicines without any evidence regarding their effectiveness, because PPIs and reflux medicines are not routinely offered to children with OME in current practice, and it is unclear whether they would be effective for treating OME or OME-related hearing loss.

Although the committee agreed antihistamines, leukotriene receptor antagonists, mucolytics, and decongestants should not be offered based on the current evidence, the committee members agreed that further research into the effectiveness of these interventions in children with OME and chronic respiratory conditions is important as there might be benefit for this subgroup, based on the evidence of risk factors and respiratory conditions that are commonly associated with OME, for which these medications might be effective.

Cost effectiveness and resource use

Two included studies (Williamson 2009; Francis 2018) reported on the cost-effectiveness of intranasal and oral steroids respectively. Neither study found steroids to be cost-effective with placebo dominating intervention in the base case utility analyses. Whilst differences in costs and effects were not statistically significant, probabilistic sensitivity analysis suggested that there was only a relatively small probability that giving steroids was cost-effective. Therefore, the committee concluded there was no cost-effectiveness evidence that would support a recommendation to give steroids.

The committee also concluded that it would not be a cost-effective use of NHS resources to recommend other non-antimicrobial pharmacological treatments for OME given the lack of evidence of clinical benefit in the studies reviewed.

Recommendations supported by this evidence review

This evidence review supports recommendations 1.5.3 and 1.5.4, the research recommendation on the effectiveness of topical nasal steroids on OME and OME-related hearing loss in children under 12 years, and the research recommendation on the effectiveness of antihistamines, leukotriene receptor antagonists, mucolytics, PPIs and decongestants on hearing in children with OME and chronic respiratory conditions.

References – included studies

Effectiveness

Steroids

Mulvaney 2023b
Mulvaney CA, Galbraith K, Webster KE, Rana M, Connolly R, Tudor-Green B, Marom T, Daniel M, Venekamp RP, Schilder AGM, MacKeith S. Topical and oral steroids for otitis media with effusion (OME) in children. Cochrane Database of Systematic Reviews 2023. Art. No.: CD015255. DOI: 10.1002/14651858.CD015255 [PMC free article: PMC10521168] [PubMed: 37750500] [CrossRef]

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Babic 2017
Babic, Irena, Baudoin, Tomislav, Trotic, Robert et al. (2017) Therapeutic efficacy of azithromycin and acetylcysteine in chronic otitis media with effusion. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 274(3): 1351–1356 [PubMed: 27873023]
Balatsouras 2005
Balatsouras, D G, Eliopoulos, P, Rallis, E et al. (2005) Improvement of otitis media with effusion after treatment of asthma with leukotriene antagonists in children with co-existing disease. Drugs under experimental and clinical research 31suppl: 7–10 [PubMed: 16444906]
Cantekin 1983
Cantekin, E I, Mandel, E M, Bluestone, C D et al. (1983) Lack of efficacy of a decongestant-antihistamine combination for otitis media with effusion (“secretory” otitis media) in children. Results of a double-blind, randomized trial. The New England journal of medicine 308(6): 297–301 [PubMed: 6337322]
Choung 2008
Choung, Yun-Hoon, Shin, You Ree, Choi, Seong Jun et al. (2008) Management for the children with otitis media with effusion in the tertiary hospital. Clinical and experimental otorhinolaryngology 1(4): 201–5 [PMC free article: PMC2671765] [PubMed: 19434268]
Commins 2000
Commins, D J, Koay, B C, Bates, G J et al. (2000) The role of Mucodyne in reducing the need for surgery in patients with persistent otitis media with effusion. Clinical otolaryngology and allied sciences 25(4): 274–9 [PubMed: 10971533]
Dusdieker 1985
Dusdieker, L B, Smith, G, Booth, B M et al. (1985) The long-term outcome of nonsuppurative otitis media with effusion. Clinical pediatrics 24(4): 181–6 [PubMed: 3884218]
Edstrom 1977
Edstrom, S; Lundin, K; Jeppsson, P H (1977) Secretory otitis media. Aspects on treatment and control. ORL; journal for oto-rhino-laryngology and its related specialties 39(2): 68–73 [PubMed: 333341]
Fraser 1977
Fraser, J G; Mehta, M; Fraser, P A (1977) The medical treatment of secretory otitis media. A clinical trial of three commonly used regimes. The Journal of laryngology and otology 91(9): 757–65 [PubMed: 335005]
Haugeto 1981
Haugeto, O.K.; Schroder, K.E.; Mair, I.W.S. (1981) Secretory otitis media, oral decongestant and antihistamine. Journal of Otolaryngology 10(5): 359–362 [PubMed: 7199092]
Hayden 1984
Hayden, G F, Randall, J E, Randall, J C et al. (1984) Topical phenylephrine for the treatment of middle ear effusion. Archives of otolaryngology (Chicago, Ill. : 1960) 110(8): 512–4 [PubMed: 6378158]
Hisamatsu 1994
Hisamatsu, K., Ganbo, T., Nakazawa, T. et al. (1994) Clinical efficacy of tranilast on otitis media with effusion in children. Auris Nasus Larynx 21(3): 150–157 [PubMed: 7532938]
Hughes 1984
Hughes, K B (1984) Management of middle-ear effusions in children. The Journal of laryngology and otology 98(7): 677–84 [PubMed: 6379082]
Khan 1981
Khan, J A; Marcus, P; Cummings, S W (1981) S-carboxymethylcysteine in otitis media with effusion. (A double-blind study). The Journal of laryngology and otology 95(10): 995–1001 [PubMed: 7028897]
Kumazawa 1989
Kumazawa, T. and Ushiro, K. (1989) Clinical evaluation of S-CMC syrup applied in the treatment of otitis media with effusion. Double blind comparative test with placebo. Acta Oto-Laryngologica, Supplement 107(458): 56–62 [PubMed: 3072830]
Mandel 1987
Mandel, E M, Rockette, H E, Bluestone, C D et al. (1987) Efficacy of amoxicillin with and without decongestant-antihistamine for otitis media with effusion in children. Results of a double-blind, randomized trial. The New England journal of medicine 316(8): 432–7 [PubMed: 2880294]
McGuiness 1977
McGuiness, R J (1977) Carboxymethylcysteine in the glue ear syndrome. The British journal of clinical practice 31(78): 105–6 [PubMed: 921885]
O’Shea 1980
O’Shea, J S, Langenbrunner, D J, McCloskey, D E et al. (1980) Diagnostic and therapeutic studies in childhood serous otitis media. Results of treatment with an antihistamine-adrenergic combination. The Annals of otology, rhinology & laryngology. Supplement 89(3pt2): 285–9 [PubMed: 6778329]
O’Shea 1982
O’Shea, J S, Langenbrunner, D J, McCloskey, D E et al. (1982) Childhood serous otitis media: fifteen months’ observations of children untreated compared with those receiving an antihistamine-adrenergic combination. Clinical pediatrics 21(3): 150–3 [PubMed: 7035052]
Rahmati 2017
Rahmati, Mohammad Bagher, Safdarian, Fatemeh, Shiroui, Babak et al. (2017) Montelukast versus inhaled mometasone for treatment of otitis media with effusion in children: A randomized controlled trial. Electronic physician 9(7): 4890–4894 [PMC free article: PMC5587009] [PubMed: 28894551]
Ramsden 1977
Ramsden, R T, Moffat, D A, Gibson, W P et al. (1977) S-carboxymethylcysteine in the treatment of glue ear: a double blind trial. The Journal of laryngology and otology 91(10): 847–51 [PubMed: 336818]
Roydhouse 1981
Roydhouse, N (1981) Bromhexine for otitis media with effusion. The New Zealand medical journal 94(696): 373–5 [PubMed: 7033848]
Saunte 1978
Saunte, C (1978) Clinical trial with Lunerin mixture and Lunerin mite in children with secretory otitis media. The Journal of international medical research 6(1): 50–5 [PubMed: 342302]
Schoem 2010
Schoem, Scott R; Willard, Alice; Combs, Jerome T (2010) A prospective, randomized, placebo-controlled, double-blind study of montelukast’s effect on persistent middle ear effusion. Ear, nose, & throat journal 89(9): 434–7 [PubMed: 20859868]
Stewart 1985
Stewart, I A, Guy, A M, Allison, R S et al. (1985) Bromhexine in the treatment of otitis media with effusion. Clinical otolaryngology and allied sciences 10(3): 145–9 [PubMed: 3896583]
van der Merwe 1987
van der Merwe, J and Wagenfeld, D J (1987) The negative effects of mucolytics in otitis media with effusion. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 72(9): 625–6 [PubMed: 3317935]

Economic

Williamson 2009
Williamson I, Benge S, Barton S, Petrou S, Letley L, Fasey N, et al. (2009) A double-blind randomised placebo-controlled trial of topical intranasal corticosteroids in 4- to 11-year-old children with persistent bilateral otitis media with effusion in primary care. Health Technology Assessment 13(37). [PubMed: 19671372]
Francis 2018
Francis NA, Waldron C-A, Cannings-John R, Thomas-Jones E, Winfield T, Shepherd V, et al. (2018) Oral steroids for hearing loss associated with otitis media with effusion in children aged 2–8 years: the OSTRICH RCT. Health Technology Assessment 2018;22(61) [PMC free article: PMC6253325] [PubMed: 30407151]

Appendices

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Economic evidence tables for review question: What is the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) for managing OME in children under 12 years? (PDF, 162K)

Appendix I. Economic model

Economic model for review question: What is the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) for managing OME in children under 12 years?

No economic analysis was conducted for this review question.

Appendix J. Excluded studies

Excluded studies for review question: What is the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) for managing OME in children under 12 years?

Steroids

See the Characteristics of excluded studies table from the Cochrane review on steroids (Mulvaney 2023b).

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Excluded effectiveness studies

Table

- Study design does not meet inclusion criteria Conference abstract

Excluded economic studies

Table

Appendix K. Research recommendations – full details

Research recommendations for review question: What is the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) for managing OME in children under 12 years? (PDF, 187K)

Final

Evidence reviews underpinning recommendations 1.5.3 to 1.5.4 and research recommendations in the NICE guideline

This evidence review was developed by NICE

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK595329PMID: 37792987

Table 1Summary of the protocol (PICO table)

Population	Children aged 6 months to 12 years with unilateral or bilateral otitis media with effusion (OME). If a trial includes children aged younger than 6 months and older than 12 years, we will only include the study if the majority of children fit our inclusion criteria or only if the trialists present outcome data by age group. Include all children regardless of any comorbidity such as Down syndrome or cleft palate Clinical diagnosis of OME will be confirmed by oto(micro)scopy or tympanometry or both
Intervention	NICE part of the review: Antihistamines Decongestants Leukotriene receptor antagonists Mucolytics PPIs (Proton pump inhibitors) and reflux medicines Steroids/Cochrane part of the review: Topical (intranasal) steroids Oral steroids
Comparison	NICE part of the review: Head-to-head comparisons between all the above intervention categories* (single or in combination, including combinations with steroids) Placebo No intervention for treating OME Please note, we will not include head-to-head comparisons between different interventions within each category (e.g., comparisons between different types of antihistamine), only head to head comparisons of interventions from different categories (e.g., a histamine versus a decongestant) Steroids/Cochrane part of the review:* topical (intranasal) steroids versus placebo topical (intranasal) steroids versus no topical treatment oral steroids versus placebo oral steroids versus no oral treatment. If trial participants have received other treatments, for example, antibiotics, mucolytics or decongestants, we will include these studies if both arms of the study received identical treatments.
Outcome	Critical NICE part of the review: Hearing proportion of children whose hearing has returned to normal; mean final hearing threshold (determined for the child or ear, depending on the unit of analysis); change in hearing threshold from baseline (determined for the child or ear, depending on the unit of analysis). Presence/persistence of OME Discontinuation of treatment Adverse events: Systemic corticosteroid side-effects Steroids/Cochrane part of the review: We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies. We will assess all outcomes in the very short term (< 6 weeks for adverse events), short term (≤ 3 months), medium term (> 3 months to ≤ 1 year) and long term (> 1 year). Hearing proportion of children whose hearing has returned to normal; mean final hearing threshold (determined for the child or ear, depending on the unit of analysis); change in hearing threshold from baseline (determined for the child or ear, depending on the unit of analysis). Disease-specific quality of life measured using a validated instrument, for example: OM8-30; Otitis Media-6 Adverse events: Systemic corticosteroid side-effects Discontinuation of treatment Important NICE Listening skills, for example, listening to stories and instructions effectively. Given that there are few validated scales to assess listening skills in children with OME, we will include any methods used by trialists. Receptive language skills, measured using a validated scale, for example: Peabody Picture Vocabulary Test – Revised; relevant domains of the Reynell Developmental Language Scales; relevant domains of the Preschool Language Scale (PLS); relevant domains of the Sequenced Inventory of Communication (SCID). Disease-specific quality of life measured using a validated instrument, for example: OM8-30; Otitis Media-6 Steroids/Cochrane part of the review: Presence/persistence of OME. Receptive language skills, measured using a validated scale, for example: Peabody Picture Vocabulary Test – Revised; relevant domains of the Reynell Developmental Language Scales; relevant domains of the Preschool Language Scale (PLS); relevant domains of the Sequenced Inventory of Communication (SCID). Listening skills, for example, listening to stories and instructions effectively. Given that there are few validated scales to assess listening skills in children with OME, we will include any methods used by trialists

: NICE: National Institute of Health and Care Excellence; OM: otitis media; OME: otitis media with effusion; PLS: Preschool Language Scale; PPI: proton pump inhibitor; SCID: Sequenced Inventory of Communication

Table 2Summary of included studies

Study

Population

Comparison

Outcomes

Mulvaney 2023b

Systematic review

Children aged 6 months to 12 years with unilateral or bilateral OME.

Number of studies: 24

Number of participants: 3248

Oral steroids vs no treatment

3 RCTs, N=542 children with OME (Acharya 2020; Choung 2008; Hussein 2017)

Oral steroids vs placebo

11 RCTs, N=1184 children with OME (Berman 1990; Francis 2008; Hemlin 1997; Lambert 1986; Macknin 1985; Mandel 2002; Niederman 1984; Podoshin 1990; Puhakka 1985; Saffar 2001; Schwartz 1980)

Nasal steroids vs no treatment

7 RCTs, N=833 children with OME (Acharya 2020; Ahmed 2022; Barati 2011; Beigh 2013; Cengel 2006; Karlidag 2002; Rahmati 2017)

Nasal steroids vs placebo

6 RCTs, N=693 children with OME (Bhargava 2014; Khanam 2022; Lildholdt 1982; Scadding 2014; Stuart 1995; Williamson 2009)

Primary:

Hearing as
(i)
return to normal; and
(ii)
mean threshold
Disease-specific quality of life
Systemic corticosteroid side-effects

Secondary:

Persistence of OME
Adverse events: local nasal
Receptive and expressive language
Cognitive development
Psychosocial development
Listening skills
Generic health-related QoL
Parental stress
Vestibular function
Number of episodes of AOM

: AOM: acute otitis media; N: number; OME: otitis media with effusion; QoL: quality of life; RCT: randomised controlled trial

Table 3Summary of included studies

Study	Population	Intervention	Comparison	Outcomes	Comments
Babic 2017 RCT Croatia	N=90 children diagnosed with bilateral chronic OME Age in months, mean (SD): 49.5 (NR, range: 24-72) Sex (male/female): 51/39	Mucolytic and antibiotic (n=30): Acetylcysteine (AC; 100mg 3 times daily, for 3 weeks) and azithromycin (AZ; dosing based on the child’s weight, for 3 days)	Antibiotic only (n=30): AZ; dosing based on the child’s weight, for 3 days	Presence/ Persistence of OME	An additional group received mucolytic only, but data from this group were not extracted for the purposes of this review as it had no direct head-to-head comparison OME diagnosed based on heterohistory data reported by parents, pneumato-oscopy, endoscopic ear examination, and tympanometry (type B bilaterally)
Balatsouras 2005 RCT Greece	N=50 children aged 6 to 13 years with a diagnosis of bilateral OME and asthma Age in years, mean (SD): 10.4 (2.1) Sex (male/female): NR	Leukotriene receptor antagonist and inhalers (n=25): Montelukast (5mg chewable tablet) taken once a day between meals for 30 days) Budesonide and terbutaline inhalers. Treatment regimen/ dosages not reported	Inhalers only (n=25): Budesonide and terbutaline inhalers. Treatment regimen/ dosages not reported	Presence/ persistence OME	OME was diagnosed using pneumatic otoscopy, tympanometry and pure-tone audiometry.
Cantekin 1983 RCT US	N=553 children aged between 7 months and 12 years who had unilateral or bilateral OME Decongestant & antihistamine group: Age in years, mean (SD): NR 7-23 months: 79/278 (28%) 2-5 years: 136/278 (49%) 6-12 years: 63/278 (23%) Sex (male/female): NR, percentages (male/female): 59%/41% Allergy diagnosed: Yes: 5% No: 94% Not recorded: 1% Placebo group: Age in years, mean (SD): NR 7-23 months: 81/275 (29%) 2-5 years: 132/275 (48%) 6-12 years: 62/275 (23%) Sex (male/female): NR, percentages (male/female): 62%/38% Allergy diagnosed: Yes: 5% No: 94% Not recorded: 1% *Numbers of participants not reported	Decongestant & antihistamine (n=278): Liquid preparation (Novafed A syryup) of pseudoephedrine hydrochloride (dosage 1.0mg/ kg of body weight) and chlorpheniramine maleate (dosage 0.09mg/ kg of body weight) administered 4 times daily for 4 weeks	Placebo (n=275): 4 weeks of placebo identical in appearance and similar in taste to the active medication, containing the same inert ingredients (Merrell-Dow)	Presence/ persistence of OME	OME diagnosed based on a decision-tree algorithm which combined independent findings obtained by a “validated” otoscopist with results of tympanometry and middle-ear muscle-reflex testing. Children in both groups received a standardised antimicrobial regimen if they had an episode of acute suppurative otitis media or acute purulent rhinitis during follow-up
Choung 2008 RCT Korea	N=84 children with OME Age in months, mean (SD): 69 (NR, range: 5 months - 12 years) Sex (male/ female): 57/27 Hearing thresholds (pure tone average): Mean air conduction threshold (SD): - Right: 26.1 (11.3) dB - Left: 26.4 (11.0) dB Mean air-bone gap (SD): - Right: 22.1 (13.6) dB - Left: 23.8 (12.1) dB Children with allergic symptoms: 34/84 (41%) Children with positive allergic skin-prick tests: 17/40 (48%) Only performed in children suspected of having allergies	Antihistamine and antibiotic and (n=15): Ebastine (0.2 cc/kg, Ebastel) Amoxicillin-clavulanate syrup (1 cc/kg, Augmex Duo syrup) Treatments taken for 2 weeks. Treatment regimens not reported.	Antibiotic (n=16): Amoxicillin-clavulanate syrup (1 cc/kg, Augmex Duo syrup) for 2 weeks. Treatment regimen not reported.	Presence/ persistence of OME	Three additional groups received the following: antibiotic and steroid; antibiotic, steroid, and antihistamine; mucolytic. Data from the first 2 groups were not of interest for this review; data from the mucolytic group could not be extracted because this group had no direct head-to-head comparison. OME diagnosed using pneumatic otoscopy, tympanography (type B or C tympanograms), and pure tone audiometry (hearing loss >25 dB)
Commins 2000 RCT UK	N=163 children aged 2 to 11 years with OME of at least 3 months duration Mucolytic group: Age in years, mean (SD): 5.1 (NR, range: 2-10) Sex (male/female): NR, ratio (male/female): 53/28 Mean hearing loss (SD): 32.1 (NR) dB Placebo group: Age in years, mean (SD): 5.7 (NR, range: 2-11) Sex (male/female): NR, ratio (male/female): 52:35 Mean hearing loss (SD): 33.8 (not reported) dB	Mucolytic (n=78): Patients <5 years of age: Mucodyne 125mg (Carbocisteine, 2.5ml) three times a day for 6 weeks; patients >5 years of age: Mucodyne 250mg (5ml) three times a day for 6 weeks	Placebo (n=85): Placebo was matched in colour and taste to the active drug Patients <5 years of age: placebo (2.5ml) three times a day for 6 weeks; patients >5 years of age: placebo (5ml) three times a day for 6 weeks	Presence/ persistence of OME	Diagnosis of OME was based on clinical otoscopy, tympanometry (type B) and an average hearing loss >25 dB. 30% of the children had grommet insertion and ≈ 13% had adenoidectomy prior to the study.
Dusdieker, 1985 RCT US	N=66 children aged 6 months to 10 years with OME who had completed a standard course of antibiotics before enrolment Pseudoephedrine group: Age in years, mean (SD): 3 (2.68) Sex (male/female): 9/11 Allergic history: 2/20 (10%) Chlorpheniramine group: Age in years, mean (SD): 2.5 (1.34) Sex (male/female): 7/15 Allergic history: 4/22 (18%) Placebo group: Age in years, mean (SD): 1.9 (1.03) Sex (male/female): 13/11 Allergic history: 5/24 (21%) Children with any of the following: asthma; eczema; allergic rhinitis	Decongestant (n=20): Pseudoephedrine syrup (4 mg/ kg/day); medication given 3 times a day Mean dose administered: 4.1 ± 0.98 mg/kg/day Antihistamine (n=22): Chlorpheniramine syrup (0.35 mg/kg/day); medication given 3 times a day Mean dose administered: 0.35 ± 0.03 mg/kg/day	Placebo (n=24): Similarly favoured placebo syrup given 3 times a day e	Presence/ persistence of OME Discontinuation of treatment (due to hyperactivity and poor sleeping)* *Could only be extracted for hyperactivity and poor sleeping because the rest of the data were not reported separately for each group	OME diagnosed by the principle investigator using pneumatic otoscopy and tympanometry (type B, or C3 if accompanied by physical findings of fluid in the middle ear).
Edstrom 1977 RCT Sweden	N=178 children with secretory otitis media. Age in years, mean (SD):: NR 0-2 years: 55/178 (31%) 3-4 years: 38/178 (21%) 5-6 years: 41/178 (23%) 7-8 years: 25/178 (14%) 9-10 years: 6/178 (3%) >10 years: 13/178 (7%) Sex (male/female): NR	Mucolytic (n=38): Bromhexine (Bisolvon) administered orally 3 times daily in the following doses until healing (but not longer than 7 weeks): 0-1 year: 2 mg 2-5 years: 3 mg 6—-12 years: 4 mg >12 years: 8 mg Antihistamine (n=43): Cinnarizin (Rinomar) administered orally twice daily in the following doses until healing (but not longer than 7 weeks): 0-1 year: 2.5 mg 2-5 years: 5 mg 6-12 years: 10 mg >12 years: 20 mg Mucolytic and antihistamine (n=46): Bromhexine and Cinnarizin administered according to the regimens above until healing (but not longer than 7 weeks)	Placebo (n=51): No information reported	Presence/ persistence of OME	Study reported data separately for the below groups, but results were combined for this review as they did not represent subgroups of interest: Children who completed a course of antibiotics 3 weeks before the study was started (assumed for AOM): n=102/178 (57%) Children without preceding symptoms of AOM and antibiotic therapy: n=76 (43%) Criteria for a diagnosis of OME included a dull tympanic membrane with impaired mobility in Siegle’s funnel (assessed during routine ENT examination) and, in most cases, impaired hearing.
Fraser 1977 RCT UK	N=85 children aged 3 to 12 years with bilateral secretory otitis media Age in years, mean (SD): 5.1 (NR, range: 3-12) Sex (male/female): 47/38 History of allergy: 9/85 (11%) Mean pure-tone thresholds* (SD): 26.7 (9.7) dB *Averaged across 0.5, 1, and 2 kHz	Decongestant (n=43): Ephedrine nose drops (0.5% ephedrine hydrochloride in 0.9% saline): two drops in each nostril given twice a day for 6 weeks. Decongestant + antihistamine (n=43): Amoxicillin-clavulanate syrup (1 cc/kg, Augmex Duo syrup) for 2 weeks. Treatment regimen not reported.	Participants were split into 8 different groups to receive a combination of any or none of the following: decongestant nose drops; combination of antihistamine and nasal decongestant; autoinflation. Results were only reported according to whether participants received each treatment or not, irrespective of the other treatments received, so data could not exclusively be extracted for groups of interest for the purposes of this review (decongestant alone; combination of decongestant & antihistamine; no treatment. However, rates of people receiving other treatments was equivalent across groups.	Mean change in hearing from baseline Authors also reported change in middle ear pressure but did not provide thresholds for resolution of OME, so this outcome has not been extracted. Authors do note in the Discussion section the number of participants who experienced resolution of OME, but this is reported as a total number for the whole cohort and per group/ intervention received, so this has not been extracted	Results relating to groups who received and did not receive autoinflation were not extracted as not of interest for this review. Participants were assessed using clinical history, pure-tone audiometry, and all diagnoses of OME were confirmed using tympanometry: a negative middle ear pressure in both ears and compliance less than 0.3cc in one or both ears.
Haugeto 1981 RCT Norway	N=77 children with secretory otitis media Age in years, mean (SD): NR, range: 1-14 Decongestant group: Age in years, mean (SD): 7.5 (NR) Sex (male/female): NR Hearing: Mean air conduction threshold >20dB: 10/36 ears (28%) Decongestant and antihistaminegroup: Age in years, mean (SD): 6.6 (NR) Gender (male/female): NR Hearing: Mean air conduction threshold >20dB: 9/49 ears (18%) Placebo group: Age in years, mean (SD): 7 (NR) Sex (male/female): NR Hearing: Mean air conduction threshold >20dB: 8/42 (19%)	Decongestant (n=22): 4-week course of phenylpropanolamine chloride (Monydrin). Further details about treatment regimen/ dosage not reported Decongestant and antihistamine (n=28): 4-week course of phenylpropanolamine chloride (Monydrin) and brompheniramine maleate (Lunerin). Further details about treatment regimen/ dosage not reported	Placebo (n=27): 4-week course of placebo. Further details not reported	Presence/ persistence of OME Number of ears with hearing returned to normal	Secretory otitis media diagnosed using pneumatic otoscopy, otomicroscopy, and impedance audiometry. Pure tone audiometry was also performed where possible.
Hayden 1984 RCT US	N=152 children aged 3 months to 10 years with persistent middle ear effusion, who returned for follow-up visits 2 weeks after treatment with a single course of an antimicrobial for an episode of AOM; n=79 completed study (characteristics reported for those who completed study only) Sex (male/female): NR, percentages (male/female): 58%/42% Phenylephrine group: Age in years, mean (SD): 4.1 (NR, range: 9 months to 10 years) Placebo group: Age in years, mean (SD): 4.0 (NR, range: 7 months to 9 years) Numbers of participants not reported; not reported separately for each group	Decongestant (n=38): 0.25% phenylephrine hydrochloride nose drops or nasal spray. One-fourth dropperful (nose drops) administered in the following pattern each week: 4 times a day on day 1, 3 times on day 2, 2 times on day 3, once on day 4, then no medication for the final 3 days of the week Participants repeatedly weekly cycles for 3-4 weeks or until OME resolved	Placebo (n=41): Placebo nose drops or nasal spray. Unclear if timing patterns matched those for the phenylephrine group	Presence/ persistence of OME (otoscopy) Presence/ persistence of OME (tympanometry) Discontinuation of treatment due to AOM Discontinuation of treatment due to use of additional medication Discontinuation of treatment due to inability to tolerate medication	Diagnostic criteria for OME at baseline were the presence of visible middle ear fluid and/ or impaired mobility of the tympanic membrane on pneumatic otoscopy, and a type B, C, or A(s) tympanogram (only type A tympanograms were considered normal). At follow-up, clinical (otoscopic) criteria are the same as at baseline (presence of visible middle ear fluid and/ or impaired mobility of the tympanic membrane on pneumatic otoscopy). However, for tympanometry, both type A and A(s) tympanograms were considered normal at follow-up and therefore reported as resolution of OME, which was different to the tympanometry diagnostic criteria used at baseline.
Hisamatsu 1994 RCT Japan	N=62 children under the age of 15 years diagnosed with OME Antihistamine and local treatment group: Age in years, mean (SD): NR 0-5 years: 13 children (23 ears) 6-15 years: 22 children (32 ears) Sex (male/female): 21 children (32 ears)/14 children (23 ears) Local treatment only group: Age in years, mean (SD): NR 0-5 years: 13 children (22 ears) 6-15 years: 14 children (26 ears) Sex (male/female): 9 children (15 ears)/18 children (33 ears) Hearing loss (air conduction level calculated using thresholds at 0.5, 1, and 2 kHz, with additional weight given to the threshold at 1 kHZ in calculations) was measured at baseline but not reported. Authors note that only a small number of patients had hearing loss above 15 dB	Antihistamine and local treatment (n=35): 0.05 mg/kg of Tranilast (Rizaben Granule) administered orally for 6 weeks Local treatment consisted of nasal spraying (1:5000 epinephrine) and suctioning (Dibekacin and Dexamethason were nebulized prior to ventilation therapy by catheterization or Politzer’s method) once a week when patients visited the outpatient clinic	Local treatment only (n=27): Local treatment consisted of nasal spraying (1:5000 epinephrine) and suctioning (Dibekacin and Dexamethason were nebulized prior to ventilation therapy by catheterization or Politzer’s method) once a week when patients visited the outpatient clinic	Number of ears with hearing returned to normal Presence/ persistence of OME	OME was diagnosed based on the findings of the eardrum noted through the use of an operating microscope, mobility of the eardrum noted through the Bruning’s otoscope, and their subjective symptoms with reference to pure tone audiometry, tympanometry, and more (complete information about diagnostic criteria not reported).
Hughes 1984 RCT Germany	N=83 children with a clinical diagnosis of MEE, no history of previous ENT surgery , and normal palatal function. Patient characteristics not reported.	Mucolytic (n=27): Mucodyne (carbocisteine) + Actifed placebo. For both, children <5 years were given 5ml twice daily; children >5 years were given 5 ml 3 times daily. Further information about dosages not reported Decongestant and antihistamine (n=20): Mucodyne placebo + Actifed (Pseudoephedrine hydrochloride + triprolidine hydrochloride). For both, children <5 years were given 5ml twice daily; children >5 years were given 5 ml 3 times daily. Further information about dosages not reported Mucolytic, decongestant and antihistamine (n=20): Mucodyne + Actifed. For both, children <5 years were given 5ml twice daily; children >5 years were given 5 ml 3 times daily. Further information about dosages not reported	Placebo (n=16): Mucodyne placebo + Actifed placebo. For both, children <5 years were given 5ml twice daily; children >5 years were given 5 ml 3 times daily	Presence/ persistence of OME	OME diagnosis based on patient’s symptoms, previous medical history, physical examination, and tympanometry. Most children also had audiograms, though number is not reported.
Khan 1981 RCT UK	N=60 children with bilateral OME Age in years, mean (SD): 7.3 (NR, range: 5-14) Sex (male/female): 39/21	Mucolytic, antihistamine and decongestant (n=19): Bromhexine and brompheniramine, phenylephrine, and phenylpropanolamine were given at the following dosages, according to age: 4 years: 4.5mls 3 times a day 5-9 years: 5mls 3 times a day 10-14 years: 10mls 3 times a day After 1-28 days all children underwent myringotomies, and children with mucoid MEE had VTs inserted Not clear when (i.e., pre- or post-operatively) or for how long medications were taken but trial ended 1 month after operation in each case Mucolytic (n=20): SCMC/ carbocisteinewas given at the following dosage, according to age: 4 years: 4.5mls 3 times a day 5-9 years: 5mls 3 times a day 10-14 years: 10mls 3 times a day After 1-28 days all children underwent myringotomies, and children with mucoid MEE had VTs inserted Not clear when (i.e., pre- or post-operatively) or for how long medications were taken but trial ended 1 month after operation in each case	Placebo (n=19): Medications were given at the following dosages, according to age: 4 years: 4.5mls 3 times a day 5-9 years: 5mls 3 times a day 10-14 years: 10mls 3 times a day After 1-28 days all children underwent myringotomies, and children with mucoid MEE had VTs inserted Not clear when (i.e., pre- or post-operatively) or for how long medications were taken but trial ended 1 month after operation in each case	Number of children with hearing returned to normal	OME diagnosed based on clinical history, otoscopic examination, and audiology (including tuning fork testing and pure-tone audiometry). OME criteria were bilateral reduced hearing, retracted tympanic membrane with diminished light reflexes, and an air-bone gap.
Kumazawa 1989 RCT Japan	N=214 children with OME who weighed 18 to 33kg and were 5 to 10 years old Mucolytic group (n=104): Age in years, mean (SD): NR <5 years: 8/104 (8%) 5-6 years: 61/104 (59%) 7-8 years: 24/104 (23%) 9-10 years: 8/104 (8%) >11 years: 3/104 (3%) Sex (male/female): 61/43 Placebo group: Age in years, mean (SD): NR <5 years: 12/110 (11%) 5-6 years: 58/110 (53%) 7-8 years: 28/110 (25%) 9-10 years: 11/110 (10%) >11 years: 1/110 (1%) Sex (male/female): 63/47	Mucolytic (n=104): 5% SCMC syrup (50mg SCMC per 1ml syrup) administered 3 times daily after meals for 4 consecutive weeks (30 mg/kg/day in 1 dosage each, i.e., 4 ml for patients weighing 18 kg-23 kg, 5 ml for 23 kg-28 kg and 6 ml for 28 kg-33 kg) Antibiotics (penicillin origin or cefaclor) were allowed for use upon myringotomy prior to administration of the syrup, for a maximum of 3 days	Placebo (n=110): Placebo syrup indistinguishable from active drug by odour, taste, or appearance, administered orally 3 times daily after meals for 4 consecutive weeks (amount to match active drug) Antibiotics (penicillin origin or cefaclor) were allowed for use upon myringotomy prior to administration of the syrup, for a maximum of 3 days	Presence/ persistence of OME Discontinuation of treatment due to side-effects	OME diagnosed based on observations of MEE, dullness and retraction of the eardum, standard audiometry, and tympanometry.
Mandel 1987 RCT US	N=474 infants and children aged 7 months to 12 years with OME Antibiotic, decongestant and antihistamine group: Age in years, mean (SD): NR 7-23 months: 37% 2-5 years: 48% 6-12 years: 16% Sex (male/female): NR, percentages (male/female): 36%/64% Allergy diagnosed: No: 99% Yes: 1% Unknown: 0% Mean speech awareness thresholds at baseline/ child (SD): 23.25 (9.28) dB Antibiotic only group: Age in years, mean (SD): NR 7-23 months: 33% 2-5 years: 49% 6-12 years: 18% Sex (male/female): NR, percentages (male/female): 36%/64% Allergy diagnosed: No: 97% Yes: 3% Unknown: 1% Mean speech awareness thresholds at baseline/ child (SD): 23.00 (11.74) dB Only reported for 57/158 (36%) participants who had data at baseline and 4-week follow-up **Only reported for 50/160 (31%) participants who had data at baseline and 4-week follow-up	Antibiotic, decongestant and antihistamine (n=158): Antibiotic (amoxicillin): liquid suspension, 40mg/kg/day divided into 3 doses for 2 weeks Decongestant-antihistamine: liquid preparation of pseudoephedrine hydrochloride and chlorpheniramine maleate (Novafed A) administered in a dose of 1.0 mg/kg and 0.09mg/kg of each drug respectively 4 times daily for 4 weeks	Antibiotic only (n=160): Antibiotic (amoxicillin): liquid suspension, 40mg/kg/day divided into 3 doses for 2 weeks Placebo identical in appearance and similar in taste to decongestant-antihistamine, and containing the same inert ingredients, administered for 4 weeks	Presence/ persistence of OME Mean final hearing threshold	OME diagnosed based on standardised ENT examination (including pneumatic otoscopy).
McGuiness 1977 RCT UK	N=36 children with non-suppurative otitis media and intact tympanic membranes Patient characteristics not reported.	Mucolytic (n=20): 5ml of SCMC delivered 3 times a day orally for 14 days No surgery performed during trial	No treatment (n=16): No surgery performed during trial	Change in hearing threshold	Diagnosis of OME made based on clinical history, appearance of tympanic membrane, and pure-tone audiometry. Authors do not explicitly report the use of otoscopy or tympanometry, but examination of tympanic membrane presumed to have been done using otoscopy.
O’Shea 1980/1982 RCT US	N=55 children aged 3 to 9 years with the following: first known diagnosis of serous otitis media within 1 month prior to the trial; rectal temperature less than 38.4 C or an oral temperature less than 37.8 C; no externally obvious ear or nose deformities Age in years, mean (SD): 6 (NR, range: 3-9) Sex (male/female): 33/22 Mean hearing loss (air and bone conduction): Not reported. All participants had, in at least 1 ear, hearing loss (air conduction) >15 dB at ≥2 consecutive frequencies, and no hearing loss (bone conduction) >10 dB	Antihistamine and decongestant (n=27): Combination of diphenhydramine and pseudoephedrine, each taken 5 mg/kg/day orally in 3 divided doses. Duration of treatment not reported	Placebo (n=28): Similar tasting placebo taken in comparable volume orally in 3 divided doses. Duration of treatment not reported	Presence/ persistence of OME Number of children with hearing returned to normal Change in hearing threshold from baseline	Diagnosis of serous otitis media made based on the following criteria: Fluid in at least 1 middle ear and no bulging of either tympanic membrane, assessed using pneumatic otoscopy In at least 1 ear, hearing loss (air conduction) >15 dB at ≥2 consecutive frequencies, and no hearing loss (bone conduction) >10 dB At least one ear with a flat (type B) tympanogram on impedance tympanometry
Rahmati 2017 RCT Iran	N=143 children aged 2 to 6 years with a diagnosis of OME Leukotriene receptor antagonist group: Age in months, mean (SD): 43.05 (19.08) Sex (male/female): 32/27 No treatment group: Age in months, mean (SD): 41.27 (15.90) Sex (male/female): 31/13	Leukotriene receptor antagonist (n=59): 4ml Montelukast per day for 1 month. Further information regarding dosage not reported	No treatment (n=44): No further details reported	Presence/ persistence of OME	One additional group received Mometasone but data for this group were not extracted as not of interest for this review. OME diagnosed based on “symptoms and examination”. Further detail not reported; however, OME diagnosis was confirmed by tympanometry at baseline.
Ramsden 1977 RCT UK	N=52 children with OME who had not had previous surgery Age in years, mean (SD): NR, range: 3-9 Sex (male/female): NR Mean duration of hearing loss (range): 14 (2-48) months	Mucolytic (n=18): SCMC given in the following amounts dependant on participant age: 3-4 years: 5ml twice daily; 5-10 years: 5ml three times daily. Further information about dosage not reported	Placebo (n=19): Placebo given in the following amounts dependant on participant age: 3-4 years: 5ml twice daily; 5-10 years: 5ml three times daily	Presence/ persistence of OME	OME was diagnosed based on the following criteria (otoscopic diagnosis and shape of compliance curve considered to be the most important criteria): Subjective clinical assessment based on a history of fluctuating hearing loss, the otoscopic appearance of the tympanic membrane and a negative Rinne test Conductive hearing loss on pure tone audiometry A flat curve on the middle ear compliance instrument
Roydhouse 1981 RCT New Zealand	N=113 children aged ≤14 years seen at the ENT clinic who had OME which did not resolve after phase 1 of the trial Mucolytic + antihistamine group: Age in years, mean (SD): 6.7 (2.5) Sex (male/female): 31/26 Placebo + antihistamine group: Age in years, mean (SD): 6.5 (1.9) Sex (male/female): 34/22	Mucolytic + antihistamine (n=57): Bromhexine taken for 1 month with dosage depending on age of the participant, plus a refill after 1 month: ≥7 years: 16mg twice daily; ≤6 years: 10ml bromhexine elixir (4mg/ 5ml) three times daily. Participants also took: ≥7 years: Chlorpheniramine maleate long-acting 8mg twice daily and pseudoephedrine 30 or 60mg twice daily ≤6 years: Chlorpheniramine maleate elixir (2mg/ 5ml) combined with pseudoephedrine elixir (30mg/ 5ml), 5ml three times daily	Placebo + antihistamine (n=58): Placebo taken for 1 month, plus a refill after 1 month Participants also took: ≥7 years: Chlorpheniramine maleate long-acting 8mg twice daily and pseudoephedrine 30 or 60mg twice daily ≤6 years: Chlorpheniramine maleate elixir (2mg/ 5ml) combined with pseudoephedrine elixir (30mg/ 5ml), 5ml three times daily	Presence/ persistence of OME	OME diagnosed on clinical grounds and confirmed with impedance audiometry (participants had to have a B- or C-type curve with a peak pressure <-300mm water) In phase 1 of the trial, participants were given specific measures to improve the health of the nose and sinuses (including the use of nasal sprays), and non-specific measures to improve general resistance to infection
Saunte 1978 RCT Norway	N=21 children with secretory otitis media who met the following criteria: reduced hearing ability recognised by the child or their parent for ≥14 days; minimum hearing threshold ≥20 dB measured using audiometry; reduced mobility of the ear drum found on otoscopy; if the child had previously had AOM, it must be cured and the child must be without symptoms for ≥2 weeks; normal hearing ability prior to the OME Antihistamine and decongestantgroup: Age in years, mean (SD): 6.3 (NR, range: 3-10) Sex (male/female): NR Atopic heredity to allergic rhinitis to a moderate degree: 4/11 (36%) Mean hearing threshold at baseline/ear (SE): 0.5 kHz (14 ears): 27.5 (1.6) dB 1 kHz (14 ears): 27.1 (2.2) dB 2 kHz (7 ears): 29.3 (3.7) dB Placebo group: Age in years, mean (SD): 5.8 (NR, range: 1-12) Sex (male/female): NR Atopic heredity to allergic rhinitis to a moderate degree: 5/10 (50%) Mean hearing threshold at baseline/ear (SE): 0.5 kHz (10 ears): 36.0 (4.2) dB 1 kHz (12 ears): 35.0 (3.3) dB 2 kHz (10 ears): 33.5 (3.4) dB	Antihistamine and decongestant (n=11): Either Lunerin mixture (0.4mg brompheniramine maleate and 1.7mg phenylpropanolamine hydrochloride per ml) or Lunerin mite (tablet, 6mg brompheniramine maleate and 25mg phenylpropanolamine hydrochloride). The child/ their parents had a free choice whether to use tablet or mixture. Children taking tablets took 1 in the morning and 1 in the afternoon Mixture dosages were age dependent: 3-4 years: 7.5ml, 3 times a day 6-10 years: 10 ml, 3 times a day >11 years: 15 ml, 3 times a day	Placebo (n=10): Same appearance and taste to Lunerin (unclear if children in this group were also offered a choice between tablet or mixture)	Change in hearing threshold from baseline	OME diagnosed based on medical history, a reduced mobility of the ear drum on otoscopy, and minimum hearing threshold ≥20 dB measured using audiometry.
Schoem 2010 RCT US	N=38 children aged 2 to 6 years presenting with persistent MEE in at least one ear for ≥2 months Patient characteristics not reported.	Leukotrine receptor antagonist (n=19): 4mg of oral montelukast once an evening for 1 month. Further information regarding dosage not reported	Placebo (n=19): 4mg of placebo once an evening for 1 month	Presence/ persistence of OME	Diagnosis of OME was confirmed by otoscopy and validated independently via tympanometry.
Stewart 1985 Cross-over RCT New Zealand	N=95 children aged 3 to 8 years attending the ENT Clinic of Dunedin Hospital during the study dates, who met the following criteria: proven effusion in at least 1 ear by otomicroscopy and type-B tympanogram; no other significant ear pathology; no previous ear surgery; no antibiotic treatment over the study period; no underlying structural abnormality, e.g., Down’s syndrome, cleft palate Bromhexine group: Age in months, mean (SD): 67.0 (NR) Sex (male/female): NR, ratio (male/female): 60/40 Placebo: Age in months, mean (SD): 66.0 (NR) Sex (male/female): NR, ratio (male/female): 58/42 *Numbers of participants in each group at baseline not reported. Authors note patient characteristics for each group reported at baseline overlap to some extent since some children received both placebo and bromhexine	Mucolytic: Bromhexine tablets: for children aged 3-5 years, 8mg (1 tablet) 3 times daily; for children aged 6-8 years, 16mg (2 tablets) 3 times daily Drugs were issued every 2 weeks in batches which included 6 extra doses The results from 1 group which took bromhexine for the full 8 weeks of the trail (did not cross-over) is extracted for the purpose of this review	Placebo: Placebo tablets were not readily distinguishable from the active drug Drugs were issued every 2 weeks in batches which included 6 extra doses The results from 1 group which took placebo for the full 8 weeks of the trail (did not cross-over) is extracted for the purpose of this review	Presence/ persistence of OME	OME diagnosed using otomicroscopy and impedance tympanometry.
van der Merwe 1987 RCT South Africa	N=60 patients with OME seen in routine outpatient clinics Age in years, mean (SD): NR. 91% of participants were <12 years Sex (male/female): 40/20 Mucolytic group: Hearing thresholds (pure-tone audiometry of free-field audiometry; n=58 ears)/ ear: Right ear <15dB: 8/29 (27%) Left ear <15dB: 7/29 (23%) Right ear 15-30dB: 13/29 (45%) Left ear 15-30dB: 14/29 (48%) Right ear >30dB: 8/29 (27%) Left ear >30dB: 8/29 (27%) Placebo group: Hearing thresholds (pure-tone audiometry of free-field audiometry; n=29 ears each side, 58 ears total): Right ear <15dB: 8/29 (27%) Left ear <15dB: 6/29 (21%) Right ear 15-30dB: 12/29 (42%) Left ear 15-30dB: 15/29 (51%) Right ear >30dB: 9/29 (31%) Left ear >30dB: 10/29 (35%) These patient characteristics not reported separately per group *Results reported as percentages and converted to number of events assuming number of ears is the same at each time point; data extracted from figure and numbers do not add up exactly to totals ears reported at baseline for placebo group	Mucolytic (n=29): Bromhexine taken for 1 month using the following dosage regimens depending on age: <1 year: 1.25ml (2.5mg) 3 times a day 1-5 years: 2.5ml (5mg) 3 times a day 6-10 years: 4ml (8mg) 3 times a day >10 years: 8ml (16mg) 3 times a day	Placebo (n=31): Placebo taken for 1 month. Treatment regimen not further described.	Presence/ persistence of OME Number of ears with hearing returned to normal	OME diagnosed based on ENT examination, with emphasis on tympanic membrane appearance and movement, pure-tone audiometry and tympanometry

: AC: acetylcysteine; AOM: acute otitis media; AZ: azithromycin; dB: decibel; dBHL: decibel hearing level; ENT: ears, nose and throat; MEE: middle ear effusion; N: number; NR: not reported; OME: otitis media with effusion; RCT: randomised controlled trial; SCMC: S-carboxymethylcysteine; SD: standard deviation; SE: standard error; VT: ventilation tube

Table 4Economic evidence profile of a systematic review of economic evaluations of budesonide for maintenance of remission in Crohn’s disease

Study

Limitations

Applicability

Other comments

Incremental

Uncertainty

Costs

Effect

Cost effectivenss

Williamson 2009

Mometasone furoate 50 µg (intranasal steroids)versus placebo nasal spray

Minor limitations

Directly applicable¹

Economic evaluation alongside a randomised controlled trial

£11

-0.0166 QALYs

Intranasal steroids dominated by placebo

Probabilistic sensitivity analysis showed there was a 24% probability of intranasal steroids being cost-effective at a cost-effectiveness threshold of £20,000 per QALY

Francis 2018

Oral prednisolone versus oral placebo

Minor limitations

Directly applicable¹

Economic evaluation alongside a randomised controlled trial

£145

-0.015 QALYs

Oral steroids dominated by placebo

Probabilistic sensitivity analysis showed a 17% probability of oral steroids being cost-effective at a cost-effectiveness threshold of £20,000 per QALY rising to 22% at a threshold of £30,000 per QALY

1: HUI3 (Health Utilities Index 3) was used in preference to EQ-5D to generate QALYs as it is a well validated instrument in children and is likely to have greater sensitivity and less ceiling effects in this population

Study	Code [Reason]
Balli, R. (1980) Controlled trial on the use of oral acetylcysteine in the treatment of glue-ear following drainage. European Journal of Respiratory Diseases 61(suppl111): 158	- Study design does not meet inclusion criteria Conference abstract
Bellussi, L., Ciferri, G., De Seta, E. et al. (1984) Effect of 2-(alpha-thenoylthio)propionylglycine in the treatment of secretory otitis media. Current Therapeutic Research - Clinical and Experimental 36(3): 596–605	- Intervention/ comparator does not meet inclusion criteria Study compares an acyl glycine (propionylglycine) to placebo and to propionylglycine plus NSAID
Bellussi, L, Bernocchi, D, Ciferri, G et al. (1989) Sobrerol in the treatment of secretory otitis media in childhood. The Journal of international medical research 17(3): 277–86 [PubMed: 2767330]	- Study design does not meet inclusion criteria Non-comparative study
Bonci, M and Bozzi, A (1994) Mucoregulatory therapy in secreting disease of the middle ear. Minerva medica 85(3): 83–87 [PubMed: 8196848]	- Article not available in English
Burton, M.J. and Rosenfeld, R.M. (2007) Extracts from The Cochrane Library: Antihistamines and/or decongestants for otitis media with effusion (OME) in children. Otolaryngology - Head and Neck Surgery 136(1): 11–13 [PubMed: 17210325]	- Systematic review, studies assessed for inclusion
Butler, C C and MacMillan, H (2001) Does early detection of otitis media with effusion prevent delayed language development?. Archives of disease in childhood 85(2): 96–103 [PMC free article: PMC1718883] [PubMed: 11466181]	- Systematic review, studies assessed for inclusion
Cantekin, E I, Bluestone, C D, Rockette, H E et al. (1980) Effect of decongestant with or without antihistamine on eustachian tube function. The Annals of otology, rhinology & laryngology. Supplement 89(3pt2): 290–5 [PubMed: 6778330]	- Outcomes do not meet inclusion criteria Study looks at effect of decongestants with or without antihistamines on eustachian tube function
Carmona, N; Garcia, M; Fuentes Rejon, T (1997) Serous otitis media. Comparative study of carbinoxamine-pseudofedrina vs astemizole-pseudoephedrine. Revista alergia Mexico 44: 70–73 [PubMed: 9377115]	- Article not available in English
ChiCTR-TRC-12002227 (2012) A randomized, double-blinded and placebo-controlled multicenter clinical trial to evaluate the efficacy and safety of Myrtol Standardized Enteric Coated Soft Capsules (Children) in the treatment of Otitis Media with Effusion (OME) in Children. ChiCTR [www.chictr.org]	- Article not available
Combs, Jerome T (2004) The effect of montelukast sodium on the duration of effusion of otitis media. Clinical pediatrics 43(6): 529–33 [PubMed: 15248005]	- Population does not meet inclusion criteria Participants had AOM
de Castro, FJ; Jackson, PL; Reed, KD (2001) Efficacy of oral leukotriene together with inhaled steroid in serous otitis media. Pediatric research 49(4): 14a	- Study design does not meet inclusion criteria Conference abstract
Dewan, Karuna and Lieu, Judith (2018) A Clinical Trial of Proton Pump Inhibitors to Treat Children with Chronic Otitis Media with Effusion. The journal of international advanced otology 14(2): 245–249 [PMC free article: PMC6354470] [PubMed: 30256198]	- Data not reported in sufficient detail to extract Results were reported for hearing loss, but insufficient data reported to extract (no measure of deviation or additional statistics for each hearing outcome measure).
Elbeltagy, Reem and Abdelhafeez, Marwa (2022) Outcome of Gastroesophageal Reflux Therapy in Children with Persistent Otitis Media with Effusion. International archives of otorhinolaryngology 26(1): e058–e062 [PMC free article: PMC8789499] [PubMed: 35096159]	- Study design does not meet inclusion criteria Non-randomised trial
Elcock, H W and Lord, I J (1972) Bromhexine hydrochloride in chronic secretory otitis media--a clinical trial. The British journal of clinical practice 26(6): 276–8 [PubMed: 4557897]	- Study design does not meet inclusion criteria Non-randomised trial
Eliopoulos, P, Balatsouras, D, Sterpi, P et al. (2004) Improvement of otitis media with effusion after treatment of asthma by leukotriene antagonists in children with co-existing disease. International journal of pediatric otorhinolaryngology 68(5): 651 [PubMed: 16444906]	- Study design does not meet inclusion criteria Conference abstract
Ertugay, Cigdem Kalaycik, Cingi, Cemal, Yaz, Aytekin et al. (2013) Effect of combination of montelukast and levocetirizine on otitis media with effusion: a prospective, placebo-controlled trial. Acta oto-laryngologica 133(12): 1266–72 [PubMed: 23972320]	- Outcomes do not meet inclusion criteria Insufficient presentation of results - authors report the mean difference in otoscopic/ tympanometry scores for each group but do not report the number of participants with improvement to ‘normal’ category. Tympanometry scores are also insufficiently explained to determine which category would equate to a normal ear
Eyibilen, Ahmet, Aladag, Ibrahim, Guven, Mehmet et al. (2009) The effectiveness of nasal decongestants, oral decongestants and oral decongestant-antihistamines in the treatment of acute otitis media in children. Kulak burun bogaz ihtisas dergisi : KBB = Journal of ear, nose, and throat 19(6): 289–93 [PubMed: 20030596]	- Population does not meet inclusion criteria Participants had AOM
Garabedian, EN, Ducroz, V, Manach, Y et al. (1999) Effect of loratadine (L) syrup in the treatment of otitis media with effusion (OME): randomized double-blind placebo (P) controlled trial. Journal of allergy and clinical immunology 103(1part2): 255	- Article not available
Griffin, G.H., Flynn, C., Bailey, R.E. et al. (2006) Antihistamines and/or decongestants for otitis media with effusion (OME) in children. Cochrane Database of Systematic Reviews: cd003423 [PubMed: 17054169]	- Systematic review, studies assessed for inclusion
Griffin, Glenn and Flynn, Cheryl A (2011) Antihistamines and/or decongestants for otitis media with effusion (OME) in children. The Cochrane database of systematic reviews: cd003423 [PMC free article: PMC7170417] [PubMed: 21901683]	- Systematic review, studies assessed for inclusion
Grundfast, K M (1981) A review of the efficacy of systemically administered decongestants in the prevention and treatment of otitis media. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery 89(3pt1): 432–9 [PubMed: 6115352]	- Study design does not meet inclusion criteria Narrative review
Guo, Y and Sun, XM (2004) Clinical observation on Biyan Qingdu Granule and ambroxol hydrochloride in treating secretory otitis media. Zhong xi yi jie he xue bao [Journal of Chinese integrative medicine] 2(4): 277291 [PubMed: 15339416]	- Article not available in English
Jiang, Z, Liu, W, Zhao, C et al. (2004) Adjuvant treatment of anisodamine to acute serous otitis media. Lin chuang er bi yan hou ke za zhi [Journal of clinical otorhinolaryngology] 18(7): 406–407 [PubMed: 15499981]	- Article not available in English
Kjellman, N I, Harder, H, Lindwall, L et al. (1978) Longterm treatment with brompheniramine and phenylpropanolamine in recurrent otitis media--a double-blind study. The Journal of otolaryngology 7(3): 257–61 [PubMed: 357754]	- Population does not meet inclusion criteria Participants were required to have a history of AOM or secretory otitis media (SOM) but only 8/ 44 (18%) had SOM at entry to trial
Klein, S W, Olson, A L, Perrin, J et al. (1980) Prevention and treatment of serous otitis media with an oral antihistamine. A double-blind study in pediatric practice. Clinical pediatrics 19(5): 342–7 [PubMed: 6767576]	- Population does not meet inclusion criteria Participants had to have AOM but serous otitis media (SOM) was not a requirement for entry into the study
Kripke, Clarissa (2007) Decongestants and antihistamines do not relieve symptoms of otitis media with effusion. American family physician 75(7): 1001 [PubMed: 17427613]	- Study design does not meet inclusion criteria Conference abstract
La Mantia, I and Andaloro, C (2018) Effects of salso-bromo-iodine thermal water in children suffering from otitis media with effusion: a randomized controlled pilot study. La Clinica terapeutica 169(1): e10–e13 [PubMed: 29446785]	- Intervention/ comparator does not meet inclusion criteria Study compares the efficacy of a natural medicine (seawater) vs iodine
La Mantia, I, Varricchio, A, Di Girolamo, S et al. (2019) The role of bacteriotherapy in the prevention of adenoidectomy. European review for medical and pharmacological sciences 23(1suppl): 44–47 [PubMed: 30920631]	- Intervention/ comparator does not meet inclusion criteria Study compared bacteriotherapy (Streptococcus oralis 89a nasal spray) to placebo
Lesser, T H; Clayton, M I; Skinner, D (1986) Efficacy of medical treatment as an adjunct to surgery in the treatment of secretory otitis media. The Journal of laryngology and otology 100(12): 1347–50 [PubMed: 3543180]	- Population does not meet inclusion criteria OME was confirmed using pure tone audiometry and microscopy, not tympanometry/ otoscopy
Malik, Sohail Ahmad, Muhammad, Raza, Yousaf, Muhammad et al. (2014) Effectiveness of conservative treatment in the management of secretory otitis media. Journal of Ayub Medical College, Abbottabad : JAMC 26(3): 337–40 [PubMed: 25671942]	- Study design does not meet inclusion criteria Non-randomised study
Malm, L (1985) Oral decongestants in acute rhinitis, acute sinusitis, acute otitis media and secretory otitis media: prognostic implications. Workshop Treatment of Ear, Nose and Throat Infections 1: 99–106	- Article not available
Malm, L and White, P (1992) Beta-agonists and surfactant in eustachian tube function. Acta oto-laryngologica. Supplementum 493: 133–6 [PubMed: 1353282]	- Study design does not meet inclusion criteria Commentary
Manrique, MJ, Hern?ndez, J, Huarte, A et al. (1987) Treatment of serous otitis media with ambroxol. Acta pedi? Trica espa? Ola 45(1): 17–20	- Article not available in English
Mel-Hennawi, D and Ahmed, M R (2015) Outcome evaluation of clarithromycin, metronidazole and lansoprazole regimens in Helicobacter pylori positive or negative children with resistant otitis media with effusion. The Journal of laryngology and otology 129(11): 1069–72 [PubMed: 26521817]	- Study design does not meet inclusion criteria Commentary
Miller, T, Bauknight, R S, Swanson, G C et al. (1977) Evaluation of oral decongestants in the treatment of serous otitis media. Transactions of the Pacific Coast Oto-Ophthalmological Society annual meeting 58: 243–52 [PubMed: 79247]	- Population does not meet inclusion criteria No baseline characteristics provided for participants (e.g. age, setting), and it is unclear from text whether the included participants were children
Moller, P (1980) Negative middle ear pressure and hearing thresholds in secretory otitis media. A double-blind crossover study with Lunerin. Scandinavian audiology 9(3): 171–6 [PubMed: 7003687]	- Outcomes do not meet inclusion criteria Insufficient presentation of results for a crossover RCT
Moore, R A, Commins, D, Bates, G et al. (2001) S-carboxymethylcysteine in the treatment of glue ear: quantitative systematic review. BMC family practice 2: 3 [PMC free article: PMC57002] [PubMed: 11580867]	- Systematic review, studies assessed for inclusion
Moran, D M, Mutchie, K D, Higbee, M D et al. (1982) The use of an antihistamine-decongestant in conjunction with an anti-infective drug in the treatment of acute otitis media. The Journal of pediatrics 101(1): 132–6 [PubMed: 6177846]	- Population does not meet inclusion criteria Participants have AOM
Moran, DM, Mutchie, KD, Higbee, MD et al. (1982) Use of an antihistamine decongestant in conjunction with an anti infective drug in the treatment of acute otitis media. Journal of pediatrics 101: 132–136 [PubMed: 6177846]	- Duplicate
Nsouli, S. (2014) The efficacy of a nasal antihistamine azelastine hydrochloride and corticosteroid fluticasone propionate for the treatment of serous otitis media. Annals of Allergy, Asthma and Immunology 113(5suppl1): a110	- Study design does not meet inclusion criteria Conference abstract
Nsouli, S. (2010) The efficacy of a nasal antihistamine olopatadine for the treatment of serous otitis media in children. Annals of Allergy, Asthma and Immunology 105(5): a9	- Study design does not meet inclusion criteria Conference abstract
Olson, A L, Klein, S W, Charney, E et al. (1978) Prevention and therapy of serous otitis media by oral decongestant: a double-blind study in pediatric practice. Pediatrics 61(5): 679–84 [PubMed: 351537]	- Population does not meet inclusion criteria Participants have AOM
Ortega del Alamo, P; Rivera, RT; Sanz, FR (2005) The effect of AM3 in the resolution of otitis media with effusion (OME) in paediatric patients. Acta otorrinolaringologica espanola 56(1): 1–5 [PubMed: 15747716]	- Article not available in English
Otten, F W and Grote, J J (1990) Otitis media with effusion and chronic upper respiratory tract infection in children: a randomized, placebo-controlled clinical study. The Laryngoscope 100(6): 627–33 [PubMed: 1693411]	- Intervention/ comparator does not meet inclusion criteria Study compares the following groups: placebo vs decongestant + antibiotic vs maxillary sinus drainage + placebo vs axillary sinus drainage + decongestant + antibiotic. Antibiotics will be investigated in Cochrane systematic review
Ovesen, T, Felding, J U, Tommerup, B et al. (2000) Effect of N-acetylcysteine on the incidence of recurrence of otitis media with effusion and re-insertion of ventilation tubes. Acta oto-laryngologica. Supplementum 543: 79–81 [PubMed: 10908985]	- Outcomes do not meet inclusion criteria Recurrence of OME after VT extrusion and treatment with active drug, not presence/ persistence, is reported
Park, K; Choung, YH; Mo, JY (2005) Do we need antibiotics or antihistamines for treatment of otitis media with effusion in the tertiary hospital?. 5th Extraordinary International Symposium on Recent Advances in Otitis Media . Amsterdam, The Netherlands, April 24-27, 2005: 166abstractnop0403	- Study design does not meet inclusion criteria
Renou, G, Ketari, M, Toutée, JP et al. (1989) Medical treatment of seromucous otitis. Revue de laryngologie - otologie - rhinologie 110(3): 327–328 [PubMed: 8638061]	- Article not available in English
Rukholm, G., Wong, J., Lui, B. et al. (2016) Role of empiric anti-reflux therapy in pediatric otitis media with effusion-a pilot study. European Journal of Pediatrics 175(11): 1658	- Study design does not meet inclusion criteria Conference abstract
Safak, M A, Kilic, R, Haberal, I et al. (2001) A comparative study of azithromycin and pseudoephedrine hydrochloride for otitis media with effusion in children. Acta oto-laryngologica 121(8): 925–9 [PubMed: 11813896]	- Intervention/ comparator does not meet inclusion criteria Study compared a decongestant with two different antibiotics regimens
Samim, E, Kilic, R, Akmansu, H et al. (1998) Secretory otitis media treatment with azitromycine compared to decongestant: a double-blind, randomized controlled trial. 21st Politzer Society Meeting . Antalya, Turkey, 8-11 June, 1998	- Study design does not meet inclusion criteria Conference poster
Sorri, M., Sipila, P., Palva, A. et al. (1982) Can secretory otitis media be prevented by oral decongestants?. Acta Oto-Laryngologica 94(suppl386): 115–116	- Population does not meet inclusion criteria Diagnostic criteria for OME for inclusion to study not reported
Suzuki, M; Kawauchi, H; Mogi, G (1999) Clinical efficacy of an antiallergic drug on otitis media with effusion in association with allergic rhinitis. Auris, nasus, larynx 26(2): 123–9 [PubMed: 10214889]	- Population does not meet inclusion criteria Included participants are aged between 5-38 years but it is unclear what percentage of participants are under 12. Based on means and SDs of each group (11.9 +/− 10.8 and 9.0 +/− 7.2), significant number of participants likely to be over 12 years
Testa, B, Testa, D, Mesolella, M et al. (2001) Management of chronic otitis media with effusion: the role of glutathione. The Laryngoscope 111(8): 1486–9 [PubMed: 11568588]	- Intervention/ comparator does not meet inclusion criteria Study compares an atioxidant (glutathione) to placebo
Theoharides, T C, Manolidis, S S, Vliagoftis, H et al. (1994) Treatment of secretory otitis media with local instillation of hydroxyzine. International archives of allergy and immunology 103(1): 95–101 [PubMed: 8260856]	- Outcomes do not meet inclusion criteria The outcome ‘rate of relapse’ initially appears to refer to number of participants with recurring MEE requiring repeat grommet insertion, however only the number of grommet rejections appears to be reported for all groups at all time points. Recurrence of MEE is not consistently reported and not extractable for all groups as necessary for comparison
Topazio, D., Passali, F., Cama, A. et al. (2019) Intranasal hyaluronic acid improves the audiological outcomes of children with otitis media with effusion. Indian Journal of Otology 25(3): 155–161	- Intervention/ comparator does not meet inclusion criteria Study compares a hyaluronic acid nasal spray to saline solution
Torretta, S, Marchisio, P, Rinaldi, V et al. (2017) Endoscopic and clinical benefits of hyaluronic acid in children with chronic adenoiditis and middle ear disease. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 274(3): 1423–1429 [PubMed: 27695944]	- Intervention/ comparator does not meet inclusion criteria Study assesses the efficacy of saline vs hyaluronic acid
van Heerbeek, Niels; Ingels, Koen J A O; Zielhuis, Gerhard A (2002) No effect of a nasal decongestant on eustachian tube function in children with ventilation tubes. The Laryngoscope 112(6): 1115–8 [PubMed: 12160284]	- Outcomes do not meet inclusion criteria Outcome reported is Eustachian tube function as measured using different tests (forced-response test, pressure equilibration test, and sniff test). Presence of OME/ MEE not reported as an outcome - Population does not meet inclusion criteria Diagnostic criteria for OME for inclusion to study not reported
Varricchio, A, De Lucia, A, Varricchio, A M et al. (2017) Sinuclean Nebules treatment in children suffering from otitis media with effusion. International journal of pediatric otorhinolaryngology 94: 30–35 [PubMed: 28167007]	- Intervention/ comparator does not meet inclusion criteria Study compares saline to alternative medicine (Sinuclean; water solution containing plant extracts)
Williamson, I (2011) Otitis media with effusion in children. Clinical evidence 2011(nopagination) [PMC free article: PMC3275303] [PubMed: 21477396]	- Systematic review, studies assessed for inclusion
Williamson, I. (2007) Otitis media with effusion in children. BMJ clinical evidence 2007 [PMC free article: PMC2943809] [PubMed: 19454116]	- Systematic review, studies assessed for inclusion
Wing, L W (1978) Bisolvon and Actifed in the conservative management of glue ear. The Medical journal of Australia 1(5): 289–90 [PubMed: 661686]	- Study design does not meet inclusion criteria Conference abstract
Witmer, A; Wells, A M; Seymour, R J (1998) A comparison of the effectiveness of pharmacologic treatment of otitis media with effusion in children: integrative and meta-analysis. The online journal of knowledge synthesis for nursing 5: 4 [PubMed: 12874714]	- Systematic review, studies assessed for inclusion
Zhou, Xufeng, Jin, Xiulin, Yang, Linhong et al. (2022) Efficacy and safety of ambroxol hydrochloride in the treatment of secretory otitis media: a systematic review and meta-analysis. Annals of translational medicine 10(3): 142 [PMC free article: PMC8904990] [PubMed: 35284532]	- Systematic review, studies assessed for inclusion

Study	Code [Reason]
Petrou, Stavros, Dakin, Helen, Abangma, Giselle et al. (2010) Cost-utility analysis of topical intranasal steroids for otitis media with effusion based on evidence from the GNOME trial. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research 13(5): 543–51 [PubMed: 20345546]	- Duplicate analysis

Evidence reviews for non-antimicrobial pharmacological interventions for children with OME

Non-antimicrobial pharmacological interventions for children with OME

Review question

Introduction

Summary of the protocol

Table 1

Methods and process

Steroids

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Effectiveness evidence

Included studies

Steroids

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Excluded studies

Summary of included studies

Steroids

Table 2

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Table 3

Summary of the evidence

Steroids

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Important or possible important benefits or harms

No important difference or no evidence of an important difference between interventions

No evidence available

Economic evidence

Included studies

Excluded studies

Summary of included economic evidence

Table 4

Economic model

The committee’s discussion and interpretation of the evidence

The outcomes that matter most

The quality of the evidence

Steroids

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Benefits and harms

Steroids

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Cost effectiveness and resource use

Recommendations supported by this evidence review

References – included studies

Effectiveness

Steroids

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Economic

Appendices

Appendix A. Review protocol

Appendix B. Literature search strategies

Appendix C. Effectiveness evidence study selection

Appendix D. Evidence tables

Appendix E. Forest plots

Appendix F. GRADE tables

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Appendix I. Economic model

Economic model for review question: What is the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) for managing OME in children under 12 years?

Appendix J. Excluded studies

Excluded studies for review question: What is the effectiveness of non-antimicrobial pharmacological interventions (such as steroids, antihistamines, leukotriene receptor antagonists, mucolytics and decongestants) for managing OME in children under 12 years?

Steroids

Antihistamines, leukotriene receptor antagonists, mucolytics and decongestants

Excluded effectiveness studies

Table

Excluded economic studies

Table

Appendix K. Research recommendations – full details

Table 1Summary of the protocol (PICO table)

Table 2Summary of included studies

Table 3Summary of included studies

Table 4Economic evidence profile of a systematic review of economic evaluations of budesonide for maintenance of remission in Crohn’s disease