Scolaris Content Display Scolaris Content Display

Base de datos Cochrane de Revisiones Sistemáticas Protocolo - Intervención

Intratympanic glucocorticoids for sudden sensorineural hearing loss

Declaraciones de intereses de los autores

Versión publicada: 07 octubre 2009 Historial de versiones

https://doi.org/10.1002/14651858.CD008080

Esta versión no es la más reciente

ver la versión actual 22 julio 2022
Contraer todo Desplegar todo

Abstract

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

To assess the efficacy, the effectiveness and the risks of adverse events of intratympanically applied glucocorticoids versus placebo therapy, versus no therapy or versus systemic application of glucocorticoids for treating unilateral sudden idiopathic sensorineural hearing loss, when given as a primary therapy or as a secondary (i.e. rescue or salvage) therapy after failure of systemic treatment.

Background

Description of the condition

Definition

Idiopathic sudden sensorineural hearing loss (ISSHL) is a sudden decrease in sensorineural hearing sensitivity of unknown aetiology. It is usually unilateral and the degree of severity can vary from mild hearing loss to anacusis (total deafness). It may also be accompanied by vertigo and tinnitus. There is no international consensus on the definition of ISSHL in terms of the degree of hearing threshold change or the number of specific frequencies that need to be affected on pure‐tone audiological testing (Plontke 2007).

Epidemiology

The incidence of sudden sensorineural hearing loss has been estimated to be 5 to 20 per 100,000 in industrial countries (Byl 1977; Hughes 1996; Stokroos 1996), however according to recent studies in Germany the incidence may be much higher: 160 and 400 per 100,000 (Klemm 2009; Olzowy 2005). The mean age of patients included in randomised controlled trials (RCTs) is between 45 and 55. Men and women are equally affected. ISSHL in childhood is rare (Desloovere 1988; Klemm 2007; Mosges 2009; Plontke 2007; Plontke 2009; Probst 1992; Tucci 2002; Tran Ba Huy 2005).

Aetiology

Various theories to explain ISSHL have been proposed, for example viral infection, vascular occlusion, breaks of labyrinthine membranes, immune‐mediated mechanisms and abnormal cellular stress responses within the cochlea, however none of these hypotheses have been proven convincingly in humans (Merchant 2005; Merchant 2008).

Treatment modalities for ISSHL

Treatment modalities for ISSHL are mostly based on the above aetiopathogenetic hypotheses and include glucocorticosteroids, rheological drugs (e.g. dextran, hydroxyethyl starch, pentoxyphylline and naftidrofuryl), vasodilators, anaesthetics, osmotically active substances, antioxidants, thrombocyte aggregation inhibitors, fibrinogen reduction through drugs or apheresis or rheopheresis, hyperbaric oxygen therapy, antiviral therapy, NMDA receptor antagonists, immunosuppressants or antiapoptotic substances (Conlin 2007a; Plontke 2005). Treatment of ISSHL with systemic glucocorticoids, hyperbaric oxygen and vasodilators have been assessed in Cochrane Reviews (Agarwal 2009; Bennett 2007; Wei 2006). Systemic glucocorticosteroids are widely used for ISSHL worldwide (Plontke 2005), however the Cochrane Review concluded that "the value of steroids in the treatment of ISSHL remains unclear since the evidence from randomised controlled trials is contradictory in outcome, in part because the studies are based upon too small a number of patients" (Wei 2006). This is also supported by another recent meta‐analysis (Conlin 2007b). Moreover, possible side effects of short‐term, high and medium‐dose glucocorticosteroid therapy include risk of metabolic complications, such as glucose intolerance and diabetes mellitus, hypertension, increased intraocular pressure and glaucoma, psychotropic effects, risk of hypothalamic‐pituitary‐adrenal‐axis suppression, gastrointestinal bleeding, bone loss, avascular necrosis of the femoral or humeral head and potential infections. However it is only possible to speculate whether or not these side effects occur, and if so how often, since systematic data recording and publication of these proposed side effects is still insufficient, especially during treatment of ISSHL.

Description of the intervention

Pharmacokinetic studies in animals and humans have shown that only high doses of systemic glucocorticoids will result in detectable drug levels in the inner ear perilymph and that substances applied to the round window membrane lead to significantly higher drug levels in the inner ear fluids compared to systemic application (Bachmann 2001; Bird 2007; Chandrasekhar 2000; Niedermeyer 2003; Parnes 1999). Thus, applying drugs locally may be more effective in treating sudden sensorineural hearing loss and may avoid systemic complications and side effects.

Intratympanic treatment with glucocorticoids

Local intratympanic application of drugs for the treatment of inner ear diseases has advantages over systemic treatment. These are i) the bypassing of the blood‐labyrinthine barrier, resulting in ii) higher concentrations in the inner ear fluids despite the lower total amount of drug given and iii) avoiding the major unwanted effects of systemically administered medications.

Intratympanic injection of glucocorticoids for ISSHL was pioneered by Silverstein (Silverstein 1996) and Parnes (Parnes 1999). During the last decade, a rapidly growing number of reports have been published on treatment results of intratympanic application of glucocorticoids for inner ear disorders, especially for sudden sensorineural hearing loss and more studies, including randomised controlled trials, are ongoing (Haynes 2007; Lustig 2004; Marzo 2005; Plontke 2005a; Rauch 2004). These studies mainly used dexamethasone or methylprednisolone preparations as a primary or a second line ('rescue', 'salvage', 'reserve') therapy. Although these studies have shown intratympanic treatment with glucocorticoids to be relatively safe, efficacy is difficult to assess since only few studies compared their findings with a control group (Choung 2006; Haynes 2007; Kakehata 2006; Kiliç 2007; Lautermann 2005; Plontke 2005; Roebuck 2006; van Wijck 2007), and only four randomised trials have so far been published (Battaglia 2008; Ho 2004; Plontke 2009; Xenellis 2006).

Why it is important to do this review

Reviews on this topic to date are incomplete and non‐systematic. There is uncertainty as to i) whether intratympanic glucocorticoids are better than placebo or no treatment, ii) whether intratympanic administration of glucocorticoids will lead to better results than systemic drug administration, iii) if so, which drug or drug delivery strategy will lead to the best outcome and iv) what risks of adverse events are associated with this approach in inner ear therapy. A Cochrane Review is therefore warranted to assess the benefits and harms of intratympanic glucocorticoid treatment for ISSHL.

Objectives

To assess the efficacy, the effectiveness and the risks of adverse events of intratympanically applied glucocorticoids versus placebo therapy, versus no therapy or versus systemic application of glucocorticoids for treating unilateral sudden idiopathic sensorineural hearing loss, when given as a primary therapy or as a secondary (i.e. rescue or salvage) therapy after failure of systemic treatment.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

Female and male adults and children of any race with an unilateral idiopathic sudden sensorineural hearing loss (ISSNHL) (i.e. sudden sensorineural hearing loss of unknown aetiology) with or without vertigo, and with or without tinnitus.

We will exclude studies of intratympanic treatment with glucocorticoids for sudden bilateral hearing loss or for conditions or symptoms which indicate that the hearing loss was not idiopathic (e.g. acoustic trauma, Ménière's disease, fluctuating hearing loss, endolymphatic hydrops, suspected retro‐cochlear lesion, hearing loss due to ear surgery, perilymph fistula or barotrauma, middle ear inflammation or effusion, or conductive hearing loss).

Types of interventions

Glucocorticoids (also referred to as steroids), e.g. dexamethasone, (methyl‐)prednisolone, hydrocortisone, which were applied as one of the two treatment strategies:

  • as primary intratympanic treatment; or

  • as secondary (rescue/salvage/reserve) treatment after failure of systemic therapy.

The intervention will be delivered using one of the following drug delivery systems (i.e. routes of intratympanic drug administration):

  • single or repeated intratympanic injection with or without volume stabilisation and with or without visualisation of the round window membrane; or

  • continuous or discontinuous drug application via partly or fully implantable pump systems.

We will include trials studying the following comparisons:

  • intratympanic glucocorticoids versus no treatment;

  • intratympanic glucocorticoids versus placebo;

  • intratympanic glucocorticoids versus systemic glucocorticoids;

  • intratympanic plus systemic glucocorticoids versus systemic glucocorticoids alone.

Types of outcome measures

Primary outcomes

Change in hearing threshold with pure tone audiometry (pure tone average).

Secondary outcomes

  • Proportion of patients whose hearing is improved. 

  • Mean level of improvement in those whose hearing is improved.

  • Change in hearing threshold with speech audiometry.

  • Frequency specific changes with pure tone audiometry.

  • For patients with profound pre‐treatment hearing loss: percentage of patients reaching serviceable hearing, defined as maximum percentage of correctly understood monosyllables equal or greater than 50%.

  • Minor and serious adverse events.

  • Effect on tinnitus and vertigo

Search methods for identification of studies

We will conduct systematic searches for randomised controlled trials. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.

Electronic searches

We will search the following bibliographic databases:

  • the Cochrane Ear, Nose and Throat Disorders Group Trials Register;

  • the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue);

  • PubMed;

  • EMBASE;

  • CINAHL;

  • AMED;

  • ISI Web of Science;

  • BIOSIS Previews;

  • CAB Abstracts;

  • LILACS;

  • KoreaMed;

  • IndMed;

  • PakMediNet;

  • China National Knowledge Infrastructure;

  • ICTRP (International Clinical Trials Registry Platform)

  • mRCT (the metaRegister of Controlled Trials); and

  • Google.

Subject strategies for databases will be modelled on the search strategy designed for CENTRAL (see Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by the Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in The Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1, Box 6.4.b. (Handbook 2008)).

Searching other resources

We will search reference lists of retrieved articles and we will contact authors of published trials and other experts in the field. Pharmaceutical companies/manufacturers will be contacted for information on possible unpublished trials. We will search PubMed, TRIPdatabase, NHS Evidence ‐ ENT & Audiology and Google to retrieve existing systematic reviews possibly relevant to this systematic review, so that we can scan their reference lists for additional trials. Abstracts from conference proceedings will be sought via the Cochrane Ear, Nose and Throat Disorders Group Trials Register.

Data collection and analysis

Selection of studies

After scanning all search results, we will retrieve full texts of reports which loosely meet the inclusion criteria. Three authors will review these and apply the inclusion criteria independently. Any differences in opinion about which studies to include in the review will be discussed openly and, if consensus cannot be reached, referred to the Cochrane ENT Group Co‐ordinating Editor.

Data extraction and management

Data from each study will always be extracted by one author and rechecked by one of the other authors. We will perform data extraction using a standardised data form.

In cases where important data are missing from a study, one author (preferably the contact author) will contact the authors of the study requesting additional information.

We will document the following details for each study.

  • Methods (allocation, blinding).

  • Participants (inclusion and exclusion criteria including ages, diagnostic criteria, additional diagnosis/symptoms such as vertigo and/or tinnitus, setting).

  • Interventions (time point of start of intervention, primary therapy or secondary/rescue therapy after failure of systemic treatment, dosage and type of steroid, drug delivery strategy, duration of intervention, concomitant treatments).

  • Outcomes (definitions of hearing improvement, tinnitus and vertigo, adverse events, number of and reasons for drop‐outs and patients lost to follow up).

Assessment of risk of bias in included studies

Assessment of the risk of bias of the included trials will be undertaken independently by SP and CM with the following to be taken into consideration, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2008):

  • sequence generation;

  • allocation concealment;

  • blinding;

  • incomplete outcome data;

  • selective outcome reporting; and

  • other sources of bias.

We will use the Cochrane 'Risk of bias' tool in RevMan 5 (RevMan 2008), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry. This involves answering a pre‐specified question whereby a judgement of 'Yes' indicates low risk of bias, 'No' indicates high risk of bias, and 'Unclear' indicates unclear or unknown risk of bias.

Data synthesis

We will compare primary (change in hearing threshold in the pure tone audiogram) and secondary outcome criteria (change in hearing threshold in speech audiometry, risk of adverse events, frequency specific changes in pure tone audiometry, change in vertigo and tinnitus) between the treatment groups. We intend to perform both an intention‐to‐treat and a per protocol analysis.

The studies will be divided into those using intratympanic treatment as a primary therapy and those using it as a secondary (rescue/salvage) therapy.

The summary statistic in the meta‐analysis for the primary outcome will be the mean difference (MD) of the absolute mean change in dB (baseline/post‐therapy) in hearing threshold between two groups in each trial, measured by pure tone audiogram.

Subgroup analysis and investigation of heterogeneity

Before the analysis we will formally check the data from the different trials for heterogeneity, by means of the Chi² test. Due to the low power of the test (because we expect only few studies with small sample sizes) we will set a significance level of 0.1. We will estimate the impact of heterogeneity using the I² statistic. We will only start meta‐analysis when a group of studies are identified which are sufficiently homogeneous.

Depending on the available data the following further subgroup analyses appear of interest:

  • degree of hearing loss at initial presentation;

  • age of patients;

  • presence of vertigo and/or tinnitus;

  • time before start of intratympanic treatment;

  • duration of intratympanic treatment;

  • drug delivery strategy/system used (e.g. intratympanic injection or continuous delivery etc.);

  • dose of intratympanic treatment.

The possibility of analysing such subgroups will depend on the number of studies available and sufficient quality. A sensitivity analysis and a summary measure of effect might not be appropriate if the number of included trials is low.