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Meta-Analysis
. 2017 Jan;38(1):19-30.
doi: 10.1097/MAO.0000000000001254.

Hearing Changes After Intratympanically Applied Steroids for Primary Therapy of Sudden Hearing Loss: A Meta-analysis Using Mathematical Simulations of Drug Delivery Protocols

Affiliations
Meta-Analysis

Hearing Changes After Intratympanically Applied Steroids for Primary Therapy of Sudden Hearing Loss: A Meta-analysis Using Mathematical Simulations of Drug Delivery Protocols

Arne Liebau et al. Otol Neurotol. 2017 Jan.

Abstract

Objective: Controlled and uncontrolled studies with primary intratympanic or combined intratympanic and systemic application of glucocorticosteroids for idiopathic sudden hearing loss were analyzed by means of a meta-analysis in an attempt to establish optimal local drug delivery protocols.

Study design: A total of 25 studies with 28 treatment groups between January 2000 and June 2014 were selected that adequately described drug delivery protocols. Cochlear drug levels were calculated by a validated computer model of drug dispersion in the inner ear fluids based on the concentration and volume of glucocorticoids applied, the time the drug remained in the middle ear, and the specific timing of injections. Various factors were compared with hearing outcome, including baseline data, individual parameters of the application protocols, calculated peak concentration (Cmax), and total dose (area under the curve).

Results: There was no dependence of hearing outcome on individual parameters of the application protocol, Cmax, or area under the curve. Final hearing threshold was notably independent of delay of treatment.

Conclusion: During primary intratympanic or combined steroid therapy of idiopathic sudden hearing loss, the tendency toward early treatment having a positive effect on hearing improvement is thought to be a "sham effect," likely related to spontaneous recovery. Change in pure-tone average may not be an adequate outcome parameter to assess effectiveness of the intervention, as it depends on the degree of initial hearing loss. Final pure-tone average provides a better alternative.

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Figures

Figure 1
Figure 1
Flowchart summarizing the selection of studies included in the current analysis. IT=intratympanic, Dex = dexamethasone, MP = methylprednisolone.
Figure 2
Figure 2
Upper part Examples for time courses of calculated drug concentrations in scala tympani in the 500 – 4000 Hz region after injection for different application protocols according to Dispenza et al. 2011 (55), Li et al. 2013 (78), Battaglia et al. 2008 (62), Roebuck et al. 2006 (79), and Plontke et al. 2009 (80) respectively. Lower part: Example time courses of calculated drug concentrations in scala tympani in the 500 – 4000 Hz region over the total duration of treatment for different treatment protocols: Left: daily injections for 8 days, 5 mg/ml, 0.35 ml, for 30 min application time according to Hong et al. 2009 (68). Right: 4 injections over 14 days, 5 mg/ml, 0.55 ml, for 30 min application time according to Bae et al. 2013 (54).
Figure 3
Figure 3
Dependence of change in pure tone average (PTA hearing gain) on: (a) use of dexamethasone formulation for injection, (b) use of methylprednisolone formulation for injection, (c) total number of injections, (d) frequency of injections, (e) application time of the injection, (f) duration of treatment, (g) age of patients and (h) time of endpoint measurement.
Figure 4
Figure 4
Dependence of change in pure tone average (PTA hearing gain) on the calculated maximum intra-cochlear drug concentrations (Cmax) or total doses (AUC) in the scala tympani within the 500 – 4000 Hz region for dexamethasone and methylprednisolone: (a) dexamethasone Cmax, (b) dexamethasone AUC, (c) methylprednisolone Cmax, (d) methylprednisolone AUC .
Figure 5
Figure 5
Dependence of change in pure tone average (PTA hearing gain) on: (a) the start of treatment (treatment delay) after onset of ISSHL, (b) hearing threshold (PTA) at the beginning of treatment. Dependence of the final hearing threshold (final PTA) on: (c) the start of treatment (treatment delay) after onset of ISSHL, (d) hearing threshold (PTA) at the beginning of treatment.
Figure 6
Figure 6
Dependence of the PTA at the beginning of treatment on the delay of treatment after onset.
Figure 7
Figure 7
Dependence of change in pure tone average (PTA hearing gain) and final hearing threshold (final PTA) on hearing threshold at the beginning of (“PTA before”) treatment (see figure 5b, 5d). PTA hearing gain, final PTA, and PTA before treatment of each group are arranged at the y-axis and study results are sorted by increasing PTA before treatment on the x-axis. Larger hearing loss at start of therapy is compensated by higher hearing gain resulting in similar final hearing thresholds (final PTA) with a tendency for a poorer prognosis with larger hearing loss before treatment.

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