Hearing Changes After Intratympanic Steroids for Secondary (Salvage) Therapy of Sudden Hearing Loss: A Meta-Analysis Using Mathematical Simulations of Drug Delivery Protocols

Abstract

Objective: The use of glucocorticoids for secondary (salvage/rescue) therapy of idiopathic sudden hearing loss (ISSHL), including controlled and uncontrolled studies with intratympanic injections or continuous, catheter mediated applications, were evaluated by means of a meta-analysis in an attempt to define optimal local drug delivery protocols for ISSHL.

Study design: A total of 30 studies with 33 treatment groups between January 2000 and June 2014 were selected based on sufficiently detailed description of application 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 drug remained in the middle ear, and on 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, AUC).

Results: There was no dependence of hearing outcome on individual parameters of the application protocol, Cmax or AUC. Hearing gain and final hearing thresholds were independent of treatment delay.

Conclusion: Based on the available data from uncontrolled and controlled randomized and non-randomized studies no clear recommendation can be made so far for a specific application protocol for either primary or secondary (salvage) intratympanic steroid treatment in patients with ISSHL. For meta-analyses, change in pure tone average (PTA) may not be an adequate outcome parameter to assess effectiveness of the intervention especially with inhomogeneity of patient populations. Final PTA might provide a better outcome parameter.

Figure 1

Flowchart of the study selection process. IT = intratympanic, Dex = dexamethasone, MP = methylprednisolone.

Figure 2

Dependence of change in pure tone average (PTA hearing gain) on: (a) dexamethasone concentration used for the injection (IT) or continuous application through an implanted catheter, (b) methylprednisolone concentration used for the injection (IT) or continuous application through an implanted catheter, (c) total number of injections. Continuous application through an implanted catheter is referred to continuously (cont.) on x-axis. Single injections through an implanted catheter is plotted by their number of injections on x-axis. (d) frequency of injections. Continuous application through an implanted catheter is referred to continuously (cont.) on x-axis. Single injections through an implanted catheter is plotted by the days between injections. (e) application time during injection. For continuous application the application time is referred to the whole duration of treatment. For single injections through an implanted catheter the application time is referred to the duration of a single injection, (f) duration of treatment, (g) time of endpoint measurement, (h) age of patients. * = groups with continuous application are excluded from regression analysis.

Figure 3

Dependence of change in pure tone average (PTA hearing gain) on the calculated maximum intracochlear drug concentrations (C_max) or total doses (AUC) in scala tympani within the range corresponding to the 500 – 4000 Hz region: (a) dexamethasone C_max, (b) dexamethasone total dose (AUC), (c) methylprednisolone C_max, (d) methylprednisolone AUC.

Figure 4

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 5

A and B: Mean hearing change (a) and mean final hearing threshold (b) for primary therapy of ISSHL from a previous analysis (13) and data from a more recent study suggesting a concentration effect (triangles) (51). C and D: Dependence of the average final hearing threshold (final PTA) on group size for primary (c) (13), and secondary (d) treatment.

Figure 6

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”) primary (a) and secondary (b) treatment of ISSHL (see figure 4b, 4d; figure 5a taken from Liebau et al. 2017 (13), with permission, © Otology & Neurotology - Wolters Kluwer Health, 2017). 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. In primary therapy (a) 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. In secondary treatment (b) final hearing thresholds decreases more strongly with increasing PTA before because the compensation by increasing hearing gain is less pronounced.