**1.6 Administrated glucocorticoids**

*The Human Auditory System - Basic Features and Updates on Audiological Diagnosis and Therapy*

diseases is known as noninvasive route of drug delivery, due to lack of damaging of tympanic membrane. Adverse effects of systemic delivery may be one of the purposes of discontinuation of the therapy. The presence of *blood-labyrinth barrier* (BLB) in the inner ear is one of the causes of problems with reaching high concentration of drug.

This study was the first study which was carried out in the Institute of Physiology and Pathology of Hearing World Hearing Center and will be continued with different groups of patients and different implants and algorithms of glucocorticoid administration. The aim of the study was to evaluate different regimes of administration of glucocorticoids: dexamethasone and dexamethasone/prednisone to *partial deafness* treatment (PDT) patients who underwent cochlear implantation on the hearing preservation. Implant used in the study was the MED-EL implant with an electrode length of 28 mm (Flex 28). The impact of administrated glucocor-

**1.5 The experience in using glucocorticoids in PDT patients**

ticoids on hearing was measured in six different periods:

3.One month after activation of audio processor

4.Six months after activation of audio processor

5.Nine months after activation of audio processor

*Scheme of steroid administration in the first subgroup of patients.*

6.One year (12 months) after activation of audio processor

sone was administrated intravenously at the same dose to each patient.

Forty-six patients were enrolled to the trial and then divided randomly into three subgroups. Patients from the first subgroup underwent intravenous steroid therapy (**Figure 1**). According to the scheme, 30 min before implantation, dexamethasone at the dose of 0.1 mg/kg body mass was administrated intravenously to patients from the first subgroup. For the next 3 consecutive days in every 12 h, dexametha-

Patients from the second subgroup underwent prolonged (combined) steroid therapy: oral and intravenous. Three days prior to the surgery, prednisone was administrated orally at a dose of 1 mg/kg body mass/day. Then, 30 min before the cochlear implantation surgery, dexamethasone was administrated intravenously at a dose of 0.1 mg/kg body mass. For the next 3 consecutive days in every 12 h, dexamethasone was administrated intravenously (the same as in the first subgroup). For the next 3 days, prednisone was administrated orally at the dose of 1 mg/kg body mass/day. After this period, the dose of prednisone was reduced (10 mg per every

2.During activation of audio processor

1.Preoperatively

**162**

**Figure 1.**

According to the protocol of this study, two different algorithms of administration with two different glucocorticoids were proposed in the study. Although both substances belong to the same pharmacological group, both of them have different pharmacokinetics and pharmacodynamic properties. Dexamethasone is a synthetic glucocorticoid (*molecular weight 392.46 g/mol*) with anti-inflammatory, anti-allergic, and immunomodulating activity. In common practice dexamethasone is administrated *intravenously* or off-label, e.g., *transtympanic injections*. After *intravenous* administration the mean time to peak concentration (Cmax) is between 10 and 30 min, and the half-life (t1/2) is from 2.2 to 3.8 h. Transport proteins are responsible for transport and distribution of dexamethasone in blood. Dexamethasone is mainly metabolized by the liver and eliminated with the bile. Only 2.6% of the chemically unchanged dose is eliminated via kidneys.

Prednisone is a synthetic glucocorticoid (derivative of cortisone) and classified according to the *Anatomical Therapeutic Chemical (ATC) Classification System* as H02 AB 07. Prednisone is *prodrug* which converts into *active metabolite—prednisolone* (higher anti-inflammatory activity). According to characteristic of medical product and literature data, bioavailability of prednisone administrated orally is between 70 and 90%. The mean time to peak concentration (Cmax) is between 1 and 2 h. Half-life (t1/2) is between 3.4 and 3.8 h in plasma and 18–36 h in tissue. Binding prednisone with plasma proteins is between 70 and 73% (binding prednisolone (active metabolite) to the plasma proteins is higher (90–95%)). Similar to dexamethasone, prednisone is metabolized mainly by the liver and eliminated with the bile. Pharmacodynamic and pharmacokinetic data were based on characteristics of medical products: dexamethasone and prednisone.

## **1.7 Methodology of the study: primary and secondary outcomes and inclusion and exclusion criteria**

The primary outcome variables were mean values of hearing thresholds averaged across all 11 frequencies (125–8000 Hz). The secondary outcome variable was hearing preservation (HP). Hearing preservation (HP) was calculated by comparing hearing thresholds in the 1-year postoperative period with the preoperative hearing thresholds, according to the hearing preservation (HP) formula (below) and converted to three levels: minimal, partial, and complete hearing preservation.

$$\text{HP} = \left(1 - \frac{\text{PTA} \, post-\, \text{PTA} \, pre}{\text{PTA} \, max-\, \text{PTA} \, pre}\right) \* \, 100 \, \text{t}\, \text{d} \tag{1}$$

In this equation, *PTApre* is the pure tone average measured preoperatively, *PTApost* is the pure tone average measured postoperatively, and *PTAmax* is the maximal sound intensity generated by a standard audiometer, usually 120 dB hearing level (HL), and *HP* is the rate of hearing preservation in percentage [19].

The protocol of this prospective clinical trial was approved by the Bioethics Commission. Patients enrolled to the study suffered from severe-to-profound hearing loss and were classified according to Prof. H. Skarżyński *partial deafness treatment (PDT) classification* into two groups: *partial deafness treatment-electrical* stimulation (PDT-EC) and *partial deafness treatment-electroacoustic* stimulation (PDT-EAS) (**Figure 3**) [20, 21].

Inclusion and exclusion criteria were in accordance with the consensus of the international *HEARRING* group on hearing preservation in cochlear implant. Study eligibility criteria included participants ≥18 years of age with a cochlear duct length of ≥27.1 (measured by computer tomography), with:


Exclusion criteria included suffering from severe diseases when the steroid treatment could worsen the patient's condition or when there would be a possibility of interaction between medication intake by patients and steroids. Nonparametric tests were used in the study due to discrepancies in the number of participants between all subgroups, small number of participants in the study, and violation of normal distribution of pure tone audiometry results [18].
