Comparison of electrode impedance measures between a dexamethasone-eluting and standard Cochlear™ Contour Advance® electrode in adult cochlear implant recipients
Introduction
Electrode impedances are measured as part of routine clinical practice during the programming procedure for cochlear implant devices, primarily to confirm normal electrode function. There is increasing evidence that lower electrode impedance post-surgery is indicative of a reduction in the post-surgical cascade of inflammation, fibrosis and osteoneogenesis. Such evidence primarily stems from research with steroid-eluting electrode arrays, which report reduction in infiltration of inflammatory cells to the cochlear following implantation (Farhadi et al., 2013), reduction in fibrotic tissue (Bas et al., 2016; Wilk et al., 2016; Wrzeszcz et al., 2015), a reduction in electrode impedance (Bas et al., 2016; Wilk et al., 2016), and reduction in osteoneogenesis (Chambers et al., 2019). Additionally, use of steroid-eluting electrode arrays has been shown to protect against spiral ganglion neuron loss (Bas et al., 2016; Chambers et al., 2019; Scheper et al., 2017).
A number of pre-clinical studies have investigated the impact of steroid elution on electrode impedance measures. Bas et al. (2016) reported a gradual increase in impedance (from approximately 8 to 23 kOhm) over the course of three months for a standard non-eluting cochlear implant electrode array, which was reduced or blocked in the presence of 0.1%, 1% and 10% of dexamethasone base. In that study, the arrays were only briefly stimulated at one, three, seven, 14, 30, 60 and 90 days, rather than daily as would be expected in a clinical scenario. Wilk et al. (2016) also examined impedance change over the course of 3 months, comparing a non-eluting array with a 1% and 10% dexamethasone-eluting array, with electrodes stimulated for 1 h once weekly. As for the Bas et al. (2016) study, electrode impedance was significantly lower for the dexamethasone-eluting arrays compared to the non-eluting array at three months post-implantation. In addition, this study demonstrated a moderate correlation between fibrosis and electrode impedance, with the reduction of both in the presence of dexamethasone, similar to the previously reported association between intracochlear fibrotic tissue response post-implantation and electrode impedance measures (Tykocinski et al., 2005, 2001).
In addition to the pre-clinical investigations, the impact of local steroid administration on electrode impedance in cochlear implant recipients has been examined clinically. Early investigations indicated that local steroid delivery at the time of implantation could reduce electrode impedance in adult (Enticott et al., 2011; Paasche et al., 2009) and pediatric populations (De Ceulaer et al., 2003). De Ceulaer et al. (2003) found impedances in the steroid groups were significantly lower than in the non-steroid groups two months post-surgery (approximately 1 kOhm), however whether this was maintained to 12 months depended on the electrode type used (Straight or Contour®). Paasche et al. (2009) observed a significant difference in impedance between control and steroid groups at three months (of approximately 2 kOhm), although this effect did not reach statistical significance at three years post-surgery. It was noted that the steroid effect was greater on the basal and middle electrodes. It is of interest to note that electrode impedances reduced over time in both the steroid and the control groups. More recently a double-blind randomized placebo-controlled trial showed a small but statistically significant reduction in electrode impedances, by 1–2 kOhm on the middle array electrode contacts, between one and 12 months after surgery when topical methylprednisolone was applied to the round window during surgery (Enticott et al., 2011). However there are challenges with local steroid application as the time taken for diffusion into the perilymph is too slow for its clinical application during surgery (Chang et al., 2009), and recent pharmacokinetic modelling suggests that dexamethasone will be eliminated before it reaches the apex of the cochlea (Salt and Plontke, 2018).
Elution of corticosteroids from the implanted electrode array provides a clinically viable alternative to previously tested topical or systemic routes of administration and has the additional benefit of enabling a prolonged delivery of the drug directly into the cochlea. The viability and safety of steroid elution from cochlear implant electrodes has previously been reported in a number of pre-clinical studies (Astolfi et al., 2016; Bas et al., 2016; Douchement et al., 2015; Eshraghi et al., 2011; Farhadi et al., 2013; Liu et al., 2015; Nguyen et al., 2015; Niedermeier et al., 2012; Stathopoulos et al., 2015, 2014; Wilk et al., 2016).
This is a first-time-in-human study of a dexamethasone-eluting investigational electrode array. The effect of dexamethasone elution on electrode impedances, from the time of cochlear implant surgery to two years post-implantation, was examined. A comparison of the pattern of electrode impedance for the drug-eluting electrode array to the pattern for a standard electrode array of the same design was conducted.
Section snippets
Investigational device
The drug-eluting electrode (DEE) array is based on the standard commercially available CI24RE(CA) cochlear implant electrode array, augmented with 40% w/w Dexamethasone in Liquid Silicone Rubber (Nusil MED1-4234) within a segment (“back-strap”) of the intracochlear electrode and the electrode array tip (refer Fig. 1). In all other aspects, the investigational device is identical in design to the Contour Advance array, with equivalence of form, fit and function verified in pre-clinical in-vitro
Impedance MP1+2
Estimated marginal mean MP1+2 impedance measures are shown across time and electrode region for Control and DEE groups (Fig. 2). Significant differences between group mean impedance values at different time points are indicated on the graph as asterisks (∗p < 0.05, ∗∗p < 0.01 and ∗∗∗p < 0.001). The group mean impedance averaged across all electrodes and time points was significantly lower for DEE than for the Control group (F (1, 24.16) = 40.6, p < 0.0001), with mean values of 5.6 and 8.9 kOhm
Discussion
Both conventional (MP1+2) and 4-point impedances were consistently lower in the interventional device over the two year observational period. For MP1+2 impedance, the magnitude of the steroid effect of approximately 2 kOhms, was similar to that described by Paasche et al. (2009) after the basal turn of the cochlea was irrigated with triamcinolone prior to electrode insertion. However, in the present study this effect was maintained for the duration of the period of observation, while after
Conclusion
This study measured electrode impedances in subjects implanted with a dexamethasone-eluting electrode array compared with a control group implanted with an otherwise identical standard array. A significant difference in the pattern of group mean impedance values between devices was observed, with lower impedance for the dexamethasone-eluting device. While there were potentially confounding effects relating to differences in the rate of adoption of each of the surgical techniques between the
CRediT authorship contribution statement
Robert Briggs: Investigation. Stephen O ’Leary: Conceptualization, Investigation, Writing - original draft, Writing - review & editing. Catherine Birman: Investigation. Kerrie Plant: Conceptualization, Methodology, Project administration, Formal analysis. Ruth English: Project administration, Formal analysis, Writing - original draft. Pamela Dawson: Formal analysis, Writing - original draft. Frank Risi: Conceptualization, Resources. Jason Gavrilis: Investigation, Formal analysis. Karina Needham:
Acknowledgements
The authors would like to thank the subjects who participated in the study, and the participating cochlear implant centres and their staff for supporting the study. The authors would also like to thank Leanne Babic who was responsible for audiological data collection at the Sydney Cochlear Implant Centre, and the surgeons Melville Da Cruz, Richard Kennedy, Claire Iseli, Simon Ellul, Simone Boardman, and Michael Tykocynski who contributed through implantation of the Control group subjects.
We
References (46)
- et al.
Cochlear implant and inflammation reaction: safety study of a new steroid-eluting electrode
Hear. Res.
(2016) - et al.
Electrode array-eluted dexamethasone protects against electrode insertion trauma induced hearing and hair cell losses, damage to neural elements, increases in impedance and fibrosis: a dose response study
Hear. Res.
(2016) - et al.
Factors influencing the efficacy of round window dexamethasone protection of residual hearing post-cochlear implant surgery
Hear. Res.
(2009) - et al.
Predicting the effect of post-implant cochlear fibrosis on residual hearing
Hear. Res.
(2005) - et al.
Effects of a dexamethasone-releasing implant on cochleae: a functional, morphological and pharmacokinetic study
Hear. Res.
(2015) - et al.
Relations between cochlear histopathology and hearing loss in experimental cochlear implantation
Hear. Res.
(2013) - et al.
Delayed loss of hearing after hearing preservation cochlear implantation: human temporal bone pathology and implications for etiology
Hear. Res.
(2016) - et al.
Pharmacokinetic principles in the inner ear: influence of drug properties on intratympanic applications
Hear. Res.
(2018) - et al.
Endolymphatic hydrops is prevalent in the first weeks following cochlear implantation
Hearing Research
(2015) - et al.
Chronic electrical stimulation of the auditory nerve using high surface area (HiQ) platinum electrodes
Hear. Res.
(2001)
Four-point impedance as a biomarker for bleeding during cochlear implantation
Sci. Rep.
Intratympanic versus intravenous delivery of methylprednisolone to cochlear perilymph
Otol. Neurotol.
Intratympanic versus intravenous delivery of dexamethasone and dexamethasone sodium phosphate to cochlear perilymph
Otol. Neurotol.
Electrode impedance in adults and children using the Nucleus 24 cochlear implant system
Cochlear Implants Int.
Protecting against electrode insertion trauma using dexamethasone
Cochlear Implants Int.
The effect of systemic steroid on hearing preservation after cochlear implantation via round window approach: a Guinea pig model
Otol. Neurotol.
Intracochlear tPA infusion may reduce fibrosis caused by cochlear implantation surgery
Acta Otolaryngol.
Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids
Clin. Pharmacokinet.
Long-term evaluation of the effect of intracochlear steroid deposition on electrode impedance in cochlear implant patients
Otol. Neurotol.
Dexamethasone eluting electrodes for cochlear implantation: effect on residual hearing
Cochlear Implants Int.
Methylprednisolone applied directly to the round window reduces dizziness after cochlear implantation: a randomized clinical trial
Audiol. Neurotol.
Local drug delivery to conserve hearing: mechanisms of action of eluted dexamethasone within the cochlea
Cochlear Implants Int.
Dexamethasone eluting cochlear implant: histological study in animal model
Cochlear Implants Int.
Cited by (30)
Towards the optimization of drug delivery to the cochlear apex: Influence of polymer and drug selection in biodegradable intracochlear implants
2023, International Journal of PharmaceuticsAnimal Models of Hearing Loss after Cochlear Implantation and Electrical Stimulation
2022, Hearing ResearchCitation Excerpt :Additional recommendations include the use of non-ototoxic antibiotics and analgesics if indicated for surgical recovery. The effect of extended or topical steroid administration on hearing preservation has been inconsistent across human studies (Briggs et al. 2020, Cho et al., 2016; Skarżyńska et al., 2018; Sweeney et al., 2015). However, dexamethasone is routinely administered at the time of surgery for post-anesthetic anti-emetic purposes in human patients.
Therapeutics for hearing preservation and improvement of patient outcomes in cochlear implantation—Progress and possibilities
2022, Hearing ResearchCitation Excerpt :These studies vary widely on key experimental details including method, metrics, model, and duration which make comparison challenging. For example, some earlier studies included dexamethasone in acetate form (Stathopoulos et al., 2014), while later studies apply dexamethasone base which has more favourable pharmacokinetics when administered via intracochlear route (Ahmadi et al., 2019; Astolfi et al., 2016; Bas et al., 2016; Briggs et al., 2020; Eshraghi et al., 2019; Manrique-Huarte et al., 2020; Needham et al., 2020; Wilk et al., 2016). While the guinea pig is most often the animal model of choice, published studies exploring long-term dexamethasone eluting electrode arrays to-date have utilised rat, gerbil, or macaque.
Systemic methylprednisolone for hearing preservation during cochlear implant surgery: A double blinded placebo-controlled trial
2021, Hearing ResearchCitation Excerpt :Injection of triamcinolone acetonide into the basal turn of the cochlea before implantation has been associated with lower impedances for up to 4 years after surgery (Paasche et al., 2006; Paasche et al., 2009). In a recent RCT, we have shown that elution of dexamethasone base from a cochlear implant with a perimodiolar array reduces impedances for up to 24 months following implantation (Briggs et al., 2020); the effects on impedance were larger than in any other study to date. It isn't yet clear how locally administered steroids act to reduce electrode impedance, although our recent observation that steroid-elution not only reduces monopolar impedances, but also four-point impedance (Briggs et al., 2020) supports the notion that steroids may be reducing intracochlear fibrosis, and thus lowering the bulk impedance in the vicinity of electrodes.