Acta Oto-Laryngologica

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Evaluation of prednisolone and prednisolone

sodium succinate concentrations in human
plasma and inner ear perilymph during cochlear
implantation 24 h after intratympanic injection

Edoardo Covelli, Chiara Filippi, Roberto Filipo, Giancarlo Palumbo, Carmen

Di Giovanni, Haitham H. Elfarargy & Maurizio Barbara

To cite this article: Edoardo Covelli, Chiara Filippi, Roberto Filipo, Giancarlo Palumbo, Carmen
Di Giovanni, Haitham H. Elfarargy & Maurizio Barbara (2022): Evaluation of prednisolone
and prednisolone sodium succinate concentrations in human plasma and inner ear perilymph
during cochlear implantation 24 h after intratympanic injection, Acta Oto-Laryngologica, DOI:
10.1080/00016489.2022.2146747

To link to this article: https://doi.org/10.1080/00016489.2022.2146747

Published online: 01 Dec 2022.

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ACTA OTO-LARYNGOLOGICA
https://doi.org/10.1080/00016489.2022.2146747

RESEARCH ARTICLE

Evaluation of prednisolone and prednisolone sodium succinate concentrations

in human plasma and inner ear perilymph during cochlear implantation
24 h after intratympanic injection
Edoardo Covellia , Chiara Filippia, Roberto Filipoa, Giancarlo Palumbob, Carmen Di Giovannic,
Haitham H. Elfarargya,d and Maurizio Barbaraa
a
Department of neuroscience, mental health, and sense organs (NEMOS), Sant’ Andrea University Hospital, Sapienza University, Rome, Italy;
b
Department of Medicine Surgery and Dentistry, University of Salerno, Fisciano, Italy; cDepartment of Pharmacy medicine, University of
Naples Federico II, Napoli, Italy; dOtorhinolaryngology Department, Kafrelsheikh University, Kafrelsheikh, Egypt

ABSTRACT ARTICLE HISTORY

Background: The use of intratympanic (IT) steroids has drastically increased over the past 10–15 years Received 9 September 2022
to manage many otological pathologies. Revised 28 October 2022
Objectives: This study aimed to compare the concentrations of prednisolone and prednisolone Accepted 30 October 2022
sodium succinate (SS) in the plasma and inner ear perilymph of participants who underwent cochlear
KEYWORDS
implantation 24 h after IT injection. Cochlear implant;
Materials and methods: It was a prospective comparative randomized study. Twenty participants intratympanic injection;
received an IT injection of prednisolone SS
24 h before the cochlear implantation. The other five par- perilymph; prednisolone;
ticipants received an IT saline injection and represented the control group. Perilymph and blood were round window membrane
sampled during the cochlear implantation surgery.
Results: Both prednisolone and prednisolone SS were still present in perilymph
24 h after the IT
administration. Only prednisolone was present in the blood plasma of seven participants (35%).
Conclusion: IT injection of prednisolone SS resulted in high perilymph concentrations of prednisolone
and prednisolone SS, which could stay in the perilymph for at least 24 h. Using a mini-endoscope dur-
ing the IT injection may effectively detect barriers infront of the round window membrane, increasing
the drug concentration in the inner ear.
Significance: IT injection is an effective method for delivering prednisolone to the inner ear.

Introduction concentration of methylprednisolone and dexamethasone in

The use of intratympanic (IT) steroids has drastically
increased over the past 10–15 years to manage many oto-
logical pathologies such as idiopathic sudden sensorineural
hearing loss, either as first-line therapy or salvage therapy,
autoimmune inner ear disorders, and Meniere’s disease [1,2].
IT steroids administration can reduce systemic drug con-
centration and side effects while delivering high doses to the
inner ear [3]. Although IT injection is the most suitable way
to achieve high steroid concentrations in the perilymph with
minimal systemic side effects, the drug’s concentration, dur-
ation, and efficacy are challenging to evaluate [4,5]. In this
regard, among the factors that can be considered for a dif-
ferent outcome, one should assess the presence of anatom-
ical barriers like a plug or false membranes, loss of drug
through the Eustachian tube, and, finally, variable pharma-
cokinetics in the perilymph [6]. In 2000, a study on forty
guinea pigs found that the concentration of dexamethasone
in the perilymph after IT injection was higher than that
obtained after intravenous (IV) injection [7]. Bird et al.
[8,9] published the first two works that evaluated the
human perilymph and plasma after IT injection and IV
administration. They have shown that the IT administration
of corticosteroids results in a much higher concentration of
drugs in the perilymph and a lower concentration in the
plasma than after IV administration. These studies’ sampling
time was 1–3 h after steroid treatment.
Prednisolone is the active metabolite of its prodrug pred-
nisolone SS. Prednisolone is thought to be metabolized by
cytochrome P450 enzyme, specifically CYP3A4. The main
metabolic pathways are 6-hydroxylation by CYP3A4 and
reduction in the 20-ketone group of prednisolone. The
excretion of prednisolone occurs by urination, and roughly
20% of the dose gets excreted in its unchanged form [10].
The present study aimed to compare the concentrations
of prednisolone Sodium Succinate (SS) and prednisolone,
the prodrug and the active form, in perilymph and plasma
of cochlear implant surgery recipients, where the steroid
was administered intratympanically 24 h before the surgical
procedure. This study aimed to assess the effectiveness of
the IT injection as a drug delivery method into the
inner ear.

CONTACT Edoardo Covelli edoardo.covelli@uniroma1.it NESMOS Department, Sant Andrea Hospital, Faculty of Medicine and Psychology, Sapienza
University, Rome 00189, Italy
ß 2022 Acta Oto-Laryngologica AB (Ltd)
2 E. COVELLI ET AL.
Materials and methods
Ethics
The preoperative participants’ signed informed consent was
obtained after the discussion of the procedure of the IT
injection and perilymph and blood samples collection. All
the maneuvers involved in this study followed the principles
of the Declaration of Helsinki and were approved by the
institution review board of the Umberto I Hospital of
Rome, Italy (reference number 726/10).
Sample size calculation
The total number of CI surgeries performed during the
study period was 31. So, the sample size should be at least
24 patients with a 95% confidence interval and a 10% mar-
gin of error.
Subjects
This prospective case-series comparative randomized study
involved 25 participants who were candidates for cochlear
implantation because of bilateral profound sensorineural
hearing loss. All the participants were above 18 years old. All
the participants did not receive any corticosteroids (systemic
or local) in the previous 6 months. Patients with chronic otitis
media or inner ear anomalies were not included. The enrol-
ment of the cases was from September 2021 to June 2022.
Participants were randomized into two groups; the first group
(group A) included 20 participants who received an IT injec-
tion of prednisolone SS preoperatively, representing the study
group. At the same time, the other group (group B) involved
five cases who received preoperatively an IT injection of
saline representing the control group. A computerized
numerical system was used for the case randomization.
IT injection
The IT injection was performed 24 h before cochlear implant-
ation and under local anesthesia. A small cotton gauze soaked
with lidocaine was inserted into the external auditory canal
to be in touch with the tympanic membrane. It was left in
this position for 15 min before the maneuver. Using the
microscope, the cotton was removed, and the patient was in
the recumbent position with his head 45 from the surgeon.
The IT injection was performed in the anterior–inferior
quadrant of the tympanic membrane using a 27-gauge needle.
The patient was asked to stay in this position for 30 min
without swallowing. All the procedures were done under
complete sterilization. In group A, 25 mg of prednisolone SS
dissolved in 0.4 mL of saline was injected. While in group B,
only 0.4 mL of saline was injected.
Sampling
The posterior tympanotomy approach was used to access
the round window for the electrode insertion during the
cochlear implantation. Posterior tympanotomy was done by
opening the facial recess by drilling the bone between the
mastoid portion of the facial nerve, chorda tympani nerve,
and the incus buttress to reach the middle ear exposing the
round window. Our target was an exposed round window
membrane, so drilling the round wind niche or removing
any fibrosis or plugs hid the true round window membrane
was performed. Irrigation with saline was done to remove
any debris. Then, the perilymph was collected using a 27-
gauge microsyringe needle inserted through the exposed
true round window membrane. At the same time, a venous
blood sample was collected from the patient arm vein.
Essay
Prednisolone SS and prednisolone concentrations in plasma
and perilymph were analyzed, as reported by Zhang, with
some minor differences [11]. Briefly, 100 mL of 0.9 NaCl
solution were added to 5 mg of serum or 50 mL of peri-
lymph. Then 25 mL of 1.0 M nitric acid was added to acidify
the sample. The proteins were precipitated with 200 mL of
the mixture of acetonitrile and methanol (4:1). Samples
were centrifuged at 16000 rpm with the temperature kept
below 4  C. After centrifugation, 50 mL of supernatant was
mixed with 200 mL of mobile phase (5 mM ammonium acet-
ate and methanol, 50:50), and 10 mL of the mixture was
injected into the liquid chromatography/tandem mass spec-
trometry system (LCMS 8040, Shimadzu, Kyoto).
Prednisolone SS and prednisolone were separated on a
Kinetex XB-C18 (Phenomenex, Torrence) column 50 mm 
2.10 mm  2.6 mm using isocratic elution with 5 mM ammo-
nium acetate and methanol (60:40). The flow rate was
350 mL/min. The three compounds were detected using elec-
trospray ionization in the positive mode. The precursor-to-
product ion transitions were monitored for Prednisolone SS
and prednisolone and were (m/z) 461.30!325.00 and
361.10!343.05, respectively. The lower limit of quantifica-
tion was 0.1 mg/L, standard curves were linear up to 500 mg/
L (r > 0.999), bias was <10%, and intraday coefficients of
variation were <10%. Figure1 shows a standard HPLC-MS/
MS extracted-ion chromatogram, where HPLC-MS/MS was
the acronym of high-performance liquid chromatography
(interfaced with tandem) mass spectrometry. This was an
advanced hyphenate instrumental analytical technique,
where liquid chromatography’s high separation power is
combined with mass spectrometry’s extremely high identifi-
cation capacity. Liquid chromatography is based on the
slightly different interaction of each component of a mix-
ture, even complex, with an adsorbent material contained in
a column, through which the sample is forced using a solv-
ent (‘eluent’). With an appropriate choice of the column,
the solvent, and the operating conditions, this procedure
causes different flow rates for each component, leading to
the separation of the analytes. As this latter flow out of the
column, they are adequately conveyed in a mass spectrom-
eter where, said in a nutshell, the molecules are fragmented
into ions and separated according to the charge-to-mass
ratio; in particular, we have MS/MS when two or more

mass analyzers are coupled together to increase their ability
to distinguish even chemically very similar samples. On a
typical HPLC-MS/MS extracted-ion chromatogram on the
Y-axis, the intensity was reported, in arbitrary units, of the
signal observed at chosen mass-to-charge value for the ions
derived, as explained above, from prednisolone SS and pred-
nisolone (i.e. for the particular molecule) which depends on
the concentration of the analyte. At the same time, on the
X-axis, the retention time (RT) in minutes, i.e. the time the
molecule takes, once injected, to reach the detector, which is
correlated to the molecule’s identity, can be read. This
makes HPLC-MS/MS the technique for the quality–quanti-
tative analysis of thermolabile molecules, such as proteins,
peptides, and drugs (Figure 1).
Pharmacokinetic evaluation
The pharmacokinetic evaluation of prednisolone SS and
prednisolone was performed according to Salt et al. [12].
Calculated ADME (Absorption, Distribution, Metabolism,
and Excretion) properties described by Salt et al. evidenced
that adding polar groups to the methylprednisolone drug,
such as the phosphate or succinate, greatly enhanced aque-
ous solubility by increasing TPSA/A2 (a measure of the
topological polar surface area of the molecule). This way,
adding the succinate or phosphate groups increases the
delivered drug amount.
Statistical analysis
The statistical analysis was performed using the SPSS v28
(IBM# Inc., Chicago, IL, USA). The non-paired t-test com-
pared the independent numerical variables. At the same
time, the numerical dependent variables were compared by
Figure 1. Standard HPLC-MS/MS extracted-ion chromatogram.
ACTA OTO-LARYNGOLOGICA 3
the paired t-test. The v2 test was used to compare categor-
ical variables. Statistical significance was present if the p-
value was <.05.
Results
This study included 25 cases, 14 (56%) males and 11(44%)
females. Participants were randomized into two groups; the
first group (study group) included 20 participants who
received an IT injection of prednisolone SS 24 h before the
cochlear implantation, while the other group, the control
group, included five participants who received an IT injec-
tion of saline. The age ranged from 36 to 67 years, with a
mean of 52.36 ± 9.23. Sixteen (64%) participants received the
IT injection on the right side, while nine (36%) cases
received the IT injection on the left side. There were no
statistically significant differences between both regarding
the age, sex, and the side of the IT injection, as the p-values
were >.05 (Table 1).
In the control group, there was no prednisolone or pred-
nisolone SS in the plasma or the þ perilymph of the inner
ear. Regarding the study group, prednisolone SS was present
only in the inner ear perilymph of all cases and was not
detected in the plasma. In contrast, prednisolone was pre-
sent in the inner ear perilymph of all participants and the
plasma of seven (35%) cases. Furthermore, the concentra-
tion of the prednisolone SS in the inner ear perilymph
(4.99 ± 4.73 mg/L) was statistically higher than the inner ear
perilymph of the prednisolone (1.22 ± 1.79) as the p-value
was < .001 (Figure 2; Table 2).
Round window examination during the cochlear implant
surgery revealed a normal RW in 20 (80%) cases, with 16
participants in the study group and four in the control
group. In comparison, there was an abnormality of the RW
4 E. COVELLI ET AL.

Table 1. Comparison between the study group (steroids group) and the control group (saline group).
Steroids N ¼ 20/25 (80%) Saline N ¼ 5/25 (20%) p-Value
Age (years) Minimum 39 36 .118
Maximum 67 67
Mean ± SD 52.1 ± 8.45 53.4 ± 13.05
Sex Male 13/20 (65%) 1/5 (20%) .096
Female 7/20 (35%) 4/5 (80%)
Side Right 13/20 (65%) 3/5 (60%) .609
Left 7/20 (35%) 2/5 (40%)
RWM Normal 16/20 (80%) 4/5 (80%) .748
Abnormal 4/20 (20%) 1/5 (20%)
Prednisolone SS concentration in plasma (mg/L) Minimum 0 0 1
Maximum 0 0
Mean ± SD 0 0
Prednisolone SS concentration in the perilymph (mg/L) Minimum 0 0 <.001
Maximum 14.65 0
Mean ± SD 4.99 ± 4.73 0
Prednisolone concentration in plasma (mg/L) Minimum 0 0 .097
Maximum 5.61 0
Mean ± SD 0.61 ± 1.38 0
Prednisolone concentration in the perilymph (mg/L) Minimum 0 0 .034
Maximum 7.28 0
Mean ± SD 1.22 ± 1.79 0
SD: standard deviation; RWM: round window membrane; SS: sodium succinate.
Significant as the p-value < .05.

Figure 2. Comparison between the steroids group’s prednisolone and prednisolone SS concentrations.

in five (20%) participants, four cases in the study group,
and one patient in the control group. The abnormalities of
the RW included a false RW membrane in four cases and a
plug with fibrosis in one case.
In the study group, the included cases were divided into
two subgroups according to the normality of the round win-
dow. Statistically significant differences were found regard-
ing the concentrations of both prednisolone SS and
prednisolone in the inner ear perilymph of both subgroups,
as the p-values were <.05. In the case of a fibrotic plug
infront of the RW membrane, the prednisolone SS could
not reach the RW, and the concentrations of prednisolone
and prednisolone SS were zero (Table 3).
Discussion
Corticosteroids are currently used to manage idiopathic sud-
den sensorineural hearing loss and Meniere’s disease,
although evidence for their actual mechanism of action is
still poor. IT steroid use has been advocated for patients
who do not respond to initial systemic treatment or as first-
line therapy, especially when a contraindicated general prob-
lem is present [13].
One major controversy is the treatment’s timing and dur-
ation; this mainly depends on correct drug concentration
information. Since IT may also encompass complications, it
is essential to know whether or not the IT administration is
worth being repeated for several days. In this regard, studies
on the assay of perilymphatic concentration are welcome to
shed further light on this issue [14]. Corticosteroids are
known to influence target tissues after interacting with
intracellular glucocorticoid reception and alter the expres-
sion of specific target genes to produce metabolic and anti-
inflammatory effects. It is not currently known exactly how
corticosteroids impact the inner ear, but corticosteroid
receptors have been found in the cochlea of rats and
 ACTA OTO-LARYNGOLOGICA 5

Table 2. Comparison between the steroids group’s prednisolone and prednisolone SS concentrations.
Prednisolone SS Prednisolone p-Value
Concentration in plasma (mg/L) Minimum 0 0 .031
Maximum 0 5.61
Mean ± SD 0 0.61 ± 1.38
Concentration in the perilymph (mg/L) Minimum 0 0 <.001
Maximum 14.65 7.28
Mean ± SD 4.99 ± 4.73 1.22 ± 1.79
SS: sodium succinate; SD: standard deviation.
Significant as the p-value < .05.

Table 3. Comparison between the normal and abnormal RW cases of the steroids group.
Normal RW N ¼ 16/20 Abnormal RW N ¼ 4/20 p-Value
Prednisolone SS concentration in plasma (mg/L) Minimum 0 0 1
Maximum 0 0
Mean ± SD 0 0
Prednisolone SS concentration in the perilymph (mg/L) Minimum 0.41 0 .017
Maximum 14.65 0.57
Mean ± SD 6.18 ± 4.56 0.25 ± 0.24
Prednisolone concentration in plasma (mg/L) Minimum 0 0 .105
Maximum 5.61 0
Mean ± SD 0.76 ± 1.51 0
Prednisolone concentration in the perilymph (mg/L) Minimum 0.15 0 .048
Maximum 7.26 0
Mean ± SD 1.53 ± 1.89 0
SS: sodium succinate; SD: standard deviation.
Significant as the p-value < .05.

humans [15]. In experimental animal conditional, higher
concentrations of corticosteroid have been shown in peri-
lymph when administrated IT, compared with the oral, IV,
or peritoneal treatment [11].
Previous studies tried to assess the features of methyl-
prednisolone and dexamethasone in the human perilymph
extracted during cochlear implant surgery, showing that
their concentration was much more significant in the peri-
lymph than in the plasma. In 2007 Bird et al. reported peri-
lymphatic and plasma concentrations of methylprednisolone
30 min and 3 h after IT administration in two groups: one
who received an IT injection and the other IV administra-
tion [8]. In another study, the authors studied dexametha-
sone concentrations in plasma, and human perilymph after
IV and IT administration performed 30 min and 2 h before
cochlear implant surgery [9].
The present study has taken into account a longer time,
steroid administration performed
24 h before CI surgery. In
this study, we verified if, after 24 h, there was still sufficient
drug coverage and defined the optimal frequency of adminis-
tration with practical advantages in defining a clinical protocol.
For both steroid tested, i.e. prednisolone and prednisolone SS,
statistically significant evidence of higher perilymph concentra-
tion than plasma levels was found. This finding would demon-
strate that, after 24 h, high doses of cortisone could be found
in the cochlea, both as a prodrug and active drug.
Consequently, IT steroid can be administered either once a
day to increase the drug concentration or every two days since
it has been shown it was present even after 24 h.
An additional finding from our study was that in 37% of
participants, a low plasma concentration of prednisolone
was found, possibly due to accidental absorption through
the eustachian tube or gastrointestinal uptake. The present
study also reveals that IT steroids treatment could determine
systemic uptake, even at a low dosage.
Four participants (within the study group) with anatom-
ical barriers, such as round window membranes or plugs,
presented significantly reduced steroid levels as a prodrug
or active drug in the inner ear. Those features could be the
cause of the efficacy of IT steroid therapy in a small number
of participants. So, Plontke et al. [16] recommended using
the microendoscope during the IT injection to detect any
barriers in front of the RW membrane to increase efficiency
and the inner ear concentration of the intratympanically
injected drug. Moreover, Bozzato et al. [17] used a multi-
purpose mini-endoscope for the IT injection. Using this
type of endoscope not only detected the anatomic barriers
in front of the RW membrane but also could remove them
by using drilling instrumentations and irrigation through
the functioning channels. This could ensure the delivery of
the required drug to the inner ear by eliminating
these barriers.
On the other side, one of the main targets during coch-
lear implantation is hearing preservation, which may
improve postoperative outcomes. The systematic review of
Shaul C et al. [18] concluded that administering systemic or
topical glucocorticosteroids significantly improved low and
high-frequency hearing. According to our study, IT injection
of prednisolone SS 24 h before the cochlear implantation
resulted in high concentrations in the inner ear perilymph,
especially if there were no barriers in front of the RWM. So,
this can be applied as a protocol for hearing preservation
during cochlear implantation for further research.
Conclusions
It is possible to conclude that steroids, when administered
intratympanically, achieve a high perilymphatic concentra-
tion concerning the plasma levels, lasting at least 24 h. This
information could be helpful in the clinical practice for
6 E. COVELLI ET AL.
planning the therapeutical timing of an IT prednisolone
treatment for the proposed inner ear disorders. Using a
mini-endoscope during the IT injection is recommended to
detect any barrier infront of the RW membrane and remove
it, increasing the inner ear perilymph concentration of
the drug.
Author contributions
E.C. designed the work; C.F. acquired and analyzed data; R.F. acquired
and analyzed data; G.P. acquired and analyzed data; C.G. drafted,
revised, and approved the manuscript; H.H.E. drafted, revised,
approved the manuscript; M.B. agreed to be accountable for all aspects
of the work and performed the included surgeries.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Edoardo Covelli http://orcid.org/0000-0003-0863-5943
Haitham H. Elfarargy http://orcid.org/0000-0001-5303-2012
Maurizio Barbara http://orcid.org/0000-0003-0740-0384
Data availability statement
The data presented in this study are available on request from the cor-
responding author.
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