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Address for correspondence : Yee-Hyuk Kim, MD, Department of Otorhinolaryngology-Head and Neck Surgery, Catholic University of Daegu School of Medicine, 3056-6 Daemyeong 4-dong, Nam-gu, Daegu 705-718, Korea
Tel : +82-53-650-3189, Fax : +82-53-650-4533, E-mail : corin9525@hanmail.net
Introduction
Sudden sensorineural hearing loss (SSNHL) is considered as an otologic emergency. Evaluation of treatments has been hampered by the low incidence of SSNHL, unknown natural history and the tendency for spontaneous hearing recovery (30-60%).1) The spontaneous hearing improvement in untreated patients usually occurs within 2 weeks after the onset of hearing loss.2) After 2 weeks of the onset of hearing loss, it becomes difficult to expect a spontaneous recovery. The current treatment of choice for hearing loss is either oral or intravenous administration of systemic steroids. However, the effectiveness of steroids in the treatment of idiopathic SSNHL still remains unproven.3) Treatment modalities that have been tried include the use of combination of corticosteroids, vasodilators, anti-viral agents, diuretics, hyperbaric oxygen, stellate ganglion block and low-salt diet.3)
Intratympanic steroids are being increasingly used as a therapeutic option for SSNHL because of the advantages of intratympanic steroid injection like, nil occurrences of systemic effects of steroid treatment and increase in the amount of steroid entering the inner ear when compared to systemic injections. In particular, intratympanic steroids have been shown to be effective as a salvage treatment for SSNHL patients, who had no relief from the initial systemic treatment.4,5,6)
Endolymphatic dexamethasone level shows the highest concentration within 1-2 hours after intratympanic dexamethasone injection and then there is a sharp reduction.7) We consider that it is useful to maintain a high concentration of dexamethasone in the endolymph by highly frequent intratympanic steroid injection (ITSI) therapy. The purpose of this study was to compare the efficacy of systemic steroid therapy with systemic combined high frequency ITSI therapy.
Subjects and Methods
Study design and patients
The study included hospitalized patients that were diagnosed with SSNHL between August 2008 and January 2010. The diagnostic criteria for SSNHL were the acute onset of hearing loss of 30 dB or more over at least three contiguous audiometric frequencies, which may have occurred within 3 days. The treatments were initiated within 7 days after the occurrence of SSNHL.
A total of 46 SSNHL patients were divided into 2 different treatment groups on a random basis. One group (systemic steroid IV group, 27 patients) was treated with systemic dexamethasone therapy and the other group (combined ITSI group, 19 patients) was treated with systemic dexamethasone and frequent intratympanic dexamethasone injection. In the systemic steroid IV group, dexamethasone was administered intravenously for 5 days followed by tapered doses orally for 10 days. In the combined ITSI group, intratympanic dexamethasone was administered 5 times per day for 5 consecutive days (from 9 AM to 9 PM at intervals of 3 hours) in addition to intravenous dexamethasone administration. Informed consent was obtained from every individual study subject.
All the patients underwent medical history, physical and laboratory examinations and brain magnetic resonance image MRI scanning. Subjects with medical or central nervous system conditions, including syphilis, chronic renal disease, cardiovascular disease and retrocochlear lesion were excluded from the study. Subjects with true whirling type vertigo, family history of hearing loss, history of fluctuating hearing loss, head trauma and otologic surgery were also excluded from the investigation.
Treatment protocol
All the patients in both the groups were hospitalized for 5 days and treated with intravenous dexamethasone (10 mg) (dexamethasone®, Jeil Pharm, Seoul, Korea) for 5 days and subsequently with oral methylprednisolone (Methylon®, 4 mg/1T, KunWha Pharm, Seoul, Korea) for 10 days in tapered doses (48 mg, 40 mg, 32 mg, 24 mg, each for 2 days decreasing by 8 mg each 2 day, and 12 mg at the last 2 days), after which the patients were discharged from the hospital. All the patients received carbogen (5%
CO2, 95% O2) inhalation therapy, low-salt diet, rheo-macrodex (Dextran®, DaiHan Pharm, Seoul, Korea), 400 mg of pentoxifylline (Trental®, HanDok Pharm, Seoul, Korea), 5.9 mg of flunarizine (Sibelium®, Janssen Korea, Seoul, Korea) and stellate ganglion block. In combined ITIS group, the patients were treated with intratympanic de-xamethasone injection in addition to the above-mentioned treatment. All the patients of combined ITIS group underwent ventilation tube insertion at the time of admission under topical anesthesia with 10% xylocaine spray. With the patient in the supine position and with the head tilted 45° to the healthy side, approximately 0.3 mL of 5 mg/mL dexamethasone (dexamethasone®, Jeil Pharm, Seoul, Korea) was instilled using a 25-gauge spinal needle through the ventilation tube. During this procedure, the patients were instructed to avoid swallowing or speaking for 20 minutes. The ventilation tube was extracted at the first visit to the outpatient department.
Measurement of auditory function and statistics
Pure tone audiograms were obtained before initiation of treatment and on every single day during the hospitalization. During the follow-up, hearing was assessed at 15 days, 4 weeks, and 8 weeks after the initiation of treatment. Hearing levels were expressed as the average of air conduction thresholds at 500, 1,000, 2,000, and 4,000 Hz and
Siegel's criteria8) was employed to assess any improvements in hearing. Statistically significant differences were tested by the independent t-test with
p<0.05 defined as the cutoff value for statistical significance (Table 1).
Results
Typically, 46 patients were included in the analysis, and were divided into the systemic steroid IV group (27 patients) and the combined ITSI group (19 patients). Both the groups matched well with respect to age, sex, site of SSNHL, initial pure tone audiometry, and period from onset of SSNHL to their first visit to the hospital (Table 2).
The overall rate of hearing improvement was 74.0% (20/27 patients) in the systemic steroid IV group and 73.6% (14/19 patients) in the combined ITSI group. The gain in hearing improvement was 33.0 dB in the systemic steroid IV group and 41.5 dB in the combined ITSI group. There were no significant differences in hearing improvement
(p=0.476) in both the groups (Table 3).
Moreover, there were no significant complications during or after ITSI, including tympanic membrane perforation, otitis media, vertigo and tinnitus.
Discussion
The mainstay of treatment for sudden sensorineural hearing loss is a conventional systemic steroid therapy, although its efficacy has not yet been proven3) and recently there have been great advancements in the clinical studies with respect to intratympanic steroid injections.
Intratympanic steroid injections have various advantages.9) The procedure can be done readily under local anesthesia in an outpatient department and the complications of systemic steroid therapy such as, immunosuppression, weight gain, osteoporosis, avascular necrosis of femoral neck, mood swings, and skin and endocrine disturbances can be avoided because of very less systemic absorption.10) Intratympanic steroid injections are locally directed, only towards the affected ear and significantly maintains the levels of steroids in the inner ear when compared to the systemic routes of administration.7)
However, there are also some disadvantages associated with ITSI such as pain, transient vertigo, rarely tympanic membrane perforation and otitis media. Nevertheless, tympanic membrane perforation and otitis media was not observed in the present study.
So far, the known facts about the absorption and metabolism of steroids in the inner ear are that the injected steroids pass through the round window and act on the steroid receptors in the inner ear and that the concentration of the endolymph is higher than that of the perilymph. Also, the concentration of the perilymph is significantly higher than that of systemic steroid therapy.7,11) The injected steroids that have passed through the round window can be observed within 15 minutes of injection, but cannot be observed after 24 hours, which means that the functioning time is limited to 24 hours12) and the maximum concentration is demonstrated within 1-2 hours of injection, which then reduces rapidly in the cochlea.7)
Hydrocortisone, methylprednisolone and dexamethasone are most commonly used and the study of Parnes, et al.7) using guinea pigs has reported even distributions of three different steroids in the perilymph regardless of the routes of administration, but, methylprednisolone lasted for a longer time in the perilymph when compared to hydrocortisone and dexamethasone. Park, et al.13) compared the efficacy of the additional methylprednisolone and dexamethasone intratympanic injections with the combined drug therapies and reported that there was a significant improvement in the hearing of the methylpredni-solone injection group, though it was more painful than dexamethasone injection. Consequently, in the present study, because of less painfulness of dexamethasone injection, the associated problems of less efficacy than methylprednisolone and less time of lasting were solved based on multiple applications.
In a number of studies on intratympanic injections, steroids were injected either once a day or 4-5 times a week, but the present report questioned the effect of multiple injections per day considering the metabolism of steroids. As can be seen from the results, there was no difference between the outcome of the systemic steroids therapies and that of the combined therapies of systemic steroids therapies and intratympanic steroids injections.
The results from the present study resembled the results from the study of Ahn, et al.14) which stated that the outcome of systemic steroids therapy was not different from the outcomes of the combined therapy of intratympanic steroids injection once a day in addition to the systemic steroids therapy. Conversely, Battaglia, et al.15) reported that the combined therapy exhibited better outcomes.
It could be questioned as why the outcomes were different despite the fact that Ahn, et al.14) injected one dose of steroids every other day, whereas Battaglia, et al.15) injected one dose a week. There are a few points, which are different in both the studies. First of all, there was a difference in the control groups in both the studies, the control group of Battaglia was too small to be compared. Secondarily, the combined therapy was given only for the first 5 days as a primary therapy in the study of Ahn, et al.14) while Battaglia, et al.15) administered the intratympanic steroids injection once a week for 4 consecutive weeks. In the present study, multiple doses of intratympanic steroid injections were given on every single day for the first 5 days of admission.
It could be assumed that long-term steroids therapies may be required in the cases of sudden hearing loss with due consideration of all the numerous previous studies that have reported satisfactory outcomes from the salvage therapy, and the intratympanic steroids injections when systemic steroids therapies have failed.4,5,6) However, the efficacy of the salvage therapy should be interpreted cautiously. because the outcomes of the salvage therapy also varied depending on the duration of the therapy and the point of commencement. In view of the metabolism of steroids within the inner ear, the steroid in the inner ear cannot be detected in 24 hours.9) Therefore, it seems doubtful whether once a week of steroids injection is really an effective way of treatment. Also, when the salvage therapy is initiated early, the interpretation of the outcome can fall under natural improvement and can lead to confusion.9)
The major drawback of the present study was the smaller size of the control group and further studies with bigger control groups are necessary, but the outcome of the therapy in this study, which was to maintain a high level of steroid concentration considering its pharmacokinetics, showed no further improvement when compared to the existing therapies. However, a method that can maintain steroid concentration for the long-term is under research and when it is devised, the efficacy of the treatment will be expected to improve.16,17)
Conclusion
The therapeutic effect of a combination of highly frequently administered intratympanic dexamethasone and systemic steroid therapy was not superior to only systemic steroid injection therapy.
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