Abstract
Sudden Sensory-Neural Hearing Loss (SSNHL) is one of the most important otologic emergency. Although adding intratympanic (IT) steroids to systematic steroid may be beneficial, the exact timing of the IT injections to provide the best response needs further investigations. To compare different protocols in treting sudden sensorineural hearing loss. We performed a clinical trial study on 120 patients from October 2021 to February 2022. All patients were prescribed 1 mg/Kg daily oral prednisolone. After randomization to three groups, the control group received standard twice a week IT steroid injections in 12 days (four total injections) while intervention groups 1 and 2 received once and twice a day IT injections for ten days. Audiometric study repeated 10–14 days after the last injection and assessed based on the Siegel criteria. We used the Chi-Square, Analysis of Variance (ANOVA), Kruskal–Wallis’s tests where appropriate. The most clinical improvement was found in the standard treatment group, and group-2 had the greatest number of patients with no improvement; however, no overall significant difference was observed among the three groups (p-value: 0.066; Pearson Chi-Square). Less frequent IT injections in patients already on systemic steroids provide similar results to more frequent injections.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12070-023-03641-4.
Keywords: Sudden hearing loss, Intratympanic injection, Dexamethasone
Introduction
Sudden Sensory-Neural Hearing Loss (SSNHL) is an otolaryngology emergency that could significantly affect the patient’s quality of life if left untreated or even undertreated [1]. SSNHL is defined as an acute decrease (over 72 h) of ≥ 30 dB in three consecutive frequencies. It is mostly unilateral, and vertigo, tinnitus, and ear fullness are common accompanying symptoms. The incidence of SSNHL varies from 5 to 27 in 100,000 in the United States(US). The incidence might be an underestimation as some cases resolve spontaneously in 30–65% of cases. Although the exact etiology remains unknown, it is supposed that the two main etiologies are viral infection vascular pathologies and autoimmune disorders. Prognostic factors are age, depth of hearing loss, the interval between the symptom onset and treatment initiation and vertigo at the presentation. [2]
The management includes systemic and local steroids, antivirals, some vasodilators, hyperbaric oxygen, and other conventional therapies; however, the exact efficacy of each treatment modality is still under debate[3].The current guideline published by American academy of otolaryngology and head and neck surgery recommend systemic steroid for initial therapy but controversy remains for the use of intratympanic steroid as initial or salvage therapy [2]. Jung et al. found that the combination of systemic and local steroids provides more favorable results than systemic steroids alone [4], but whether the timing of injections influences outcomes is not elucidated yet. Herein, we aimed to assess the efficacy of intratympanic (IT) dexamethasone with different timing of the American Academy of Otolaryngology-Head and Neck Surgery protocol in patients who take systemic prednisolone.
Methods
Patient Population and Interventions
We implemented a multi-center double-blinded clinical trial study on 120 patients with SSNHL who were referred to tertiary University hospitals of Tehran and Mashhad,the biggest cities of Iran from October 2021 to February 2022. We included patients with idiopathic SSNHL (diagnosed with audiometry) as established by the American Academy of Otolaryngology-Head and Neck Surgery guideline: a decrease in hearing of 30 decibels affecting at least 3 consecutive frequencies. aged 18–60 years and symptom onset of 72 h to less than 30 days who consented to participate. Patients were excluded from the study in the presence of a previous genetic or acquired sensorineural hearing loss or anomaly of the inner ear, those previously prescribed other medications, pregnant and breastfeeding women, and those with evidence of acute or chronic otitis media. PTA was calculated as the mean of thresholds of four frequencies (500 Hz, 1000 Hz, 2000 Hz, 4000 Hz). After establishing the diagnosis based on history and audiometry findings, all patients were prescribed the standard treatment of 1 mg / Kg daily oral prednisolone. Via sealed envelopes, the eligible patients are randomized into one control group (40 participants) and two intervention groups (40 participants each). Injection of 4-mg dexamethasone sodium phosphate per dose in the middle ear cavity in the control group was performed according to the standard guidelines of the American Academy of Otolaryngology three times (every four days) in a 12-day period. The other two intervention groups were administered the same injection dose over ten days, once a day in the first intervention group (group 1) and twice a day in the second intervention group (group 2). Audiometric study repeated 10–14 days after the last injection. We used Siegel criteria to compare the audiometric studies; we also asked patients for residual vertigo at the last visit. The Ethical Committee of approved this study under the ethical code of …1399.232.
Intratympanic Injection
We used 10% Xylocaine spray to anesthetize the tympanic membrane (TM). While the patients were positioned supine and head tilted toward the other ear, dexamethasone was injected via a 25-gauged spinal needle in antroinferior quadrent of tympanic membrane. We forbid patients from swallowing and speaking for at least half an hour.
Statistical Analysis
Data were analyzed by SPSS 23 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.) software. The threshold of statistical significance is considered 0.05. We used the Analysis of Variance (ANOVA) test to compare three groups if the variables were normally distributed; otherwise, we used Kruskal–Wallis’s test.
Results
The mean age of participants of standard treatment group (twice a week injections) and intervention groups 1 (daily injection) and 2 (twice a day injections) were 52.0 ± 9.12 (mean: 52; range: 28–83), 48.0 ± 12.8 (mean: 50; range: 21–66), and 48.0 ± 11.2 (mean: 49; range: 27–64) years, respectively; with no significant difference (p-value: 0.568; Kruskal–Wallis’s test). The mean interval from symptom onset and treatment initiation for the standard treatment group and groups 1 and 2 were 11.9 ± 6.8 (mean: 14; range:1–30), 10.3 ± 7.1 (mean: 10; range: 1–27), and 11.6 ± 7.4 (mean: 12.5; range: 2–29) days, respectively; with no significant difference (p-value 0.418; Kruskal–Wallis’s test).
The frequency of vertigo before treatment initiation was not statistically significant among groups and is illustrated in Table 1. Comparing groups 1 and 2 showed a significant difference in the vertigo frequency (p-value: 0.041; Pearson Chi-Square).
Table 1.
The frequency of vertigo among patients
| Groups | Standard (Twice a week) | 1 (Once a day) | 2 (Twice a day) | p-value* | |
|---|---|---|---|---|---|
| Vertigo | Present | 14 (35%) | 12 (30%) | 21 (52.5%) | 0.096 |
| Absent | 26 (65%) | 28 (70%) | 19 (47.5%) | ||
*Chi-Square test was used for comparison
Table 2 shows the response to treatment based on the Siegel criteria plus vertigo improvement between three groups. The most clinical improvement was found in the standard treatment group, and group-2 had the greatest number of patients with no improvement; however, no overall significant difference was observed among the three groups (p-value: 0.066; Pearson Chi-Square). Vertigo improvement also showed no difference (p-value: 0.243; Pearson Chi-Square), but it should be noted that only 47 participants reported their vertigo status.
Table 2.
Response to treatment based on the Siegel criteria and vertigo improvement between three groups (the first p-value obtained from Chi-Square test on Siegel classification among three groups; the second p-value obtained from Kruskal–Wallis’s test on mean differences of total pre- and post PTA results between three groups)
| Groups | Standard (Twice a week) | 1 (Once a day) | 2 (Twice a day) | p-value* | P-value† | |
|---|---|---|---|---|---|---|
| Response to Treatment | Complete Recovery | 16 (40%) | 14 (35%) | 9 (22.5%) | 0.066 | 0.364 |
| Partial Recovery | 7 (17.5%) | 11 (27.5%) | 6 (15%) | 0.037 | ||
| Slight Improvement | 4 (10%) | 2 (5%) | 3 (7.5%) | 0.399 | ||
| No Improvement | 13 (32.5%) | 13 (32.5%) | 22 (55%) | 0.007 | ||
| Vertigo Improvement | Complete Improvement | 11 (78.6%) | 9 (75%) | 11 (54.2%) | 0.243 | |
| Partial Improvement | 3 (21.4%) | 1 (8.3%) | 8 (38.1%) | |||
| No Improvement | 0 (0%) | 2 (16.7%) | 2 (9.5%) | |||
*Chi-Square test was used for comparison of treatment response categories between groups
†Kruskal–Wallis’s test was used for comparison of the mean difference of pre- and post-PTA between groups
Table 3 shows the association between the treatment outcome and the interval from symptom onset to treatment initiation. The shorter treatment interval was significantly associated with better outcomes for the standard treatment group (p-value: 0.038), while it was insignificant in the two other intervention groups. We also evaluated the association of age and response to treatment in Table 4; None of the groups showed a significant association.
Table 3.
The association of the treatment outcome and the treatment onset interval
| Groups | Standard (Twice a week) | 1 (Once a day) | 2 (Twice a day) | p-value* | |
|---|---|---|---|---|---|
| Vertigo | Present | 14 (35%) | 12 (30%) | 21 (52.5%) | 0.096 |
| Response to Treatment | Complete Recovery | Partial Recovery | Slight Improvement | No Improvement | p-value* | |
|---|---|---|---|---|---|---|
| Groups | Standard (Twice a week) | 11.4 ± 6.5 | 7.7 ± 5.4 | 10.2 ± 6.2 | 15.5 ± 6.8 | 0.038 |
| 1 (Once a day) | 9.2 ± 7.1 | 9.9 ± 5.9 | 7.5 ± 6.4 | 12.3 ± 8.3 | 0.769 | |
| 2 (Twice a day) | 8.8 ± 5.4 | 10.5 ± 5.9 | 10.0 ± 6.1 | 13.4 ± 8.4 | 0.563 | |
*Kruskal–Wallis’s test was used for comparison
Table 4.
Response to treatment based on age
| Groups | Standard (Twice a week) | 1 (Once a day) | 2 (Twice a day) | p-value* | |
|---|---|---|---|---|---|
| Vertigo | Present | 14 (35%) | 12 (30%) | 21 (52.5%) | 0.096 |
| Groups | Treatment Response | Age | p-value* | |
|---|---|---|---|---|
| 40 ≤ | > 40 | |||
| Standard (Twice a week) | Complete Recovery | 4 (50%) | 12 (37.5%) | 0.855 |
| Partial Recovery | 0 (0%) | 7 (21.9%) | ||
| Slight Improvement | 0 (0%) | 4 (12.5%) | ||
| No Improvement | 4 (50%) | 9 (28.1%) | ||
| Total | 8 (100%) | 32 (100%) | ||
| 1 (Once a day) | Complete Recovery | 4 (50%) | 10 (31.3%) | 0.396 |
| Partial Recovery | 2 (25%) | 9 (28.1%) | ||
| Slight Improvement | 0 (0%) | 2 (6.3%) | ||
| No Improvement | 2 (25%) | 11 (34.4%) | ||
| Total | 8 (100%) | 32 (100%) | ||
| 2 (Twice a day) | Complete Recovery | 2 (20%) | 7 (24.1%) | 0.418 |
| Partial Recovery | 1 (10%) | 5 (17.2% | ||
| Slight Improvement | 0 (0%) | 3 (10.3%) | ||
| No Improvement | 7 (70%) | 14 (48.3%) | ||
| Total | 10 (100%) | 29 (100%) | ||
*Chi-Square test was used for comparison
Table 5 presents mean, median, and range of pre- and post-treatment changes in SDS (speech discrimination score) and SRT (speech reception threshold). All groups showed a significant SDS increase and SRT decrease. Total changes in SDS and SRT are compared in Table 6; none showed a significant association.
Table 5.
The mean, median, and range of pre- and post-treatment changes in SDS (speech discrimination score) and SRT (speech reception threshold)
| Variables | Groups | Before Treatment | After Treatment | p-value* |
|---|---|---|---|---|
| SDS | Standard (Twice a week) | 87.7 ± 17.5 | 92.7 ± 13.8 | 0.022 |
| 9 (20–100) | 96 (35–100) | |||
| 1 (Once a day) | 81.8 ± 23.1 | 91.1 ± 15.0 | 0.004 | |
| 91 (10–100) | 96 (40–100) | |||
| 2 (Twice a day) | 83.3 ± 25.4 | 91.3 ± 20.2 | < 0.001 | |
| 92 (10–100) | 100 (10–100) | |||
| SRT | Standard (Twice a week) | 62.1 ± 21.2 | 38.5 ± 24.3 | < 0.001 |
| 55 (16–110) | 35 (10–110) | |||
| 1 (Once a day) | 61.4 ± 24.9 | 47.0 ± 32.4 | 0.003 | |
| 55 (10–110) | 35 (15–110) | |||
| 2 (Twice a day) | 71.1 ± 22.0 | 56.5 ± 34.3 | < 0.001 | |
| 62.5 (40–115) | 47 (15–110) |
*Wilcoxon signed rank test was used for comparison
Table 6.
Total changes in SRT and SDS in different groups
| Groups | Standard (Twice a week) | 1 (Once a day) | 2 (Twice a day) | p-value* |
|---|---|---|---|---|
| SDS Changes | 5.0 ± 15.3 | 9.3 ± 22.2 | 8.9 ± 16.4 | 0.724 |
| 4.0 (− 25–80) | 4.0 (− 36–90) | 4.5 (− 12–62) | ||
| SRT Changes | − 23.6 ± 19.9 | − 14.4 ± 32.4 | − 14.6 ± 17.8 | 0.130 |
| − 20 (− 70 – 40) | − 20 (− 95–70) | − 17.5 (− 50–20) |
* Kruskal–Wallis’s test was used for comparison
Discussion
We evaluated three groups of participants with SSNHL and similar baseline characteristics treated with systemic prednisolone plus IT dexamethasone, but they differed in injection intervals. Vertigo frequency as reported by the patient did not differ between the control and intervention groups; however, group 2 had significantly higher patients with vertigo than group 1. The standard treatment group had the most patients (16 participants, 40%) with complete recovery, while group 2 had the most patients in the no improvement group. This might be due to the higher number of patients with vertigo in group 2, especially compared to group 1. All patients in no improvement groups had longer intervals from symptom onset to treatment initiation, but only the difference in the standard group showed a statistically significant result. While no relation with age was observed, the pre- and post-treatment SDS and SRT measures showed improvement in all groups, but the changes in these measures were not statistically significant among the three groups.
The labyrinthine-blood barrier restricts systemic steroid passage to endolymph and decreases the concentration of systemic steroids in the endolymph fluid; therefore, concentrations of glucocorticoids may not be enough for treatment [5]. Multiple animal studies confirmed that the IT route of steroid delivery to the inner ear provides higher concentrations in the endolymph fluid than the systemic route; thus, lower doses of medications are required [6]. Hargunani et al. showed that although steroids are detectable in the inner ears of the rats 15 min after the IT injection, it becomes undetectable 24 h after injection; thus, long exposure to steroids may benefit SSNHL patients [7].
Suzuki et al. implemented a similar study to ours, where they performed four injections during a four-week (long-interval) or one-week (short-interval) period [8]. The age, days from onset to treatment, and timing of the injections did not become statistically relevant with treatment outcome. They found that vertigo at presentation, contralateral hearing loss, and the initial hearing level were significantly associated with treatment outcome. Such insignificance should be interpreted with caution as systemic treatment may blur the effects of IT treatment. Studies on patient populations with contraindications for systemic steroids can better elucidate the exact effect; As Shewel et al. explained the dose importance in IT treatment by performing a study on patients with contraindications for systemic steroid use and found 26.5 dB and 17.65 dB hearing gain in 10 mg and 4 mg dexamethasone groups, respectively [9]. Inversely, patients who could be prescribed systemic treatment may benefit from less frequent IT injections and subsequent lower related complications. It is also possible that the long follow-up period signifies the natural healing process of the SSNHL affects the outcome of studies; Sugihara and colleagues performed two IT injections of steroids in three intervals of 1–4, 5–10, and 11–30 days. They found no significant results after 11–30 days of the treatment.
Chou et al. evaluated the effects of continued steroid therapy (via tube insertion into the TM and three dexamethasone drops twice daily) on SSNHL patients [10]. Unlike our results, they concluded that near-continuous intratympanic steroid perfusion improves the PTA results more than the intermittent IT injection group, but similar to our study, SDS improved significantly. This discrepancy needs further studies, but the ventilation tube insertion may cause TM injury in the patients. One possibility for their results is that steroids had more time to induce their effects than our study.
Our results were strengthened by comparing two intervention groups with the American Academy of Otolaryngology standard protocol. However, the present study was limited by not collecting data regarding co-morbidities of our participants (i.e., diabetes, hypertension, etc.). It is also unknown that the frequent IT injections in the intervention groups can cause TM injury and hearing impairment? [11]. Finally, although our sample size is larger than previous studies, future studies are required to provide more robust conclusions regarding the appropriate timing and dose of injections, route of delivery (IT injection versus TM tube insertion plus steroid drops), and medication formulation of systemic and IT steroid.
Conclusion
The present study on SSHL patients treated with systemic steroids showed that less frequent IT injections provide a similar outcome to more frequent injections. However, more studies are required to elucidate the role of more frequent injections in those with contraindications to systemic steroids.
Supplementary Information
Below is the link to the electronic supplementary material.
Data Availability
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.
Declarations
Conflict of interest
None.
Ethical Approval
This study protocol was reviewed and approved by the Ethical Committee of Approval Number: REC.1399.232. Written informed consent was obtained for participation in this study.
Footnotes
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Supplementary Materials
Data Availability Statement
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.