Intratympanic Steroid Therapy in Moderate Sudden Hearing Loss: A Randomized, Triple-Blind, Placebo-Controlled Trial

Transcription

1 The Laryngoscope VC 2013 The American Laryngological, Rhinological and Otological Society, Inc. Intratympanic Steroid Therapy in Moderate Sudden Hearing Loss: A Randomized, Triple-Blind, Placebo-Controlled Trial Roberto Filipo, MD; Giuseppe Attanasio, MD, PhD; Francesca Y. Russo, MD; Marika Viccaro, MD; Patrizia Mancini, MD; Edoardo Covelli, MD Objectives/Hypothesis: To investigate the efficacy of an intratympanic steroid as a first-line therapy in patients affected by moderate idiopathic sudden sensorineural hearing loss (ISSNHL). Study Design: Prospective, randomized, triple-blind, placebo-controlled trial. Methods: Fifty patients presenting with moderate idiopathic sudden sensorineural hearing loss involving all frequencies from 250 Hz to 8,000 Hz (a flat audiogram) were enrolled. Patients were randomized into two groups of 25 each. The first group (intratympanic steroid) underwent a daily intratympanic administration of prednisolone for 3 consecutive days. Subjects in the second group (control) received a daily intratympanic injection of a saline solution for 3 consecutive days. Audiometric tests were performed at day 7 after the beginning of therapy (T1), and then 10 and 30 days after T1. The patients in both groups who did not show a complete recovery at T1 were treated with oral prednisone at a tapering dose. Results: In the intratympanic steroid group, 19 out of 25 patients presented at T1 complete recovery (76%), whereas in the control group the number patients who recovered completely at T1 was five out of 25 (20%). The mean pure-tone average (PTA) recorded at T1 shows a statistically significant improvement in the hearing threshold of the first group compared to the control group (P <.01). Conclusions: The mean PTA recorded after the first-line approach (T1) demonstrated a significant therapeutic action of the short-duration intratympanic steroid therapy on moderate ISSNHL, with a flat audiogram shape, compared to the natural course of the disease and the placebo effect at that time point. Key Words: Deafness, audiometric test, pure-tone average, hearing threshold, prednisolone. Level of Evidence: 1b. Laryngoscope, 123: , 2013 From the Department of Sensory Organs, Sapienza University of Rome, Rome, Italy. Editor s Note: This Manuscript was accepted for publication July 25, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Giuseppe Attanasio, MD, Department of Sensory Organs, Sapienza University of Rome, Viale del Policlinico 155, Rome, Italy. giuseppe.attanasio@uniroma1.it DOI: /lary INTRODUCTION Idiopathic sudden sensorineural hearing loss (ISSNHL) is most commonly defined as a loss of at least 30 db in three contiguous frequencies over a time course of 72 hours or less. Klemm et al. reported an incidence of 160 patients per 100,000 in an epidemiologic study performed in Germany. 1 Moreover, according to a study performed in Japan, the number of patients treated for ISSNHL increased from 4,000 in 1972 to 35,000 patients in Most ISSNHL is unilateral, and only between 0.44% and 4.9% is bilateral. 3 5 The causes of ISSNHL are unknown, limiting the ability to implement effective treatment. The most reliable theories include viral infection, vascular occlusion, intralabyrinthine membrane rupture, perilymphatic fistula, and autoimmunity. 6 According to this multifactorial origin, treatment of ISSNHL still remains controversial, and different protocols have been suggested including glycerol infusion, antiviral agents, hyperbaric chamber, multivitamin complex, and low-salt diets. Steroids, on the basis of their anti-inflammatory effect, have become the most widely accepted treatment for ISSNHL, 7 within the limits of well-known serious side effects that may pose a restriction to its systemic use. For this reason, intratympanic (IT) administration of steroids has become the most innovative medical strategy for patients affected by ISSNHL. 8,9 This therapeutic approach was initially proposed as a salvage therapy after failure of conventional therapies, 10,11 but it is now increasingly used as a first choice. 12,13 However, the studies that employed IT steroids as a first-line therapy lacked the use of a placebo control, and it was not possible to assess whether the hearing recovery originated from the steroid itself or from the natural course of the disease. The purpose of this randomized, triple-blind, placebo-controlled trial is to investigate the efficacy of the IT steroid protocol as a first-choice therapy in patients affected by moderate ISSNHL with a flat audiometric curve shape. MATERIALS AND METHODS Study Design The study design consisted of a randomized, triple-blind, placebo-controlled trial, during which patients received either

2 Fig. 1. Trial profile. IT ¼ intratympanic; T1 ¼ beginning of the treatment; T2 ¼ 10 days after T1; T3 ¼ 30 days after T1. *Up to 3 days from the onset of the idiopathic sudden sensorineural hearing loss (SSNHL). prednisolone (IT steroid group) or placebo (control group) by means of IT injection. The study population consisted of 50 patients, 36 male and 16 female, mean age years, who presented with moderate ISSNHL involving all the frequencies from 250 Hz to 8,000 Hz (a flat audiogram). They were recruited at the ear, nose, and throat (ENT) emergency room of the Department of Sensory Organs, Sapienza University of Rome, or were sent by four private ENT practitioners between August 2011 and March Inclusion criteria were diagnosed ISSNHL within 3 days from the onset, no previous therapy for ISSNHL, and age between 15 and 85 years. Exclusion criteria were hypertension and diabetes in a noncompensated status, history of ischemic disorders (stroke, heart attack), Meniere s disease, retrocochlear diseases, autoimmune hearing loss (HL), trauma, fluctuating HL, radiation-induced HL, noise-induced HL, or any other identifiable etiology responsible or triggering sudden HL. The 50 patients were randomized into two groups. The IT steroid group consisted of 25 patients, 14 male and 11 female, mean age at diagnosis years, pure-tone average (PTA) at entrance 53.7 db (minimum 40.8 db, maximum 70 db). The therapeutic protocol of this group consisted of intratympanic administration of 0.3 ml of prednisolone (Deltacortene Sol; Bruno Farmaceutici, Rome, Italy) at a dose of 62.5 mg/ml once a day for 3 consecutive days. The control group included 25 patients, 16 male and nine female, mean age at diagnosis years, PTA at entrance 52.3 db (minimum 38.5 db, maximum 70 db), who received an IT injection of 0.3 ml of a saline solution (0.9% sodium chloride) once a day for 3 consecutive days. All patients underwent a first audiometric test at study entry (T0). After the IT phase, further audiometric tests were performed on the seventh day from the beginning of the treatment (T1), and then 10 days (T2) and 30 days (T3) after T1 (Fig. 1). The patients of both groups who did not show a complete recovery at T1 were treated with 8 days of oral prednisone at a tapering dose (62.5 mg per day for 4 days, followed by 37.5 mg for 2 days, and 25 mg for the last 2 days). The research protocol was submitted and received ethical approval by the ethics committee of the Policlinico Umberto I of Rome (reference number 726/10, September 16, 2010). According to the protocol established by the ethics committee, all of the patients were informed of the fact that they were eligible to enter in a tripleblind trial, and a team of two otolaryngologists explained to them the aim of the study, the possible consequences of the two treatment approaches, the recent literature findings; informed written consent was obtained from all of the patients who were enrolled. Injection Technique The IT injection procedure, already described in a previous study, 13 was performed on an outpatient basis. The integrity of the external and tympanic membrane was evaluated with the aid of a microscope. Local anesthesia was performed by means of a cotton-sponge soaked with 10% lidocaine solution (Xylocaine, 10 mg/dose; AstraZeneca Korea, Seoul, South Korea) placed on the tympanic membrane. The sponge was removed after 20 minutes, and the external canal was cleared of any remaining fluid. Patients were placed in a supine position, with their head tilted 40 to 45 to the healthy side, and then a 25- gauge spinal needle was introduced in the posterior-inferior tympanic membrane. The solution (steroid or saline) was perfused into the middle ear. Following the injection, patients were asked to avoid moving their head, speaking, or swallowing for 30 minutes. Standard Assessment All patients underwent routine serological tests, high-resolution computed tomography (HRCT) of the temporal bone, and magnetic resonance imaging (MRI) of the brain, specifically of the cerebello-pontine angle with gadolinium. Audiometric Data Patients were all evaluated using standardized methods for pure-tone threshold audiometry. PTA was calculated as the mean of thresholds at the six frequencies (250, 500, 1,000, 2,000, 4,000, and 8,000 Hz). Evaluation of Hearing Improvement Furuhashi classification was used in the evaluation of audiological improvement, 14 with outcomes being classified as complete recovery, marked improvement, slight improvement, or no recovery (Table I). Statistical Analysis All patients underwent audiological examination, and the mean PTA value for the pre- and post-treatment phase was calculated for each patient as the mean of PTA value at the six examined frequencies. Due to the non-gaussian distribution of the data, Wilcoxon nonparametric test was performed to compare the two experimental groups and to compare data within the groups. Fisher exact test was performed to compare the number of patients who reached complete recovery at T1 in the two groups. RESULTS A total of 50 patients enrolled in the study were randomized into two groups; the study was conducted as a triple-blind study. There were no dropouts during the study. The two groups were found to be homogeneous for the PTA at study entry (P ¼.59). In the IT steroid group, 19 out of 25 patients presented a complete recovery (76%) at T1, whereas in the control group the number of patients who recovered completely at T1 was five out of 25 (20%). Therefore, regarding the hearing outcome, there was a significant difference between the two TABLE I. Criteria Used to Define Audiological Improvement. Complete recovery Marked improvement Slight improvement No recovery Criteria PTA 25 db or identical to the contralateral nonaffected ear PTA improvement >30 db PTA improvement between 10 and 30 db PTA improvement <10 db PTA ¼ pure-tone average (250, 500, 1,000, 2,000, 4,000, 8,000 Hz). 775

3 TABLE II. Hearing Outcomes. Steroid Group T1 T2 (6 Patients) Control Group T3 Final Follow-up T1 T2 (20 Patients) T3 Final Follow-up Complete 19 (76%) 19 (76%) 5 (20%) 13 (35%) 18 (72%) Marked 2 (8%) 2 (8%) Slight 3 (12%) 3 (12%) No recovery 1 (4%) 1 (4%) 20 (80%) 7 (65%) 7 (28%) T2 column refers to patients who did not recover at T1 and underwent oral steroid therapy. groups in favor of the IT steroid group (P ¼.0002). Marked recovery was obtained at T1 by two patients in IT steroid group (8%), and no patients in control group. An improvement of PTA between 10 and 30 db showed that slight improvement was reached, respectively, in 12% of patients (3/25) in the IT steroid group and no patients in the control group. Failure of the treatment (no recovery) at T1 was recorded, respectively, in 1/25 patients in IT steroid group (4%) and 20/25 patients (80%) in control group (Table II). In both study groups, the patients who did not show a complete recovery at T1 were treated with oral prednisone at a tapering dose for 8 days. In the control group, the second audiometric examination performed at T2 (10 days after T1) demonstrated an improvement of the hearing threshold; 13 out of the 20 patients who underwent systemic steroid administration reached complete recovery, and the remaining seven patients did not show recovery. The five patients in the IT steroid group who did not show a complete recovery in the first study phase did not improve their hearing threshold with systemic steroid administration. The mean PTA recorded in the two groups at T1 showed a statistically significant improvement in the hearing threshold of the IT steroid group (P <.0001) and an improvement in the control group (P ¼.043), with a statistically significant difference between the two study groups in favor of the IT steroid group (P <.0001). The audiometric examination performed at T2 demonstrated the trend of a better outcome in the hearing threshold of the IT steroid group. Figure 2 summarizes the mean PTA improvement from T0 to T3. The last audiometric test performed 30 days after T1 (T3) did not show any significant variation of the results observed at T2. More audiological data concerning the two groups are represented in Figure 3, in which the average hearing threshold value at each of the six frequencies is shown for both study groups at every audiometric examination at T0, T1, T2, and T3. The figure shows that the hearing improvement involved all of the frequencies, with a slightly lower improvement of the high frequencies. The audiometric curves of patients who showed a complete, marked, or slight recovery maintained a flat shape. Minor adverse effects in both groups were mild pain in the injection site (four patients) and short duration vertigo (six patients). No persistent tympanic membrane perforation occurred. No patients showed Fig. 2. Comparison of the pure-tone average (PTA) improvement in the two study groups. IT ¼ intratympanic; T0 ¼ study entry; T1 ¼ beginning of the treatment; T2 ¼ 10 days after T1; T3 ¼ 30 days after T1. **P < Fig. 3. Average hearing threshold values (db) for each frequency in the two groups. IT ¼ intratympanic; T0 ¼ study entry; T1 ¼ beginning of the treatment; T2 ¼ 10 days after T1; T3 ¼ 30 days after T1. 776

4 significant alterations of serum glucose and blood pressure values after the oral administration of prednisone. The HRCT, MRI, and the routine blood tests were negative for all of the patients. DISCUSSION The present study is the first investigation in which a high-dosage short-duration IT prednisolone treatment has been compared to placebo administration in patients presenting moderate ISSNHL with a flat audiogram shape. The evaluation of the effectiveness of a first-line therapeutic approach for ISSNHL, should take into account the potential spontaneous recovery, which is thought to mostly occur during the first week from the onset of symptoms. In fact, recovery is strictly a function of time. 15 IT administration of steroids has been considered in recent years a valid alternative to systemic therapy, because it allows the highest intracochlear drug concentration, with no risk of systemic side effects. 16 Moreover the IT route allows the steroid treatment in patients presenting comorbidities that would exclude them from the systemic treatment. Nevertheless the real efficacy of this technique compared to systemic treatment has not yet been demonstrated in the literature. Most studies have shown the benefits of IT steroids in the treatment of ISSNHL patients in whom previous systemic therapy have failed. 10,11 Moreover, up to now the comparison with a placebo treatment has only been investigated after failure of first-line steroid therapy, 17 but an IT placebo-controlled study as a first-line approach has never been carried out. In this context, the present study is the first to demonstrate that IT administration of a steroid, as a first-line therapy in patients affected by moderate ISSNHL, leads to a rapid recovery of the hearing threshold, and this effect is related to the action of the drug and not to the injection technique. Patients were selected on the basis of a flat audiometric curve to reach the best compromise between the low spontaneous recovery rate and the better sensitivity to systemic steroid therapy. 7,15 In this way it was possible to enroll a control group in which, after failure of the first treatment phase with a placebo, a systemic steroid was administrated within the first 7 days from the beginning of the therapy. In the IT steroid group, the complete recovery rate after the first treatment phase was 76%, whereas in the control group it was only 20%. The following systemic steroid treatment administered in all patients of both groups who did not recover completely led to similar hearing outcomes for the two study groups (complete recovery in 19/25 in the IT group and 18/25 in the control group). The delay of 7 days in the beginning of steroid therapy in the control group did not modify the chances of recovery for the patients. Moreover, in the second phase of the protocol, none of the patients in the IT group demonstrated an ulterior improvement of the hearing threshold. The two groups did not show any variation of the hearing threshold in T3 compared to T2. These results, even though related to a single type of audiometric curve, suggest that systemic steroid therapy cannot be considered as a salvage therapy in case of IT steroid treatment failure. Furthermore, no spontaneous recovery occurred during the second week from the onset of symptoms in patients who underwent a firstline therapy with IT steroids. The mean PTA recorded in the two groups at T1 showed a statistically significant improvement in the hearing threshold of IT steroid group (P <.0001) as well as an improvement in control group (P ¼.043), with a statistically significant difference between the two study groups in favor of the IT steroid group (P <.0001). The audiometric examination performed at T2 demonstrates the trend of a better outcome in the hearing threshold of the IT steroid group. Figure 2 summarizes the mean PTA improvement from T0 to T3. The last audiometric test performed 30 days after T1 (T3), did not show any significant variation of the results observed at T2. The choice of using only PTA improvement as a recovery criteria was in line with the other recent studies in which a comparison with placebo had been performed. 17,18 The lack of a speech discrimination audiometry was a shortcoming of this study. A speech audiometry would have added ulterior information concerning the hearing recovery. Nevertheless, in a recent review of the analysis of improvement criteria used to evaluate recovery in patients with ISSNHL, it was stated that the mean PTA improvement after treatment might be a more objective outcome measure. 19 In the literature, only one other study has been recently performed that compares the effect of prednisolone and placebo as a fist-line approach in the treatment of unilateral ISSNHL. 18 In this randomized, triple-blind, placebo-controlled trial, the authors affirm that in ISSNHL, oral administration of prednisolone in a customary dosage does not seem to influence recovery. In this trial, almost 80% of the enrolled patients with ISSNHL presented before the treatment a hearing impairment involving the low or mid frequencies. The number of patients presenting a flat audiogram (with the involvement of all frequencies) at study entrance was only one in the prednisolone group and three in the placebo group. Results at the final follow-up showed that in both groups, complete recovery was reached by 18 patients. In the prednisolone group, the only patient who presented a flat audiogram had a complete recovery, whereas in placebo group none of the three patients who presented a flat audiogram at study entrance reached complete recovery. However, in the present study all the patients presented a flat audiogram. These data influence hearing outcomes and can explain the different conclusions of the two studies. Moreover, some differences in the study setting are present, such as the route of administration (IT vs. oral) and the evaluation criteria of hearing improvement (six frequencies in the present study instead of three frequencies). CONCLUSION The mean PTA improvement recorded in the steroid group at T1, after the first-line approach, clearly demonstrates a significant therapeutic action of IT steroid 777

5 therapy on moderate ISSNHL with a flat audiogram shape, compared to the natural course of the disease and to the placebo effect at that time point. The results obtained at T3, after 1 month follow-up, confirm the efficacy of steroid therapy, whether IT or systemic, as a first choice in ISSNHL. In fact, there was no significant difference in the complete recovery percentage, but only in marked or slight improvement. The percentage of patients who showed no improvement after 1 month was significantly higher in the control group than the IT group (28% vs. 4%). BIBLIOGRAPHY 1. Klemm E, Deutscher A, Mosges R. A present investigation of the epidemiology in idiopathic sudden sensorineural hearing loss [in German]. Laryngorhinootologie 2009;88: Teranishi M, Katayama N, Uchida Y, Tominaga M, Nakashima T. Thirtyyear trends in sudden deafness from four nationwide epidemiological surveys in Japan. Acta Otolaryngol 2007;127: Fetterman BL, Luxford WM, Saunders JE. Sudden bilateral sensorineural hearing loss. Laryngoscope 1996;106: Yanagita N, Murahashi K. Bilateral simultaneous sudden deafness. Arch Otorhinolaryngol 1987;244: Oh JH, Park K, Lee SJ, Shin YR, Choung YH. Bilateral versus unilateral sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2007; 136: Eisenman D, Arts HA. Effectiveness of treatment for sudden sensorineural hearing loss. Arch Otolaryngol Head Neck Surg 2000;126: Wilson WR, Byl FM, Laird N. The efficacy of steroids in the treatment of idiopathic sudden hearing loss. A double-blind clinical study. Arch Otolaryngol 1980;106: Moskowitz D, Lee KJ, Smith HW. Steroid use in idiopathic sudden sensorineural hearing loss. Laryngoscope 1984;94: Ho HG, Lin HC, Shu MT, Yang CC, Tsai HT. Effectiveness of intratympanic dexamethasone injection in sudden-deafness patients as salvage treatment. Laryngoscope 2004;114: Plaza G, Herraiz C. Intratympanic steroids for treatment of sudden hearing loss after failure of intravenous therapy. Otolaryngol Head Neck Surg 2007;137: Moon IS, Lee JD, Kim J, Hong SJ, Lee WS. Intratympanic dexamethasone is an effective method as a salvage treatment in refractory sudden hearing loss. Otol Neurotol 2011;32: Battaglia A, Burchette R, Cueva R. Combination therapy (intratympanic dexamethasone þ high-dose prednisone taper) for the treatment of idiopathic sudden sensorineural hearing loss. Otol Neurotol 2008;29: Filipo R, Covelli E, Balsamo G, Attanasio G. Intratympanic prednisolone therapy for sudden sensorineural hearing loss: a new protocol. Acta Otolaryngol 2010;130: Furuhashi A, Matsuda K, Asahi K, Nakashima T. Sudden deafness: longterm follow-up and recurrence. Clin Otolaryngol 2002;27: Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86: Slattery WH, Fisher LM, Iqbal Z, Friedman RA, Liu N. Intratympanic steroid injection for treatment of idiopathic sudden hearing loss. Otolaryngol Head Neck Surg 2005;133: Wu HP, Chou YF, Yu SH, Wang CP, Hsu CJ, Chen PR. Intratympanic steroid injections as a salvage treatment for sudden sensorineural hearing loss: a randomized, double-blind, placebo-controlled study. Otol Neurotol 2011;32: Nosrati-Zarenoe R, Hultcrantz E. Corticosteroid treatment of idiopathic sudden sensorineural hearing loss: randomized triple-blind placebo-controlled trial. Otol Neurotol 2012;33: Seggas I, Koltsidopoulos P, Bibas A, Tzonou A, Sismanis A. Intraympanic steroid therapy for sudden hearing loss: a review of the literature. Otol Neurotol 2011;32: