Early Detection Of Ototoxicity Research Articles

Study of streptomycin-induced ototoxicity: protocol for a longitudinal study

Hearing impairment is due to various causes including ototoxicity from aminoglycosides. The susceptibility to aminoglycosides increases in the presence of certain mitochondria gene mutations. There is unrestrained use of aminoglycosides in many developing nations which may worsen the burden of hearing impairment in these countries but there is lack of data to drive required policy changes. Streptomycin (an aminoglycoside) is part of the drug regimen in re-treatment of tuberculosis. Exploring the impact of streptomycin ototoxicity in tuberculosis patients provides a unique opportunity to study aminoglycoside ototoxicity within the population thus providing data that can inform policy. Also, since streptomycin ototoxicity could adversely affect treatment adherence in tuberculosis patients this study could enable better pre-treatment counseling with subsequent better treatment adherence. Patients on tuberculosis re-treatment will be recruited longitudinally from Direct Observation Therapy-Short course centers. A baseline full audiologic assessment will be done before commencement of treatment and after completion of treatment. Early detection of ototoxicity will be determined using the American Speech and Hearing Association criteria and genetic analysis to determine relevant mitochondria gene mutations will be done. The incidence of ototoxicity in the cohort will be analyzed. Both Kaplan–Meier survival curve and Cox proportional hazards tests will be utilized to determine factors associated with development of ototoxicity and to examine association between genotype status and ototoxicity. This study will provide data on the burden and associated predictors of developing aminoglycoside induced ototoxicity. This will inform public health strategies to regulate aminoglycoside usage and optimization of treatment adherence and the management of drug-induced ototoxicity among TB patients. Furthermore the study will describe mitochondrial gene mutations associated with ototoxicity in the African population.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2429-5) contains supplementary material, which is available to authorized users.

Does Vincristine affect Cochlear function in children with acute lymphoblastic leukaemia?

Context: Vincristine chemotherapy has dose dependent ototoxicity. Early detection of ototoxicity is better with otoacoustic emissions and high frequency audiometry than conventional pure tone audiometry. The study was done to see if vincristine treatment interferes with hearing sensitivity in children.Methods and Material: A prospective study was conducted on twenty-three children with acute lymphoblastic leukemia (ALL) on Multi Center Protocol (MCP 841).These were subjected to conventional audiometry, high frequency audiometry and distortion product otoacoustic emissions (DPOAEs) before starting chemotherapy. The follow up audiological evaluation after early intensive phase chemotherapy (approximately 6 months) was conducted in thirteen children, who received 12 doses of vincristine (1.4 mg/m2), cranial irradiation of 1800cGy (>3 years) as per protocol and antibiotics as per clinical demands.Results: Baseline audiological evaluation was normal. Follow-up evaluation DPOAEs showed a declining tendency, however changes did not reach statistical significance. Differences in median hearing thresholds prior and post treatment in higher frequency audiometry were also minimal which was not statistically significant. Conventional audiometric thresholds were not altered.Conclusions: The reduction in the signal noise ratio of DPOAE, and reduced hearing sensitivity in high frequencies in post chemotherapy in comparison with baseline measures cannot be ignored though it has failed to reach the level of statistical significance. children on vincristine should have a pre chemotherapy and follow up audiological evaluation with DPOAE The results of the present study needs to be strengthened by including larger sample and long term follow up.Bangladesh J Medicine Jan 2016; 27(1) : 3-7

An audiological profile of patients infected with multi-drug resistant tuberculosis at a district hospital in KwaZulu-Natal.

BackgroundThe increased incidence of multi-drug-resistant tuberculosis (MDR-TB) and the consequent use of aminoglycosides with their ototoxic potential necessitate a better understanding of the audiological pattern of infected patients.ObjectiveTo describe the occurrence and nature of hearing loss in patients with MDR-TB receiving aminoglycosides over a period of 6 months.MethodsBaseline and five consecutive monthly audiological assessments were conducted on 52 adults at a hospital in KwaZulu-Natal. A longitudinal descriptive study was implemented. A conventional audiological test battery, extended high frequency audiometry and otoacoustic emission testing were conducted. Data were analysed using SPSS version 19 statistical software package.ResultsDecreased hearing was the most common audiological symptom experienced. Bilateral sensorineural hearing loss was predominant. Ototoxic hearing loss was noted in 27 participants (52%) in 1 month post-treatment. Hearing loss progressed from mild to moderate at post-treatment one, to moderate to severe at post-treatment three and severe to profound at post-treatment five. Changes in hearing function were noted in 52 participants (100%) by post-treatment five. High and ultra-high frequencies were most affected. Speech discrimination scores deteriorated over time. The number of patients with absent distortion product otoacoustic emissions increased over treatment duration.ConclusionThe greatest effects were observed in the high frequencies before manifesting in the lower frequencies. This highlights the importance of inclusion of high frequency audiometry in the early detection of ototoxicity which can go undiagnosed with traditional audiometry. The high prevalence of hearing loss has implications for the provision of audiological service to this patient population.

Chelation-induced ototoxicity in thalassemic patients: Role of distortion-product otoacoustic emissions and various management parameters

Context and Aims: A limited number of studies have been conducted for the assessment of hearing loss in thalassemic patients on regular chelation therapy and even fewer studies were conducted using otoacoustic emissions (OAEs). The present study was conducted to assess the prevalence of ototoxicity in multiple transfused thalassemic patients on regular iron chelation therapy (with desferrioxamine [DFO] and deferasirox), to compare the efficacy of OAEs (distortion-product OAEs [DPOAEs]) with that of pure tone audiometry (PTA) for hearing assessment and to correlate ototoxicity with age, mean hemoglobin (Hb), serum ferritin levels, dose and duration of chelation therapy, and therapeutic index Settings and Design: This was a prospective, observational study conducted in a tertiary care hospital. Subjects and Methods: Thirty thalassemic patients undergoing regular iron chelation therapy with DFO and deferasirox were included in this prospective study. Hearing assessment was done using otoscopy, tympanometry, PTA, and DPOAEs between January 1, 2010, and June 30, 2010. Follow-up studies were conducted after 12 months of chelation therapy using the same tests. Patients with and without ototoxicity were compared with respect to age, mean Hb, serum ferritin levels, dose and duration of chelation therapy, and therapeutic index. Statistical Analysis Used: Statistical analysis was carried out using the Student's t-test for normally distributed data and Pearson Chi-square test for categorical data. For nonparametric variables, Mann–Whitney and Wilcoxon tests were applied. Results: Using DPOAEs, 36% of patients were detected having a hearing deficit at the start of the study which increased to 46% at the end of study, whereas using PTA, the detection of hearing loss was 10% and 23%, respectively. DPOAE analysis showed a statistically significant decrease in the signal to noise ratio after 1 year of therapy at 4000 Hz, 5714 Hz, and 8000 Hz with maximum number of patients showing abnormality at 5714 Hz. The analysis revealed no significant difference between the affected and unaffected groups with respect to age, sex, height, weight, serum ferritin level, mean Hb, cumulative dose, mean daily dose and duration of chelation, or therapeutic index. Conclusions: Despite DFO doses usually felt to be low risk for ototoxicity (<40 mg/kg/day), we found a high rate of ototoxicity in our patients using DPOAEs (46%). No variables were identified that reliably predict ototoxicity. We impress on the need for regular audiological screening using DPOAEs for early detection of ototoxicity.

Sensorineural Hearing Loss in β-thalassemia Patients Treated with iron Chelation

The predictive value of pure-tone audiometry (PTA) in the early detection of ototoxicity has been questioned, particularly in the higher frequencies. Otoacoustic emissions testing appears to be more sensitive to cochlear insult than conventional PTA. We conducted a cross-sectional descriptive study to compare the efficacy of distortion-product otoacoustic emissions (DPOAE) testing with that of PTA as a method of audiologic monitoring. Our study group was made up of 159 patients (318 ears)-69 males (43.4%) and 90 females (56.6%), aged 5 to 61 years (mean: 23.59 ± 12.55). All patients had been diagnosed with either β-thalassemia major (BTM) or β-thalassemia intermedia (BTI), and all had received at least 1 year of treatment within the previous year with an iron chelator-either deferasirox, desferrioxamine (deferoxamine in the United States), deferiprone, or a combination of desferrioxamine and deferiprone. PTA and DPOAE evaluations were performed by the same audiologist using the same audiometer for all patients. In the right ears, the overall incidence of ototoxicity as manifested by sensorineural hearing loss was 39.0% on PTA and 22.0% on DPOAE testing; in the left ears, the corresponding figures were 27.7 and 19.5%, respectively. There were no statistically significant differences in the incidence of ototoxicity between the BTM and BTI groups with any of the four different drug regimens on PTA (p = 0.765, p = 0.378, p = 0.265, and p = 0.579, respectively) or on DPOAE testing (p = 0.890, p = 0.263, p = 0.390, and p = 0.340, respectively). Based on these data, we found no significant difference between PTA and DPOAE testing in their ability to detect ototoxicity. We conclude that periodic testing with both PTA and DPOAE is necessary for patients with suspected β-thalassemia in order arrive at a prompt diagnosis and initiate timely management.

Protective effects of sodium thiosulfate for cisplatin-mediated ototoxicity in patients with head and neck cancer

Conclusions: Intra-arterial high-dose cisplatin chemoradiation (CRT-IA) with sodium thiosulfate (STS) causes relatively less severe cisplatin ototoxicity than intravenous cisplatin chemoradiation without STS (CRT-IV). The results of this study also suggest that early detection of ototoxicity is possible by testing the hearing loss at ultra-high frequencies. Objectives: To investigate protective effects of STS against cisplatin ototoxicity. Methods: Between 2011 and 2013, 18 patients with head and neck carcinomas were treated with intra-arterial infusions of high-dose cisplatin (range 100–180 mg/body, mean 111 mg/body; range 2–5 courses, mean 3.6 courses) and systemic administration of cisplatin (range 66–185 mg/body, mean 130 mg/body; range 1–3 courses, mean 2.6 courses) and concurrent radiation therapy (range 60–70 Gy, mean 69 Gy). Cisplatin was neutralized by STS in CRT-IA but not in CRT-IV. Results: Intra-arterial infusion in the high-dose cisplatin group caused significant hearing loss at ultra-high frequencies of 10 and 12 kHz (p = 0.028, 0.039, respectively), whereas the group receiving systemic administration of cisplatin had significant hearing loss at high frequencies of 8 and 10 kHz (p = 0.016, 0.027, respectively).

G93 Aminoglycoside use and ototoxicity monitoring in UK CF units

BackgroundCystic fibrosis (CF) patients are at high risk of aminoglycoside ototoxicity, causing hearing loss, tinnitus or balance problems which can have significant social and psychological implications. The incidence of aminoglycoside...

Detection of Ototoxicity

Ototoxicity monitoring is particularly critical in patients receiving platinum-based chemotherapy or long-term aminoglycoside antibiotic administration. Furthermore, as new otoprotective agents are developed, audiologists need to not only be able to monitor for ototoxicity but know the various criteria for early detection of ototoxicity and how to grade ototoxic adverse events. The three primary methods for ototoxicity monitoring are conventional audiometry, high-frequency audiometry, and otoacoustic emissions. However, early detection and adverse event criteria depend primarily on conventional and high-frequency audiometry. No consensus exists on determining significant changes in otoacoustic emissions secondary to ototoxic drugs. Also, no consensus exists on how to monitor for tinnitus, although it is a common complication in these patients. Currently, tinnitus surveys can be helpful. A baseline evaluation is critical for accurate interpretation of auditory threshold results. Thus, a team approach is needed to ensure adequate care of these children. For clinical trials and in reading the literature, audiologists need to be aware of the American Speech Language Hearing Association's 1994 criteria for detection of ototoxic change, and the Common Terminology Criteria for Adverse Events, Brock, and the Change scales for classification of adverse events. These methods and scales are reviewed and discussed.

Distortion-product otoacoustic emission: Early detection in deferoxamine induced ototoxicity

Objective Deferoxamine therapy in lifelong transfusion-dependent anaemias, as beta-thalassemia major, is associated with an increased risk of ototoxic changes. With increasing survival rates, prevention and/or early detection of ototoxicity are important for providing management options. The predictive value of pure-tone audiometry in early detection of ototoxicity has been questioned, particularly in the higher frequencies. Otoacoustic emissions appear to be more sensitive to cochlear insult than the conventional pure-tone audiometry. The aim of our study was to compare the efficacy of otoacoustic emissions (distortion-product otoacoustic emissions) with that of pure-tone audiometry as method of audiological monitoring. Methods Baseline audiometric (0.25–8 kHz) and otoacoustic emission testing (distortion-product otoacoustic emissions) was conducted in a group of patients with beta-thalassemia major, 60 of whom met the criteria for inclusion in the study. Comparisons were performed between baseline measurements and those recorded after 20 months. Distortion-product otoacoustic emissions were obtained as DP-grams. The DP-gram amplitude was determined for each child. Results Threshold changes from baseline were found to be statistically significant from 4 to 8 kHz in 68.4% of the subjects ( P < 0.01). Distortion-product otoacoustic emissions demonstrated a significant threshold shift and a decreased amplitude in the frequencies >3 kHz ( P < 0.05). Furthermore, DP-gram amplitude also reduced significantly at 3 kHz ( P < 0.05) without any similar change in pure-tone audiometry. Conclusions As ototoxicity screening tool DP-gram was extremely sensitive and superior to pure-tone audiometry. Their use is recommended for regular monitoring of cochlear function, aiming in prevention of permanent damage.

The effect of treatment with vincristine on transient evoked and distortion product otoacoustic emissions

Vincristine chemotherapy is mainly associated with neurotoxic effects. The ototoxicity of vincristine has been related to high dosage, while low and moderate doses do not seem to induce significant hearing impairment when measured by pure tone or speech audiometry. Otoacoustic emissions have been reported to be more sensitive in early detection of ototoxicity than conventional pure tone audiometry. The present study was directed at determining whether vincristine treatment interferes with outer hair cell function in the absence of measurable changes in pure tone audiometry. We studied prospectively a cohort of ten children suffering from leukemia. All children were subjected to tympanogram, stapedial muscle reflex, pure tone audiometry, transient evoked (TEOAEs) and distortion product (DPOAEs) otoacoustic emissions on day 1 and on day 22 of treatment with vincristine. TEOAEs were analyzed in terms of emission level and reproducibility as a function of frequency. DPOAEs were obtained as DP-grams and were analyzed in terms of amplitude. The analyzed parameters of TEOAEs and DPOAEs revealed a declining tendency, although changes did not reach statistical significance. Pure tone audiometry and stapedial reflex thresholds were not altered. For the population of this study, vincristine did not seem to cause significant alterations of otoacoustic emissions' recordings and consequently significant outer hair cell damage.

Early Detection of Ototoxicity Using 1/6th-Octave Steps

The National Center for Rehabilitative Auditory Research has developed a protocol to provide early identification of ototoxicity for patients receiving ototoxic medications. The initial work involved patients with relatively good high-frequency hearing and resulted in the use of an individualized, sensitive frequency range separated by 1/6th-octave intervals. This protocol tested pure-tone frequencies at 1/6th-octave steps above 9 kHz, but only conventional audiometric frequencies were tested below 9 kHz. More recently, the testing protocol was expanded to include 1/6th-octave testing below 9 kHz. The primary question of interest was to determine whether adding 1/6th-octave test frequencies below 9 kHz would increase the ototoxicity detection rate for patients with poorer hearing. Results indicated 76 of the 210 (36.2%) ears that demonstrated initial ototoxic hearing change would have been missed or detected later if only conventional frequency testing was conducted.Therefore, for individuals with poorer hearing, expanding the use of the 1/6th-octave test protocol provides earlier identification of ototoxicity.

Early Detection of Ototoxicity

Early Detection of Ototoxicity

Comparison of ABR Stimuli for the Early Detection of Ototoxicity: Conventional Clicks Compared with High Frequency Clicks and Single Frequency Tonebursts

Effective objective testing methodology is needed for early detection of the effects of ototoxicity on hearing in patients. The requirements for such testing include responses that are: 1) reliable across test sessions; 2) sensitive to ototoxic change ( > 8 kHz), and 3) recordable in a time-efficient manner. Auditory brainstem responses (ABR) appear well suited to this task however, conventional clicks stimulate primarily mid-frequencies (1-4 kHz) and high frequency tonebursts require too much time. We hypothesized that delivery of a band of high frequencies (a high frequency "click"), would elicit reliable and useful ABRs. In the current study, flat and sloped HF (high frequency) clicks with a bandwidth of 8-14 kHz were used. The purpose was to compare brainstem responses elicited by tonebursts, two HF clicks and conventional clicks. The results show that the reliability of responses to the HF clicks were comparable to the tonebursts and further, both HF clicks produced responses slightly larger than tonebursts.

Evoked otoacoustic emissions — an approach for monitoring cisplatin induced ototoxicity in children

Objectives: Cisplatin chemotherapy is associated with an increased risk of ototoxic changes. The incidence of hearing loss after the 1st cisplatin-infusion session is only scarcely mentioned in the international literature. With increasing survival rates, prevention and/or early detection of ototoxicity are important for providing management options. The predictive value of pure-tone audiometry in early detection of ototoxicity has been questioned, particularly in the higher frequencies. Otoacoustic emissions appear to be more sensitive to cochlear insult than the conventional pure-tone audiometry. The aims of our study was (a) to define the extent of hearing damage in children after the 1st cisplatin-infusion session (50 mg/m 2); and (b) to compare the efficacy of otoacoustic emissions (transient evoked otoacoustic emissions, distortion-product otoacoustic emissions) with that of pure-tone audiometry as methods of audiological monitoring. Methods: Baseline audiometric (0.25–8 kHz) and otoacoustic emission testing (transient evoked otoacoustic emissions, distortion-product otoacoustic emissions) was conducted in 19 children, 12 of whom met the criteria for inclusion in the final study. Comparisons were performed between baseline measurements and those recorded after the 1st cisplatin course. Transient evoked otoacoustic emissions were analyzed in terms of emission level and reproducibility as a function of frequency (0.8–4 kHz). Distortion-product otoacoustic emissions were obtained as DP-grams and I/Q functions at 4,6 and 8 kHz. The DP-gram amplitude, the dynamic range and the detection thresholds from the I/Q functions were determined for each child. Results: Threshold changes from baseline were founded to be statistically significant from 4–8 kHz in 50% of the children ( P<0.01). Transient evoked otoacoustic emissions revealed a significant decrease in the emission level and in the reproducibility at the highest frequency tested (4 kHz, P<0.01), reflecting the results seen in pure-tone audiometry. Distortion-product otoacoustic emissions demonstrated a significant threshold shift, a reduced dynamic range and a decreased amplitude in the frequencies >3 kHz ( P<0.05). Furthermore, DP-gram amplitude also reduced significantly at 3 kHz ( P<0.05) without any similar change in pure-tone audiometry. Conclusions: A significant high-frequency hearing loss is identified in children even after one low-dose cisplatin-infusion session. As ototoxicity screening tools DP-grams were extremely sensitive and superior to pure-tone audiometry and/or transient evoked otoacoustic emissions. Their use is recommended for regular monitoring of cochlear function, aiming in prevention of permanent damage. Some suggestions for reducing the potential for cisplatin ototoxicity (chemoprotective agents, gene therapy, inhibition of apoptosis) are also discussed.

Evoked Otoacoustic Emissions as Objective Screeners for Ototoxicity

Ototoxicity produces hearing losses that are irreversible. The only certain method of preventing debilitating ototoxicity is to detect it as early as possible in the treatment regimen so that medications can be substituted, doses changed, and/or the mode of administration altered. With increasing survival rates of patients requiring ototoxic medication (e.g., aminoglycosides, cisplatin), early detection of ototoxicity is important for providing effective management options. A protocol including the use of otoacoustic emissions to detect and monitor the impact of ototoxicity will be presented.

Delay in Hearing Loss Following Drug Administration

The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.

Early detection of ototoxicity by high-frequency audiometry: A case study

The effect of an ototoxic aminoglycoside antibiotic (tobramycin) on the hearing acuity of an adult Black female cardiac patient was evaluated with a new type of high-frequency audiometer. Results indicated the effectivity of this audiometer for the early detection of ototoxicity. The possibility of higher susceptibility ototoxic damage in Blacks due to a higher concentration of melanin in the inner ear is discussed.

Ototoxicity and the role of high‐frequency audiometry

Ototoxicity is one of the unwanted side effects of a number of medical drugs. Within this category of drugs, aminoglycocides antibiotics and platinum derivates are the most well known. Cis‐platinum and carboxy platinum are often used as anticancer drugs, for example, in cases of testicular and ovarian malignancy. Auditory damage may be reduced by changes in dose, way of administration, and composition of the medical drug treatment. In these cases, early detection of ototoxicity is vital. As ototoxicity appears to be most pronounced in the higher frequencies, it can be assessed at an earlier stage by using high‐frequency audiometry from 8 to 20 kHz. The reference curves in this frequency region are strongly age related. In addition, we have investigated the precision of the measurement. In spite of inaccuracies of headphone positioning, which may influence high‐frequency thresholds above all, standard deviations were obtained as for audiometry in the normal‐frequency range. Finally, some case studies will illustrate the importance of high‐frequency audiometry.