Effects of cisplatin and thiosulfate upon auditory brainstem responses of guinea pigs

Two side effects which limit the use of cisplatin in cancer chemotherapy are severe nephrotoxicity and ototoxicity. The concurrent administration of sodium thiosulfate with cisplatin reportedly protects from cisplatin nephrotoxicity, however, protection from ototoxicity has not been documented. The purpose of this study was to examine the efficacy of using thiosulfate to ameliorate the ototoxic effects of cisplatin. Toward this end, the effects of cisplatin alone, cisplatin administered concurrently with sodium thiosulfate (CIS/THIO), and sodium thiosulfate alone on the auditory brainstem response (ABR) of guinea pigs were compared. ABR waveforms, comparing latencies, amplitudes and response thresholds, were monitored before, immediately after, and 30 days post treatment. Sodium thiosulfate administered with cisplatin (CIS/THIO) consistently protected animals from hearing loss and surprisingly yielded significant increases in amplitude when compared to baseline and saline controls. However, ABRs of CIS/THIO animals returned toward baseline values after 30 days.     

Ototoxic impact of cisplatin in pediatric oncology patients

OBJECTIVE: To describe hearing changes in a group of 28 children (age range, 8-180 mo) undergoing protocol-based cisplatin therapy. METHODS: Conventional, play audiometry, visual reinforcement audiometry (VRA), immittance audiometry, transient click evoked otoacoustic emissions (OAEs), and auditory brainstem response (ABR) evoked potentials were used to assess peripheral sensitivity and for threshold determination. RESULTS: Bilateral symmetrical high-frequency sensorineural hearing loss was noted in 9 of the 28 children (26%). Hearing loss was evident as early as 1 month after chemotherapy and as late as 50 months and was not dependent on individual or cumulative dosage of cisplatin. CONCLUSIONS: 1) Presence of sensorineural hearing loss was independent of individual and/or cumulative dosage of cisplatin; 2) audiologic assessment should be incorporated into a child's periodic medical evaluations after chemotherapy treatment, as onset of sensorineural hearing loss cannot be predicted; 3) personal hearing aids may be indicated for those children with hearing loss affecting the low- to mid-frequencies; a personal assistive listening device (frequency modulated system) may be more appropriate for losses above 3000 Hz; and 4) evaluation and intervention by a speech-language pathologist may be indicated to address possible articulation or language development problems consequent to hearing loss.     

Dependence of Auditory Brainstem Response on Click Polarity and High-Frequency Sensorineural Hearing Loss

An investigation is presented on the effect of click polarity upon the auditory brainstem response (ABR) in cases of simulated high-frequency hearing loss. A high-frequency hearing loss was simulated in 12 normal subjects by applying a high-pass noise masker, the noise cutoff frequency being varied in half-octave steps through the range of audiometric frequencies. With this paradigm, the effects of click polarity on the ABR are similar to those reported in patients with high-frequency hearing loss, including changes in waveform morphology and substantial peak latency shifts. To evaluate the role of individual cochlear frequency channels in a more direct way, half-octave narrow-band responses were determined by pair-wise subtraction of the high-pass-noise-masked responses. As far as ABR peak latencies are concerned, stimulus polarity effects tend to increase towards the lower frequency bands. Thus, the selective elimination of the contribution to the ABR of cochlear high-frequency channels can be held responsible for the increased dependence of ABR on click polarity observed in high-frequency hearing loss. However, statistical evaluation of peak I, III and V latencies, both in high-pass-noise-masked and in narrow-band ABRs, reveals that the latency effects are not systematic between subjects. Mechanisms producing the observed rarefaction-condensation differences, possible explanations for the large intersubject variability and the consequences for clinical interpretation of ABR are discussed.     

Dependence of auditory brainstem response on click polarity and high-frequency sensorineural hearing loss.

An investigation is presented on the effect of click polarity upon the auditory brainstem response (ABR) in cases of simulated high-frequency hearing loss. A high-frequency hearing loss was stimulated in 12 normal subjects by applying a high-pass noise masker, the noise cutoff frequency being varied in half-octave steps through the range of audiometric frequencies. With this paradigm, the effects of click polarity on the ABR are similar to those reported in patients with high-frequency hearing loss, including changes in waveform morphology and substantial peak latency shifts. To evaluate the role of individual cochlear frequency channels in a more direct way, half-octave narrow-band responses were determined by pair-wise subtraction of the high-pass-noise-masked responses. As far as ABR peak latencies are concerned, stimulus polarity effects tend to increase towards the lower frequency bands. Thus, the selective elimination of the contribution to the ABR of cochlear high-frequency channels can be held responsible for the increased dependence of ABR on click polarity observed in high-frequency hearing loss. However, statistical evaluation of peak I, III and V latencies, both in high-pass-noise-masked and in narrow-band ABRs, reveals that the latency effects are not systematic between subjects. Mechanisms producing the observed rarefaction-condensation differences, possible explanations for the large intersubject variability and the consequences for clinical interpretation of ABR are discussed.     

ABR evaluation of ototoxicity in cancer patients receiving cisplatin or carboplatin.

The development of ototoxicity was evaluated using auditory brainstem response (ABR) in cancer patients randomized to receive a cisplatin-based chemotherapy (cisplatin dose: 70 mg/m2) or a carboplatin-based chemotherapy (carboplatin dose: 250 mg/m2). The ABR measurements were performed in a sound-treated room using 2000 clicks of alternating polarity at an intensity of 100 dB PESPL presented to the patients at a rate of 21 clicks per second. Of 59 patients, 21 (9 in the cisplatin group and 12 in the carboplatin group) met our pre-established criteria and were included in the ototoxicity study. Two patients of the cisplatin group developed evidence of clinically occult ototoxicity after two cycles of chemotherapy; the latency of wave V of the ABR increased significantly from 5.874 to 6.336 msec and from 5.826 to 6.458 msec in both patients; these patients had a hearing loss detected by conventional audiometry (125 to 8,000 Hz) after five and six cycles of chemotherapy, respectively. None of the 12 examined carboplatin patients developed ABR-measured ototoxicity or abnormal audiograms during treatment. Our results suggest that ABR might prove to be useful in detecting early hearing deterioration from cisplatin.     

Astragalosides reduce cisplatin ototoxicity in guinea pigs

Cisplatin is known to cause high-frequency neurosensory hearing loss. While reactive oxygen species have been shown to play a role, reactive nitrogen species have been implicated, but not proven to be involved, in cisplatin ototoxicity. The purpose of the present study was to investigate the role of nitric oxide (NO) in cisplatin ototoxicity by administering astragalosides, a natural antioxidant, in conjunction with cisplatin. Guinea pigs were injected with cisplatin, astragalosides or both. Auditory brainstem-evoked responses (ABRs) were measured before and 3 days after cisplatin administration. The cochlear tissue was then assayed for NO and malondialdehyde (MDA), and cochleae were also examined by scanning electron microscopy. Cisplatin alone caused significant ABR threshold shifts at all stimuli tested, whereas astragalosides alone caused no shifts. There was a significant reduction in threshold shift for clicks, 8-kHz and 16-kHz tone bursts (but not 32 kHz) when astragalosides was given with cisplatin. Both the MDA concentration and the NO concentration in the astragalosides/cisplatin group were significantly lower than those of the cisplatin group. Correspondingly, the loss of outer hair cells in the astragalosides/cisplatin group was much less than that in the cisplatin group. This suggests that astragalosides reduces cisplatin ototoxicity by its antioxidant property.     

Intracochlear administration of thiourea protects against cisplatin-induced outer hair cell loss in the guinea pig

Amelioration of cisplatin-induced side-effects is of great clinical importance. Local administration of a cytoprotective agent to the inner ear offers a possibility to prevent cisplatin-induced ototoxicity without risk of interference with the antitumour effect. The ideal substance for local administration has yet to be identified. Thiourea (TU) has unique properties that make it an interesting candidate. This study was initiated to test the hypothesis that TU given by local administration protects against cisplatin ototoxicity in the guinea pig. After baseline auditory brainstem response (ABR) assessment, the left cochlea was implanted with a microtip catheter connected to an osmotic pump filled with either 27 mg/ml TU in artificial perilymph (AP), or AP administered for the full duration of the study. Three days post-implant, animals with normal ABRs received an intravenous injection of 8 mg/kg body-weight cisplatin. Five days after the cisplatin treatment ABRs were reassessed, animals decapitated and bilateral cytocochleograms prepared. TU-treated ears demonstrated significantly lower outer hair cell (OHC) loss as compared to contralateral untreated ears, and significantly lower OHC loss compared to AP-treated ears. ABR threshold shift did not differ significantly between the two groups. It can be postulated that TU demonstrates partial protection against cisplatin-induced ototoxicity.     

Aminoguanidine reduces cisplatin ototoxicity

Cisplatin is known to cause high-frequency neurosensory hearing loss. While reactive oxygen species have been shown to play a role, reactive nitrogen species have been implicated, but not proven to be involved, in cisplatin ototoxicity. The purpose of the present study was to investigate the role of nitric oxide (*NO) in cisplatin ototoxicity by administering aminoguanidine (AG), a relatively specific inhibitor of inducible nitric oxide synthase (iNOS), in conjunction with cisplatin. Rats were injected with cisplatin, AG, or both. Auditory brainstem evoked responses (ABR) were measured before and 3 days after cisplatin administration. The cochlear tissue was then assayed for *NO and malondialdehyde. Cisplatin alone caused significant ABR threshold shifts at all stimuli tested, whereas AG alone caused no shifts. There was a significant reduction in threshold shift for clicks and 16 kHz tone bursts (but not 32 kHz) when AG was given with cisplatin. The malondialdehyde concentration (but not the *NO concentration) in the AG/cisplatin group was significantly lower than that of the cisplatin group. This suggests that AG reduces cisplatin ototoxicity by directly scavenging hydroxyl radicals. The iNOS pathway may play a role in the generation of free radicals and hearing loss resulting from cisplatin administration, but this conclusion was not supported by our data.     

cis-platinum ototoxicity in children

Despite the recognized ototoxicity of cis-platinum, a clinical outline for the audiologic evaluation of patients receiving this drug has not been clearly defined. In a practical approach to this problem, the audiograms of 48 pediatric patients referred for monitoring during planned cis-platinum therapy were reviewed. Eleven patients tested with auditory brain-stem response (ABR) audiometry demonstrated several limitations of this modality. Fourteen children underwent initial ABR testing followed by at least two pure-tone audiograms. The remaining 23 patients had their hearing evaluated by pure-tone audiometry only. Various factors such as patient age, cis-platinum dosage, and cranial radiation exposure were analyzed for apparent effect. Younger patients tended to be more susceptible to audiologic changes with the administration of cis-platinum. The proportion of patients who demonstrated a hearing loss increased with successive dosing as did the severity of the hearing loss. Prior exposure to cranial radiation was strongly linked to the development of hearing loss following cis-platinum therapy. Guidelines are presented regarding the use of clinical audiometry in the screening of these pediatric oncology patients.     

Amelioration of Cisplatin-Induced ototoxicity by fosfomycin

The continued chemotherapeutic application of cisplatin (cis-diamminedichloroplatinum [II]) necessitates reduction of its doselimiting toxicity without decreasing its tumoricidal effect. This research project evaluated the efficacy of fosfomycin, a phosphonic acid antibiotic, in decreasing or ameliorating the ototoxicity (high frequency sensorineural hearing loss) and nephrotoxicity (renal tubular necrosis and interstitial nephritis) of cisplatin. Experimentally, fosfomycin effectively inhibits aminoglycoside-induced ototoxicity and nephrotoxicity in animals and humans. The efficacy of fosfomycin in blocking platinum-induced toxicity in the guinea pig was evaluated histologically and functionally using cytocochleography and light microscopy of the organ of Corti and the auditory brain stem evoked response (ABR), and light microscopy of renal corticomedullary tissues, small bowel, liver, lung, and peripheral nerve. The results demonstrate that fosfomycin ameliorates the acute renal tubular necrosis and interstitial nephritis and markedly inhibits the elevation of ABR thresholds and simultaneous outer hair cell loss that can result from cisplatinum administration. Fosfomycin should be considered apotential antidote for the dose-limiting ototoxicity and nephrotoxicity of cisplatin chemotherapy.     

Auditory sensitivity in children using the auditory steady-state response

OBJECTIVE: To determine the effectiveness of auditory steady-state response (ASSR) as a measure of hearing sensitivity in young children suspect for significant hearing loss. DESIGN: Within-subject comparisons of click auditory brainstem response (ABR) thresholds and ASSR thresholds. SUBJECTS: The study population comprised 42 children suspect for hearing loss and subsequently referred for hearing assessment using electrophysiologic techniques. MAIN OUTCOME MEASURES: Electrophysiologic threshold responses for click ABR and ASSR stimuli (0.5, 1, 2, and 4 kHz) for right and left ears. RESULTS: Based on ABR and ASSR thresholds, 50% of the subjects demonstrated significant hearing loss in the severe to profound range. In some subjects, ASSRs were present at higher stimulus levels when click ABRs were absent. Significant correlations (P<.05) were found between high-frequency ASSR and click ABR thresholds for this study sample. For some subjects, ASSR findings suggested differences between ears that were not observable from the no-response click ABR results. CONCLUSIONS: Auditory steady-state response testing may provide additional information for children who demonstrate hearing levels in the severe to profound range. This information may be helpful when selecting the ear for cochlear implantation for a young hearing-impaired child. Multiple objective methods, such as ABR and ASSR testing, may be needed to determine accurate hearing sensitivity for young children being considered for sensory devices, and in particular, cochlear implants.     

Application of antioxidants and other agents to prevent cisplatin ototoxicity

OBJECTIVE/HYPOTHESIS: To review the recent data from experiments performed in this laboratory to test the hypothesis that cisplatin ototoxicity is related to depletion of glutathione and antioxidant enzymes in the cochlea and that the use of antioxidants or protective agents would protect the cochlea against cisplatin damage and prevent hearing loss. STUDY DESIGN/METHODS: Data were reviewed from experiments performed in this laboratory. Control rats were treated intraperitoneally with cisplatin 16 mg/kg. Experimental rats were given cisplatin in combination with one of the following protective agents: diethyldithiocarbamate, 4-methylthiobenzoic acid, ebselen, or lipoic acid. Animals in each group underwent auditory brainstem response (ABR) threshold testing before and 3 days after treatment. Cochleae were removed after final ABR testing and analyzed for glutathione and activities of the enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and malondialdehyde. RESULTS: Rats in the control group receiving cisplatin were found to have significant ABR threshold shifts. This was accompanied by a reduction of glutathione and the activity of antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase) and an elevation of malondialdehyde. Experimental animals had preservation of ABR thresholds and levels of glutathione, antioxidant enzyme activity, and malondialdehyde that were similar to untreated animals. CONCLUSION: Cisplatin ototoxicity appears to be initiated by fee-radical production, which causes depletion of glutathione and antioxidant enzymes in the cochlea, and lipid peroxidation, manifested by an increase in malondialdehyde. These effects were blocked by each of a series of antioxidant compounds given in combination with cisplatin. A mechanism for cisplatin ototoxicity is elaborated with a proposed plan of chemoprevention using agents with different mechanisms of action. These substances could be used alone or in combination to reduce the severity of cisplatin ototoxicity in patients.     

Influence of pH on the ototoxicity of cisplatin: a round window application study

Cisplatin is an antineoplastic agent that produces a number of dose-limiting side effects, including ototoxicity. We investigated the effect of pH on cisplatin ototoxicity. Auditory brainstem responses (ABR) were recorded in chinchillas. Then the auditory bullae were opened and acidic (pH=6.5), neutral (pH=7.4) or alkaline (pH=10.2) phosphate-buffered saline (PBS) was applied to the round window membrane. After 30 min, any remaining solution was removed and cisplatin solution was applied to the round window membrane. After 3 days, follow-up ABRs were performed and the cochleae were processed for morphological analysis. Neutral PBS+cisplatin administration resulted in profound threshold changes at all frequencies. Acidic PBS+cisplatin administration showed had a trend of increased threshold changes, but the change did not reach statistical significance. However, the degree of hair cell loss was significantly higher than that of the neutral PBS-cisplatin group. Alkaline PBS significantly reduced cisplatin-induced threshold changes (P<0.05) compared to the neutral PBS group. Because the pH of cisplatin solution was 6.0, pH 6.0 PBS was applied to round window membrane. This acidic PBS solution did not cause any hearing impairment. These results demonstrate that pH can modulate the ototoxic effects of cisplatin.     

Hearing genes and cisplatin deafness: a pilot study

OBJECTIVE: Cisplatin commonly is used to treat pediatric solid tumors. A major dose-limiting toxicity is sensorineural hearing loss. Which patients experience ototoxicity after treatment with cisplatin must reflect individual susceptibility, since it is not seen in all similarly treated patients. We hypothesized that mutations or polymorphisms in hearing genes are more common in patients who experience ototoxicity than in the general population. STUDY DESIGN: We completed retrospective mutation screening of GJB2 and SLC26A4 and screened for three mtDNA mutations in patients with a history of childhood cancer who developed severe hearing loss at cumulative cisplatin doses of less than 400 mg/M2. MATERIALS AND METHODS: Patients younger than 21 years of age who experienced severe hearing loss after cisplatin were identified using the Childhood Cancer Survivor Study database. Archival DNA from buccal washes of 11 patients was used for mutation screening and detection. RESULTS: With the exception of one patient (9.1%) who was a carrier for the 35delG mutation, no mutant alleles were found. Given the reported prevalence of the 35delG mutation in the general population of 2.5%, this result is not significant (P = .35). CONCLUSIONS: It is not likely that any of the five hearing genes we examined contribute to cisplatin ototoxicity. Further study may be warranted to look at other hearing genes as possible predictors of cisplatin ototoxicity.     

Age-Related Changes in the Relationship Between Auditory Brainstem Responses and Envelope-Following Responses

Hearing thresholds and wave amplitudes measured using auditory brainstem responses (ABRs) to brief sounds are the predominantly used clinical measures to objectively assess auditory function. However, frequency-following responses (FFRs) to tonal carriers and to the modulation envelope (envelope-following responses or EFRs) to longer and spectro-temporally modulated stimuli are rapidly gaining prominence as a measure of complex sound processing in the brainstem and midbrain. In spite of numerous studies reporting changes in hearing thresholds, ABR wave amplitudes, and the FFRs and EFRs under neurodegenerative conditions, including aging, the relationships between these metrics are not clearly understood. In this study, the relationships between ABR thresholds, ABR wave amplitudes, and EFRs are explored in a rodent model of aging. ABRs to broadband click stimuli and EFRs to sinusoidally amplitude-modulated noise carriers were measured in young (3–6 months) and aged (22–25 months) Fischer-344 rats. ABR thresholds and amplitudes of the different waves as well as phase-locking amplitudes of EFRs were calculated. Age-related differences were observed in all these measures, primarily as increases in ABR thresholds and decreases in ABR wave amplitudes and EFR phase-locking capacity. There were no observed correlations between the ABR thresholds and the ABR wave amplitudes. Significant correlations between the EFR amplitudes and ABR wave amplitudes were observed across a range of modulation frequencies in the young. However, no such significant correlations were found in the aged. The aged click ABR amplitudes were found to be lower than would be predicted using a linear regression model of the young, suggesting altered gain mechanisms in the relationship between ABRs and FFRs with age. These results suggest that ABR thresholds, ABR wave amplitudes, and EFRs measure complementary aspects of overlapping neurophysiological processes and the relationships between these measurements changes asymmetrically with age. Hence, measuring all three metrics provides a more complete assessment of auditory function, especially under pathological conditions like aging.     

Auditory brain stem responses of premature infants to bone-conducted stimuli: a feasibility study

The feasibility of bone conduction auditory brain stem response (ABR) audiometry in intensive care nursery neonates was investigated. Forty premature infants were tested with both air- and bone-conducted stimuli. Bone-conducted stimuli resulted in more identifiable ABRs and a greater number of subjects passing the hearing screening. The findings of this study suggest that bone conduction ABR audiometry is a feasible technique with premature infants. Due to the lower frequency composition of the bone-conducted click, it may be more effective than an air-conducted click when the immature cochlea is being evaluated.     

Ototoxicity of cisplatin in children

BACKGROUND: The ototoxicity of cisplatin has long been well known for its damage to hair cells. However, the results of published studies vary widely with respect to the intensity and frequency of auditory damage. METHODS: We analyzed the data of 13 young children that have been treated with cisplatin for varying tumor diseases in established combination chemotherapy. The study focused on these major questions: How high is the rate of cisplatin-related incidents of hearing loss in relation to age, sex, nature of tumor, and total dosage of the administered cisplatin? How much does the supplementary application of further ototoxic medications affect the ototoxicity itself? RESULTS: Eight of 13 children examined showed regular hearing capacities in conformity with their age-group, 3 showed a bilateral, and one child showed an one-sided loss of auditory capacity. Deterioration of preexisting auditory damage was observed in one child. No relation to age, sex, nature of tumor, or dosage of administered cisplatin was established. Bilateral hearing loss occurred in three of these children, which indicates that possible synergy of aminoglycoside antibiotics and cisplatin should be investigated with respect to ototoxicity. CONCLUSION: The results indicate that cisplatin, especially in combination with other ototoxic drugs, can lead to severe hearing loss in young children. Since factors other than the possible synergy discusses above favorable to the development of auditory damage cannot be specified, every child under cisplatin therapy should undergo auditory checkups at brief intervals.     

应用畸变产物耳声发射和扩展高频测听对顺铂耳毒性的临床研究

目的：应用0．5—16kHz畸变产物耳声发射(distortion product otoacoustic emissions,DPOAE)和扩展高频测听对顺铂耳毒性进行临床研究。方法:对24例应用顺铂进行初次化疗的妇科肿瘤病人于化疗前后分别进行0．5—16kHz DPOAE、常频纯音测听及扩展高频测听检查，比较DPOAE和常频纯音测听、扩展高频测听的结果。结果：顺铂化疗后扩展高频区纯音听阈升高，DPOAE在3kHz、4kHz处及扩展高频区下降明显。结论：常频DPOAE较常频纯音测听更敏感，和扩展高频测听检查一样均可用于顺铂耳毒性的监测。扩展高频DPOAE可能比常频DPOAE更敏感。DPOAE与纯音听闻可能并非一一对应关系。病人对顺铂的易感性可能随着年龄的增加逐渐减低。     

Auditory brain stem response (ABR) in unilateral hearing loss

Auditory brain stem responses (ABRs) were reported with two groups of patients with confirmed and suspected unilateral hearing loss. Evidence of acoustic crossover of click stimuli when the difference in click thresholds for the two ears exceeds approximately 60 db is presented. In such a circumstance, the ABR presumably elicited from the test ear can, in fact, be a reflection of a crossover response from the non-test ear. In clinical practice, appropriate contralateral ear masking should be employed when ABR audiometry is carried out with infants and adults with suspected unilateral hearing loss.     

Specificity of auditory brainstem response audiometry criteria in acoustic neuroma screening as a function of deviations of reference values in patients with cochlear hearing loss

Summary On the basis of 79 patients with cochlear hearing loss, the statistical distribution of two criteria commonly used in auditory brainstem response audiometry (ABR) was analyzed: the interaural V latency difference (ILD V) and the interaural difference of IN interpeak interval (ID I–V). The distribution of both criteria was Gaussian. By evaluating their standard deviations the percentages of statistical false-positives were estimated. The estimated results were 24% false-positive findings using the decision criterion ILD V > 0.2 ms and 5.4% false-positive findings using ID IN > 0.3 ms. This corresponds closely to the actual false-positive ABR rates obtained in this sample: 21.5% and 6.3%, respectively. In a separate series of 301 unselected cases with asymmetric sensorineural hearing loss, 29 ABRs were suspect for retrocochlear pathology. In 20 patients, ABRs were absent due to severe hearing loss. Retrocochlear pathology could be confirmed in only 2 cases (both from the group with ABR present). Thus, 47 ABRs (15.7% of 299) were false-positive.