Associations between medical conditions and auditory dysfunction in US Veterans.

OBJECTIVE: To examine associations between non-otologic medical conditions and auditory dysfunction. DESIGN: Cross-sectional analysis of baseline data from the Noise Outcomes in Service members Epidemiology (NOISE) study. Logistic regression was used to estimate the association between medical conditions (0, 1, and 2 or more conditions) and auditory dysfunction (hearing loss pure tone average ≥20 dB HL and tinnitus), adjusting for key confounders including noise exposure. Secondarily, the association between specific medical conditions and auditory dysfunction was examined. All variables were self-reported. STUDY SAMPLE: United States military Veterans (n = 580) with mean age 34.1 years (standard deviation = 9.2), who were within approximately 2.5 years of separation from service. RESULTS: Compared to Veterans reporting no medical conditions, Veterans reporting two or more had increased odds on low-frequency hearing loss and on tinnitus but not on high or extended-high frequency hearing loss. Furthermore, specific conditions sleep disorder and arthritis were associated with auditory dysfunction. CONCLUSIONS: Non-otologic medical conditions were associated with low-frequency hearing loss and tinnitus in this sample of young Veterans. This suggests medical conditions may play a role in Veterans' hearing health. Whether management of medical conditions earlier in life reduces the risk of hearing loss and tinnitus requires further study.

Development and validation of a cisplatin dose-ototoxicity model.

BACKGROUND: Cisplatin is effective in the treatment of several cancers but is a known ototoxin resulting in shifts to hearing sensitivity in up to 50-60% of patients. Cisplatin-induced hearing shifts tend to occur first within an octave of a patient's high frequency hearing limit, termed the sensitive range for ototoxicity (SRO), and progress to lower frequencies. While it is currently not possible to know which patients will experience ototoxicity without testing their hearing directly, monitoring the SRO provides an early indication of damage. A tool to help forecast susceptibility to ototoxic-induced changes in the SRO in advance of each chemotherapy treatment visit may prove useful for ototoxicity monitoring efforts, patient counseling, and therapeutic planning. PURPOSE: This project was designed to (1) establish pretreatment risk curves that quantify the probability that a new patient will suffer hearing loss within the SRO during treatment with cisplatin and (2) evaluate the accuracy of these predictions in an independent sample of Veterans receiving cisplatin for the treatment of cancer. STUDY SAMPLE: Two study samples were used. The Developmental sample contained 23 subjects while the Validation sample consisted of 12 subjects. DATA COLLECTION AND ANALYSIS: Risk curve predictions for SRO threshold shifts following cisplatin exposure were developed using a Developmental sample comprised of data from a total of 155 treatment visits obtained in 45 ears of 23 Veterans. Pure-tone thresholds were obtained within each subject's SRO at each treatment visit and compared with baseline measures. The risk of incurring an SRO shift was statistically modeled as a function of factors related to chemotherapy treatment (cisplatin dose, radiation treatment, doublet medication) and patient status (age, pre-exposure hearing, cancer location and stage). The model was reduced so that only statistically significant variables were included. Receiver-operating characteristic (ROC) curve analyses were then used to determine the accuracy of the risk curve predictions in an independent Validation sample of observations from over 62 treatment visits obtained in 24 ears of 12 Veterans. RESULTS: Only cumulative cisplatin dose and pre-exposure hearing were found to be significantly related to the risk for hearing shift. The dose-ototoxicity risk curve predictions developed from the Developmental sample yielded area under the ROC curve accuracy estimates of 0.85 when applied to an independent Validation sample. CONCLUSIONS: Cumulative cisplatin dose in combination with pre-exposure hearing provides an indication of whether hearing will shift in the SRO in advance of cisplatin administration. The validated dose-ototoxicity risk curves described herein can be used before and during treatment to anticipate hearing loss. While having such a tool would not replace serial hearing testing, it would be of great benefit to an ototoxicity monitoring program. It would promote relevant pretreatment counseling. Furthermore, for those found to be at risk of SRO shifts within the speech frequencies, the oncology treatment plan could incorporate anticipated dosing adjustments that could stave off the impact that ototoxicity might bring.

Distortion-product otoacoustic emission test performance for ototoxicity monitoring.

INTRODUCTION: A nonbehavioral method for monitoring ototoxicity in patients treated with cisplatin is needed because patients enduring chemotherapy may not be well or cooperative enough to undergo repeated hearing tests. Distortion-product otoacoustic emissions (DPOAEs) provide a nonbehavioral measure of auditory function that is sensitive to cisplatin exposure. However, interpreting DPOAE findings in the context of ototoxicity monitoring requires that their accuracy be determined in relation to a clinically accepted gold standard test. OBJECTIVES: Among patients receiving cisplatin for the treatment of cancer, we sought to (1) identify the combination of DPOAE metrics and ototoxicity risk factors that best classified ears with and without ototoxic-induced hearing changes; and (2) evaluate the test performance achieved by the composite measure as well as by DPOAEs alone. DESIGN: Odds of experiencing hearing changes at a given patient visit were determined using data collected prospectively from 24 Veterans receiving cisplatin. Pure-tone thresholds were examined within an octave of each subject's high-frequency hearing limit. DPOAE were collected as a set of four response growth (input/output) functions near the highest f2 frequency that yielded a robust response at L2 = L1 = 65 dB SPL. Logistic regression modeled the risk of hearing change using several DPOAE metrics, drug treatment factors, and other patient factors as independent variables. An optimal discriminant function was derived by reducing the model so that only statistically significant variables were included. Receiver operating characteristic curve analyses were used to evaluate test performance. RESULTS: At higher cisplatin doses, ears with better hearing at baseline were more likely to exhibit ototoxic hearing changes than those with poorer hearing. Measures of pre-exposure hearing, cumulative drug dose, and DPOAEs generated a highly accurate discriminant function with a cross-validated area under the receiver operating characteristic curve of 0.9. DPOAEs alone also provided an indication of ototoxic hearing change when measured at the highest DPOAE test frequency that yielded a robust response. CONCLUSIONS: DPOAEs alone and especially in combination with pre-exposure hearing and cisplatin dose provide an indication of whether or not hearing has changed as a result of cisplatin administration. These promising results need to be validated in a separate sample.

Tinnitus onset rates from chemotherapeutic agents and ototoxic antibiotics: results of a large prospective study.

BACKGROUND AND PURPOSE: To report on the incidence and relative risk of tinnitus onset from a variety of drug therapies known to be ototoxic. Two main questions were asked: (1) What is the prevalence and incidence of tinnitus among patients treated with cisplatin, carboplatin, or ototoxic antibiotic therapies? (2) Do commonly reported treatment or subject factors confound or modify the incidence of tinnitus onset? DATA COLLECTION AND ANALYSIS: A prospective observational study design was used to evaluate occurrence of significant otologic changes in 488 veterans (962 ears) receiving chemotherapeutic agents (cisplatin, carboplatin), ototoxic antibiotics (primarily aminoglycoside), or nonototoxic drugs (control medications). A subset of 260 veterans lacking tinnitus prior to drug exposure was used to compare rates of tinnitus onset. Subjects were tested prior to, during, and following their treatment. Planned comparisons using logistic regression, analysis of variance (ANOVA), and chi(2) statistics were made among groups by the type of medication taken, age, presence of preexisting hearing loss, days on drug, and cumulative dose of drug. RESULTS: Baseline tinnitus rates were high (nearly 47%) relative to the general population of a similar age. Subjects with exposure to ototoxic medications had significantly increased risk for developing tinnitus. Those on chemotherapeutic agents were found to have the greatest risk. Cisplatin elevated the risk by 5.53 times while carboplatin increased the risk by 3.75 over nonototoxic control medications. Ototoxic antibiotics resulted in borderline risk (2.81) for new tinnitus. Contrary to other reports, we did not find that subject factors (increased age or pre-existing hearing loss) or treatment factors (days on drug or cumulative dose) contributed to rates of tinnitus onset during treatment. CONCLUSIONS: This large prospective study confirms that new tinnitus during treatment is associated with chemotherapy and with certain ototoxic antibiotic treatment. Cisplatin and carboplatin were found to be the most potent ototoxic agents causing tinnitus at much greater numbers than the other drugs studied. Implications for counseling and audiological resource allocation are discussed.

Factors affecting sensitivity of distortion-product otoacoustic emissions to ototoxic hearing loss.

OBJECTIVES: (1) To determine the ototoxicity detection rate (sensitivity) for distortion-product otoacoustic emissions (DPOAEs) testing in adults who received ototoxic medications and experienced pure-tone threshold changes during the course of treatment; (2) to determine the extent to which DPOAE sensitivity to ototoxicity depends on the type of drug administered (platinum or antibiotic), magnitude of ototoxic threshold shifts, pre-exposure pure-tone threshold, and DPOAE data; and (3) to build a model to predict DPOAE sensitivity. DESIGN: DPOAE and audiometric data were obtained as part of a prospective Veterans Affairs study investigating methods of ototoxicity monitoring. Data were analyzed from 90 ears of 53 subjects receiving ototoxic medications and showing significant hearing changes in at least one ear. Pure-tone threshold data were obtained at frequencies from 0.5 to 20 kHz, using 1/6-octave precision near the upper frequency limit of hearing. DPOAE data are reported for f2's from 0.8 to 8.0 kHz in 1/6-octave increments using primary levels (L1/L2) of 65/59 dB SPL and a primary frequency ratio (f2/f1) of 1.2. Test results were evaluated at various times during drug treatment to determine whether DPOAE level changes were associated with behavioral hearing changes. Univariate and multivariate analysis techniques were used to determine factors that affected DPOAE sensitivity to ototoxic damage. RESULTS: Of the 90 ears examined, 82 (91%) had DPOAEs that could be monitored for changes. Sixty-four of these 82 ears (78%) had DPOAEs that were reduced or absent following drug treatment. DPOAE sensitivity to ototoxicity was unrelated to the type of ototoxic drug administered. Rather, DPOAE sensitivity depended on the magnitude of postexposure hearing changes and on variables related to pre-exposure audiogram and DPOAE measurements. Behavioral hearing changes not detected by DPOAEs were small on average (<7 dB). DPOAE sensitivity was reduced in ears with poorer pre-exposure hearing, and in ears with measurable DPOAE frequencies limited to f2's below 2.5 kHz or more than one octave from the frequency region where hearing change occurred. Results of logistic regression modeling showed that DPOAEs present at f2's greater than 2.5 kHz were associated with the eventual success of ototoxicity monitoring with DPOAEs. However, independent variables examined could not explain differences in the relative timing of behavioral and DPOAE changes. A roughly equivalent proportion of ears experienced DPOAE changes before, during, or after behavioral hearing changes. CONCLUSIONS: DPOAEs are a useful screening tool for ototoxicity in adults with pre-exposure hearing loss, but are less sensitive compared with a behavioral test method that targets thresholds near the upper limit of a subject's audible frequency range. Ears successfully monitored for ototoxicity with DPOAEs are those with better pre-exposure hearing, greater postexposure hearing changes, and baseline DPOAEs near the highest behavioral test frequencies and present at high f2's. Results suggest that successful monitoring of ototoxicity with DPOAEs may be predicted clinically by assessing the measurable DPOAE f2 frequency range and its relation to the highest behavioral test frequencies.

Tinnitus Screener: Results From the First 100 Participants in an Epidemiology Study.

PURPOSE: In the Noise Outcomes in Servicemembers Epidemiology Study, Veterans recently separated from the military undergo comprehensive assessments to initiate long-term monitoring of their auditory function. We developed the Tinnitus Screener, a four-item algorithmic instrument that determines whether tinnitus is present and, if so, whether it is constant or intermittent, or whether only temporary tinnitus has been experienced. Predictive validity data are presented for the first 100 Noise Outcomes in Servicemembers Epidemiology Study participants. METHOD: The Tinnitus Screener was administered to participants by telephone. In lieu of a gold standard for determining tinnitus presence, the predictive validity of the tinnitus category assigned to participants on the basis of the Screener results was assessed when the participants attended audiologic testing. RESULTS: Of the 100 participants, 67 screened positive for intermittent or constant tinnitus. Three were categorized as "temporary" tinnitus only, and 30 were categorized as "no tinnitus." Tinnitus categorization was predictively valid with 96 of the 100 participants. CONCLUSIONS: These results provide preliminary evidence that the Screener may be suitable for quickly determining essential parameters of reported tinnitus. We have since revised the instrument to differentiate acute from chronic tinnitus and to identify occasional tinnitus. We are also obtaining measures that will enable assessment of its test-retest reliability.

Evaluation of insert earphones for high-frequency bedside ototoxicity monitoring.

Ototoxic hearing loss is usually detected earliest through monitoring of the highest audible frequencies in individuals administered ototoxic medications. Conducting ototoxicity monitoring may require testing patients in the hospital room. This study evaluated the use of insert earphones for obtaining reliable threshold responses at bedside. Twenty adult subjects were tested during two different sessions in the sound booth and on the ward. Thresholds were obtained for frequencies from 5 to 16 kHz and at 2 kHz with the use of the KOSS Pro/4X Plus earphones and Etymotic ER-4B MicroPro insert earphones. Results indicate that ER-4B insert earphones are as reliable as KOSS earphones for testing on the ward for high-frequency ototoxicity monitoring.

A Store-and-Forward Tele-Audiology Solution to Promote Efficient Screenings for Ototoxicity during Cisplatin Cancer Treatment.

BACKGROUND: Tele-audiology improves access, controls cost, and improves efficiency of many aspects within health care. We have developed and validated a device, the ototoxicity identification device (OtoID), which enables remote hearing monitoring by a patient during chemotherapy treatment. Aspects of the design such as patient self-testing and texting of results to the audiology clinic are important features of this device. PURPOSE: The purpose of this article is to present the efficacy and effectiveness of the OtoID hearing screener. RESEARCH DESIGN: A repeated measures design was used in this study. STUDY SAMPLE: Twenty-one veterans undergoing cisplatin chemotherapy were recruited in this study. DATA COLLECTION AND ANALYSIS: Participants were tested using the OtoID at each cisplatin treatment by an audiologist using the manual mode of test and the participant using the automated mode of test. Test sensitivity and specificity were developed from the detection (yes/no) of an American Speech-Language-Hearing Association (ASHA) change in hearing. RESULTS: The OtoID had a test sensitivity of 80.6% and specificity of 85.3%. A logistic regression model analysis of the probability of an ASHA shift identified by the automated OtoID was conducted. Separate models were fit to establish effects of age, average baseline thresholds in the sensitive range for ototoxicity (SRO), and dose of cisplatin on the probability of a positive hearing change result. Interactions were also included to evaluate these effects on the sensitivity and false-positive rates of the automated test. Results indicated no statistically significant effects of age, of baseline hearing in the SRO frequencies, or of cisplatin dose. CONCLUSIONS: The OtoID automated test can be recommended for use. The automated test provides significant personnel efficiencies. The modem with simple text messaging function recently added to the device improves on these efficiencies.

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.

Proposed comprehensive ototoxicity monitoring program for VA healthcare (COMP-VA).

Prevention and rehabilitation of hearing loss and tinnitus, the two most commonly awarded service-connected disabilities, are high priority initiatives in the Department of Veterans Affairs (VA). At least 4,000 Veterans, most with significant hearing loss, will receive cisplatin this year, with more than half sustaining permanent hearing shift and nearly 40% developing new tinnitus. With improved survivability following cancer treatment, Veterans treated with cisplatin are approached with the dual goals of effective treatment and preserved quality of life. This article describes COMP-VA, a comprehensive ototoxicity monitoring program developed for VA patients receiving cisplatin. The program includes an individualized pretreatment prediction model that identifies the likelihood of hearing shift given cisplatin dose and patient factors. It supports both manual and automated hearing testing with a newly developed portable audiometer capable of performing the recommended procedures on the chemotherapy unit during treatment. It also includes objective methods for identifying outer hair cell changes and predicting audiogram changes using distortion-product otoacoustic emissions. We describe this program of evidence-based ototoxicity monitoring protocols using a case example to give the reader an understanding of how this program would be applied, along with a plan for future work to accomplish the final stages of program development.

OtoID: new extended frequency, portable audiometer for ototoxicity monitoring.

Portability of equipment is an increasingly important component in the practice of audiology. We report on a new device, the OtoID, that supports evidence-based ototoxicity testing protocols, provides capability for hearing testing on the hospital treatment unit, and can automate patient self-testing. The purpose of this article is to report on the validation and verification of the OtoID portable audiometer in 40 subjects both young and old, with and without hearing impairment. Subjects were evaluated by an audiologist using the manual hearing test program and then self-tested via an automated testing program. Testing was done in a sound booth and on a hospital treatment unit. Therefore, data were collected in four conditions (booth vs hospital unit and automated vs manual testing) and analyzed for testing bias, repeatability, and American Speech-Language-Hearing Association-significant ototoxicity false-positive rate. Repeatable hearing threshold results were obtained on all subjects who performed the test, regardless of hearing status or testing location.

Development and evaluation of a portable audiometer for high-frequency screening of hearing loss from ototoxicity in homes/clinics.

Cancer treatment often requires patients to be exposed to drugs that can damage hearing. Drugs such as cisplatin can cause permanent damage to hearing if not detected early. Damage typically occurs first in the more basal regions of the cochlea which are specific for high-frequency (HF) hearing and progresses to more apical regions that are relevant to speech understanding. Monitoring of HF hearing loss can be an effective means for early detection of ototoxicity caused by chemotherapy. Once ototoxicity is detected, the oncology medical team could adjust the drug dosage or switch to medications that are less ototoxic. Telehealth technology may improve access to ototoxicity monitoring. Patients could monitor their own hearing using a device that alerts healthcare professionals in the event of a change in hearing. A portable audiometer is currently not available that is 1) capable of automatic or manual (by an audiologist) operation; 2) designed with precision pure-tone functionality up to 20 kHz; and 3) able to remotely transfer health status information to a healthcare professional. This paper describes the design of a technology, the ototoxicity identification (OtoID), that includes a portable audiometer with HF test functionality that meets ANSI/ASA S3.6-2010 standards and is capable of reliably detecting a person's drug-related hearing changes relative to a baseline period (i.e., before ototoxic drugs) using an automated test. The system includes a wireless cellular modem capable of notifying a remote healthcare professional in the event that a significant change in hearing has occurred in the patient. The system was evaluated on test subjects within a sound-proof booth, a noisy hospital ward, and within their homes. Results indicate that the OtoID system can be used by patients to effectively monitor hearing changes remotely within their home or in a hospital ward, ultimately enabling early detection of ototoxicity and potentially avoiding hearing loss.

Instrumentation system upgrade supports mobile personalized healthcare delivery.

Clinicians and patients need mobile tools to detect ototoxic change early and prevent hearing loss. We report on the development of an upgrade of our existing desktop-based clinical-audiological instrumentation into a mobile instrument platform which efficiently supports personalized ototoxicity monitoring on the hospital wards as well as clinic by a trained clinician. Our new wireless-enabled system also serves as the instrumentation platform for the next phase of our work which is remote healthcare delivery with patient-guided at-home ototoxicity monitoring using an evidence-based individualized SRO protocol.

Hearing health and care: the need for improved hearing loss prevention and hearing conservation practices.

Hearing loss affects 31 million Americans, particularly veterans who were exposed to harmful levels of noise during military functions. Many veterans also receive treatment with ototoxic medications, which may exacerbate preexisting hearing loss. Thus, hearing loss is the most common and tinnitus the third most common service-connected disability among veterans. Poor implementation of hearing protection programs and a lack of audiometric testing during medical treatment leave veterans vulnerable to unrecognized and untreated hearing loss until speech communication is impaired. Individualized audiometric testing techniques, including assessment of high frequencies, can be used in clinical and occupational settings to detect early hearing loss. Antioxidants also may alleviate cochlear damage caused by noise and ototoxicity. Ultimately, hearing loss prevention requires education on reducing occupational and recreational noise exposure and counseling on the risks and options available to patients. Technological advances will improve monitoring, allow better noise engineering controls, and lead to more effective hearing protection.

An efficient test protocol for identification of a limited, sensitive frequency test range for early detection of ototoxicity.

A primary focus of research at the National Center for Rehabilitative Auditory Research (NCRAR) has been to develop methodology for rapid and efficient early detection of ototoxicity. It has been shown that an individualized, limited frequency range can be identified, which is sensitive to early ototoxic changes in the auditory system. In this study, a rapid identification protocol for identifying the uppermost target frequency within this sensitive range of ototoxicity (SRO) was investigated. In 36 of 42 ears, the target frequency found with the rapid identification protocol was the same as that found with the full-frequency baseline testing. Where differences occurred, target frequencies obtained by the two methods did not differ by more than one-half octave. This rapid identification protocol results in considerable time savings in ototoxicity monitoring, which will result in the capability to include more patients in a monitoring program.