Evidence of the label ototoxicity in medicines marketed in Denmark

Ototoxic side effects such as sensorineural hearing loss and tinnitus can be caused by acute salicylate intoxication. Bilateral symmetric sensorineural hearing loss involving all tested frequencies is a typical pattern of hearing loss in acute salicylate intoxication, which usually resolves within 2 or 3 days without any specific treatment for ototoxicity. Herein, we report a case of suicidal aspirin intoxication resulting in sudden bilateral hearing loss and vertigo. The patient exhibited spontaneous downbeat nystagmus, and the mechanism underlying this characteristic nystagmus is discussed.

Patient Benefits of Audiology, Pharmacy Collaboration

Best known for its remarkable effectiveness in successfully treating testicular cancer in adults, cisplatin is a platinum-based chemotherapeutic agent used in many multimodal pediatric cancer treatment regimens. Children with neuroblastoma, hepatoblastoma, retinoblastoma, germ cell tumors, osteosarcoma, medulloblastoma, and other brain tumors are routinely treated with cisplatin, and/or its newer and less toxic analog, carboplatin. The mechanism of action of these drugs involves covalent binding to purine DNA bases, leading to cellular apoptosis. The dose-limiting factors in the administration of platinum-based drugs are generally nephrotoxicity (cisplatin) or myelosuppression (carboplatin), but cisplatin in therapeutic doses is highly ototoxic. Carboplatin, although with substantially less ototoxic potential than cisplatin, is associated with a high risk for hearing loss when used in combination with cisplatin and when used in myeloablative doses as conditioning for hematopoietic stem-cell transplantation in children. Ototoxicity from cisplatin manifests initially as bilateral high frequency sensorineural hearing loss, progressing in severity to the speech ranges with increasing cumulative doses. The hearing loss is caused by sensory hair cell destruction that begins at the base of the cochlea, where high frequency sounds are processed, and continues toward the cochlear apex, where lower frequency sounds are affected. Hearing loss from cisplatin or carboplatin is permanent and may have a delayed onset, with progressive loss occurring many years after completion of therapy. Young children are particularly sensitive to this unfortunate adverse effect. Children treated for high-risk neuroblastoma, for example, are likely to sustain moderate to severe therapy-related hearing loss, with high potential for difficulties in speech discrimination and language acquisition, diminished academic achievement compared with peers with normal hearing, the potential for lifelong impairment of language and academic skills, and diminished quality of life. Although often underappreciated, even hearing loss restricted to high frequency ranges (4,000-8,000 Hz) can have a significant impact on language development, verbal abilities, and reasoning skills in young children. This is of particular concern with patients treated in early childhood for embryonal malignancies because the ototoxic effects are concurrent with the developmental period in which the process of acquiring speech and language skills is so critical. As described by Brock et al in this issue of Journal of Clinical Oncology, efforts to find a method to prevent or mitigate the ototoxic effect of therapeutic doses of platinum drugs in children without diminishing its effectiveness in killing cancer cells is ongoing but has yet to be realized in the clinical setting. One of the key issues in designing a clinical research study to evaluate preventative interventions is having a valid and reliable outcome measure that is standardized, practical, and widely accepted. Such a hearing loss measure needs to reflect the unique aspects of testing children of different ages and capabilities. Although in 1991 Brock et al published a pediatricspecific hearing loss scale for cisplatin exposure, the measure used to monitor and categorize severity of hearing loss in therapeutic trials has been the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 3.0, which requires a baseline evaluation before treatment initiation and then measures change in hearing level as treatment progresses. The NCI-CTCAE v3.0 scale was not specialized to children and has many inherent problems for clinical research purposes, including the fact that baseline measurements are often difficult to obtain in pediatric patients, particularly in very ill patients. In addition, obtaining true auditory thresholds (response to lowest intensity level) can be challenging in pediatric patients. Instead, only minimal response levels are often obtainable, which makes calculating a true decrease in hearing sensitivity difficult and potentially inaccurate. The NCI-CTCAE v3.0 also does not specify test frequencies. Greater emphasis should be placed on the higher frequencies than the lower frequencies when determining cisplatin-induced ototoxicity in children. NCI-CTCAE v3.0 toxicity grades 3 and 4, usually dose-limiting in clinical trials, are defined by subjective measures that are left to interpretation and may differ among audiologists. Although the most recent version of the NCICTCAE, version 4.03, significantly improves on the previous 3.0 version by identifying specific test frequencies for pediatric patients and defining more objective measures, problems with measuring change in hearing compared with baseline measurements and the somewhat subjective nature of defining grades 3 and 4 still remain. Several other hearing loss grading scales have been introduced over the years, as shown in Table 1, including a modification of the 1991 Brock et al scale by Chang and Chinosornvatana in 2010. In the new measure presented by Brock et al, a grading scale based on JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 19 JULY 1 2012

Clinically used drugs and chemical agents may potentially cause adverse effects to the human auditory and vestibular systems. Many of them, such as aminoglycosides and cisplatin, can play a critical role in the treatment of serious or life-threatening diseases; others, like loop diuretics or salycilates, offer such important therapeutical effects compared to the ototoxic side effects that the ototoxicity risk can be considered to be of minor importance. The problem of ototoxic side effects is more acute in developing countries, where highly effective and low-cost drugs are more easily prescribed without adequate monitoring. Medical awareness of doses, forms of administration, populations at risk, and possible synergism is necessary in order to develop appropriate care in the prescription of drugs with ototoxic side effects. Relatively recent issues such as risk-benefit analysis, patient-informed consent, and quality-of-life considerations, particularly when life expectancy can be low, are also to be considered. At present, a uniform method of monitoring for all potentially ototoxic therapeutics does not seem reasonable or practical. It is recommended, however, that individual auditory function be noted for a particular drug being employed. Protocols and exams should be easy, quick, sensitive, reliable, and as objective as possible. Benefits of audiological monitoring include the opportunity to change the patient's treatment course, improvement of patient and family awareness of the impact of hearing impairment, and timely prescription of amplification devices. Finally, particular attention should be paid to high-risk populations such as neonatal intensive care unit patients.

Undiagnosed and therefore untreated permanent paediatric hearing loss can have a detrimental impact on a child's speech, language, social and educational development, and quality of life. Therefore, early diagnosis is required for successful treatment with hearing aids to minimise the negative impact of hearing loss. Newborn hearing screening programmes may have decreased the average age at diagnosis of hearing loss worldwide, but outcomes vary widely between countries. In this study, we therefore aimed to assess the median age of children at diagnosis of permanent unilateral and bilateral hearing loss in Eastern Switzerland. In this retrospective cohort study, children born in Eastern Switzerland with permanent hearing loss diagnosed at the Division of Paediatric Audiology at the Cantonal Hospital of St Gallen (the tertiary referral centre for Eastern Switzerland) were included. The study period was from 1 January 2014 to 31 December 2019. The primary endpoint was age at diagnosis of permanent unilateral or bilateral hearing loss. Descriptive data collected were the type and WHO grade of hearing loss, the status of newborn hearing screening and other information such as path of referral and place of residence. In total, 107 children with permanent hearing loss were included in this study. Overall, the median age at diagnosis was 45.0 months (interquartile range [IQR] 5.7-74.8). The median age at diagnosis for children with bilateral hearing loss was 25.8 months (IQR 3.6-70.5), compared to 63.1 months (IQR 11.4-88.5) for children with unilateral hearing loss. For children with bilateral hearing loss, the median age at diagnosis was lower with higher WHO grades of hearing loss: 65.6 months (IQR 11.1-131.6) for grade I vs 4.5 months (IQR 2.2-6.0) for grade IV. Children with bilateral hearing loss and a documented failed newborn hearing screen were diagnosed early: median age at diagnosis 4.0 months (IQR 2.2-12.3). In conclusion, the age at diagnosis of paediatric permanent hearing loss in our study is variable and, in some cases, late. This applies particularly to bilateral hearing loss that should have been diagnosed by the newborn hearing screen in congenital cases and unilateral hearing loss.

Neurofibromatosis type 2 and auditory brainstem implantation

Changing the time intervals between cisplatin cycles alter its ototoxic side effect

The number of children identified early with mild bilateral and unilateral hearing loss (MUHL) has increased over the past 3 decades due to population-based newborn hearing screening initiatives. Early identification involves additional hearing-related services for these children in the early years. Despite the growing number of children, little information exists regarding their use of health care services. We examined overall health care utilization for this population of children with hearing loss in a Canadian pediatric center as well as the factors associated with audiology and early intervention service utilization. As part of a longitudinal MUHL research program, we examined health care utilization in a population-based cohort of 182 children with MUHL who were identified in one Canadian pediatric center from 2014 to 2018 and followed up to 6 years. Audiologic characteristics were collected prospectively, and health care utilization data were collected retrospectively through administrative databases. Descriptive statistics were used to summarize health care encounters. We used negative binomial regression models to examine the relationship between several clinical factors including age of diagnosis, degree, and laterality (unilateral/mild bilateral) of hearing loss, use of hearing technology, developmental concerns, and services used in audiology and early intervention. The 182 children were diagnosed at a median age of 4.1 months (interquartile range: 1.9, 55.7) and mean follow-up time was 48.6 (SD: 20.0) months. A total of 9867 hospital encounters were recorded in the medical chart including 2247 audiology, 3429 early intervention, and 701 Ear Nose and Throat service encounters. For audiology services, health care utilization (rate of visits per month of follow-up) was related to whether hearing loss was mild bilateral or unilateral, use of hearing aid(s), progressive hearing loss, developmental concerns, and age of diagnosis. Children with mild bilateral hearing loss had 68% more visits compared with children with unilateral hearing loss. Children with hearing aid(s) had 86%more visits than those without amplification. During the study period, 68.1% of children had at least one early intervention visit. In multivariable regression, after controlling for time followed, earlier age at diagnosis, bilateral hearing loss, use of hearing aid(s), progressive hearing loss, more severe hearing loss, and developmental concerns were all significantly associated with more early intervention service utilization. Our findings provide a comprehensive profile of hearing-related services provided to a population-based cohort of early-identified children with MUHL. Children with mild bilateral loss required more audiology services than those with unilateral hearing loss. Two-thirds of the children with MUHL utilized some early intervention services. Use of hearing aid(s), bilateral hearing loss, progressive hearing loss, and earlier age of diagnosis result in more service utilization for both audiology and early intervention. Understanding the intensity of care use among various subgroups of children with hearing loss can shed light on the impact of these hearing losses and inform resource planning.

Evidence from school-aged children suggests that the ease with which children listen varies with the presence of hearing loss and the acoustic environment despite the use of devices like hearing aids. However, little is known about the ease of listening in preschool-aged children with hearing loss-an age at which rapid learning occurs and increased listening difficulty or effort may diminish the required capacity to learn new skills. To this end, the objectives of the present study were to (i) assess parent-reported aided ease of listening as a function of hearing loss configuration (hearing loss in one versus both ears) and device configuration among children with hearing loss in one ear (unilateral hearing loss), and (ii) investigate factors that influence children's ease of listening. Parents of 83 children with normal hearing, 54 aided children with bilateral hearing loss (hearing loss in both ears), and 139 children with unilateral hearing loss participated in the study. Of the 139 children with unilateral loss, 72 were unaided, 54 were aided with a device on the ear with hearing loss (direct aiding) and 13 were aided with a device that routed signals to the contralateral normal hearing ear (indirect aiding). Mean age of children was 40.2 months (1 SD = 2.5; range: 36 to 51). Parents completed the two subscales of the Parents' Evaluation of Aural/Oral Performance of Children+ (PEACH+) questionnaire, namely functional listening and ease of listening. Individual percent scores were computed for quiet and noisy situations. Linear mixed-effects models were used to assess the effect of hearing loss configuration and device configuration in children with unilateral hearing loss. Multiple regression was used to assess factors that influenced ease of listening. Factors included hearing thresholds, age at first device fit, consistency in device use, condition (quiet/noise), presence of developmental disabilities, and functional listening abilities. Children with direct aiding for their hearing loss, either unilateral or bilateral, had similarly lower functional listening skills and ease of listening than their normal hearing peers. Unaided children with unilateral hearing loss had lower functional listening skills and ease of listening than their normal hearing peers in noise but not in quiet. All aided children with unilateral hearing loss, irrespective of direct or indirect aiding had lower functional listening skills and ease of listening relative to normal hearing children in both quiet and noise. Furthermore, relative to unaided children with unilateral hearing loss, those with indirect aiding had lower functional listening and ease of listening. Regression analyses revealed functional listening as a significant predictor of ease of listening in all children with hearing loss. In addition, worse degrees of hearing loss and presence of noise reduced ease of listening in unaided children with unilateral hearing loss. Bilateral hearing loss is associated with poorer-than-typical ease of listening in preschoolers even when aided. The impact of unilateral hearing loss on ease of listening is similar to that observed in children with bilateral hearing loss, despite good hearing in one ear and aiding. Given increased difficulties experienced by children with unilateral loss, with or without a device, additional strategies to facilitate communication abilities in noise should be a priority.

Acetylic acid, such as aspirin, is one of the most commonly used medication in Western societies. Aspirin overdosage causes ototoxic side effects in some patients, such as bilateral mild to moderate sensorineural hearing loss and tinnitus. Recent literature describes, that salicylates act as competitive inhibitors of Cl- anions at the anion-binding site of prestin, the motor protein of the outer hair cell. This molecular mechanism correlates well with the clinical audiological mainstays of aspirin-induced hearing loss, dose dependency, cochlear site of hearing loss and reversibility. We report about a young man with an acute moderate aspirin intoxication resulting in asymmetric hearing loss of 50 dB HL and tinnitus for five days. Otoacoustic emissions were absent on the first day of intoxication but could be measured again on the fifth day after the intoxication. As the ototoxic side effects resolve with in two or three days, no specific treatment is necessary for ototoxicity. Medical treatment of acute or chronic aspirin intoxications aims to decrease further drug absorption by gastrointestinal decontamination and to accelerate elimination by alkaline diuresis. Only in severe intoxications hemodialysis may be considered to treat neurologic, pulmonal, renal or cardial complications.

This study investigates whether the nutritional state of guinea pigs is a risk factor for the ototoxic side effects of cisplatin, gentamicin, and gentamicin in combination with ethacrynic acid. A normal nutritional state was maintained with a standard 18.5% protein diet while nutritional deficiency was produced by feeding a 7% protein diet. Hearing loss was measured by auditory evoked brainstem responses. Guinea pigs on the low protein diet had a significantly higher drug-induced hearing loss. Cisplatin-induced hearing loss was 32 dB in undernourished animals but 10 dB in normal animals (18 kHz). The difference for gentamicin was 74 dB versus 42 dB (18 kHz). Gentamicin in combination with 20 mg ethacrynic acid/kg body weight produced a hearing loss of 95 dB in animals on a low protein diet and 12 dB in animals on a full protein diet. The enhanced ototoxicity was not based on differences in drug pharmacokinetics since serum levels of platinum and gentamicin did not differ between the groups. These results demonstrate that the severity of ototoxic side effects is influenced by nutritional factors. They also imply that animals on a restricted diet may be a more appropriate model for severely compromised patients undergoing pharmacotherapy.

Sudden hearing loss associated with tacrolimus in a liver transplant recipient

In this study, we aimed to describe differences in diagnosis and both auditory and speech/language intervention utilization between children with permanent unilateral hearing loss as compared with bilateral hearing loss. A retrospective cohort study was performed of children evaluated in a multidisciplinary hearing loss clinic at a tertiary care pediatric hospital. Children aged 0 to 18 years with either permanent unilateral or bilateral hearing loss were included. One hundred fourteen children with unilateral hearing loss and 268 children with bilateral hearing loss were studied for a total of 382 children. There were no demographic differences between children with permanent unilateral versus bilateral hearing loss. Rates of newborn hearing screening and referred screening results were similar between those with unilateral and bilateral hearing loss. Despite similar rates of referred newborn hearing screening, those with bilateral hearing loss were diagnosed at a younger age (mean 3.6 years, SD 3.8 years) as compared with those with unilateral hearing loss (mean 5.0 years, SD 4.2 years). Children with unilateral hearing loss had similar severity of hearing loss in their poorer hearing ear as compared with children with bilateral hearing loss, yet they were significantly less likely to be fitted with hearing devices (53% versus 78%) or receive speech/language therapy (36% versus 54%) as compared with children with bilateral hearing loss. Multivariate analysis found that bilateral hearing loss and earlier age of hearing loss diagnosis were associated with hearing device use. Early diagnosis and intervention for childhood hearing loss have a significant impact on a child's educational success and social relationships. However, little is known about differences in diagnosis and resource utilization between children with permanent unilateral hearing loss versus bilateral hearing loss. Children with unilateral hearing loss were diagnosed at a later age and were less likely to utilize hearing devices or speech/language therapy compared with those with bilateral hearing loss, despite having similar severity of hearing loss in the poorer hearing ear. There is a strong body of evidence that children with unilateral hearing loss have improved hearing outcomes with hearing devices, which suggests there is room for improvement in identifying unilateral hearing loss and providing adequate services to optimize educational success. However, speech therapy is generally implemented in response to language delays. Therefore, children with unilateral loss may have lower rates of language delays as compared with those with bilateral hearing loss, thereby explaining differences in speech therapy utilization.

The results of clinical use of routine high frequency audiometry in monitoring the ototoxic side effects of platinum and its derivatives are described in this prospective study. After demonstrating the reproducibility of the technique, we discuss the first results of an analysis of ototoxic side effects in 75 patients (150 ears). Significant differences in the pattern of hearing loss were registered for the different platinum treatment groups (cisplatin 20 mg/m2, cisplatin 50 mg/m2, and carboplatin 350 mg/m2). In the groups receiving cisplatin 50 mg/m2 and carboplatin 350 mg/m2, 42% and 25%, respectively, of the investigated ears proved to be undamaged, versus 9% undamaged in the group receiving cisplatin 20 mg/m2 (p less than .01). Ototoxic hearing loss started mainly (46% to 70%) in the higher frequencies (10,000 to 18,000 Hz) and developed into a broader-range hearing loss (1,000 to 18,000 Hz) during treatment in 13% to 43% (p less than .01). The onset of hearing damage was influenced by the patient's age (p less than .001) and the existence of a troubled otologic history (p less than .05). The study demonstrates the important role of high frequency audiometry in early detection and monitoring of ototoxic damage.

An automated auditory brainstem response (ABR) method-the ALGO-1 Plus- has been developed for hearing screening in healthy neonates. The aim of this study was to test the validity of this automated ABR screening method in at-risk neonates in a neonatal intensive care unit. Two hundred and fifty at-risk neonates were selected for screening according to the criteria of the American Joint Commerce on Infant Hearing. All 250 neonates were screened with the ALGO-1 Plus for bilateral hearing loss. When two consecutive screenings pointed to bilateral hearing loss ("refer") further audiological investigations were performed and where necessary therapeutic measures were taken. All children who "passed" the screening unilateral or bilateral enrolled in a nationwide behavioural screening programme at the age of 9 months as well as in a 6-monthly follow up programme documenting speech and language development. A total of 245 (98%) neonates passed the ALGO-1 screening, 230 (92%) at the first attempt and 15 (6%) at the second attempt. Five (2%) were referred with bilateral hearing loss. One of these died of congenital rubella shortly after screening and bilateral congenital hearing loss of > 35 dB was confirmed in the other 4. None of the infants who passed the screening were discovered to have moderate to severe bilateral hearing loss (> 40 dB) with behavioural screening (n = 183/233) or at follow up (n = 233/233). In this study, all at-risk neonates with bilateral congenital hearing loss were detected with ALGO-1 Plus screening. No false-negatives were discovered. The ALGO-1 Plus infant hearing screener can be used as a valid automated ABR-screener to detect hearing loss in at-risk neonates in a neonatal intensive care setting.