|Year : 2016 | Volume
| Issue : 3 | Page : 193-198
Chelation-induced ototoxicity in thalassemic patients: Role of distortion-product otoacoustic emissions and various management parameters
Vikram Bhardwaj1, Rohit Verma1, Hemant Chopra1, Praveen Sobti2
1 Department of Otolaryngology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Paediatrics, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||8-Aug-2016|
Dr. Rohit Verma
Department of Otolaryngology, Dayanand Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
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.
Keywords: Chelation therapy, Ototoxicity, Thalassemia
|How to cite this article:|
Bhardwaj V, Verma R, Chopra H, Sobti P. Chelation-induced ototoxicity in thalassemic patients: Role of distortion-product otoacoustic emissions and various management parameters. Indian J Otol 2016;22:193-8
|How to cite this URL:|
Bhardwaj V, Verma R, Chopra H, Sobti P. Chelation-induced ototoxicity in thalassemic patients: Role of distortion-product otoacoustic emissions and various management parameters. Indian J Otol [serial online] 2016 [cited 2021 Apr 11];22:193-8. Available from: https://www.indianjotol.org/text.asp?2016/22/3/193/187983
| Introduction|| |
The introduction of chelating agents capable of removing excessive iron from the body has dramatically increased life expectancy in patients with thalassemia major.
Desferrioxamine (DFO) was the first iron chelator used clinically in the 1970s. It significantly improved survival mainly as a result of decreasing cardiac iron toxicity. Deferiprone is an oral iron chelating agent and is a synthetic analog of mimosine, an iron chelator isolated from Mimosa pudica. It mobilizes iron from iron storage proteins (ferritin, hemosiderin) and iron transfer proteins (transferrin, lactoferrin) to form water-soluble complexes which are excreted in urine. Deferasirox was the third iron chelator to be introduced. It is an ideal iron chelator as it has a high and specific affinity for Fe 3+, a long half-life and it can be given once daily orally ensuring a better compliance. It binds to iron in 2:1 ratio and promotes its excretion mainly through feces. Although credited with improving life expectancy in thalassemic patients, the chelating agents are associated with a wide variety of multisystem side effects. Among the three, DFO and deferasirox have been reported to be associated with ototoxicity.,
Some of the early studies in the 1970s and 1980s reported association of ototoxicity with age, serum ferritin levels, and DFO dose.,, A therapeutic index was obtained by dividing the mean daily DFO dose (mg/kg) by the serum ferritin level (ng/ml) and was reported to be helpful in predicting ototoxicity. However, subsequent studies have found no association between age or ferritin levels and ototoxicity. Most of the studies were done only on DFO and did not employ otoacoustic emissions (OAEs) for hearing assessment which are considered to be a better predictor of outer hair cell (OHC) damage.
The present study was conducted with three main objectives, i.e., to assess the prevalence of ototoxicity in thalassemic patients on regular chelation therapy, to compare the efficacy of OAEs (distortion-product otoacoustic emissions [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.
| Subjects and Methods|| |
Thirty thalassemic patients undergoing regular iron chelation therapy with DFO and deferasirox between January 1, 2010, and June 30, 2010, were included in this prospective study after applying the relevant inclusion and exclusion criteria. Follow-up studies were conducted after 12 months of chelation therapy.
Selected patients were examined otoscopically and initial audiometric tests (tympanometry, DPOAEs, and PTA) were performed on their scheduled transfusion visits between January 1, 2010, and June 30, 2010. They were followed up after 12 months of chelation therapy with same tests. In the intervening transfusion visits, records were maintained about the drugs received, their dosage, Hb, serum ferritin, auditory symptoms, weight, and height. Cumulative dose of DFO and deferasirox was calculated at the start of the study and over the 12 months follow-up period. Mean daily dosage (mg/kg/day) was calculated as the total 12 months dose divided by 365 divided by weight. Mean serum ferritin levels were calculated as the sum of all observations over 12 months period divided by a number of observations. Mean Hb was also calculated in the same way. Therapeutic index was calculated as per Porter et al., i.e., mean daily dose (mg/kg/day) divided by the serum ferritin (ng/ml). Duration of treatment was calculated as the time from the initiation of therapy to the time of follow-up study. PTA, DPOAE, and tympanometry recordings were done in standard sound-treated room with noise levels within permissible limits according to ANSI (1977) standards.
PTA was conducted using the commercial audiometer ARPHI 2009 and the audiometric headphones, telephonic TDH39 with tone stimulus ranging from 0.25 to 8 kHz (0.25, 0.5, 1, 2, 4, and 8 kHz) and BC thresholds with bone vibrator B-70 with tone stimulus ranging from 0.25 to 4 kHz (0.25, 0.5, 1, 2, and 4 kHz) using the standard modified Hughson-Westlake technique. The response was labeled as hearing loss according to the WHO classification (1980). The hearing thresholds on audiometry were measured in both ears separately. As the findings were very similar, they were expressed as the mean of right and left ears. Pure tone average was calculated as average of hearing threshold at 2, 4, and 8 kHz. Tympanometry and stapedial reflex tests were performed with the SIEMENS SD 30 tympanometer.
DPOAEs were recorded using the commercial NEUROAUDIO OAE equipment using NEUROSOFT 7 version according to the DP-gram procedure. Conventionally, f1 < f2 with f2 corresponding to the audiometric frequencies of 1, 2, 3, 4, 6, and 8 kHz. Low-tone DPOAEs are not considered to be of particular value to the drug-induced ototoxicity, which is characterized by high-frequency hearing loss. The stimuli presented had the following characteristics:
- f2/f1 ratio of 1.22
- L1 = 65 dB SPL, L2 = 55 dB SPL
- f2 at 1000, 1429, 2000, 2857, 4000, 5714, and 8000 Hz.
The DPOAEs emitted were recorded by the microphone and were analyzed. The DPOAEs were considered indicative of cochlear damage when revealed a signal/noise ratio (SNR) <6 dB in at least three frequencies. The DPOAEs were measured independently in each ear; we considered the patient to have altered cochlear function regardless of whether abnormalities were unilateral or bilateral. Comparisons were made between the baseline PTA and DPOAEs and those conducted after 12 months follow-up period.
Having collected and analyzed the data, 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|| |
Of the 30 patients selected for the study, 22 were males and 8 females. The average age of the group was 120 months/10 years with minimum age being 44 months/3.6 years and maximum age being 21.5 years. The mean height and weight of the group were 124 cm and 24.5 kg, respectively. The mean Hb level of the group was 10.63 g% with 24 patients on oral deferasirox, four on DFO, and two on a combination of both. In all our patients, the therapeutic index was found to be well below the recommended 0.025.
The number of patients showing hearing loss using PTA increased from 3 (10%) at the start of the study to 7 (23.3%) on follow-up observation. Similarly using DPOAEs, the number of patients with hearing deficit was 11 (36%) at the start of study which increased to 14 (46%) at follow-up observation [Table 1].
|Table 1: Prevalence of hearing deficit using pure tone audiometry and otoacoustic emissions at first and follow-up observation|
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[Table 1] shows that as a tool for detecting ototoxicity, OAEs are better predictors as compared to conventional PTA. Second, it shows progression of ototoxicity with continuation of chelation therapy. To compare the changes in DPOAEs after 1 year of therapy, Wilcoxon test was applied between SNR values at first and follow-up observations. The analysis showed a significant decrease in the DPOAE levels after 1 year of therapy at 4000 Hz for left ear, and 5714 Hz and 8000 Hz for both left and right ears [Table 2].
|Table 2: Comparison of distortion-product otoacoustic emissions at first and follow-up observation|
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As shown in [Table 2], serial no. 1 compares the SNR at 1000 Hz for right ear at first and follow-up observations. Pairs 1–7 compare SNR on right ear at each successive frequency from 1 to 8 kHz. Similarly, serial numbers 8–14 compare SNR on left ear at each successive frequency. Meanwhile, standard deviation and P values for each frequency for both right and left ear are then calculated.
Similarly, comparing changes in PTA values at first and follow-up observations, the analysis showed a significant decrease in threshold values at frequencies of 2000, 4000, and 8000 Hz but not at lower frequencies of 250, 500, and 1000 Hz [Table 3].
|Table 3: Comparison of pure tone average at first and follow-up observation|
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Prevalence of DPOAE abnormalities was studied at each particular frequency and it showed greater abnormality at higher frequencies of 4, 6, and 8 kHz with maximum number of patients showing abnormality at 5714 Hz [Table 4].
|Table 4: Prevalence of distortion-product otoacoustic emission abnormalities at particular frequencies|
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[Table 4] shows the relationship between the number of patients with OAE abnormalities (Y-axis) and the primary frequency (X-axis) ranging from 1000 to 8000 Hz. Dotted green line represents right ear and straight red line represents left ear. The graph shows greater abnormality at higher frequencies of 4, 6, and 8 kHz. The maximum number of patients shows abnormality at 5714 Hz. The abnormality is almost symmetrical in both ears. A relatively high number of patients show abnormalities at 1000 Hz, which could be attributed to the ambient noise.
Furthermore, the study 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 [Table 5].
|Table 5: Study of various management parameters with respect to hearing loss|
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| Discussion|| |
Thalassemia is among the most common genetic disorders worldwide, but if managed well, patients can live near-normal lives. With chronic transfusions, iron overload is inevitable and the patient will succumb to its effects if not adequately chelated. Chelation therapy using DFO and deferasirox has been very effective in prolonging survival of thalassemic patients. However, with increased survival rates, other side effects of therapy such as ototoxicity have come into focus which may limit the use of these drugs in the long run. Hearing loss has an impact on the surviving child's education, social integration, and personality development. The most important clinical outcomes of ototoxicity are the risk of delayed speech development in infants and younger children owing to impaired recognition of high-frequency consonant sounds. Therefore, primary prevention and/or early detection of hearing loss are important for providing management options. There are relatively few studies examining chelation-induced ototoxicity in children. The majority of the studies published are limited in their sample size, have collected data retrospectively, or have used PTA technique, which is not reliable for assessment of hearing loss in young uncooperative patients. We used both conventional PTA and DPOAE for detection of chelation-induced cochlear damage. This methodology, although does not establish the hearing threshold, can be used for screening of hearing abnormalities at an early stage based on pathophysiology of ototoxicity.
Prevalence and progression of hearing deficit
Using PTA, the prevalence of hearing deficit in our group was found to be 23%. On the other hand, 46% of our patients showed a hearing deficit at the end of study using DPOAEs. Styles and Vichinsky also reported a similar prevalence at 29% using PTA, but they did not employ DPOAEs as screening tool. Chen et al. reported a prevalence of 20% hearing deficit using PTA and 33% using DPOAEs. Karimi et al. reported a hearing deficit ranging from 27% to 44% using PTA. Chiodo et al. in 1997 reported hearing loss in 29% of their patients on DFO using PTA.
Screening procedure of choice
Our study found hearing deficit in 23% of patients on chelation therapy when the evaluation is done by PTA. This percentage increases to 46% when the hearing function is evaluated by DPOAEs, thus confirming previous findings that evoked OAEs can be regarded as a more sensitive technique for early detection of hearing loss, with the additional advantage that they do not require full patient cooperation. Thus, DPOAEs are more sensitive and superior to PTA for regular monitoring of cochlear functions. Moreover, DPOAEs are noninvasive, rapid, objective, easy to use, sensitive, and can be carried out in infants and sedated patients bedside using portable equipment. All these advantages offered by DPOAE testing makes it an ideal procedure for auditory screening in patients suspected of developing drug-induced ototoxicity.
Effect of various management parameters on hearing loss
When considering the affected patients with respect to various management parameters, our analysis found no significant relationship between ototoxicity and age, sex, height, weight, serum ferritin level, mean Hb, cumulative dose, and mean daily dose and duration of chelation therapy. In our population, all patients had therapeutic index below 0.025 but still 46% patients showed evidence of ototoxicity. Thus, we have observed that therapeutic index cannot be taken as a reliable predictor of ototoxicity.
Early studies conducted in the 1970s and 1980s reported significant correlation of DFO ototoxicity with DFO dose and the degree of iron overload. Porter et al. described risk factors for DFO ototoxicity, which include a dose more than 35 mg/kg per 24 h for at least 3 months, serum ferritin level of <2000 ng/ml, and therapeutic index of more than 0.025. An iron overload was considered protective against ototoxicity. Low iron overload may result in an increase in iron-free DFO available to chelate trace metals such as Zn in the cochlea. This may lead to inhibition of key metalloenzymes such as tyrosinase or lipoxygenase within the cochlea leading to OHC damage. Styles and Vichinsky reported no significant differences between the affected and unaffected groups with respect to age, DFO dose or duration, ferritin, or therapeutic index. In 2008, another study was undertaken by Shamsian et al. which too found no significant differences between sensorineural hearing loss (SNHL) and non-SNHL patients in age, sex, serum ferritin level, age of the first transfusion, starting age of deferoxamine infusion, or duration and dosage of DFO therapy.
Safe dose to prevent ototoxicity
The recommended dose of DFO is 20–60 mg/kg/day with maximum of 50 mg/kg/day and for deferasirox is 20–40 mg/kg/day. A dose <50 mg/kg/day has been conventionally considered low risk for ototoxicity. Of thirty patients, 29 had mean daily dose of <40 mg/kg/day for both DFO and deferasirox. However, despite receiving chelation therapy dose in a range conventionally considered low risk for ototoxicity, a large number of our patients (46%) showed auditory involvement. Thus, we can say that no dose can be considered entirely safe and ototoxicity may be dependent on individual susceptibility or other factors which are yet unknown. Karimi et al. have recommended routine audiologic assessment at least once every 2 years using PTA for a prompt diagnosis and management of hearing complications. However, our study reveals a significant change in both PTA threshold and DPOAE values over 1 year of chelation. Thus, we recommend annual audiological screening using DPOAEs in patients on chelation therapy with preferably a baseline record before starting chelation.
Resolution of ototoxicity with dose reduction
Some previous studies have reported complete resolution of all auditory symptoms with immediate dose reduction while others have reported only partial improvement or stabilization.,,, Thus, serial audiometric evaluations would help in detecting chelation-induced hearing loss at an early stage and may prevent permanent hearing loss by altering chelation therapy wherever possible. However, the effect of dose reduction on resolution of ototoxicity was not analyzed in our study which was purely an observational study.
Limitations of our study
It was a purely observational study with no attempt being made to change the management course. The number of patients was small and most of the patients were already on chelation therapy at the start of the study. Hence, pretherapy baseline audiological status was not known. Furthermore, the effect of dose reduction on auditory function improvement was not studied.
| 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%). Some previous studies have shown a correlation between ototoxicity and dose, duration, or therapeutic index of chelation therapy. However, no variables were identified in our study that could reliably predict ototoxicity. We impress on the need for regular audiological screening using DPOAEs (over conventional PTA) for early detection of ototoxicity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]