Contralateral Suppression of Distortion Product Otoacoustic Emissions in Children with Cystic Fibrosis : Effects of Tobramycin

Transcription

1 J Am Acad Audiol 9 : (1998) Contralateral Suppression of Distortion Product Otoacoustic Emissions in Children with Cystic Fibrosis : Effects of Tobramycin Bharti Katbamna* Douglas. Homnick' John H. Marks' Abstract The role of the medial efferent system in altering and/or regulating outer hair cell function in the mammalian cochlea has been proposed by a number of investigators. This study measured contralateral suppression of distortion product otoacoustic emissions (DPOAEs) in cystic fibrosis (CF) patients, treated for lung infections with low to moderate cumulative doses of tobramycin, to ascertain the contributions of the efferent-based mechanisms in the development of ototoxicity. The results showed significant suppression of DPOAEs in tobramycin-treated children compared to both nondrug-treated CF and normal children of similar ages. Since DPOAE amplitudes were comparable across the drug-treated and control groups of subjects, pronounced DPOAE suppression in the drug-treated group may be attributed to the instability of the cochlear amplifier induced by the tobramycin treatment. These findings also suggest that enhanced contralateral suppression may be the first sign of a developing ototoxicity. Key Words: Contralateral suppression, cystic fibrosis, distortion product otoacoustic emissions, tobramycin Abbreviations : CF = cystic fibrosis, DPOAEs = distortion product otoacoustic emissions he efferent-mediated effect of contralateral stimulation first became apparent T when Buno (1978) reported changes in single afferent nerve fiber activity during contralateral stimulation in animals. The suppression of 1 action potential by contralateral noise was subsequently documented in human subjects (Folsom and Owsley, 1987). Changes in otoacoustic emissions, specifically decrease in amplitude and/or modification of spectral characteristics of spontaneous (Mott et al, 1989), transient (Collet et al, 1990; Veuillet et al, 1991), *Department of Speech Pathology and Audiology, Western Michigan University, Kalamazoo, Michigan ; tdivision of Pediatric Pulmonology, Michigan State University, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan Reprint requests : Bharti Katbamna, Department of Speech Pathology and Audiology, Western Michigan University, Kalamazoo, MI ; Tel. (616) ; Fax. (616) ; katbamna@wmich.edu and distortion product (Moulin et al, 1992) otoacoustic emissions (DPOAEs), during contralateral stimulation in human subjects have also been reported more recently. These changes indicate that contralateral stimulation alters ipsilateral outer hair cell function, most likely at the level of the efferent synapses due to their connections at the basal pole of the outer hair cells. The precise role of the medial efferent system in altering and/or regulating outer hair cell function in the mammalian cochlea has been proposed by a number of investigators. Kohonen (1965) first speculated on the potential of the olivocochlear efferent system in mediating the toxic effects of aminoglycoside antibiotics based on the apparent correlation between the pattern of outer hair cell loss and the distribution of efferent innervation within the organ of Corti. His findings have since been corroborated by many other investigators (e.g., Hiel et al, 1993 ; Pujol, 1994). Moreover, the demonstration of increased kanamycin-induced hair cell damage 172

2 Contralateral Suppression of DPOAEs and Tobramycin/Katbamna et al subsequent to the sectioning of the crossed olivocochlear bundle (Capps and Duvall, 1976) supports the notion of a protective role of the efferent system on cochlear function. Conversely, however, the role of the efferent system in potentiating aminoglycoside ototoxicity has been suggested by studies that have shown loss of the suppressive effects associated with crossed olivocochlear bundle stimulation in cats following systemic aminoglycoside treatment (Brown, 1972 ; Brown and Daigneault, 1973). Likewise, the findings of a rapid and reversible loss of contralateral suppression on the ipsilaterally evoked compound action potential (Smith et al, 1994), as well as transient otoacoustic emissions (Aran et al, 1994) upon gentamicin treatment in guinea pigs, suggest the neuromuscular blocking potential of aminoglycosides (Aran, 1990). The goal of the present study was to investigate the effects of tobramycin on the contralateral suppression of DPOAEs to determine if comparable efferent-based mechanisms contribute to the development of ototoxicity in human subjects. The measurements were performed in a group of cystic fibrosis (CF) patients who received low to moderate cumulative doses of tobramycin for chronic lung infections, but who, otherwise, demonstrated normal cochlear function. Subjects METHOD Thirteen CF patients (nine who received low to moderate cumulative doses of tobramycin and four who received no aminoglycosides) and nine normal children between 7 to 14 years of age were tested. The CF patients were recruited from the Kalamazoo Center for Medical Studies-Cystic Fibrosis Center and the normal subjects were recruited from the Department of Pediatrics at the Kalamazoo Center for Medical Studies. All CF patients were screened to rule out the intake of additional ototoxic drugs such as vancomycin or diuretics, whereas the control groups consisting of the aminoglycoside-free CF patients and the normal children were screened for negative history of any ototoxic drug intake. Procedures Conventional ( khz) audiometry, high-frequency (-20 khz) audiometry, tympanometric screening, and DPOAE measurements were performed on all subjects. Conventional and high-frequency measurements were obtained with a Beltone 2000 audiometer equipped with TDH-50P and Senheiser HD 250 earphones, respectively. DPOAE measurements were made with an ER-C probe sealed in the outer ear canal (with a disposable foam earplug), and controlled by the Mimosa Acoustics CUBeDIS system (version 5.21 software). Each subject was examined for the presence of DPOAEs evoked with low- to moderate-level stimuli before the experimental measurements. Toward this end, two primary tones (L1= 55 db SPL; L2 = 40 db SPL ; averaging time 2 seconds) with an f2/fl ratio of 1.2 were swept from 8.0 to 1.6 khz at 3 points/octave intervals. DPOAEs were considered to be present if their amplitudes exceeded the noise floor by 6 db, since a 6-dB DPOAE-noise floor separation corresponded to a 5 percent probability of false positive responses with the CUBeDIS algorithm (Kimberley et al, 1997). Suppression DPOAE data were generated routinely by measuring DPOAEs in the presence of a contralateral white noise delivered simultaneously via an insert tubephone at 40, 50, and 60 db SPL (Williams and Brown, 1995). Suppression measurements were-restricted to 1.6 to 3.2 khz due to the limitations in the frequency response curve of the insert tubephones used to deliver white noise (i.e., rapid decline in the acoustic energy above 4.0 khz associated with a roll-off rate of 42 db/octave). Both ears of each subject were tested, the order of test administration (right vs left ear) being counterbalanced within each subject group. Drug Dosage Data The cumulative dosage of tobramycin received by each CF patient was defined as the total aggregrate dose in mg/kg received during the last 5 years of therapy. Both inpatient and outpatient charts were reviewed retrospectively to compile these data. Due to the young age of the subjects, aggregate doses measured over the last 5 years provided a fairly accurate estimate of the overall drug exposure. However, additional treatments prior to the enrollment of the CF patients into the CF center could not be absolutely ruled out. The compiled cumulative dosages for the CF patients in this study did not exceed 1250 mg/kg, these drug dosages being categorized in the low to moderate range. Statistical Analyses All statistical analyses were performed with the BMDP statistical package (BMDP statistical software [version 7.0], Inc., Los Angeles, 173

3 Journal of the American Academy of Audiology/Volume 9, umber 3, June 1998 CA). A three-factor analysis of variance (AOVA; one between-subjects, two within-subjects design) was used to evaluate differences in hearing thresholds across the conventional and high-frequency measurements, that is, the between-subjects factor analyzed differences among the three subject groups and the two within-subjects factors analyzed right-left ear differences and differences in hearing thresholds across the entire frequency range. The results of immittance measurements were analyzed with three separate two-factor (one between, one within) AOVAs to identify group and ear differences in each of the three measurement parameters (i.e., ear canal volume, peak admittance, and peak pressure). To measure the effects of contralateral white noise on the three subject groups, a four-factor AOVA (one between, three within design) was used. In this analysis, the between-subjects factor delineated group differences, whereas the within-subjects factors measured the effects of the three repeated measures (i.e., ear, noise level, and DPOAE frequency differences). A post hoc analysis (Scheffe procedure) was performed to identify pairs of groups that contributed to the overall significance of the F ratio. RESULTS ympanometric screening performed prior T to the experimental DPOAE measurements showed normal middle ear functions bilaterally in all subjects. The means and standard deviations of the immittance measures shown in Table 1 corroborate these findings. Moreover, there were no significant differences in the ear canal volume, peak admittance, and peak pressure measures obtained from the three subject groups, or between the two ears tested. Results of conventional ( khz) and high-frequency (-20 khz) audiometry are shown in Figures 1A and 1B, respectively. The three-factor AOVA showed no significant differences among either the hearing thresholds of the three subject groups across the entire frequency range or the two ears. The mean hearing thresholds varied from one test frequency to another for all subject groups as,expected and seen in Figure 1 (F = 239.1, df = 13, p =.0001) ; however, there were no significant interactions among the three factors. Baseline DPOAE measurements obtained with Ll and L2 stimulation levels of 55 db SPL and 40 db SPL, respectively, and without contralateral white noise from the three subject groups are shown in Figure 2. Although the Group Table 1 Means and Standard Deviations of the Immittance Findings Obtained from the Three Subject Groups ormal CF-C CF-E Ear canal volume (cc) Right 0.92± ± Left 0.88 ± ± ± 0.21 Peak admittance (cc) Right 0.79± ±0.40 Left 0.79 ± ± ± 0.35 Peak pressure (dapa) Right Left 16± ±18 CF-C = CF-Control (nondrug treated) ; CF-F = CF- Experimental (drug treated). drug-treated CF group showed slightly lower signal-to-noise (S/) ratios, due in part to elevated noise floors below 4.0 khz, the responses were comparable across the three subject groups. Furthermore, all subjects, regardless of subject group, showed more than 6-dB DPOAE-noise floor separation across the test frequency range. The results of the four-factor AOVA used to evaluate group differences in the contralateral application of the noise stimulus and the effects of the three repeated measures are shown in Table 2. These analyses show significant effects of all of the four factors, that is, group differences and differences in the responses of the two ears, the three levels of white noise, and the four frequencies of measurement, but no interaction among any factors. The suppression effects on each of the three subject groups as the noise levels increase from 40 to 60 db SPL are shown in Figure 3. It is clear from this figure that even though the initial S/ ratios were lower in the drug-treated CF group, increase in noise levels from 40 to 60 db SPL produced significant suppression only in this group, the nondrug-treated CF and normal groups of subjects showing essentially no suppression effects. These impressions were corroborated by the results of the post hoc Scheffe analysis. The Scheffe procedure indicated that the means of the normal (17.53) and nondrug-treated CF (18.82) groups were identical (critical difference = 1.86, p <.05 ; mean difference = -1.29), and did not contribute to the overall main effect. However, mean differences in the normal and the drug-treated CF groups (mean difference = 5.12), as well as the nondrug-treated CF and drug-treated CF groups (mean difference = 6.40), exceeded the critical difference of 1.86 at the probability level of 5 percent, thereby accounting for the statistical 174 4W -~ 't

4 Contralateral Suppression of DPOAEs and Tobramycin/Katbamna et al A - m v B - c J 30 R J 50 y tm 7 0 a` 2 v 90 c Frequency (khz) -O- orm CF-C -.~- CF-E Frequency (khz) - -O- orm CF-C -0- CF-E Figure l Mean hearing thresholds (standard deviations designated by error bars) showing overlapping hearing profiles across the three subject groups for both (A) conventional and (B) high-frequency measurements. significance of the grouping factor. Thus, contralateral application of white noise produced significant reduction in the S/ ratios measured in the tobramycin-treated CF group but not the nondrug-treated CF or the control groups of subjects. Further, these group differences did not appear to be related to sound pressure level differences of the white noise in the ear canals of the subjects tested. The mean ear canal volumes independent of the ear tested, as determined by immittance measurements, were 0.90 cc, 0.78 cc, and 0.91 cc, respectively, for the normal, the nondrug-treated CF, and the drugtreated CF groups (see Table 1). As noted above, these differences were not statistically signifi- J a CO m a v.q E Q L- J F2 (khz) -#- orm -0- CF-C -A- CF-E Figure 2 Baseline DPOAE responses (standard deviations designated by error bars) displaying essentially similar DPOAE amplitudes (filled symbols) but slightly elevated noise floors (open symbols) below 4.0 khz in the drug-treated CF group (CF-E) compared to the normal (orm) and the CF control (CF-C) groups. cant. A preliminary retrospective examination showed that sound pressure levels in the ear canal varied by no more than 4 db, when subjects with 0.8-cc versus those with 0.9-cc ear canal volumes were tested. The effect of the three levels of white noise on the S/ ratios regardless of the subject group or the ear tested are shown in Figure 4. As seen in this figure, the overall suppression produced by higher noise levels (60 db SPL) was larger than lower noise levels (40 db SPL) at all frequencies except 1.6 khz, making the results of this repeated measure statistically significant. At 1.6 khz, 50 db SPL of white noise produced the greatest decline in the S/ ratios, the higher level of 60 db SPL being only slightly less efficient than 50 db SPL. Significant ear differences were also revealed. Figures 5A and 5B show the overall differences in the right versus left ear measurements and the effect of the three levels of noise on the two ears tested, respectively. These illustrations indicate that even though the overall S/ ratios associated with the left ear were lower than those of the right ear (see Fig. 5A), the application of white noise did not produce significant differences in suppression across the two ears (see Fig. 5B). These findings are substantiated by the lack of significant interaction between the main effects of ear and level (E X L; Table 2). These ear differences were also observed across all groups, that is, regardless of the subject group tested, the left ear showed lower SI ratios than the right ear, again as reflected by the nonsignificant interaction between the main effects of ear and group (E X G; see Table 2). Thus, the ear effect appears to be related to the 175

5 Journal of the American Academy of Audiology/Volume 9, umber 3, June 1998 Table 2 Results of the Four-Factor AOVA Source Sum of Squares of Mean Square F Tail Probability Mean Group (G) * 1 error EAR (E) * E x G error Level (L) * L x G error E x L ExLxG error Frequency (F) * F x G error E x F ExFxG error L x F LxFxG error ExLxF ExLxFxG error *Indicates significant differences. initial asymmetry in the S/ ratios but not due to differential suppression effects on the two ears. Figures 3 through 5 also show the differences in the S/ ratios across the frequency range of measurement. The S/ ratios were largest at khz and smallest at 1.6 khz, with intermittent values for the remaining frequencies in this test range. These differences were generally maintained regardless of the test ear, the subject group, or the noise levels used for generating suppression, thus accounting for the statistical significance of the main effect of frequency, as well as the lack of interactions with all of the other factors F2 (khz) -0-- orm -4- CF-C _&.- CF-E F2 (khz) Figure 3 DPOAE measurements showing pronounced suppression effects of contralateral white noise (the four measurements, i.e., baseline followed by those with 40, 50, and 60 db SPL noise plotted sequentially) in the drug-treated CF group (CF-E) compared to the normal (orm) and the CF control (CF-C) subject groups. Baseline 40 db 50 db ME 60 db Figure 4 The effect of contralateral white noise on the DPOAE S/ ratios regardless of groups or ears tested showing maximum suppression with 60 db SPL compared to the other noise levels at all frequencies except 1.6 khz. 176

6 B 1 4. _ Contralateral Suppression of DPOAEs and TobramycinfKatbamna et al M Left ear Right ear + Left ear --e- Right ear Figure 5 DPOAE measurements showing right-left differences (right > left), when averaged across (A) all noise levels and subject groups and (B) each noise level for each ear regardless of the subject group (baseline results followed by 40, 50, and 60 db SPL noise results). DISCUSSIO T he major finding of the present study was that contralateral noise produced significant suppression of DPOAE amplitudes in CF patients who received low to moderate cumulative doses of tobramycin, compared to both nondrug-treated CF and normal children of similar ages. Since the control groups of children displayed comparable baseline DPOAE levels, but little or no suppression effects, enhanced suppression in the drug-treated group may be attributed to the instability of the cochlear amplifier itself and/or exaggeration of recruitment-like features of an unstable cochlear amplifier associated with tobramycin intake. Suppression enhancement associated with aminoglycoside treatment, however, has not been documented in other human or animal models. For example, Smith et al (1994) showed that the suppression effect of contralateral noise on ipsilaterally evoked eighth cranial nerve compound action potentials declined within minutes of a single intramuscular dose of gentamicin in guinea pigs. Furthermore, the suppression effects were completely abolished by 1.5 to 2.0 hours of the injection of gentamicin. However, the contralateral suppressive effects were restored within 96 hours postinjection in all subjects. Likewise, Aran et al (1994) reported a rapid and reversible loss of contralateral suppression on ipsilaterally evoked transient otoacoustic emissions following similar gentamicin injections in guinea pigs. The outcomes of both of these animal studies suggest that aminoglycoside ototoxicity may be mediated by the medial cochlear-efferent system, and that cochlear ototoxicity may be efficaciously monitored through the measurement of contralateral suppression effects. Furthermore, cochlear integrity as measured by the presence and/or absolute level of otoacoustic emissions may not reflect the early or primary ototoxic effects of aminoglycosides. The results of the present study corroborate the above described findings in guinea pigs. They indicate that drug-induced changes in the cochlear amplifier may first become apparent as alterations in contralateral suppression effects, and that increments in suppression may precede the reduction and complete loss of suppression in the course of developing ototoxicity. The outcomes of this study also showed a strong right-left asymmetry; however, this lateral asymmetry was related to the initial differences in the DPOAE responses obtained from the two ears rather than differences in the contralateral suppression effects measured in the two ears. The right ear showed larger S/ ratios compared to the left ear, and these differences prevailed when the contralateral stimulus was applied across the two ears. Small differences in the ear canal volumes and the hearing sensitivity of the right versus the left ears could account for this finding, even though these differences were statistically insignificant in this study. Recent studies have correlated such ear differences to the presence of spontaneous emissions. For example, McFadden (1993) explained the occurrence of a larger number of spontaneous emissions in the right ear by the better hearing sensitivity in the right ears compared to the left ears, and even predicted right-left disparity 177

7 Journal of the American Academy of Audiology/Volume 9, umber 3, June 1998 of efferent input to the cochlea (right ears less inhibited than left ears) based on these observations. Khalfa and Collet (1996), on the other hand, showed greater right-sided efferent suppression in a group of young subjects and traced these outcomes to the existence of spontaneous emissions on the right side. In summary, low to moderate cumulative doses of tobramycin produced enhanced contralateral suppression of DPOAEs in children with CF. These findings suggest that improved suppression in the absence of demonstrable alterations in the baseline cochlear function may be the first indicators of developing ototoxicity. Acknowledgments. This study was supported in part by the Faculty Research and Creative Activities Support Fund Award from Western Michigan University and the Michigan State University Kalamazoo Center for Medical Studies CF Center Grant. The authors would like to acknowledge Dr. Brenda Lonsbury-Martin for her critique of an earlier version of this manuscript. We would also like to thank Chrysanthe Fooy, CF Research urse, and Marlene Pryson, CF Family Co-ordinator, for their assistance and the CF patients, as well as their families, for their participation in this study. This study was presented in part at the 1997 American Academy ofaudiology annual convention held in Ft. Lauderdale, FL. REFERECES Aran J-M. (1990). Physiopathology of sensory hair cells : in vivo and in vitro studies of aminoglycoside uptake and toxicity. Adv Audiol 7: Aran J-M, Erre J-P, Avan P. (1994). Contralateral suppression of transient evoked otoacoustic emissions in guinea pigs : effects of gentamicin. Br JAudiol 28 : Brown RD. (1972). Influence of chronic treatment with neomycin and kanamycin on l suppression produced by contralateral olivocochlear bundle stimulation in cats. Acta Otolaryngol 73 : Brown RD, Daigneault EA. (1973). eomycin : ototoxicity and the cochlear efferents. Acta Otolaryngol 76 : Buno W. (1978). Auditory nerve fiber activity influenced by contralateral ear sound stimulation. Exp eurol 59 : Capps MJ, Duvall AJ. (1976). Ototoxicity and the olivocochlear bundle. Laryngoscope 87: Collet L, Kemp DT, Veuillet E, Duclaux R, Moulin A, Morgon A. (1990). Effect of contralateral auditory stimuli on active cochlear micromechanical properties in human subjects. Hear Res 43 : Folsom RL, Owsley RM. (1987). 1 action potential in humans : influence of simultaneous contralateral stimulation. Acta Otolaryngol 3: Hiel H, Erre J-P, Aurousseau C, Bouali R, Dulon D, Aran J-M. (1993). Gentamicin uptake by cochlear hair cells precedes hearing impairment during chronic treatment. Audiology 32 : Khalfa S, Collet L. (1996). Functional asymmetry of medial olivocochlear system in humans. Towards a peripheral auditory lateralization. euroreport 7: Kimberley BP, Brown DK, Allen JB. (1997). Distortion product emissions and sensorineural hearing loss. In : Robinette MS, Glattke TJ, eds. Otoacoustic Emissions : Clinical Applications. ew York : Thieme, Kohonen A. (1965). Effect of some ototoxic drugs upon the pattern and innervation of cochlear sensory cells in the guinea pig. Acta Otolaryngol Suppl 208:1-70. McFadden D. (1993). A speculation about the parallel ear asymmetries and sex differences in hearing sensitivity and otoacoustic emissions. Hear Res 68 : Mott JB, orton SJ, eely ST, Warr WB. (1989). Changes in spontaneous otoacoustic emissions produced by acoustic stimulation of the contralateral ear. Hear Res 38 : Moulin A, Collet L, Morgon A. (1992). Influence of spontaneous otoacoustic emissions (SOAE) on acoustic distortion product input/output functions : does the medial efferent system act differently in the vicinity of an SOAE? Acta Otolaryngol 112: Pujol R. (1994). Lateral and medial efferents : a double neurochemical mechanism to protect and regulate inner and outer hair cell function in the cochlea. Br JAudiol 28 : Smith DW, Erre J-P, Aran J-M. (1994). Rapid, reversible elimination of medial olivocochlear efferent function following single injections of gentamicin in the guinea pig. Brain Res 652: Veuillet E, Collet L, Duclaux R. (1991). Effect of contralateral auditory stimulation on active cochlear micromechanical properties in human subjects. Dependence on stimulus variables. J europhysiol 65: Williams DM, Brown AM. (1995). Contralateral and ipsilateral suppression of the 2f1-12 distortion product in human subjects. JAcoust SocAm 97: