Lidocaine Hydrochloride Depression of Cochlear Microphonics and Action Potentials in the Cat

A.N.L., 2, 107-116, 1975

LIDOCAINE HYDROCHLORIDE DEPRESSION OF COCHLEAR MICROPHONICS AND ACTION POTENTIALS IN THE CAT Dominic W. HUGHES and Toshiaki YAGI, M.D. Department of Otolaryngology, Teikyo University School of Medicine, Tokyo, Japan

The depressive effects of lidocaine hydrochloride on cochlear function were observed in 18 cats. Round window cochlear microphonics and action potentials were recorded before and after lidocaine application onto the round window membrane. Lidocaine hydrochloride depressed both CM and AP and these effects were always reversible with a maximum recovery time of six hours. The times of maximum depression and recovery of cochlear function were directly related to lidocaine concentration. It seems possible that fairly reproducible, reversible cochlear lesions can be made by expanding on this study. Topical application of anesthetics to the ear has both surgical and clinical value (SUZUKI, 1973). Lidocaine hydrochloride (Xylocaine) is frequently the agent of choice in this regard and its use in surgery is fairly obvious. Clinically, lidocaine hydrochloride has an adjunctive diagnostic value wherein a transtympanic injection of this anesthetic results in a temporary and reversible depression of labyrinthine function (KAMIO et al., 1973). This effect is useful in the evaluation of the extent and nature (hypoactive, irritative and hyperactive) of inner ear lesions (YAGI and SUZUKI). Basic research directed toward the specific effects of lidocaine hydrochloride on the labyrinth is rather limited and somewhat contradictory, especially regarding the extent of recovery of function following application (RAHM et al., 1962; JENKINS et al., 1967; FERNANDEZ et al., 1959). This report describes an attempt to quantify the extent and duration of round window cochlear microphonic and action potential depression following a direct application of various concentrations of lidocaine to the round window of the cat. METHODS

Initial, light, sodium pentobarbital anesthesia (Nembutal at 18 to 22 MPK, Received for publication September 18, 1975 This study was partially supported by a USPHS Research Grant 107

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IP) was administered to 18 cats. Each animal was tracheostomized and fitted with a tracheal cannula. A muscle relaxant (Amelizol) was given I.M. and the cat was respirated. Bulla exposure was from a ventro-Iateral approach and the external auditory canal was fistulized for visualization of the tympanic membrane. The bony shell of the bulla was punctured with a scalpel and then rongeured to a 6 mm opening in the posterior ventro-Iateral quadrant. The cat was then fixed in such a position that the now visible round window niche was oriented as nearly horizontal as possible. The preparation was carried to an electrically shielded room and, using a micromanipulator under an operating microscope, a small (0.5 mm) teflon-insulated silver ball-electrode was placed directly on the round window membrane (ventro-anterior quadrant). Both cochlear microphonics (CM) and action potentials (AP) were sampled with this electrode which was not moved from its original position throughout the experiment. Auditory stimuli were delivered to the cat's ear via a short (7 cm) probe tube fitted to a TDH-39 earphone. The distal end of this probe tube was sutured into the fistulized external auditory canal. Cochlear microphonics were sampled to tone bursts at 500, 1 k, 2 k and 4 kHz with a duration of 20.0 msec and a rise-anddecay time of 1.0 msec. The AP stimulus was a 0.4 msec 3 kHz tone pip. Stimulus intensities were 99.5 dB at 500 Hz, 90.0 dB at I kHz, 82.8 dB at 2 kHz, 72.0 dB at 3 kHz and 61.2 dB at 4 kHz (dB SPL re 0.0002 dynejcm2). Audio frequencies were generated (Leader LAG-26 Audio Generator), attenuated (Kikusui Attenuator Model 984B) and finally conditioned by a digital pulse generator (Rion TG-04) and electronic switch (Rion SB-IO). Recordings were taken, triggerred by the electronic switch, of both the stimuli and the responses on a dual-beam oscilloscope (Nihon Kohden VC-7A with an AVB-2 biophysical amplifier; time constant at 0.003 sec) equipped with a camera (Nihon Kohden Continuous Recorder PC-2B). Oscilloscope tracings were photographed for later measurement. The size of the CM was determined by the peak-to-peak measurement (in microvolts) of the waveform at 10 msec post stimulus onset. The AP was analyzed both in terms of its amplitude from the baseline and its latency. Lidocaine hydrochloride (Xylocaine) without epinephrine and at concentrations of either 4 %,2 % or 1 % was used in this study. The anesthetic was supplied as a solution; i.e., 4 %, 2 % and 1 % lidocaine consisted of 40, 20 or 10 mg. (respectively) of lidocaine hydrochloride in 1.0 ml of distilled water. The pH of these solutions ranged from 6.40 to 6.60. Baseline CMs and APs were recorded over a one hour period prior to drug application. Upon obtaining reliable recordings (less than ± 5 % variability in fl V over three consecutive trials) lidocaine hydrochloride at concentrations of either 4 %, 2 % or 1 % was perfused directly,onto the round window membrane in sufficient quantity to fill the niche. The anesthetic, previously warmed to 37°C, was allowed to remain on the membrane for fixed time intervals (5, 10 or 15 min)

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and then removed by light suction. The round window was then twice rinsed with distilled water and the membrane quickly dried with a pledget of cotton. Recordings were taken every 5 or 10 min during the first hour post anesthetic application, and thereafter every 30 min until recovery was attained. An initial pilot study indicated no loss of cochlear function following applications of distilled water to the round window membrane. RESULTS

To ascertain that lidocaine hydrochloride exerts its depressive effect on the cochlea by absorption only through the round window membrane, a quantity of the drug (4 %) was perfused into the bulla and middle ear spaces. Care was taken to fill as much of the ear as possible (including the oval window area) while avoiding contact with the round window membrane. The anesthetic was allowed to remain in the ear for 5 min and then removed. Four sets of measurements were taken over the following 50 min, at which time the anesthetic was reapplied but, on this occasion, only to the round window membrane. Figure 1 is a graphic illustration of CM and AP changes subsequent to this pilot study. It can be seen that a general, rapid depression of all parameters occurred only after 200

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application of the anesthetic to the round window membrane. In view of this, the drug was thereafter applied only into the niche. Overall results can be viewed from a number of directions, some of which are presented below. All values are given in terms of the percent of loss of function. 1.

Effect of anesthetic concentration on overall responses Figure 2 is a composite illustration of anesthetic concentration effects on (A) action potential latency (in msec) and (B) percent loss of cochlear microphonic intensity. The CM values are the mean values of the four frequencies (500, 1 k, 2 k, and 4 kHz) tested at each point in time. Time is time of drug application. There appeared to be a graded response decline (of both XCM and AP) associated with anesthetic concentration both in terms of percent of loss and the time course of this loss. Note the time of maximum loss of CM at the 4 % concentrations relative to the time of maximum AP shift at the same concentrations. The maximum AP latency shift occurred approximately 2 hr after the time of maximum CM loss. In fact, at the time of maximum AP latency shift,

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the eM had recovered by approximately 20 %. Final recovery of both AP latency and eM amplitude occurred almost simultaneously. 2.

Depression of eMs in terms of frequency Figures 3 through 6 illustrate the eM losses at each frequency from a series of representative cats. The only consistent findings were that 1 kHz was always maximally depressed relative to the other 3 frequencies and 4 kHz was usually minimumly depressed (the exception was at 1 %X 10 min-Fig. 3). There were no other observed frequency related patterns; i.e. , rate of loss, time of maximum loss or time of recovery. Depression of the AP In Figs. 3 through 6, the action potential values are expressed in terms of the percent of loss of peak amplitude (measured from the baseline in microvolts). As can be seen, amplitude response patterns are quite variable. This is a probable reflection of two conditions: i.e., the rapid rate at which the AP was measured and averaging techniques were not employed. However, there was a tendency for the AP curve to quickly asymptote at some value and remain static at that value for time periods slightly longer than any of the individual eM curves. Recovery patterns seemed to be random. 3.

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1). DISCUSSION

At the outset it was felt that the relationship between lidocaine concentration and the depressive effects on cochlear function would be directly related; i.e., 4 % lidocaine would cause a rapid and strong depression followed by a slow recovery, whereas 1 % lidocaine would cause a slow, weak depression followed by a quick recovery. However, in this study, 1 and 2 % lidocaine caused a more rapid depression than 4 % lidocaine. Determination of the osmotic pressures of the various anesthetic concentrations revealed values of 1.0, 0.5 and 0.25 at concentrations of 4 %, 2 %and 1 % respectively. There is thus a large pressure gradient between low concentration lidocaine (1 %) and the endolymphatic fluid. This would result in a more rapid absorption of 1 % lidocaine through the round window membrane causing a more rapid depression of cochlear function than 4 %lidocaine.

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Also, in any study involving absorption of an agent through a membrane, obviously the functional integrity of the membrane is a limiting factor. The condition of the cat R W membrane was, at best, always judgemental and this effected all of the results. Given these rather severe limitations, a few points are still worthy of discussion. Regardless of the concentration of anesthetic applied to the R W membrane (up to 4% applied for 15 min) there was generally a total (greater than 90%) recovery of CM and AP values during the observation period (6 hr or less). The exceptions were Fig. 4, 2 kHz CM, 80 %; Fig. 3, AP, 80 %; Figs. :5 and 6, AP, 85 %. This finding is contradictory to that of RAHM et al. (1965) wherein they showed a nonreversible depression of CM even at low anesthetic concentrations (1 %for 15 min). Clinical evaluations of vestibular function following the application of lidocaine in humans (YAGI, et al.) corroborates this reversible effect. Total recovery of vestibular function was also suggested by JENKINS et al. (1967) and FERNANDEZ et al. (1959) following applications of 4 % lidocaine in the rabbit and cat. The relative times of maximum CM loss and AP latency shift (Fig. 2) suggests a sequential anesthetic effect, first on the hair cells and then on the first order neural elements. If only the cochlear hair cells were effected by the anesthetic

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then the eM amplitude and AP latency curves should parallel each other. Also, comparison of the AP latency curves (Fig. 2 A) with corresponding AP amplitude curves (Figs. 3 through 6) indicates a more rapid depression of the AP amplitude. The AP amplitude and the eM amplitude were both in the process of recovery when the maximum shift in AP latency occurred. Microphonics were taken at four frequencies in an attempt to further evaluate sequential cochlear anesthetic effects. The fairly consistent maximum loss at 1 kHz and minimum loss at 4 kHz suggests that the anesthetic moves some distance into the cochlea prior to exerting its depressive effect. Another possible, and more likely, basis for this frequency effect is that the eM recordings were taken from the round window membrane. As such, the response of all the activated hair cells on the cochlear partition was recorded. A more definitive study would involve intra-cochlear recordings at various sites along the basilar membrane. CONCLUSION

Lidocaine hydrochloride (Xylocaine at concentrations of 4 %, 2 % and 1 %) was applied directly to the round window membrane of the anesthetized cat. The anesthetic exerted a concentration-related depression on all the measured indices of cochlear function (round window cochlear microphonics and action

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potential amplitude and latency). This depression was always reversible with a maximum recovery time of 6 hr. Frequency-related depression of CM was not consistent other than the maximum depression of CM amplitude always occurred at 1 kHz. On the basis of this concentration-related, reversible depression of cochlear output, it is suggested that lidocaine anesthesia of the labyrinth could find use in the creation of reproducible, reversible ablations of cochlear function. REFERENCES FERNANDEZ, c., ALZATE, R., and LINDSAY, J. R.: Experimental observations on positional nystagmus in the cat. Ann. ORL. 68: 816-830, 1959. JENKINS, H., HONRUBIA, Y., and WARD, P. H.: Pharmacological labyrinthectomy. Ann.ORL. 78: 562-574, 1967. KAMID, T., EGAMI, T., and SUZUKI, J.: Diagosis and treatment of positional vertigo by means of anesthesia and ablation of the labyrinth. Practica Otologica (Kyoto) 66: 619-628, No. 6, 1973 (in Japanese). RAHM, W. E., STROTHER, W. F., CRUMP, J. E., and PARKER, W. F.: Effect of various anesthetics upon the ear. IV. Lidocaine hydrochloride. Ann. ORL. 71: 116-123, 1962. SUZUKI, J.: Anesthesia and surgery of the inner ear. Clin. Physiol. 3: 388-393, 1973 (in Japanese). YAGI, T. and SUZUKI, J.: Diagnosis of inner ear lesions by lidocaine inner ear anesthesia. Clin. Physiol. (in print). Request reprints from:

Dominic W. Hughes, Department of Otolaryngology, Teikyo University School of Medicine, Kaga 2-11-1, Itabashi-ku, Tokyo 173, Japan