Abstract
Purpose of the study
The aim of the present study was to evaluate the ototoxicity of Burow solution.
Procedures
Compound action potentials (CAPs) of the eighth nerve were measured before and 30 minutes after the application of the Burow solution in the middle ear cavity.
Results
Use of the original Burow solution (pH 3.5) for 30 minutes caused a significant reduction of click sounds. A 2-fold diluted Burow solution (pH 4.4) for 30 minutes caused no reduction in CAP threshold. Burow solution, pH adjusted to 4.5, caused no changes in CAP threshold at 30 minutes. At 24 hours, Burow solution (pH 3.5) caused complete abolition of CAP.
Conclusions
Burow solution is ototoxic in the guinea pig when applied in the middle ear cavity for 30 minutes or longer. In the clinical settings, it is advisable to avoid allowing the solution to contact the round window for extended times.
1
Introduction
Burow solution was developed as an ear drop by the German physician Karl August von Burow (1809-1874) . The main ingredient of this solution is 13% aluminum acetate. It is colorless and has acidic odor. The effect of this solution for controlling intractable discharge of the external ear canal and the middle ear cavity was confirmed by Mahoney and Thorp et al . In Japan, Terayama and others advocated the excellent effect of this solution on intractable chronic suppurative diseases of the external ear canal and middle ear. Excellent antibacterial and antifungal activities of this solution were reported both in vivo and in vitro . A particularly appealing feature of this solution to clinicians is its effectiveness in treating methicillin-resistant Staphylococcus aureus (MRSA) and other antibiotic-resistant bacteria and fungi. However, only 2 groups have reported about the ototoxicity of this solution . Serin et al reported no toxic effect on auditory brainstem responses (ABRs) in guinea pig, whereas Suzuki and others reported toxic effects on ABR in guinea pig. Extensive use of Burow solution by clinicians worldwide prompted us to reexamine the ototoxicity of this solution. We have found a toxic effect of this solution in guinea pig on eighth nerve compound action potentials (CAPs).
2
Materials and methods
2.1
Animals
To evaluate the ototoxicity of Burow solution, albino Hartley guinea pigs were used. Animals selected had an average body weight between 300 and 400 g and had a positive Prayer reflex.
2.2
Burow solution
The solution was freshly prepared by the pharmacy department of our university hospital according to the British Pharmacopeia formula , and the pH was measured and adjusted before each experiment.
2.3
Anesthetics
The animals were anesthetized with sodium pentobarbital (30 mg/kg) and were secured in a custom-made head holder. Xylocaine (AstraZeneca PLC, Osaka, Japan) 0.5% was infiltrated into the surgical area before making the skin incision for access to the middle ear cavity.
2.4
Surgery
The bulla was exposed using a retroauricular incision. A small hole, about 2 mm in diameter, was made using a dental drill, and the round window membrane was visualized with a ×40 operating microscope.
2.5
Sound system
Asynchronous tone-bursts of 4 and 8 kHz (1-millisecond rise and fall time, 10-millisecond plateau time) and click sounds were given as stimuli at a pulse rate of 20 beats/s, from 80 dB sound pressure level to thresholds with 10-dB increments. The speaker used was a Telephonics TDH-39P (Bio-logic Systems Corp., Mundelein, IL, USA), and the sound source was placed 10 cm away from the auricle. The free-field sound pressure was monitored and calibrated with a Brüel & Kjær (Naerum, Denmark) half-inch condenser microphone.
2.6
Recording system and CAP measurement
An 0.08-mm-diameter Teflon-insulated silver wire with an exposed ball tip was carefully placed with a micromanipulator on the peripheral round window membrane. An Ag/AgCl reference electrode was placed in the neck muscles. The obtained CAP responses were averaged 200 times with a Traveler Express ER-22 (Biologic Systems Corp, Mundelein, IL, USA).
2.7
Drug application
After the initial CAP was measured, the middle ear cavity was filled with Burow solution. The amount of fluid necessary to fill the middle ear cavity was about 0.2 mL. At 30 minutes, the middle ear cavity was thoroughly dried using a tissue paper wick. We evaluated the following: (1) saline control, (2) the effect on the action potential threshold of Burow solution (pH 3.5) at 30 minutes after topical application, (3) the effect of 2-fold diluted Burow solution (pH 4.4) on the CAP for 30 minutes, (4) the effect of Burow solution adjusted to pH 4.5 with boric acid, and (5) the effect of a 10-minute application of Burow solution followed by thorough washing with isotonic saline solution. In the last condition, the CAP was measured at 10 and 30 minutes. (6) In a separate animal group, the effect of Burow solution at 24 hours was also studied.
Repeated measurements from the same animal were not done due to the possibility of introducing infection.
This protocol was approved by Fukuoka University Animal Ethics Committee.
2.8
Analysis of the data
A threshold response was defined as an N1-P1 signal with an amplitude of 10 μ V. The change in the sound pressure level in decibels before and after drug application was defined as a change in hearing.
The threshold change before and after drug application was compared, and a paired t test was used to define statistical significance.
2.9
Bacteriology
The bacteriostatic activity of Burow solution was studied using a disk diffusion assay.
Bacteria obtained from patients of our clinic were diluted to 10 6 Colony Forming Unit/mL and cultured on an agar plate for 24 hours. Burow solution, either 50 or 75 μ L, was dropped on an 8-mm-diameter disk and placed on the agar plate. At another 24 hours, the diameter of zones of inhibition of bacterial growth on the agar plate was measured.
Bacteria studied were as follows: Pseudomonas aeruginosa , P aeruginosa (mucoid), multidrug resistant P aeruginosa , β -lactamase–negative ampicillin-resistant Haemophilus influenzae , MRSA, penicillin-resistant Streptococcus pneumoniae , and Moraxella catarrhalis .
2
Materials and methods
2.1
Animals
To evaluate the ototoxicity of Burow solution, albino Hartley guinea pigs were used. Animals selected had an average body weight between 300 and 400 g and had a positive Prayer reflex.
2.2
Burow solution
The solution was freshly prepared by the pharmacy department of our university hospital according to the British Pharmacopeia formula , and the pH was measured and adjusted before each experiment.
2.3
Anesthetics
The animals were anesthetized with sodium pentobarbital (30 mg/kg) and were secured in a custom-made head holder. Xylocaine (AstraZeneca PLC, Osaka, Japan) 0.5% was infiltrated into the surgical area before making the skin incision for access to the middle ear cavity.
2.4
Surgery
The bulla was exposed using a retroauricular incision. A small hole, about 2 mm in diameter, was made using a dental drill, and the round window membrane was visualized with a ×40 operating microscope.
2.5
Sound system
Asynchronous tone-bursts of 4 and 8 kHz (1-millisecond rise and fall time, 10-millisecond plateau time) and click sounds were given as stimuli at a pulse rate of 20 beats/s, from 80 dB sound pressure level to thresholds with 10-dB increments. The speaker used was a Telephonics TDH-39P (Bio-logic Systems Corp., Mundelein, IL, USA), and the sound source was placed 10 cm away from the auricle. The free-field sound pressure was monitored and calibrated with a Brüel & Kjær (Naerum, Denmark) half-inch condenser microphone.
2.6
Recording system and CAP measurement
An 0.08-mm-diameter Teflon-insulated silver wire with an exposed ball tip was carefully placed with a micromanipulator on the peripheral round window membrane. An Ag/AgCl reference electrode was placed in the neck muscles. The obtained CAP responses were averaged 200 times with a Traveler Express ER-22 (Biologic Systems Corp, Mundelein, IL, USA).
2.7
Drug application
After the initial CAP was measured, the middle ear cavity was filled with Burow solution. The amount of fluid necessary to fill the middle ear cavity was about 0.2 mL. At 30 minutes, the middle ear cavity was thoroughly dried using a tissue paper wick. We evaluated the following: (1) saline control, (2) the effect on the action potential threshold of Burow solution (pH 3.5) at 30 minutes after topical application, (3) the effect of 2-fold diluted Burow solution (pH 4.4) on the CAP for 30 minutes, (4) the effect of Burow solution adjusted to pH 4.5 with boric acid, and (5) the effect of a 10-minute application of Burow solution followed by thorough washing with isotonic saline solution. In the last condition, the CAP was measured at 10 and 30 minutes. (6) In a separate animal group, the effect of Burow solution at 24 hours was also studied.
Repeated measurements from the same animal were not done due to the possibility of introducing infection.
This protocol was approved by Fukuoka University Animal Ethics Committee.
2.8
Analysis of the data
A threshold response was defined as an N1-P1 signal with an amplitude of 10 μ V. The change in the sound pressure level in decibels before and after drug application was defined as a change in hearing.
The threshold change before and after drug application was compared, and a paired t test was used to define statistical significance.
2.9
Bacteriology
The bacteriostatic activity of Burow solution was studied using a disk diffusion assay.
Bacteria obtained from patients of our clinic were diluted to 10 6 Colony Forming Unit/mL and cultured on an agar plate for 24 hours. Burow solution, either 50 or 75 μ L, was dropped on an 8-mm-diameter disk and placed on the agar plate. At another 24 hours, the diameter of zones of inhibition of bacterial growth on the agar plate was measured.
Bacteria studied were as follows: Pseudomonas aeruginosa , P aeruginosa (mucoid), multidrug resistant P aeruginosa , β -lactamase–negative ampicillin-resistant Haemophilus influenzae , MRSA, penicillin-resistant Streptococcus pneumoniae , and Moraxella catarrhalis .
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