A proposed protocol for monitoring ototoxicity in patients who take cochleo-or vestibulotoxic drugs. (Original Article).

Abstract

No widely accepted protocol or guideline exists for monitoring ototoxicity in patients who take powerful and potentially cochleotoxic and/or vestibulotoxic agents. Many physicians in other specialties who prescribe these drugs do not understand the important role of otolaryngologists and audiologists in pretreatment counseling and the need for follow-up assessments of and evaluation t their patients' auditory function. Based on our combined experience of more than SO years, we have developed a uniform yet flexible approach to monitoring cochlear and vestibular function in these patients. We discuss the mechanisms of ototoxic agents, risk factors for ototoxicity, the need for ongoing communication among the various disciplines, and the methods and timing of monitoring.

Introduction

No universally accepted protocol or standard of care exists for monitoring aural function in patients with serious infections or cancer who take potentially ototoxic agents. (1-4) A rigid standard would certainly not be practical in light of the complexity of the issues involved and the wide variety of potentially ototoxic agents. Some basic protocols have been discussed, 5-7 but textbooks on sensorineural hearing loss do not offer a complete guideline for preventing and monitoring ototoxicity.

We believe it would be helpful to codify an understanding of what it is that we wish to accomplish in such cases. Based on our combined 50 years of clinical experience in a variety of institutions and clinical settings, we have developed a basic protocol for monitoring ototoxicity figure). In this article, we describe our recommendaions, with emphasis on the mechanisms of ototoxic agents, risk factors for ototoxicity, the importance of interdisciplinary communication, and the specific methods and timing of monitoring.

Ototoxic drugs

Physicians typically strive to select the most cost-effective and least toxic medication available, but in some circumstances the standard of care dictates the use of powerful, potentially toxic drugs (table 1). Although physicians attempt to achieve a drug concentration only high enough to produce an adequate clinical effect and therapeutic result, ototoxicity can occur even in patients who take an appropriate dose and in those who have normal peak and trough levels. In fact, ototoxicity can occur after only a single dose.

Initially, agents that are toxic to the cochlea destroy outer hair cells in the basal turn of the cochlea, which causes a high-frequency sensorineural hearing loss. Later, as the effects of these agents progress apically through the cochlea, a flat sensorineural hearing loss occurs. Aminoglycoside antibiotics concentrate in the perilymph and endolymph. Some (amikacin, dihydrostreptomycin, and kanamycin) are primarily and/or initially cochleotoxic, while others (streptomycin and gentamicin) destroy vestibular hair cells before cochlear hair cells. Most of these drugs, when given for long periods of time or when their serum concentrations are high, most often cause a loss of both cochlear and vestibular hair cells. Oftentimes, the destruction of hair cells continues for weeks after the treatment is discontinued. Some agents (aspirin and quinine) have a temporary effect on the cochlea, while others cause a permanent hearing loss. Loop diuretics can cause reversible hearing loss at lower dosages, but not in all patients. (8) Whenever possible, the physician should counsel the patient about the potential for ototoxicity and other risks, as well as the benefits of treatment, prior to the initiation of therapy.

Risk factors for ototoxicity

The key to preventing ototoxicity is early detection. An important component of early detection is an awareness of the risk factors that can predispose patients to druginduced ototoxicity:

* previous use of an ototoxic agent

* simultaneous exposure to multiple ototoxic agents

* administration of an ototoxic agent for more than 14 days

* administration of multiple courses of an ototoxic drug

* administration of an aminoglycoside in combination with a loop diuretic

* high serum levels of an ototoxic agent (a consequence of a failure to monitor peak and trough levels)

* pre-existing sensorineural hearing loss with evidence of outer-hair-cell loss

* impaired renal function (apropos to agents that are excreted by the kidney) and compromised hepatic function (apropos to agents that are excreted by the liver)

* age (the elderly are at higher risk)

* genetic factors (e.g., hypersensitivity to an ototoxic drug)

Interdisciplinary communication

A coordinated and cooperative effort should be maintained among the patient's primary care and/or specialist physician, the otolaryngologist, and the audiologist so that cochleo- or vestibulotoxicity can be detected early. It is particularly essential that the otolaryngologist and the audiologist be made aware of the name of the drug, the dosage, any changes in the medication regimen, the manner of the drug's absorption and excretion, the status of the patient's kidney and liver function, and the patient's risk factors for ototoxicity.

Conversely, the otolaryngologist and/or audiologist should relay to the patient's treating physician the results of ototoxicity monitoring tests and any changes in the patient's otologic status. The audiologist might be the first member of the management team to recognize subtle changes in the patient's clinical symptoms or abnormalities in cochlear and vestibular function. Input from the audiologist is critical.

Methods of monitoring

The otolaryngologist should ensure that the audiologist is familiar with the parameters of peak and trough levels. Peak levels are usually measured 1 hour following the administration of a drug, and trough levels are measured 15 minutes prior to the administration of the next dose. With some exceptions, peak and trough levels are generally measured once a week. For patients who have abnormal kidney or liver function, these levels might be measured daily. Kidney and liver function should be assessed before treatment is initiated. For patients whose rate of excretion is decreased, the physician might consider lowering the dosage, although there is no absolute clinical evidence that doing so will prevent ototoxicity. Ototoxicity can also occur in patients whose renal and hepatic function is normal.

In addition, monitoring of blood pH, electrolyte, and oxygen saturation levels might be appropriate for some patients. Evaluation of the drug's protein-binding effects might also be advisable.

When monitoring for ototoxicity, we cannot rely on audiometric testing alone. By the time audiometric testing reveals a hearing loss, it might be too late to reverse it. We recommend that the following tests be performed routinely at every visit:

* conventional audiometry (a significant change is defined as a 15-dB shift at one or more frequencies (9) or a 20-dB shift at one frequency (10))

* determination of the speech discrimination score

* high-frequency audiometry (to 18 kHz) if the patient is able to undergo this test

* acoustic impedance testing

* acoustic immittance testing

* auditory brainstem-evoked response testing for very young patients and for patients who are critically ill or confined in some way

* otoacoustic emissions testing

* electronystagmography when applicable

* clinical symptoms checklist review

Monitoring the robustness of otoacoustic emissions and noting changes in the response over time might provide an early indication of hair-cell damage. If otoacoustic emissions are not elicited during the baseline evaluation, repeat testing might not be necessary.

Electronystagmography is necessary when a drug is being used that is known to have a vestibulotoxic effect so that changes in vestibular function can be detected early. Although cessation of the drug at the first sign of vestibular irritability might not necessarily change the progression of the vestibular abnormality, early detection might spare the cochlear function. However, drug discontinuation can lead to immediate or delayed symptoms, including tinnitus, vertigo, and hearing loss.

A review of the clinical symptoms checklist should be made during every visit. The otolaryngologist or audiologist should ask the patient if he or she has experienced tinnitus, vertigo, or a change in hearing status, and the patient should be instructed to immediately report any onset of or change in these symptoms.

Many drugs can have an effect on testing results, even though they are not necessarily ototoxic themselves (table 2). By either depressing or stimulating the central nervous system, some medications elicit hyper- or hypoactive responses. Tranquilizers cause central nervous system depression, alcohol and anticonvulsants produce cerebellar dysfunction, and antihypertensives can cause orthostatic hypotension and subsequent dizziness. (11) Therefore, when possible, and with the treating physician's approval, the patient should discontinue taking any such agent prior to undergoing monitoring tests. It is especially important that the effects of these substances be taken into account when testing vestibular function by electronystagmography.

Many patients who require monitoring for ototoxicity are extremely ill, and any vestibulotoxic effects and changes in hearing that they experience are often masked by their overall poor medical status. Furthermore, transporting such patients to the audiology unit might not be possible, and patient cooperation might be limited. Therefore, a flexible and compassionate approach to monitoring these patients is necessary. Even if bedside testing is the only available method of monitoring these patients, it is certainly preferable to no testing at all.

Timing of monitoring tests

Before the initiation of treatment, each patient should undergo a baseline evaluation with the tests previously mentioned. The same battery of tests should be conducted at every subsequent visit (figure). In addition to the baseline evaluation, testing should be performed within 24 hours before the initiation of treatment, once a week during the treatment course, immediately prior to the initiation of each new treatment cycle, and at the completion of treatment. Also, post-treatment follow-up assessments should take place at 2 weeks, 4 weeks, 12 weeks, and 6 months.

The timing of an immediate or delayed adverse drug reaction cannot be predicted. The time of onset varies according to the specific drug that is used and the length of treatment. Therefore, the timing of monitoring visits might need to be adjusted. Decisions as to making such adjustments should take into consideration the clinical experience of the physician, the audiologist, and the institution as a whole.

When a monitoring test detects a change from a baseline value, the change must be confirmed by repeat testing. Once a change has been reconfirmed, the patient should be monitored daily until the parameter in question has stabilized.

As is the case with very ill adults, monitoring children can be challenging. The protocol used to monitor older children can be modeled on the paradigm used for adults, but for very young children it might be necessary to rely only on objective tests, such as otoacoustic emissions testing, tympanometry, and auditory brainstem-evoked response testing. Also, when evaluating a newborn or infant, it is necessary to take into consideration any drugs that might have been administered to the mother and that might have passed through the placenta to the patient in utero.

Management of ototoxicity

At the first indication that an ototoxic effect has occurred, the physician has several options:

* a reduction in the amount of the dose

* a change in the timing of the dosage schedule

* a temporary discontinuation of therapy so that the ear can "rest"

* a switch to a less ototoxic drug

If the treating physician does switch the patient to a different drug, a new baseline must be established to ensure proper monitoring. In some cases, the physician will not be able to change the drug regimen because of the intensity or severity of the patient's illness. When ototoxicity occurs, referral for vestibular and/or aural rehabilitation is indicated, particularly for patients who experience permanent hearing loss.

Although our protocol allows for some flexibility, we recommend that otolaryngologists and audiologists follow it as closely as possible in order to develop a cohesive and consistent approach to monitoring patients at risk. Good communication among the patient, the audiologist, and all involved physicians is imperative so that the patient receives the highest standard of care. Adherence to these guidelines will afford us the opportunity to maximize our ability to prevent ototoxicity in patients who take powerful lifesaving medications.

Table 1.

Ototoxic drugs and other substances

Aminoglycoside antibiotics

Amikacin *
Dibekacin [ss]
Dihydrostreptomycin *
Gentamicin +
Kanamycin *
Lividomycin *
Neomycin *
Netilmicin [ss]
Sisomicin *
Streptomycin +
Tobramycin [ss]

Other antibiotics

Chloramphenicol
Clindamycin
Erythromycin
Lincomycin
Polymixin B
Ristocetin
Vancomycin
Viomycin

Antineoplastic drugs

Carboplatin
Cisplatin
Floxuridine
Fluorouracil
Methchlorethamine
Methotrexate
Nitrogen mustard
Procarbazine

Loop diuretics

Bumetanide
Ethacrynic acid
Furosemide
Piretamide

Organic solvents

Styrene
Trichloroethylene

Antimalarials

Carbon sulfide
Chloroquine
Quinine
Toluene

Other drugs and substances

Alcohol
Analine dyes
Anesthetics
Arsenic
Aspirin
Caffeine
Carbon monoxide
Cocaine
Deferoxamine
Ethambutol
Gold
Isoniazid
Lead
Lidocaine
Manganese
Mercury
Oil of Chenopodium
Polybrene
Tin
Tobacco

* Primarily cochleotoxic.

+ Primarily vestibulotoxic.

(ss) Both cochleo-and vestibulotoxic.

Table 2.

Drugs that might interfere with the results of monitoring tests

Antineoplastic drugs  Other drugs

Azacitidine           Atropine
Busulfan              Chloral hydrate
Chlorambucil          Chlordiazepoxide
Cisplatin             Chlorpromazine
Cyclophosphamide      Cimetidine
Cytarabine            Diazepam
Dacarbazine           Dobutamine
Dibromodulcitol       Dopamine
Estramustine          Ephedrine
Floxuridine           Fentanyl
Fludarabine           Haloperidol
Fluorouracil          Hydroxyzine
Ifosfamide            Meperidine
Lomustine             Metoclopramide
Mercaptopurine        Midazolam
Methotrexate          Morphine
Streptozocin          Pentobarbital
Thiopeta              Phenylephrine
                      Prochlorperazine
                      Promethazine
                      Ranitidine
                      Scopolamine
                      Secobarbital
                      Temazepam

References

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(2.) Leonard G, Owen-Black F, Schramm V. Diseases of the inner ear and sensorineural deafness. In: Bluestone CD, Stool SE, eds. Pediatric Otolaryngology. Philadelphia: W.B. Saunders, 1983:271-7.

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(5.) Rybak LP, ed. Ototoxicity. Otolaryngologic Clinics of North America. Vol. 26. Philadelphia: W.B. Saunders, 1993.

(6.) American Speech-Language-Hearing Association. Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA 1994;36(Suppl 12):l1-9.

(7.) Campbell KC, Durrant J. Audiologic monitoring for ototoxicity. Otolaryngol Clin North Am 1993;26:903-14.

(8.) Meyerhoff WL, ed. Diagnosis and Management of Hearing Loss. Philadelphia: W.B. Saunders, 1984:74-5.

(9.) Finley RS, Fortner CL, deJongh CA, et al. Comparison of standard versus pharmacokinctically adjusted amikacin dosing in granulocytopenic cancer patients. Antimicrob Agents Chemother 1982;22:193-7.

(10.) Lerner SA, Schmitt BA, Seligsohn CA, Matz GJ. Comparative study of ototoxicity and nephrotoxicity in patients randomly assigned to treatment with amikacin or geatamicin. Am 3 Med 1986:80(Suppl 6B):98-104.

(11.) Baloh RW, Honrubia V. Clinical Neurophysiology of the Vestibular System. Philadelphia: F.A. Davis, 1990:259-62.

From North Shore Otolaryngology Associates, Manhasset, N.Y.

Reprint requests: Rachel Vasquez, CCC-A, Director. Division of Hearing and Balance Disorders, North Shore Otolaryngology Associates, 333 E. Shore Rd., Suite 200, Manhasset, NY 11030. Phone: [phone]; tax: [phone]; e-mail:[e-mail]