A. Chemotherapeutic Agents and Ototoxicity

The most commonly reported ototoxic chemotherapeutic agents include the following:

The most commonly used chemotherapeutic agent and a major ototoxic agent among these compounds is cisplatin. Figure 14-2 shows a progressive loss of hearing in a patient receiving cisplatin. Cisplatin is a divalent platinum compound which produces a dose-limiting permanent, high-frequency sensorineural hearing loss and peripheral neuropathy as well as a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. The potential for dose-limiting and permanent cochlear (neuro) toxicity remains despite present methods of hypertonic saline, prehydration, and mannitol diuresis prior to drug administration. As pointed out by Schweitzer³¹ the biochemistry, pharmacokinetics, biodistribution, and immunologic mechanisms of platinum complexes are still undefined. There is significant variability in presentation and susceptibility to cisplatin-mediated ototoxicity. Ototoxicity resulting from treatment may be subjectively experienced as hearing loss and tinnitus. The tinnitus may be transient or permanent.³² Tinnitus may accompany hearing loss, particularly at high frequencies, or may be present without any sign of hearing impairment. The overall early incidence of tinnitus, where clearly specified in clinical trials, is about 7% (range 2% to 36%). The tinnitus is commonly transient, disappearing a few hours to a weeks after discontinuation of treatment.

Hearing loss due to cisplatin is well documented. The high-frequency hearing loss may cause difficulties in speech discrimination with background noise and may also involve middle-frequency ranges, with inhibition of speech communication even in quiet surroundings.^32,33 The hearing loss in most cases is permanent but recovery has been described.³³

Although the cochlear toxicity of cisplatin is well documented histologically and functionally there are still a few reports confirming cisplatin-induced vestibular toxicity.^34,35

Nitrogen mustard, the first clinically useful chemotherapeutic agent, has limited modern application owing to severe toxicity. The toxicity has been characterized by irreversible sensorineural hearing loss and tinnitus.

Vincristine sulfate induces a dose-related peripheral and autonomic neuropathy and there are few reported case of vincristine-induced ototoxicity.^36,37

B. Anti-inflammatory Drugs and Ototoxicity

A side effect of salicylates and many non-steroidal anti-inflammatory drugs (NSAIDs) is ototoxicity manifesting as mild to moderate reversible hearing loss and tinnitus. Aspirin ototoxicity occurs in 11 per 1,000 patients, with a much higher incidence reported for the long-acting aspirins.^38,39 Elderly patients are at a significantly high risk of salicylate toxicity even at lower salicylate doses.⁴⁰ Quinine ototoxicity is quite similar to salicylate clinical manifestations and has a mechanism distinct from that of salicylates. The increasing popularity of quinine for treatment of nocturnal leg cramps makes quinine ototoxicity a relevant clinical problem. The manifestations of salicylate ototoxicity are quite well-known: nausea, vomiting, tinnitus, hearing loss, headache, mental changes, and increased respiration.⁴¹ The hearing loss is typically mild to moderate and bilaterally symmetric. It may be flat or just in the high-frequencies. Recovery usually occurs twenty-four to seventy-two hours after cessation of the drug. Temporary high-frequency hearing loss with tinnitus after aspirin treatment has occurred in normal volunteers.⁴² Tinnitus also occurs with salicylates with the usual frequency of tinnitus being in the 7 to 9 kHz range.⁴² Tinnitus may be used as an initial sign of salicylate ototoxicity and may be used as a baseline in patients with normal initial hearing.⁴³ It is believed that the mechanism of salicylate ototoxicity is related to reversible biochemical or metabolic changes in the cochlear rather than any permanent morphologic abnormality. NSAIDs are a heterogeneous group of compounds that share therapeutic actions and side effects of salicylates.⁴¹ In one study, five patients suffered hearing loss while receiving naproxen, and only two recovered their hearing after discontinuing the drug.⁴⁴ Rarely, there may a significant and permanent loss of hearing shortly after the start of a non-steroidal agent (Figure 14-3).

Quinine ototoxicity is manifested both by auditory and vestibular dysfunction. Toxicity is called cinconchism and presents as deafness, vertigo, tinnitus, headache, nausea, and visual loss. Transient hearing loss, usually a first side effect, occurs a few hours after initiating high-dose therapy as, for example, in the treatment of malaria. With prolonged treatment for malaria, 20% of patients can be expected to suffer hearing loss.⁴⁵ The sensorineural hearing loss is usually reversible bilaterally and symmetric, particularly affecting the high-frequencies first. Tinnitus, similar to that, is caused by salicylates. Vestibular effects of quinine are also recognized. Low serum quinine concentrations, which may occur among tonic beverage drinkers, may lead to clinically significant vestibular changes. Blood quinine levels of 0.2 mg/ml found in pilots who died in aviation accidents suggested that quinine toxicity may have played a causative role.⁴⁶ Prolonged administration of high-dose quinine in many patients led to loss of outer hair cells. There may also be an effect on cochlear blood flow.⁴⁷

C. Erythromycin Ototoxicity

Even though erythromycin was first introduced in 1952, it has been only since the mid-70's that ototoxicity has been recognized as a potential complication.⁴⁸ An extensive number of case reports of transient and rarely permanent hearing loss, secondary to erythromycin as reported by Brummett.⁴⁹ There are two new similar antibiotics, clarithromycin and azithromycin which have the potential for ototoxicity.^50,51 Brummett suggests that when parenteral forms of these agents become available that ototoxicity may be manifest. The ototoxicity due to erythromycin and its analogues is related to dosage. Of note is the fact that the hearing losses due to erythromycin appear to occur in speech frequencies at the same time the deficit occurs at higher frequencies. For this reason, the patient can easily recognize a change in hearing, a significant difference from the hearing loss resulting from aminoglycoside antibiotics which begin at the very high frequencies and can go unnoticed for some period of time.

D. Vancomycin Ototoxicity

Vancomycin, originally introduced in the late 1950's and still used for partial resistance to Staphylococcus aureus infection, was initially replaced by methicillin, but reintroduced in the early 80's because of its effect against methicillin-resistance S. aureus infections. Because of its mycin suffix, vancomycin was, and still is, often mistakenly identified as an aminoglycoside antibiotic. The first case of ototoxicity due to vancomycin was reported by Geraci and colleagues.⁵² Other reports are catalogued by Brummett.⁴⁹ It is clearly less toxic that an aminoglycoside, so the initial concern may have been because of the incorrect belief that vancomycin was an aminoglycoside. In most cases of reported permanent ototoxicity, the patients were treated before or during vancomycin therapy with erythromycin or an aminoglycoside antibiotic. It may well be that permanent ototoxicity could be the result of a vancomycin-induced augmentation of aminoglycoside ototoxicity.

E. Loop Diuretic Ototoxicity

As reported by Rybak,⁵³ loop diuretics are organic compounds that exert potential saliuretic effects by acting on the epithelial cells in the loop of Henle of the kidney. Unfortunately, many of the loop diuretics are ototoxic, both in clinical reports and experimental studies. Ethacrynic acid, a potent loop diuretic, is recognized as causing acute and sometimes permanent hearing loss.⁵⁴ One of the most widely used loop diuretics today, furosemide or Lasix, has a significant potential for hearing loss. Heidland and Wigand⁵⁵ found that infusion of furosemide at a constant rate of 25 mg per minute caused noticeable hearing loss in two thirds of patients. Although most cases of furosemide ototoxicity have been reversible, a number of reports describe patients with permanent deficits.^56,57 Other loop diuretics also have potential ototoxicity. One of its most significant problems is the potentiation of aminoglycoside ototoxicity by the concurrent use of loop diuretics as previously noted. As Rybak⁵³ points out, perhaps the kidney and the cochlea have some common receptors for the loop diuretics and it appears that all loop diuretics are ototoxic to some degree.

F. Topical Agent Ototoxicity

In addition to the normal environmental chemicals found in modern society, there exists the possibility that otological surgery can expose the inner ear to ototoxic chemicals. Scrub solutions used to sterilize the external ear may reach the middle ear through tympanic perforations and from there these substances can be absorbed into the inner ear via the round window.⁶⁴ Providone iodine preparations^65,66 and chlorhexidine^67,68 have both been proven to be toxic to the cochlea and vestibular sensory neuroepithelium in the inner ear after reaching the middle ear space. Therefore, surgeons should be alerted to this possibility.