You are in: eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > INNER EAR Inner Ear, OtotoxicityArticle Last Updated: Sep 6, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Ann L Edmunds, MD, PharmD, Consulting Staff, ENT Physicians; Consulting Staff, Department of Otolaryngology, Boys Town National Research Hospital Ann L Edmunds is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, and Nebraska Medical Association Coauthor(s): Pamela A Mudd, BS, MD, Resident Physician, Department of Otolaryngology, University of Colorado Health Science Center; James Kalkanis, MD, Staff Physician, Department of Surgery, Southern Illinois University School of Medicine; Frank Glatz, MD, Staff Physician, Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, Southern Illinois University School of Medicine; Kathleen CM Campbell, PhD, Director of Audiology, Professor, Department of Surgery, Division of Otolaryngology, Southern Illinois University School of Medicine; Leonard P Rybak, MD, PhD, Professor, Department of Surgery, Southern Illinois University School of Medicine Editors: Robert A Battista, MD, FACS, Assistant Professor of Otolaryngology, Northwestern University Medical School; Consulting Staff, Ear Institute of Chicago, LLC; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Gerard J Gianoli, MD, Clinical Associate Professor, Department of Otolaryngology-Head and Neck Surgery, Tulane University School of Medicine; Vice President, The Ear and Balance Institute; Chief Executive Officer, Ponchartrain Surgery Center; Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders; Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine Author and Editor Disclosure Synonyms and related keywords: ototoxicity of the inner ear, auditory system dysfunction, vestibular system dysfunction, dysequilibrium, oscillopsia, vestibulocochlear toxicity, cochleovestibular side effects INTRODUCTIONSection 2 of 10
  Ototoxicity refers to damage to the cochlea or vestibular apparatus from exposure to a chemical source, resulting in hearing loss or dysequilibrium. The propensity of specific classes of drugs to cause ototoxicity has been well established. Ototoxicity came to the forefront of clinical attention with the discovery of streptomycin in 1944. Streptomycin was used successfully in the treatment of tuberculosis; however, a substantial number of treated patients were found to develop irreversible cochlear and vestibular dysfunction (Kahlmeter, 1984). These findings, coupled with ototoxicity associated with later development of other aminoglycosides, led to a great deal of clinical and basic scientific research into the etiology and mechanisms of ototoxicity. Today, many well-known pharmacologic agents have been shown to have toxic effects to the cochleovestibular system. The list includes aminoglycosides and other antibiotics, platinum-based antineoplastic agents, salicylates, quinine, and loop diuretics. Ototoxicity is typically associated with bilateral high-frequency sensorineural hearing loss and tinnitus. Hearing loss can be temporary but is usually irreversible with most agents. Generally, antibiotic-induced ototoxicity is bilaterally symmetrical, but it can be asymmetrical. The usual time of onset is often unpredictable, and marked hearing loss can occur even after a single dose. Additionally, hearing loss may not manifest until several weeks or months after completion of antibiotic or antineoplastic therapy. Many agents (eg, certain antibiotics, antineoplastics) produce hair cell damage, which begins at the basal turn of the cochlea and proceeds toward the apex. This initially produces high-frequency sloping hearing loss, which can progress to lower (or speech) frequencies. Typical patients are unaware of hearing loss until deficits reach mild-to-moderate levels (>30 dB hearing level [HL]) in the speech frequencies. Vestibular injury is also a notable adverse effect of aminoglycoside antibiotics and may appear early on with positional nystagmus. If severe, vestibular toxicity can lead to dysequilibrium and oscillopsia. Oscillopsia, which is caused by bilateral damage to the vestibular system, is the inability of the ocular system to maintain a stable horizon, resulting in what has been described as a "jumbling of the panorama." Basic awareness of ototoxic medications and use of appropriate monitoring during treatment are important to preserve hearing. Management emphasis is on prevention, as most hearing loss is irreversible. No therapy is currently available to reverse ototoxic damage; however, basic scientists and clinicians are continually seeking to find new methods to minimize ototoxic injury while retaining the therapeutic efficacy of these agents. For severe hearing loss, amplification may be the only treatment option. For excellent patient education resources, visit eMedicine's Ear, Nose, and Throat Center. Also, see eMedicine's patient education article Hearing Loss. AMINOGLYCOSIDESSection 3 of 10
Since their introduction in 1944, multiple aminoglycoside preparations have become available, including streptomycin, dihydrostreptomycin, kanamycin, gentamicin, neomycin, tobramycin, netilmicin, and amikacin. The aminoglycosides are bactericidal antibiotics that bind to the 30S ribosome and inhibit bacterial protein synthesis. They are active only against aerobic gram-negative bacilli and staphylococci. Neomycin and kanamycin have a limited antibacterial spectrum and are more toxic than the other aminoglycosides. Although the ototoxic effects of aminoglycosides are well documented, this class of drugs is still widely used today. Aminoglycosides may be used in combination with penicillin in staphylococcal, streptococcal, and, especially, enterococcal endocarditis. An aminoglycoside should always be added to a beta-lactam antibiotic when serious Pseudomonas aeruginosa infections are treated. Advantages to using aminoglycoside antibiotics include low incidence of Clostridium difficile diarrhea relative to other antibiotics and low risk of allergic reactions. Pathophysiology Aminoglycosides have variable cochleotoxicity and vestibulotoxicity. Streptomycin and gentamicin are primarily vestibulotoxic, whereas amikacin, neomycin, dihydrostreptomycin, and kanamycin are primarily cochleotoxic. Tobramycin affects vestibular and auditory function equally. Less is known about netilmicin ototoxicity because netilmicin is used less commonly, but its ototoxic potential appears low. Aminoglycoside toxicity primarily targets renal and cochleovestibular systems; however, no clear correlation exists between degree of nephrotoxicity and ototoxicity. Cochlear toxicity that results in hearing loss usually begins in the high frequencies and is secondary to irreversible destruction of outer hair cells in the organ of Corti, predominantly at the basal turn of the cochlea. Aminoglycosides have been detected in the cochlea months after final dose administration. Aminoglycoside retention may account for delayed onset of hearing loss and prolonged susceptibility to noise-induced hearing loss, which is often observed for several months following therapy discontinuation. Several toxicity mechanisms have been described, including (1) impaired deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein synthesis; (2) impaired synthesis and degradation of prostaglandins, gangliosides, mucopolysaccharides, and lipids; and (3) disruption in metabolism and ion transport. Many of the previous observations can be explained by an interaction with phosphoinositide. This membrane lipid serves as a source of arachidonic acid and acts as an intracellular messenger involved in many of the above processes. A second potential target includes the enzyme ornithine decarboxylase, which is involved in cellular recovery following noxious stimuli. Perhaps the most promising mechanism for chronic aminoglycoside toxicity involves iron chelation leading to production of a free-radical complex. Aminoglycoside ototoxicity is likely multifactorial, and further investigation is underway. Some studies are investigating iron chelators and antioxidants as possible agents to prevent hearing loss during therapy, while other studies are exploring forms of gene therapy as future treatment options. Currently, no treatment is available apart from amplification and cochlear implantation; therefore, prevention is paramount. Epidemiology In certain countries, antibiotics are prescribed freely or are available without prescription. In these areas, aminoglycosides cause as many as 66% of cases of deaf mutism. Depending on agent and dosing, up to 33% of adult patients may have audiometric changes with aminoglycoside treatment. Vestibular toxicity is also well documented; it occurs in as many as 4% of adult patients. The incidence of patients who experience toxicity due to aminoglycosides may be decreasing because of improvements in monitoring and heightened awareness. Studies indicate that cochlear toxicity from aminoglycosides is less common in neonates and children than in adults. The incidence of aminoglycoside-induced cochlear toxicity in neonates has been estimated at around 2% (Matz, 1993). Risk factors Certain factors may put patients at increased risk for ototoxicity. Aminoglycoside ototoxicity is more likely to occur with larger doses, higher blood levels, or longer duration of therapy. Other high-risk patients include elderly patients, those with renal insufficiency, those with preexisting hearing problems, those with a family history of ototoxicity, and those receiving loop diuretics or other ototoxic or nephrotoxic medications. Signs and symptoms Clinically, acute cochlear damage may present as tinnitus. Early hearing loss may go unrecognized by the patient and initially manifest as an increase in the threshold of highest frequencies (>4000 Hz). With progression, lower speech frequencies are affected and the patient may become profoundly deaf if the drug is continued. If the drug is stopped early in the course of damage, further loss may be prevented, and partial recovery of auditory thresholds may be possible. However, the loss is usually permanent. Symptoms of vestibular toxicity typically include imbalance and visual symptoms. The imbalance is worse in the dark or in situations in which footing is uncertain. Spinning vertigo is unusual. The visual symptoms, called oscillopsia, occur only when the head is moving. Quick movements of the head are associated with transient visual blurring. This can cause difficulties with seeing signs while driving or recognizing people's faces while walking. Clinically, nystagmus may be present as an early sign. Prevention Prevention of aminoglycoside ototoxicity involves careful monitoring of serum drug levels and renal function as well as hearing evaluations before, during, and after therapy. Measure baseline audiometric function before therapy; however, this is not always possible in acute situations. Daily administration decreases incidence of ototoxicity and should be considered whenever possible. Conscientiously identify high-risk patients and select alternative antibiotics for them. Lastly, because aminoglycosides remain in the cochlea long after therapy has ended, instruct patients to avoid noisy environments for 6 months after therapy completion because they remain more susceptible to noise-induced cochlear damage. Recent animal studies have involved the administration of free-radical scavengers, iron chelators, and inhibitors of cell death pathways as possible mechanisms to prevent ototoxicity. Further clinical trials are needed to determine if the protective mechanisms demonstrated in animal studies can be replicated in patients while maintaining therapeutic effects of the aminoglycosides (Rybak, 2003). Specific aminoglycosides
OTHER ANTIBIOTICSSection 4 of 10
Macrolides Erythromycin was introduced in 1952 and has seen widespread use in clinical medicine. Generally, erythromycin is considered a safe medication. Erythromycin has been considered the substitute of choice in group A streptococcal and pneumococcal infections for penicillin-sensitive individuals. Erythromycin remains the antibiotic of choice for Legionella pneumonia and other atypical pneumonias. The first reports of ototoxicity were not noted until 1973. Since then, only sporadic cases of ototoxicity have been reported, and they have generally been reversible. These patients tended to have other risk factors, including renal failure, hepatic failure, doses of more than 4 g/d, and intravenous administration. Clinically significant hearing loss also has been reported in recipients of renal allografts who were treated with intravenous erythromycin. Onset is generally within 3 days of starting treatment. Speech frequencies may be affected rather than higher frequencies. Effects are usually reversible. Azithromycin and clindamycin are newer macrolide antibiotics. These antibiotics have seen widespread clinical use, as they have less GI side effects and a broader antimicrobial spectrum than erythromycin. However, recently, some reports have appeared regarding possible ototoxic effects (Uzun, 2001). Reports are currently sporadic and further investigation is needed. Vancomycin Vancomycin is a glycopeptide antibiotic that was introduced in the 1950s, but it was replaced by other antibiotics around 1958 because of early reports of ototoxicity. Several other reports of hearing loss are associated with its use, but many involved patients receiving concomitant aminoglycoside therapy. The data are unclear but suggest that ototoxicity is reversible in at least some individuals. No studies demonstrate conclusive evidence of ototoxicity with vancomycin administration alone and in therapeutic doses. No recommendations have been made regarding its use; however, the authors suggest caution with coadministration of vancomycin and other ototoxic agents. LOOP DIURETICSSection 5 of 10
Loop diuretics exert therapeutic effects at the loop of Henle. This class of medications includes several different chemical groups, including sulfonamides, phenoxyacetic acid derivatives, and heterocyclic compounds. These drugs are used to treat congestive heart failure, renal failure, cirrhosis, and hypertension. The most effective and frequently used diuretics (eg, ethacrynic acid, furosemide, bumetanide) can cause ototoxicity. Several less-commonly used loop diuretics also have been experimentally shown to cause ototoxicity; this group includes torsemide, azosemide, ozolinone, indacrinone, and piretanide. Pathophysiology The ototoxic effects of loop diuretics seem to be associated with the stria vascularis, which is affected by changes in the ionic gradients between the perilymph and endolymph. These changes cause edema of the epithelium of the stria vascularis. Evidence also suggests that endolymphatic potential is decreased; however, this is usually dose dependent and reversible. Ototoxicity caused by ethacrynic acid seems to develop more gradually and takes longer to resolve than that caused by furosemide or bumetanide. Overall, ototoxicity attributed to this group of medications is usually self-limited and reversible in adult patients, although irreversible hearing loss has been reported in neonates. Epidemiology Ototoxicity in estimated to occur in 6-7% of patients taking loop diuretics. Occurrence of loop diuretic ototoxicity depends on several factors, including dose, infusion rate, history of renal failure, and co-administration of other ototoxic agents. Signs and symptoms Depending on the particular loop diuretic, patients usually relate a history of hearing loss soon after taking the agent. Patients also may complain of tinnitus and dysequilibrium; however, these symptoms are less common and seldom occur without hearing loss. Some patients may experience permanent hearing loss, especially those with renal failure, those receiving high doses, or those receiving aminoglycoside antibiotics concurrently. Prevention Prevention of ototoxicity caused by loop diuretics consists of using the lowest doses possible to achieve desired effects and avoiding rapid infusion rates. Additionally, the risk factors associated with administration of these drugs must be diligently assessed, including co-administration of other ototoxic medications and history of renal failure. As potentiation and synergism of ototoxic effects of aminoglycosides and loop diuretics is well documented, co-prescription of these drugs is not recommended. ANTINEOPLASTIC AGENTSSection 6 of 10
Antineoplastic agents most commonly associated with ototoxicity are the platinum-based compounds cisplatin and, to a lesser degree, carboplatin. These agents are widely used in gynecologic, lung, central nervous system, head and neck, and testicular cancers. Antineoplastics are cell-cycle nonspecific alkylating agents that insert into the DNA helix, disrupting replication. Cisplatin is distributed widely, but the highest concentrations are found in the kidneys, liver, and prostate. Cisplatin irreversibly binds to plasma proteins and can be detected up to 6 months after completion of therapy. Carboplatin is not protein bound and is more readily cleared by the kidneys. Dose and efficacy of cisplatin and carboplatin are limited largely by adverse effects. Most notably, these agents produce nephrotoxicity and ototoxicity with increasing dose. Pathophysiology The mechanism of platinum ototoxicity appears multifactorial, but it is partially mediated by free-radical production. Platinum compounds damage the stria vascularis in the scala media and cause outer hair cell death beginning at the basal turn of the cochlea. Epidemiology Incidence and severity of ototoxicity depend on dose, infusion rate, and number of cycles, renal status, and co-administration of other ototoxic agents. Incidence and severity is also higher in the pediatric population and in patients receiving radiation therapy to the head and neck. Recent studies describe a hearing loss of 61% of children receiving platinum-based chemotherapy (Knight, 2005). This is comparable to earlier studies. Risk factors The following risk factors have been identified for development and potentiation of platinum-induced ototoxicity: (1) high dose and increasing number of cycles, (2) concurrent or past cranial irradiation, (3) age extremes, (4) dehydration, (5) co-administration of other ototoxic agents, and (6) renal failure. Signs and symptoms Patients with platinum-induced ototoxicity may report tinnitus and experience subjective hearing loss. Hearing loss associated with cisplatin toxicity is usually bilateral, sensorineural, irreversible, and progressive. High-frequency hearing is typically affected first, but loss may not appear until several days or months after the last dose. Conversely, severe hearing loss may occur after a single dose. Prevention Obtain baseline audiograms and periodic follow-up audiograms during therapy for all patients receiving these agents. Perform these studies immediately before subsequent drug cycles so the maximal effect of the previous cycle can be determined. Lastly, patients should continue to undergo audiometric testing because of significant drug retention long after completion of therapy. Also advise patients to avoid noise exposure for up to 6 months. Recent studies have explored agents such as a-tocopherol (a vitamin E derivative), D-methionine (an amino acid), salicylates, iron chelators, N-acetyl-cysteine (an antioxidant), caspase or calpain inhibitors, and even gene therapy as preventives if used in combination with platinum-based chemotherapeutic agents. These studies have shown significant benefit in animal models but must be replicated in human models while preserving the antineoplastic effects of agents such as cisplatin (Rybak, 2003). SALICYLATESSection 7 of 10
Acetylsalicylic acid, commonly known as aspirin, is used widely for its anti-inflammatory, antipyretic, and analgesic properties. Aspirin is an inhibitor of platelet aggregation and is used to treat patients with a history of transient ischemic attacks, stroke, unstable angina, or myocardial infarction. Acetylsalicylic acid is absorbed rapidly after oral administration and is hydrolyzed in the liver to its active form, salicylic acid. Therapeutic levels range from 25-50 mcg/mL for analgesic and antipyretic effects to 150-300 mcg/mL for treatment of acute rheumatic fever. However, tinnitus can occur at serum levels as low as 200 mcg/mL. Pathophysiology Salicylic acid quickly enters the cochlea, and perilymph levels parallel serum levels. Increasing levels produce tinnitus and, generally, a reversible flat sensorineural hearing loss. The mechanism is multifactorial but appears to cause metabolic rather than morphologic changes within the cochlea. Epidemiology Incidence of ototoxicity is as high as 1% and is most commonly observed in elderly patients, even at low doses. Risk factors Risk factors associated with salicylate ototoxicity include high dose, elderly age, and dehydration. Signs and symptoms Tinnitus is the most common adverse effect of salicylate toxicity. Other adverse effects include hearing loss, nausea, vomiting, headache, confusion, tachycardia, and tachypnea. Hearing loss is typically mild to moderate and bilaterally symmetric. Recovery usually occurs 24-72 hours after cessation of the drug. The onset of tinnitus has been used in the past as an early sign of ototoxicity. Later studies found that the onset of tinnitus should not be used as a predictor of serum salicylate level, as ototoxic effects can be present at low blood levels (Jung, 1993). Treatment Salicylate toxicity is treated by electrolyte monitoring and fluid administration, with the addition of alkaline diuresis, if necessary. Oxygen administration and mechanical ventilation also may be needed in severe cases. QUININESection 8 of 10
Derived from cinchona tree bark, quinine historically was used to treat malaria and for its antipyretic qualities. Use today is limited by availability of less toxic alternatives. Quinine is occasionally used to treat nocturnal leg cramps and as an adjunct to antimalarial therapy. Quinine primarily undergoes hepatic metabolism. Signs and symptoms Quinine toxicity can produce tinnitus, hearing loss, vertigo, headache, nausea, and vision loss. Hearing loss is usually sensorineural and reversible. A characteristic sensorineural notch often is present at 4000 Hz. Irreversible hearing loss rarely has been reported with quinine use. Treatment Treatment for quinine ototoxicity mainly consists of discontinuation of therapy; amplification can be used in rare cases of irreversible hearing loss. METHODS OF AUDIOLOGIC MONITORINGSection 9 of 10
Begin monitoring for signs of ototoxicity before administration of potentially damaging agents. Whenever possible (eg, with patients receiving chemotherapy), perform a baseline audiometric evaluation. Follow baseline evaluation with routine testing during and after therapy. Frequently, ototoxicity can be detected before tinnitus onset and subjective hearing loss. Pure-tone air-conduction thresholds most commonly are obtained as a baseline for monitoring and are conducted in the conventional testing range of 250-8000 Hz. This simple test yields a great deal of information, and even small changes can be easily detected. However, many ototoxic agents initially produce hearing loss in the high-frequency range, above the 8000-Hz upper limit of the standard audiogram. Routine use of high-frequency audiometry therefore is essential. This method determines pure-tone air-conduction thresholds from 10,000-20,000 Hz and makes early detection of hearing loss possible. Early detection allows modification of treatment protocol before speech frequencies are affected. However, one limitation of high-frequency audiometry is encountered in patients with preexisting high-frequency hearing loss (eg, elderly patients with presbycusis). Early detection methods are less effective in this patient population. Pure-tone bone-conduction testing is another important component of the standard audiogram. This method accurately determines true sensorineural function by bypassing the conductive system of the middle ear. Serous otitis also is commonly observed following radiation to the head and neck as an adjunct to cancer therapy. Auditory system damage caused by ototoxicity may impair ability to discriminate spoken words in addition to affecting pure-tone hearing. Word recognition testing accurately evaluates the ability of a listener to recognize individual words and thus is another important component of standard audiometry. Scores are based on the percent of phonetically balanced words a patient correctly repeats to the audiologist. A score of more than 90% is normal. Standard pure-tone audiometry monitoring cannot always be implemented because it requires an alert and cooperative patient. Infants and critically ill patients, for example, cannot be reliably tested with standard audiometry. For these patients, other techniques are available to perform reliable audiometric testing, including otoacoustic emission (OAE) and auditory brainstem response (ABR) testing. OAEs are signals produced by the cochlea, which are detected by a microphone placed in the ear canal. These emissions can occur both spontaneously and in response to sound conducted into the ear. Recordings of these emissions are made, and cochlear function can be determined across a wide range of frequencies. OAEs quickly can be obtained in infants and in comatose patients at the bedside. Testing usually takes less than 5 minutes per ear. However, patients with a history of hearing loss may have abnormal or absent OAEs. Therefore, as with other forms of audiometry, thorough baseline testing is important. ABR testing is used widely in testing the conventional frequency range, although it is still under investigation for use in high frequencies. This makes ABR of limited clinical use in monitoring ototoxicity. Immittance audiometry also is of limited use; the test is used to exclude middle ear problems that can mimic ototoxic change, but it cannot actually monitor ototoxicity. Management The primary concern is to maintain patient communication capabilities during what is generally a serious illness. Consult an audiologist early for baseline assessment. Additionally, counsel patients regarding importance of prompt reporting of symptoms such as tinnitus, hearing loss, oscillopsia, and dysequilibrium. Reassure patients that all measures will be taken to prevent any changes in hearing. Perform monitoring before, during, and after therapy, with test results immediately reported to the physician. In some instances, treatment protocols cannot be altered, and hearing loss occurs. In these cases, fit patients with hearing aids to facilitate communication; however, keep gain and maximum power output as low as possible because these patients are more susceptible to noise-induced hearing loss. Increased susceptibility to hearing loss can continue for several months after completion of aminoglycoside and platinum-compound therapy. Because of this, instruct patients to avoid excessive noise exposure for 6 months. Additionally, advise patients not to increase hearing aid maximum output during this critical time. REFERENCESSection 10 of 10
Inner Ear, Ototoxicity excerpt Article Last Updated: Sep 6, 2006 |
