Audiometric Monitoring for Ototoxicity

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Audiometric Monitoring for Ototoxicity

• Alan I. Segal, Au.D., FAAA
• Advanced Ear Nose Throat Associates PC

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Audiometric Monitoring for Ototoxicity

• Material in this presentation is adapted from the
  text Pharmacology Ototoxicity for Audiologists
  by Kathleen C. M. Campbell, Ph. D.

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Audiometric Monitoring for Ototoxicity

• Close to 200 prescription and OTC medications
  have ototoxic potential.
• Drug-induced hearing loss accounts for most
  cases of preventable hearing loss worldwide
• (Campbell, K., Pharmacology and Ototoxicity for
  Audiologists, 2007, p.171)

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Audiometric Monitoring for Ototoxicity

• Two categories of medications that have the
  greatest potential for permanent changes in
  hearing and or balance are aminoglycosides and
  anti-neoplastic agents.

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Audiometric Monitoring for Ototoxicity
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Audiometric Monitoring for Ototoxicity

• The only way to detect ototoxicity is by
  audiometric monitoring of extended high
  frequencies, above 8 KHz.

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Pathophysiology of Ototoxicity

• Hair cells in the inner ear are primarily
  affected with outer hair cells first to be
  destroyed. In the vestibular system type I hair
  cells of the crista of the semi-circular canals
  are targeted

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Outer Hair Cell Damage from Ototoxicity
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Incidence of aminoglycoside Ototoxicity

• Complicated by the fact that definitions of
  hearing loss vary from 10dB at one or more
  frequencies to 20 dB or more at 2 adjacent
  frequencies.
• Incidence ranges 20-33 for commonly used
  aminoglycosides while balance is affected in 18
  of cases.

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Risk Factors

• Long term treatment i.e. TB patients
• Impaired renal function increases drug
  half-life
• Concomitant use of loop diuretics
• Genetic mitochondrial mutations (1555 mutation)

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Aminoglycoside Ototoxicity

• Streptomycin was the first aminoglycosides
  antibiotic and the first drug effective against
  TB.
• Discovered by Selman Waksman et al in 1944.
• Adverse side effects on the kidney and inner ear
  (vestibular toxicity) were reported in 1945

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Aminoglycoside Ototoxicity

• In the last 20 years the use of aminoglycosides
  has declined in industrial societies
• In developing countries, their effectiveness and
  low cost make them popular.
• They are often sold OTC and are the most commonly
  used antibiotics worldwide.

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Aminoglycoside Ototoxicity

• With the resurgence of drug resistant TB, there
  is renewed interest in aminoglycosides
  specifically streptomycin and amikacin/kanamycin
  as part of the World Health Organization
  recommended multi drug regimen.

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Effect of Aminoglycosides on Auditory/Vestibular
Functions

• Studies of human temporal bones and experimental
  animals show inner ear hair cells are the first
  to be affected.
• Outer hair cells are targeted in the cochlea
  extending from base to apex.
• Results in high frequency hearing loss which can
  extend to frequencies important to understanding
  speech.

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Effect of Aminoglycosides on Auditory/Vestibular
Functions

• In the vestibular system, its primary effect is
  loss of vestibular hair cells in the semi
  circular canals and Utricular macula.
• This leads to oscillopsia resulting in postural
  instability and risk of fall.
• It was once believed that maintaining peak and
  trough serum levels of a drug would mitigate
  ototoxic effects.
• Current evidence shows this not to be the case at
  least for vestibular toxicity.

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Effect of Aminoglycosides on Auditory/Vestibular
Functions

• Gentamycin and streptomycin are considered more
  vestibulotoxic.
• Amikacin and Neomycin are considered more
  cochleo-toxic.

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Pharmokinetics

• Presence of the drug does not necessarily cause
  toxicity
• Concentration of the drug in the inner ear does
  not exceed the serum level
• Half life in cochlear tissue has been measured to
  exceed one month
• Traces can be detected up to 6 months following
  the end of treatment.

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Mechanisms of Aminoglycoside Ototoxicity

• Reactive Oxygen Species (ROS) formation appears
  to be key.
• Depletion of anti oxidant Glutathione (GSH)
  enhances ototoxicity while dietary
  supplementation inhibits toxicity.

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Mechanisms of Aminoglycoside Ototoxicity

• Is Aminoglycoside ototoxicity preventable?
• Medications showing promise are d-methiomine and
  salicylate.
• Two issues need to be solved before protective
  treatment can be considered.
• Effective drug levels must be maintained.
• Drug must not interfere with the anti-bacterial
  activity of the aminoglycosides.

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Mechanisms of Aminoglycoside Ototoxicity

• One clinical study found aspirin was protective
  reducing incidence of hearing loss by 75.
• Sha, S. H. , Qui, J. H. Schacht, J. (2006)
  Aspirin to prevent gentamicin-induced hearing
  loss. New England Journal of Medicine, 354,
  1856-7.

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Chemotheraputic Agents Ototoxicity - Cisplatin

• Introduced in the 1970s and is effective against
  germ cell, ovarian, endometrial, cervical,
  urothelial, head and neck, brain and lung
  cancers.
• Highest ototoxic potential and is the most
  ototoxic drug in clinical use.
• Symptoms of ototoxicity begin with tinnitus and
  high frequency hearing loss.

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Chemotheraputic Agents Ototoxicity - Cisplatin

• Incidence of hearing loss has been reported at
  11-91 with an overall incidence of 69.
• In patients with head and neck cancer treated
  with Cisplatin, about 50 develop hearing loss.

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Risk Factors for Cisplatin Ototoxicity

• Intravenous bolus administration or high
  cumulative dose
• Young children, under 5 years, or older gt 46
  years
• Renal insufficiency
• Prior cranial irradiation
• Co-administration of vincristin

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Risk Factors for Cisplatin Ototoxicity

• The best predictor of cisplatin ototoxicity is
  cumulative dose.
• The critical dose is 3-4 mg/Kg body weight.
• Ototoxicity increased dramatically when the total
  cumulative dose exceeds 400 mg/m2

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Characteristics of Cisplatin Ototoxicity

• Bilateral and permanent. High frequencies
  affected first.
• It can occur suddenly. Speech discrimination may
  be markedly affected.

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Mechanisms of Cisplatin Ototoxicity

• Hearing loss affected by free radical formation
  and anti-oxidant inhibition.
• Formation of reactive oxygen radicals produces
  glutathione depletion in the cochlea and lipid
  peroxidation.
• Induced apoptosis in hair cells causing permanent
  hearing loss.

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Carboplatin

• Introduced due to its lower nephrotoxicity than
  cisplatin.
• It is used to treat small cell lung cancer,
  ovarian and head and neck cancers.

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Carboplatin Toxicity

• The dose limiting factor had been bone marrow
  toxicity.
• Overcome with autologous stem cell rescue
  allowing larger doses to be used.
• Initial reports seemed to indicate less
  ototoxicity
• Increase in dose and effectiveness came at the
  expense of increased ototoxicity.

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Carboplatin Toxicity

• The mechanism of carboplatin ototoxicity is
  related to production of ROS (Reactive Oxygen
  Species).
• In experimental animals, pretreatment with a drug
  that inhibits glutathione (Guthionine
  sulfoximine) enhanced carboplatin ototoxicity.
• Other experiments have shown pretreatment with
  anti-oxidant (D-Methionine) reduced the ototoxic
  effect.

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Carboplatin Toxicity Summary

• For equivalent dosing, carboplatin is less toxic
  than cisplatin but higher doses of carboplatin
  are used increasing ototoxicity.

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Ototoxic Monitoring

• Ototoxicity is determined by establishing
  baseline hearing test data ideally prior to
  treatment.
• Results are compared to serial audiograms
  allowing the patient to serve as their own
  control.

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Ototoxic Monitoring

• The highest frequencies measuring 100 dB or less
  are monitored with testing ideally occurring just
  prior to each chemotherapeutic dose
• Monitoring 1-2 times per week for patients
  receiving ototoxic antibiotics.
• Post treatment evaluations are conducted as soon
  as possible after dispensing the drug and
  repeated at 1, 3 and 6 month post treatment.

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Ototoxic Monitoring

• The customized test protocol is called the
  Sensitive Range for Ototoxicity, or SRO and
  differs for each patient.
• It consists of the highest frequencies with
  thresholds 100 dB or better followed by the next
  six lower frequencies.
• The SRO is established during baseline testing
  prior to ototoxic drug administration.

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Summary

• Audiometric monitoring using the patients own
  extended high frequency thresholds as a control,
  is the most sensitive method to detect
  ototoxicity.
• The test is easily tolerated
• High frequency hearing is affected first
• Speech perception can degrade if hearing loss
  extends below 8KHz.

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Advocacy

• Prevention of hearing loss not usually first
  consideration of medical personnel
• The PA as advocate
• Potential hearing loss is quality of life
  consideration
• Hearing aids are not a cure

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