Lecture 7- Ototoxicity

Question 1

How could you define ototoxic?

Answer 1

Any source of non-mechanical damage to the ear, including:

• Several medications
• Many solvents
• Some heavy metals
• Possibly select asphyxiants

Question 2

What are aminoglycoside antibiotics?

Answer 2

• Among the most commonly used antibiotics worldwide
• Sold OTC in some countries
• Treatment for gram negative infections, including pseudomonas and mycobacterium tuberculosis
• Side effects include ototoxicity and nephrotoxicity

Question 3

What are some examples of aminoglycoside antibiotics?

Answer 3

• Gentamicin
• Neomycin
• Kanamycin
• Tobramycin
• Amikacin
• Streptomycin

Question 4

How are aminoglycosides used today?

Answer 4

• Tuberculosis
• Gentamicin used to treat infections in neonates
• Tobramycin used to treat respiratory infections in cystic fibrosis
• Gentamicin used to treat endocarditis
• Neomycin used prior to bowel surgery

Question 5

How are aminoglycosides ototoxic?

Answer 5

• Amikacin, tobramycin, and gentamicin about equally toxic
• As many as 21% of children with CF have aminoglycoside ototoxicity
• HL caused by death of sensory hair cells

Question 6

How do aminoglycoside antibiotics cause HL?

Answer 6

• Enter HC through mechano-electrical transduction channels
• Once in HC, may not be readily cleared
• High concentration –> off-target binding of ribosomes and inhibition of protein translation
• Formation of reactive oxygen species in HC
• Apoptopia death of HC

Question 7

What are audiologic manifestations of aminoglycoside ototoxicity?

Answer 7

Hearing Loss
 Bilateral, HFSN
 Onset of HL is often delayed days or weeks after onset of therapy
• Rapidity of hearing loss is dose-related
• Dependent on renal function
 Most often permanent
• Recovery may occur over a 1-6-month period
• Most likely if ototoxicity occurs early, hearing shift is <25 dB, and corrective measures are taken immediately
• Sx that present weeks after treatment are most likely permanent

Tinnitus
	Occurs before the onset of hearing loss 
	High pitched ringing
	Immediately following first treatment
	Weeks after d/c (discontinuation)

Question 8

What are vestibular manifestations of aminoglycoside ototoxicity?

Answer 8

Acute Phase
	Headache may be the first Sx
	Nausea, vomiting, imbalance 1-2 weeks
	Vertigo in upright position
•	Sitting, standing
	Inability to perceive termination of movement
	Positive Romberg

Chronic Phase
	Sx of chronic labyrinthitis
•	Difficulty with sudden movements
•	Imbalance when walking
•	Lasts up to 2 months

Compensatory Phase
 Centrally mediated
 12-18 months

Question 9

What are antineoplastic drugs?

Answer 9

• Platinum Compounds
o Cisplatinum (CDDP)- cumulative cochleotoxicity
 Among the most widely used and effective of the anti-cancer drugs
 Most ototoxic drug in clinical use
o Carboplatin- less cochleotoxicity

• Nitrogen mustard- cochleotoxic
• Vincristine or vinblastine sulfate – rare reports of cochlear toxicity
• Difluoromethylornithine- transient or permanent dose related cochlear toxicity

Question 10

How does cisplatin kill cancer cells?

Answer 10

o Cisplatin binds DNA and results in a kink in the DNA helix

o Damage to the DNA is recognized as irreversible damage to the cell and the cell proceeds to die

Question 11

What is cisplatin ototoxicity?

Answer 11

o Typically, bilateral, symmetrical, sensory, permanent

o Appears first in the high frequencies
 Can progress to low frequencies with continued treatment, higher cumulative dose

o HL time course
 Gradual onset, progressive and cumulative, or sudden
 Evidence of progression years after cisplatin is d/c

o Prevalence
 HL in 7-71% in adults
 HL ~60-70% in children
 Tinnitus, with or without HL, ~60%

Question 12

What is carboplatinum toxicity?

Answer 12

o Less cochleotoxic than Cisplatinum

o Indications are similar to Cisplatinum
 Ovarian cancer data shows response rates similar to Cisplatinum

o Histopathology
 Destruction of IHC demonstrated in animal models

Question 13

What are loop diuretics?

Answer 13

• Ethacrynic acid, furosemide (Lasix) butametanide
• Drugs that inactivate the sodium-potassium pump at the loop of Henle in the kidney
• Prevent reabsorption of sodium, potassium, chloride, and water – potent diuretics

Question 14

What are the indications for loop diuretics?

Answer 14

o	Heart failure
o	Edema
o	Hypertension
o	Ascites (fluid accumulation in the gut) from liver failure
o	Bronchopulmonary dysplasia in neonates

Question 15

What is loop diuretic ototoxicity?

Answer 15

Tinnitus

Hearing loss
 Permanent with ethacrynic acid
 Usually reversible with furosemide
 Flat, SNHL, and reversible hearing loss with use of Lasix

Rare reports of vertigo

Toxicity related to
 Dosing: slow-low is best
 Concomitant aminoglycoside Rx
 Renal function/failure

Question 16

What are chelating agents?

Answer 16

Deferoxamine (desferal) and desferasirox (exjade, jadenu)
o Chelating agent used to treat iron overload
o Beta thalassemia
o Diamond Blackman anemia
o Sickle cell disease

Deferoxamine alone or in combination: HL in 32%

Desferasirox alone: not ototoxic

Question 17

What are the indications of ototopic agents?

Answer 17

o Suppurative otitis media
o Otorrhea following myringotomy and tube placement
o Draining mastoid cavities
o Otitis externa

Question 18

Why do audiologists monitor for ototoxicity?

Answer 18

• Ensure early identification of hearing loss
• Prevent functional hearing loss
o Treatment alternatives
o Smaller or less frequent doses
o Interruption of suspension of treatment
• Care and support of patient and family
o Assist in re/habilitation, as indicated
o Ensure informed decision making
• Evaluate drug safety
o Known efficacious drugs
o Research using new or experimental treatments
o Criteria for clinical trials

Question 19

What are considerations for ototoxicity monitoring?

Answer 19

• Patient age and medical status – will this change over time?
• Underlying diagnosis – can this affect hearing?
• Purpose of monitoring – are there alternatives?
• How will a change in hearing be defined and reported?

Question 20

Why are ototoxicity grading scales beneficial?

Answer 20

o Consistency
o Objective
o Approachable numbers to the non-audiologist
o Defined parameters; operational definition
o Rank or grade the degree of hearing loss
o Provide government agencies with data to judge drug safety
o Assess effectiveness of otoprotective interventions
o Assess genetic susceptibility to ototoxicity

Question 21

What are the ASHA Ototoxicity criteria (Binary yes/no)?

Answer 21

> 20 dB decrease in pure-tone threshold at one test frequency OR

> 10 dB decrease at two adjacent test frequencies OR

Loss of response at 3 consecutive test frequencies where responses were previously attained

Threshold change confirmed on retest

Question 22

What are the advantages/disadvantages of the ASHA ototoxicity?

Answer 22

Advantage
- Provides early detection of ototoxicity

Disadvantage:

• Does not assign a grade; binary yes/no
• Patient serves as their own control

Question 23

What are the NCI Common Terminology Criteria for Adverse Events (CTCAE)?

Answer 23

o Grading of adverse events, hearing change, and/or therapeutic needs
o Hearing only graded up to Grade 4
o Graded on a scale of 0-5
 No adverse event

Grade 1: Mild Adverse Event

Grade 2: Moderate Adverse

Grade 3: Severe Adverse Event

Grade 4: Life Threatening Adverse Event

Grade 5: Fatal Adverse Event

Question 24

What is the Monitoring for FDA Approval of drugs?

Answer 24

Phase 1: safety

Phase 2: efficacy – optimum dose-response

Phase 3: large scale study to detect side effects not identified in first 2 phases

Phase 4: further evaluation on subpopulations such as children, pregnant women and the elderly

Question 25

What is the Brock Criteria (grading of hearing loss at the end of the trial)?

Answer 25

o Grade 0: Hearing thresholds less than 40 dB HL at all frequencies o Grade 1: Thresholds 40 dB HL or greater at 8000 Hz o Grade 2: Thresholds of 40 dB HL or greater at 4000-8000 Hz o Grade 3: Thresholds of 40 dB HL or greater at 2000-8000 Hz o Grade 4: Thresholds of 40 dB or greater at 1000-8000 Hz

Question 26

What is the Boston SIOP grading of hearing loss?

Answer 26

Based on sensorineural hearing thresholds in dB HL (bone conduction or air conduction with a normal tympanogram) Grade 0: <20 dB HL at all frequencies Grade 1: >20 dB HL SNHL above 4000 Hz Grade 2: >20 dB HL SNHL at 4000 Hz and above Grade 3: >20 dB HL SNHL at 2000 or 3000 Hz and above Grade 4: >40 dB HL SNHL at 2000 Hz and above

Question 27

Why are neonates administered aminoglycosides?

Answer 27

o Broad spectrum specificity toward organisms commonly encountered in neonatal sepsis o Considered clinically essential despite known ototoxicity and nephrotoxicity

Question 28

Why is rate of HL in NICU higher?

Answer 28

o Etiology largely unknown | o Aminoglycoside use is one common risk factor

Question 29

What are factors potentiating aminoglycoside ototoxicity?

Answer 29

Concurrent medications  Glycopeptide antibiotic – vancomycin  Neuromuscular blocking agents- pancuronium bromine and vecuronium bromide  Loop diuretics- Lasix Inflammatory status  Host-induced inflammatory response to infection or bacterial immunogens  Systemic inflammation 2o abdominal irradiation Genetics  Mitochondrial DNA variant, A1555G  ACMG recommends screening for this variant Noise levels in NICU  Sustained noise may potentiate ototoxicity of aminoglycosides

Question 30

What are approaches to monitoring neonates for ototoxicity?

Answer 30

JCIH recommendations regarding ototoxicity  If aminoglycosides >5 days, diagnostic audiologic follow up by 9 months of age unless there has been a toxic-level (not defined) or there is a known genetic susceptibility to aminoglycosides How do we typically test for ototoxicity?  Behavioral pure-tone thresholds in children  Baseline test followed by monitoring tests What are we looking for?  Changes in the high frequencies  Early detection No specific screening and monitoring protocol for ototoxicity in neonates

Question 31

What are some challenges in monitoring neonates for ototoxicity?

Answer 31

Timing and feasibility of test  Ototoxicity monitoring protocols recommend baseline test  80% of NICU admissions receive prophylactic or empiric treatment with aminoglycosides Focus of test  NBHS protocols looking for mild to moderate loss in mid frequencies • Do not test above 4kHz (Oae) • Broadband click (aABR)  Ototoxicity monitoring requires higher frequencies • DPOAE at 10 kHz or above not available on clinical equipment Serial ABR or OAE  Labor intensive  Difficult to interpret in premature infants (<34 weeks) Noise from medically necessary interventions  Mechanical ventilation  Acoustic and electrical artifact

Question 32

What are clinical issues specific to monitoring ototoxicity in neonates?

Answer 32

Some neonates spend several months in the NICU  Screening if often delayed until just prior to d/c  If HL is identified, may not have intervention by 6 months of age  May increase risk for neurodevelopmental delays Increased noise floors interfering with testing --> false positive screening and/or need for rescreening --> unduly stress parents

Question 33

What are recommendations for ototoxicity prevention in neonates?

Answer 33

o Minimize use of aminoglycosides o Monitor level of ambient noise in NICU and take steps to mitigate o Prenatal testing for genetic risk factors o Education of parents and NICU staff regarding the risk of progressive or late onset HL and importance of follow-up

Question 34

What are some childhood cancers treated with platinum chemotherapy?

Answer 34

``` o Osteosarcoma o Germ cell tumors o Hepatoblastoma o Medulloblastoma o Neuroblastoma o Pontine glioma ```

Question 35

What are cisplatin ototoxicity risk factors?

Answer 35

Younger age Effect of dose Cranial radiation Use of other ototoxins during treatment Genetic predisposition

Question 36

What are the impacts of cisplatin ototoxicity in children?

Answer 36

o Reduces utility of cisplatin therapy by limiting dose escalation o Precludes investigation of novel strategies to enhance cisplatin cytotoxicity o Infants and young children at critical stage of development  Speech language development  Literacy o Older children and adolescents  Educational achievement  Social-emotional development  Quality of life

Question 37

What are the impacts of minimal SNHL in children?

Answer 37

Educational performance  Lower performance as compared to normal hearing peers (grade 3) (CTBS/4) • Reading vocabulary, language mechanics, word analysis, science, spelling  Teacher perception (SIFTER) • 66% difficulty with academics • 48% reduced attention • 79% problems with communication  Retention rates • Overall 37% as compared to 3% in normal hearing peers

Question 38

What are the most common cancers in adults?

Answer 38

o Men: lung, prostate, colorectal | o Women: breast, colorectal, lung

Question 39

What are some cancers treated with platinum-based chemotherapy?

Answer 39

``` o Head and neck o Lung o Colorectal o Bladder o Germ cell o Ovarian o Testicular ```

Question 40

What are the goals of OMP?

Answer 40

o Use of standard definition of threshold shift | o Pre-treatment counseling regarding potential ototoxicity

Question 41

What are the advantages and limitations of obtaining extended high frequencies thresholds?

Answer 41

Advantages: o Monitoring above 8000 Hz more sensitive to ototoxic changes than monitoring standard test frequency range o Intrasubject variability is within standard test-retest criteria Limitations: o Requires “add-on” of extended high frequencies to audiometer o EHF plus standard frequencies make for a long test session

Question 42

What are the service delivery gaps for OMP?

Answer 42

Inconsistent referrals • Self-referral and physician referral after treatment • Multiple staff shifts and rotating residents made in-service training difficult • Insufficient lead time prior to treatment • Solutions: o Participation in oncology multidisciplinary team clinics o Referrals from pharmacy Scheduling limitations Location and space limitations Staffing limitations Logistical Barriers • Patient schedules and compliance with audiology visits • Audiology not near the oncology or infectious disease locations • Other appointments running late • Number of schedules, booths, and audiologists • Solutions: o Dedicated appointment slots/rooms/staff o Creative scheduling

Question 43

What are the advantages and limitations of ABR monitoring for ototoxicity?

Answer 43

``` Advantages:  Reliable, portable, objective  Greater dB range than OAE  May capture pre-clinical changes  Helpful in cases when patient is very ill and/or uncooperative ``` Limitations  Lengthy  Lacks frequency specificity at high stimulus levels  High frequency stimuli may not be available  May require sedation

Question 44

What are the advantages and limitations of OAE monitoring for ototoxicity?

Answer 44

Advantages:  Efficient, portable, and reliable objective tool  May capture pre-clinical changes  Helpful in cases when patient is very ill and/or uncooperative ``` Limitations  Limited ability to assess the higher frequencies  No widely accepted standard for change  Limited dB range  Obscured by ME disease  Require careful measurement ```