Lecture 7- Ototoxicity Flashcards
How could you define ototoxic?
Any source of non-mechanical damage to the ear, including:
- Several medications
- Many solvents
- Some heavy metals
- Possibly select asphyxiants
What are aminoglycoside antibiotics?
- 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
What are some examples of aminoglycoside antibiotics?
- Gentamicin
- Neomycin
- Kanamycin
- Tobramycin
- Amikacin
- Streptomycin
How are aminoglycosides used today?
- 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
How are aminoglycosides ototoxic?
- 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
How do aminoglycoside antibiotics cause HL?
- 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
What are audiologic manifestations of aminoglycoside ototoxicity?
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)
What are vestibular manifestations of aminoglycoside ototoxicity?
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
What are antineoplastic drugs?
• 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
How does cisplatin kill cancer cells?
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
What is cisplatin ototoxicity?
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%
What is carboplatinum toxicity?
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
What are loop diuretics?
- 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
What are the indications for loop diuretics?
o Heart failure o Edema o Hypertension o Ascites (fluid accumulation in the gut) from liver failure o Bronchopulmonary dysplasia in neonates
What is loop diuretic ototoxicity?
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
What are chelating agents?
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
What are the indications of ototopic agents?
o Suppurative otitis media
o Otorrhea following myringotomy and tube placement
o Draining mastoid cavities
o Otitis externa
Why do audiologists monitor for ototoxicity?
• 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
What are considerations for ototoxicity monitoring?
- 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?
Why are ototoxicity grading scales beneficial?
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
What are the ASHA Ototoxicity criteria (Binary yes/no)?
> 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
What are the advantages/disadvantages of the ASHA ototoxicity?
Advantage
- Provides early detection of ototoxicity
Disadvantage:
- Does not assign a grade; binary yes/no
- Patient serves as their own control
What are the NCI Common Terminology Criteria for Adverse Events (CTCAE)?
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
What is the Monitoring for FDA Approval of drugs?
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
What is the Brock Criteria (grading of hearing loss at the end of the trial)?
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
What is the Boston SIOP grading of hearing loss?
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
Why are neonates administered aminoglycosides?
o Broad spectrum specificity toward organisms commonly encountered in neonatal sepsis
o Considered clinically essential despite known ototoxicity and nephrotoxicity
Why is rate of HL in NICU higher?
o Etiology largely unknown
o Aminoglycoside use is one common risk factor
What are factors potentiating aminoglycoside ototoxicity?
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
What are approaches to monitoring neonates for ototoxicity?
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
What are some challenges in monitoring neonates for ototoxicity?
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
What are clinical issues specific to monitoring ototoxicity in neonates?
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
What are recommendations for ototoxicity prevention in neonates?
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
What are some childhood cancers treated with platinum chemotherapy?
o Osteosarcoma o Germ cell tumors o Hepatoblastoma o Medulloblastoma o Neuroblastoma o Pontine glioma
What are cisplatin ototoxicity risk factors?
Younger age
Effect of dose
Cranial radiation
Use of other ototoxins during treatment
Genetic predisposition
What are the impacts of cisplatin ototoxicity in children?
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
What are the impacts of minimal SNHL in children?
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
What are the most common cancers in adults?
o Men: lung, prostate, colorectal
o Women: breast, colorectal, lung
What are some cancers treated with platinum-based chemotherapy?
o Head and neck o Lung o Colorectal o Bladder o Germ cell o Ovarian o Testicular
What are the goals of OMP?
o Use of standard definition of threshold shift
o Pre-treatment counseling regarding potential ototoxicity
What are the advantages and limitations of obtaining extended high frequencies thresholds?
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
What are the service delivery gaps for OMP?
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
What are the advantages and limitations of ABR monitoring for ototoxicity?
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
What are the advantages and limitations of OAE monitoring for ototoxicity?
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
